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A Study Of PF-06463922 An ALK/ROS1 Inhibitor In Patients With Advanced Non Small Cell Lung Cancer With Specific Molecular Alterations

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ClinicalTrials.gov Identifier: NCT01970865
Recruitment Status : Completed
First Posted : October 28, 2013
Results First Posted : May 29, 2018
Last Update Posted : June 7, 2023
Sponsor:
Information provided by (Responsible Party):
Pfizer

Study Type Interventional
Study Design Allocation: Non-Randomized;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition ALK-positive Non Small Cell Lung Cancer (NSCLC) and ROS1-positive NSCLC
Interventions Drug: PF-06463922
Drug: Crizotinib
Enrollment 334
Recruitment Details  
Pre-assignment Details A total of 334 participants were enrolled in this study, and 2 of them (one each in Phase 1 and Phase 2) didn't receive any study treatment.
Arm/Group Title 10 mg QD (Phase 1) 25 mg QD (Phase 1) 50 mg QD (Phase 1) 75 mg QD (Phase 1) 100 mg QD (Phase 1) 150 mg QD (Phase 1) 200 mg QD (Phase 1) 35 mg BID (Phase 1) 75 mg BID (Phase 1) 100 mg BID (Phase 1) EXP-1 (Phase 2) EXP-2 (Phase 2) EXP-3 (Phase 2) EXP-4 (Phase 2) EXP-5 (Phase 2) EXP-6 (Phase 2) Japan Lead-In Cohort (LIC)
Hide Arm/Group Description PF-06463922 10 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. PF-06463922 25 mg was orally given once daily (QD) in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. Midazolam 2 mg was orally given QD on Day -7 and Cycle 1 Day 15. PF-06463922 50 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. PF-06463922 75 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. PF-06463922 100 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. PF-06463922 150 mg was orally given once daily (QD) in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. Midazolam 2 mg was orally given QD on Day -7 and Cycle 1 Day 15. PF-06463922 200 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. PF-06463922 35 mg was orally given twice daily (BID) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. PF-06463922 75 mg was orally given twice daily (BID) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. PF-06463922 100 mg was orally given twice daily (BID) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. Treatment-naïve participants with advanced ALK-positive NSCLC with or without asymptomatic central nervous system (CNS) metastases were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after only crizotinib therapy were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after crizotinib therapy and 1 or 2 prior regimens of chemotherapy given before or after crizotinib therapy, or participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 1 ALK inhibitor therapy other than crizotinib with or without any number of prior chemotherapy regimens in any disease setting were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 2 prior lines of ALK inhibitor therapies were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 3 prior lines of ALK inhibitor therapies were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participant scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. Participants with advanced ROS1-positive NSCLC who were treatment naïve or had any number of prior cancer therapies with or without asymptomatic CNS metastases were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. Few Japanese participants were given PF-06463922 100 mg orally once daily (QD) in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal to evaluate safety of PF-06463922 in Japanese participants, in order to support inclusion of Japanese participants in Phase 2.
Period Title: Overall Study
Started 3 3 3 13 17 3 3 3 3 4 30 27 60 66 46 47 3
Received Treatment 3 3 3 12 17 3 3 3 3 4 30 27 60 65 46 47 3
Completed 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Not Completed 3 3 3 13 17 3 3 3 3 4 30 27 60 66 46 47 3
Reason Not Completed
Death             3             1             3             4             6             3             1             3             2             1             1             4             14             19             15             10             1
Lost to Follow-up             0             0             0             1             1             0             0             0             0             0             0             0             1             0             0             0             0
Withdrawal by Subject             0             0             0             1             2             0             0             0             0             0             0             1             2             5             2             7             0
Other             0             0             0             1             0             0             0             0             0             0             0             0             0             1             0             1             0
Study ongoing             0             2             0             6             8             0             2             0             1             3             29             22             43             41             29             29             2
Arm/Group Title 10 mg QD (Phase 1) 25 mg QD (Phase 1) 50 mg QD (Phase 1) 75 mg QD (Phase 1) 100 mg QD (Phase 1) 150 mg QD (Phase 1) 200 mg QD (Phase 1) 35 mg BID (Phase 1) 75 mg BID (Phase 1) 100 mg BID (Phase 1) EXP-1 (Phase 2) EXP-2 (Phase 2) EXP-3 (Phase 2) EXP-4 (Phase 2) EXP-5 (Phase 2) EXP-6 (Phase 2) Japan Lead-In Cohort (LIC) Total
Hide Arm/Group Description PF-06463922 10 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. PF-06463922 25 mg was orally given once daily (QD) in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. Midazolam 2 mg was orally given QD on Day -7 and Cycle 1 Day 15. PF-06463922 50 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. PF-06463922 75 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. PF-06463922 100 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. PF-06463922 150 mg was orally given once daily (QD) in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. Midazolam 2 mg was orally given QD on Day -7 and Cycle 1 Day 15. PF-06463922 200 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. PF-06463922 35 mg was orally given twice daily (BID) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. PF-06463922 75 mg was orally given twice daily (BID) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. PF-06463922 100 mg was orally given twice daily (BID) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. Treatment-naïve participants with advanced ALK-positive NSCLC with or without asymptomatic central nervous system (CNS) metastases were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after only crizotinib therapy were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after crizotinib therapy and 1 or 2 prior regimens of chemotherapy given before or after crizotinib therapy, or participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 1 ALK inhibitor therapy other than crizotinib with or without any number of prior chemotherapy regimens in any disease setting were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 2 prior lines of ALK inhibitor therapies were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 3 prior lines of ALK inhibitor therapies were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participant scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. Participants with advanced ROS1-positive NSCLC who were treatment naïve or had any number of prior cancer therapies with or without asymptomatic CNS metastases were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. Few Japanese participants were given PF-06463922 100 mg orally once daily (QD) in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal to evaluate safety of PF-06463922 in Japanese participants, in order to support inclusion of Japanese participants in Phase 2. Total of all reporting groups
Overall Number of Baseline Participants 3 3 3 12 17 3 3 3 3 4 30 27 60 65 46 47 3 332
Hide Baseline Analysis Population Description
Baseline analysis population included all participants who received at least 1 dose of study treatment.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 3 participants 3 participants 3 participants 12 participants 17 participants 3 participants 3 participants 3 participants 3 participants 4 participants 30 participants 27 participants 60 participants 65 participants 46 participants 47 participants 3 participants 332 participants
67.3  (11.2) 53.7  (13) 52.7  (10) 48.2  (13.2) 49  (11.1) 55.3  (14.7) 44.7  (4.2) 61.3  (15.4) 61.3  (18.1) 50.8  (15.2) 57.4  (12.1) 57.1  (12.7) 54  (11.9) 52.2  (11.8) 51.5  (11.2) 52.8  (12.9) 44.3  (6.1) NA [1]   (NA)
[1]
Demographic data were not summarized for the whole study population.
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 3 participants 3 participants 3 participants 12 participants 17 participants 3 participants 3 participants 3 participants 3 participants 4 participants 30 participants 27 participants 60 participants 65 participants 46 participants 47 participants 3 participants 332 participants
Female
2
  66.7%
0
   0.0%
1
  33.3%
7
  58.3%
11
  64.7%
2
  66.7%
2
  66.7%
2
  66.7%
3
 100.0%
2
  50.0%
13
  43.3%
17
  63.0%
38
  63.3%
37
  56.9%
25
  54.3%
27
  57.4%
2
  66.7%
191
  57.5%
Male
1
  33.3%
3
 100.0%
2
  66.7%
5
  41.7%
6
  35.3%
1
  33.3%
1
  33.3%
1
  33.3%
0
   0.0%
2
  50.0%
17
  56.7%
10
  37.0%
22
  36.7%
28
  43.1%
21
  45.7%
20
  42.6%
1
  33.3%
141
  42.5%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
 Number Analyzed 3 participants 3 participants 3 participants 12 participants 17 participants 3 participants 3 participants 3 participants 3 participants 4 participants 30 participants 27 participants 60 participants 65 participants 46 participants 47 participants 3 participants 332 participants
White
2
  66.7%
2
  66.7%
3
 100.0%
7
  58.3%
13
  76.5%
2
  66.7%
2
  66.7%
1
  33.3%
2
  66.7%
3
  75.0%
10
  33.3%
13
  48.1%
25
  41.7%
32
  49.2%
27
  58.7%
25
  53.2%
0
   0.0%
169
  50.9%
Black
1
  33.3%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
1
  33.3%
0
   0.0%
1
  33.3%
0
   0.0%
0
   0.0%
1
   3.3%
0
   0.0%
1
   1.7%
0
   0.0%
0
   0.0%
1
   2.1%
0
   0.0%
6
   1.8%
Asian
0
   0.0%
1
  33.3%
0
   0.0%
3
  25.0%
2
  11.8%
0
   0.0%
1
  33.3%
0
   0.0%
0
   0.0%
0
   0.0%
17
  56.7%
10
  37.0%
23
  38.3%
23
  35.4%
14
  30.4%
16
  34.0%
3
 100.0%
113
  34.0%
Other
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
1
   5.9%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
1
   3.3%
2
   7.4%
1
   1.7%
3
   4.6%
2
   4.3%
3
   6.4%
0
   0.0%
13
   3.9%
Unspecified
0
   0.0%
0
   0.0%
0
   0.0%
2
  16.7%
1
   5.9%
0
   0.0%
0
   0.0%
1
  33.3%
1
  33.3%
1
  25.0%
1
   3.3%
2
   7.4%
10
  16.7%
7
  10.8%
3
   6.5%
2
   4.3%
0
   0.0%
31
   9.3%
1.Primary Outcome
Title Number of Participants With Cycle 1 Dose-Limiting Toxicities (DLTs) in Phase 1
Hide Description DLT was defined as any of the following adverse events (AEs) attributable to PF-06463922: (1) hematologic: grade 4 neutropenia for >7 days; febrile neutropenia; grade >=3 neutropenic infection; grade >=3 thrombocytopenia with bleeding; grade 4 thrombocytopenia; (2) non-hematologic: grade >=3 pancreatitis; grade >=3 toxicities (excluding grade >=3 laboratory abnormalities not requiring dose modifications) persisting after optimal treatment with standard medical therapy; symptomatic grade >=3 QTc prolongation, or asymptomatic grade >=3 prolongation that had been confirmed by repeat testing and re-evaluation by a qualified person, and persisted after correction of reversible causes; >=20% decrease from baseline in left ventricular ejection fraction (LVEF); (3) other: failure to deliver at least 16 out of the 21 prescribed daily total doses due to toxicities attributable to study drug; failure to restart dosing after 21 days (1 cycle) delay due to toxicities attributable to study drug.
Time Frame Cycle 1 (21 days)
Hide Outcome Measure Data
Hide Analysis Population Description
Maximum Tolerated Dose (MTD) evaluable population included all enrolled participants who received at least 75% of the planned PF-06463922 doses in Cycle 1. Participants who received less than 75% of the planned PF-06463922 doses in Cycle 1 due to DLT were also considered evaluable for MTD.
Arm/Group Title 10 mg QD (Phase 1) 25 mg QD (Phase 1) 50 mg QD (Phase 1) 75 mg QD (Phase 1) 100 mg QD (Phase 1) 150 mg QD (Phase 1) 200 mg QD (Phase 1) 35 mg BID (Phase 1) 75 mg BID (Phase 1) 100 mg BID (Phase 1)
Hide Arm/Group Description:
PF-06463922 10 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 25 mg was orally given once daily (QD) in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. Midazolam 2 mg was orally given QD on Day -7 and Cycle 1 Day 15.
PF-06463922 50 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 75 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 100 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 150 mg was orally given once daily (QD) in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. Midazolam 2 mg was orally given QD on Day -7 and Cycle 1 Day 15.
PF-06463922 200 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 35 mg was orally given twice daily (BID) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 75 mg was orally given twice daily (BID) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 100 mg was orally given twice daily (BID) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Overall Number of Participants Analyzed 3 3 3 11 16 3 3 2 3 3
Measure Type: Count of Participants
Unit of Measure: Participants
With DLT
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
1
  33.3%
0
   0.0%
0
   0.0%
0
   0.0%
No DLT
3
 100.0%
2
  66.7%
3
 100.0%
6
  54.5%
8
  50.0%
2
  66.7%
1
  33.3%
2
 100.0%
3
 100.0%
2
  66.7%
Data missing
0
   0.0%
1
  33.3%
0
   0.0%
5
  45.5%
8
  50.0%
1
  33.3%
1
  33.3%
0
   0.0%
0
   0.0%
1
  33.3%
2.Primary Outcome
Title Percentage of Participants With Overall and Intracranial Objective Response (Phase 2)
Hide Description Objective response (OR) refers to confirmed complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumor (RECIST) version 1.1. Intracranial OR refers to confirmed CR or PR considering only lesions within brain. Results presented here were based on independent central review.
Time Frame 3 years
Hide Outcome Measure Data
Hide Analysis Population Description
The intent-to-treat (ITT) analysis set was used for overall response assessment, and included all enrolled participants with documented ALK or ROS1 rearrangement who received at least 1 dose of PF-06463922; participants with central nervous system (CNS) metastases in the ITT analysis set were used for intracranial response assessment.
Arm/Group Title EXP-1 (Phase 2) EXP-2 (Phase 2) EXP-3 (Phase 2) EXP-4 (Phase 2) EXP-5 (Phase 2) EXP-6 (Phase 2)
Hide Arm/Group Description:
Treatment-naïve participants with advanced ALK-positive NSCLC with or without asymptomatic central nervous system (CNS) metastases were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after only crizotinib therapy were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after crizotinib therapy and 1 or 2 prior regimens of chemotherapy given before or after crizotinib therapy, or participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 1 ALK inhibitor therapy other than crizotinib with or without any number of prior chemotherapy regimens in any disease setting were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 2 prior lines of ALK inhibitor therapies were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 3 prior lines of ALK inhibitor therapies were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participant scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ROS1-positive NSCLC who were treatment naïve or had any number of prior cancer therapies with or without asymptomatic CNS metastases were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Overall Number of Participants Analyzed 30 27 59 65 46 47
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
Objective response Number Analyzed 30 participants 27 participants 59 participants 65 participants 46 participants 47 participants
90.0
(73.5 to 97.9)
74.1
(53.7 to 88.9)
50.8
(37.5 to 64.1)
41.5
(29.4 to 54.4)
34.8
(21.4 to 50.2)
36.2
(22.7 to 51.5)
Intracranial objective response Number Analyzed 8 participants 17 participants 32 participants 45 participants 38 participants 25 participants
75.0
(34.9 to 96.8)
58.8
(32.9 to 81.6)
62.5
(43.7 to 78.9)
55.6
(40.0 to 70.4)
39.5
(24.0 to 56.6)
56.0
(34.9 to 75.6)
3.Secondary Outcome
Title Percentage of Participants With Overall and Intracranial Objective Response (Phase 1)
Hide Description Objective response (OR) refers to confirmed complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumor (RECIST) version 1.1. Intracranial OR refers to confirmed CR or PR considering only lesions within brain. Results presented here were based on independent central review.
Time Frame 3 years
Hide Outcome Measure Data
Hide Analysis Population Description
The intent-to-treat (ITT) analysis set was used for overall response assessment, and included all enrolled participants with documented ALK or ROS1 rearrangement who received at least 1 dose of PF-06463922; participants with CNS metastases in the ITT analysis set was used for intracranial response assessment.
Arm/Group Title ALK Positive Population (Phase 1) ROS1 Positive Population (Phase 1)
Hide Arm/Group Description:
This reporting arm includes all Phase 1 participants who had documented ALK rearrangement.
This reporting arm includes all Phase 1 participants who had documented ROS1 rearrangement.
Overall Number of Participants Analyzed 41 12
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
Objective response Number Analyzed 41 participants 12 participants
39.0
(24.2 to 55.5)
50.0
(21.1 to 78.9)
Intracranial objective response Number Analyzed 34 participants 8 participants
41.2
(24.6 to 59.3)
50.0
(15.7 to 84.3)
4.Secondary Outcome
Title Time to Tumor Response (TTR) and Intracranial TTR (Phase 1)
Hide Description Time to tumor response (TTR) was defined as the time from the first dose of study treatment to the first documentation of objective tumor response (CR or PR). For participants whose objective response proceeded from PR to CR, the onset of PR was taken as the onset of response. TTR was only calculated for the subgroup of participants with a confirmed objective tumor response. Intracranial TTR was only calculated for participants with confirmed intracranial objective response. Results presented here were based on independent central review.
Time Frame 3 years
Hide Outcome Measure Data
Hide Analysis Population Description
TTR analysis set included all ITT participants who had confirmed objective response; intracranial TTR analysis set included all ITT participants who had CNS metastases and achieved confirmed intracranial objective response.
Arm/Group Title ALK Positive Population (Phase 1) ROS1 Positive Population (Phase 1)
Hide Arm/Group Description:
This reporting arm includes all Phase 1 participants who had documented ALK rearrangement.
This reporting arm includes all Phase 1 participants who had documented ROS1 rearrangement.
Overall Number of Participants Analyzed 16 6
Median (Full Range)
Unit of Measure: months
TTR Number Analyzed 16 participants 6 participants
1.4
(1.2 to 15.2)
1.4
(1.2 to 2.8)
Intracranial TTR Number Analyzed 14 participants 4 participants
1.4
(1.2 to 20.1)
1.4
(1.1 to 2.8)
5.Secondary Outcome
Title Duration of Response (DOR) and Intracranial DOR (Phase 1)
Hide Description Duration of Response (DOR) was defined as the time from the first documentation of objective tumor response (CR or PR) to the first documentation of disease progression or to death due to any cause, whichever occurred first. DOR was only calculated for the subgroup of participants with a confirmed objective tumor response. Intracranial DOR was only calculated for participants with confirmed intracranial objective response. Results presented here were based on independent central review.
Time Frame 3 years
Hide Outcome Measure Data
Hide Analysis Population Description
DOR analysis set included all ITT participants who had confirmed objective response; intracranial DOR analysis set included all ITT participants who had CNS metastases and achieved confirmed intracranial objective response.
Arm/Group Title ALK Positive Population (Phase 1) ROS1 Positive Population (Phase 1)
Hide Arm/Group Description:
This reporting arm includes all Phase 1 participants who had documented ALK rearrangement.
This reporting arm includes all Phase 1 participants who had documented ROS1 rearrangement.
Overall Number of Participants Analyzed 16 6
Median (95% Confidence Interval)
Unit of Measure: months
DOR Number Analyzed 16 participants 6 participants
14.06 [1] 
(4.17 to NA)
NA [1] 
(9.69 to NA)
Intra-cranial DOR Number Analyzed 14 participants 4 participants
NA [2] 
(14.06 to NA)
NA [2] 
(NA to NA)
[1]
Number of participants with confirmed objective response was too small to provide such summary statistics.
[2]
Number of participants with confirmed intracranial objective response was too small to provide such summary statistics.
6.Secondary Outcome
Title Percentage of Participants Achieving Disease Control and Intracranial Disease Control at 12 Weeks (Phase 1)
Hide Description Tumor response was evaluated according to RECIST version 1.1, and disease control was defined as confirmed complete response (CR), confirmed partial response (PR), or stable disease (SD). Intracranial assessment was only performed for participants CNS metastases. Results presented here were based on independent central review.
Time Frame 12 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
The intent-to-treat (ITT) analysis set was used for overall response assessment, and included all enrolled participants with documented ALK or ROS1 rearrangement who received at least 1 dose of PF-06463922; participants with CNS metastases in the ITT analysis set was used for intracranial response assessment.
Arm/Group Title ALK Positive Population (Phase 1) ROS1 Positive Population (Phase 1)
Hide Arm/Group Description:
This reporting arm includes all Phase 1 participants who had documented ALK rearrangement.
This reporting arm includes all Phase 1 participants who had documented ROS1 rearrangement.
Overall Number of Participants Analyzed 41 12
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
Disease control rate Number Analyzed 41 participants 12 participants
53.7
(37.4 to 69.3)
58.3
(27.7 to 84.8)
Intra-cranial disease control rate Number Analyzed 34 participants 8 participants
50.0
(32.4 to 67.6)
37.5
(8.5 to 75.5)
7.Secondary Outcome
Title Probability of First Event Being a Central Nervous System (CNS) Progression, Non CNS Progression, or Death (Phase 1)
Hide Description The probability of the first event being a CNS progression, a non-CNS progression, or death was evaluated with a competing risk approach by estimating cumulative incidence functions (range: 0-1) relative to the analysis set. The time to first event being a Competing Event (either "CNS progression" or "non CNS progression" or "Death") was defined as time from first dose until the date of that specific event. Participants not known to have any of the Competing Events were censored on the date they were last assessed for disease status for PFS. Participants who presented one type of event were counted as a competing cause of failure for the analysis of other type of events. For each type of event, the cumulative incidence function corresponding to the nearest time point preceding 1 year is presented. The results are based on independent central review.
Time Frame 3 years
Hide Outcome Measure Data
Hide Analysis Population Description
The intent-to-treat (ITT) analysis set included all enrolled participants with documented ALK or ROS1 rearrangement who received at least 1 dose of PF-06463922.
Arm/Group Title Phase 1 ITT Population
Hide Arm/Group Description:
This reporting group includes all Phase 1 participants in the ITT analysis set.
Overall Number of Participants Analyzed 53
Measure Type: Number
Unit of Measure: probability
CNS progression 0.260
Non CNS progression 0.352
Death 0.060
8.Secondary Outcome
Title Progression-Free Survival (PFS) (Phase 1)
Hide Description PFS was defined as the time from the first dose of study treatment to the first documentation of objective disease progression or to death on study due to any cause, whichever came first. Results presented here were based on independent central review.
Time Frame 3 years
Hide Outcome Measure Data
Hide Analysis Population Description
PFS analysis set included all participants with documented ALK or ROS1 rearrangement who received at least 1 dose of PF-06463922.
Arm/Group Title ALK Positive Population (Phase 1) ROS1 Positive Population (Phase 1)
Hide Arm/Group Description:
This reporting arm includes all Phase 1 participants who had documented ALK rearrangement.
This reporting arm includes all Phase 1 participants who had documented ROS1 rearrangement.
Overall Number of Participants Analyzed 41 12
Median (95% Confidence Interval)
Unit of Measure: months
5.3
(2.5 to 11.8)
10.1 [1] 
(1.6 to NA)
[1]
Number of participants with objective progression or death was too small to provide such summary statistics.
9.Secondary Outcome
Title Overall Survival (OS) (Phase 1)
Hide Description OS was defined as the time from first dose to the date of death due to any cause. For participants still alive at the time of analysis, the OS time was censored on the last date the participants were known to be alive. Estimates of OS and its 95% confidence interval were determined using Kaplan-Meier method.
Time Frame 3 years
Hide Outcome Measure Data
Hide Analysis Population Description
The intent-to-treat (ITT) analysis set included all enrolled participants with documented ALK or ROS1 rearrangement who received at least 1 dose of PF-06463922.
Arm/Group Title ALK Positive Population (Phase 1) ROS1 Positive Population (Phase 1)
Hide Arm/Group Description:
This reporting arm includes all Phase 1 participants who had documented ALK rearrangement.
This reporting arm includes all Phase 1 participants who had documented ROS1 rearrangement.
Overall Number of Participants Analyzed 41 12
Median (95% Confidence Interval)
Unit of Measure: months
22.3 [1] 
(11.4 to NA)
NA [1] 
(4.7 to NA)
[1]
A large proportion of participants in the analysis set had their OS data censored, and number of participants dead by the cutoff date of this report was small, so it's impossible to derive such summary statistics.
10.Secondary Outcome
Title Maximum Observed Plasma Concentration (Cmax) of PF-06463922 Following Single Oral Doses (Phase 1)
Hide Description Maximum observed plasma concentration (Cmax) of PF-06463922 was observed directly from data.
Time Frame Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 1 for 25 mg QD and 150 mg QD groups; pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24, 48, 72, 96 and 120 hours post-dose on Day -7 for all other groups.
Hide Outcome Measure Data
Hide Analysis Population Description
PK concentration analysis set for PF-06463922 included all participants treated who had at least 1 concentration of PF-06463922.
Arm/Group Title 10 mg QD (Phase 1) 25 mg QD (Phase 1) 50 mg QD (Phase 1) 75 mg QD (Phase 1) 100 mg QD (Phase 1) 150 mg QD (Phase 1) 200 mg QD (Phase 1) 35 mg BID (Phase 1) 75 mg BID (Phase 1) 100 mg BID (Phase 1)
Hide Arm/Group Description:
PF-06463922 10 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 25 mg was orally given once daily (QD) in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. Midazolam 2 mg was orally given QD on Day -7 and Cycle 1 Day 15.
PF-06463922 50 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 75 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 100 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 150 mg was orally given once daily (QD) in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. Midazolam 2 mg was orally given QD on Day -7 and Cycle 1 Day 15.
PF-06463922 200 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 35 mg was orally given twice daily (BID) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 75 mg was orally given twice daily (BID) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 100 mg was orally given twice daily (BID) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Overall Number of Participants Analyzed 3 3 2 12 16 3 3 3 3 4
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng/mL
50.80
(17%)
149.2
(71%)
NA [1] 
(NA%)
489.1
(45%)
595.5
(37%)
760.0
(58%)
1201
(19%)
202.2
(57%)
594.9
(27%)
507.2
(51%)
[1]
Summary statistics were not calculated when fewer than 3 participants had reportable values. Individual values are 390 and 423 ng/mL, respectively.
11.Secondary Outcome
Title Maximum Observed Plasma Concentration (Cmax) of PF-06463922 Following Multiple Oral Doses (Phase 1)
Hide Description Maximum Observed Plasma Concentration (Cmax) of PF-06463922 was observed directly from data.
Time Frame Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24 hours post-dose on Cycle 1 Day 15 (24-hour samples not collected for BID groups).
Hide Outcome Measure Data
Hide Analysis Population Description
PK concentration analysis set for PF-06463922 included all participants treated who had at least 1 concentration of PF-06463922.
Arm/Group Title 10 mg QD (Phase 1) 25 mg QD (Phase 1) 50 mg QD (Phase 1) 75 mg QD (Phase 1) 100 mg QD (Phase 1) 150 mg QD (Phase 1) 200 mg QD (Phase 1) 35 mg BID (Phase 1) 75 mg BID (Phase 1) 100 mg BID (Phase 1)
Hide Arm/Group Description:
PF-06463922 10 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 25 mg was orally given once daily (QD) in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. Midazolam 2 mg was orally given QD on Day -7 and Cycle 1 Day 15.
PF-06463922 50 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 75 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 100 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 150 mg was orally given once daily (QD) in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. Midazolam 2 mg was orally given QD on Day -7 and Cycle 1 Day 15.
PF-06463922 200 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 35 mg was orally given twice daily (BID) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 75 mg was orally given twice daily (BID) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 100 mg was orally given twice daily (BID) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Overall Number of Participants Analyzed 3 3 3 12 16 3 3 3 3 3
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng/mL
67.29
(18%)
138.1
(35%)
359.7
(27%)
429.6
(48%)
550.2
(32%)
541.0
(42%)
NA [1] 
(NA%)
NA [2] 
(NA%)
550.0
(23%)
600.5
(27%)
[1]
Summary statistics were not calculated when fewer than 3 participants had reportable values. Individual values are 760 and 1430 ng/mL, respectively.
[2]
Summary statistics were not calculated when fewer than 3 participants had reportable values. The individual value is 370 ng/mL.
12.Secondary Outcome
Title Time for Cmax (Tmax) of PF-06463922 Following Single Oral Doses (Phase 1)
Hide Description Tmax of PF-06463922 was observed directly from data as time of first occurrence.
Time Frame Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 1 for 25 mg QD and 150 mg QD groups; pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24, 48, 72, 96 and 120 hours post-dose on Day -7 for all other groups.
Hide Outcome Measure Data
Hide Analysis Population Description
PK parameter analysis set for PF-06463922 included all enrolled participants who received at least 1 dose of PF-06463922 and had sufficient information to estimate at least one of the PK parameters of interest for PF-06463922.
Arm/Group Title 10 mg QD (Phase 1) 25 mg QD (Phase 1) 50 mg QD (Phase 1) 75 mg QD (Phase 1) 100 mg QD (Phase 1) 150 mg QD (Phase 1) 200 mg QD (Phase 1) 35 mg BID (Phase 1) 75 mg BID (Phase 1) 100 mg BID (Phase 1)
Hide Arm/Group Description:
PF-06463922 10 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 25 mg was orally given once daily (QD) in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. Midazolam 2 mg was orally given QD on Day -7 and Cycle 1 Day 15.
PF-06463922 50 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 75 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 100 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 150 mg was orally given once daily (QD) in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. Midazolam 2 mg was orally given QD on Day -7 and Cycle 1 Day 15.
PF-06463922 200 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 35 mg was orally given twice daily (BID) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 75 mg was orally given twice daily (BID) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 100 mg was orally given twice daily (BID) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Overall Number of Participants Analyzed 3 3 2 12 16 3 3 3 3 4
Median (Full Range)
Unit of Measure: hours
1.98
(1.00 to 2.97)
2.00
(0.50 to 2.05)
1.25
(0.50 to 2.00)
1.09
(0.50 to 4.03)
1.96
(0.517 to 4.33)
1.05
(1.00 to 3.00)
2.00
(1.18 to 3.00)
1.20
(0.50 to 1.97)
1.23
(1.00 to 2.00)
2.00
(1.10 to 3.07)
13.Secondary Outcome
Title Time for Cmax (Tmax) of PF-06463922 Following Multiple Oral Doses (Phase 1)
Hide Description Tmax of PF-06463922 was observed directly from data as time of first occurrence.
Time Frame Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24 hours post-dose on Cycle 1 Day 15 (24-hour samples not collected for BID groups).
Hide Outcome Measure Data
Hide Analysis Population Description
PK parameter analysis set for PF-06463922 included all enrolled participants who received at least 1 dose of PF-06463922 and had sufficient information to estimate at least one of the PK parameters of interest for PF-06463922.
Arm/Group Title 10 mg QD (Phase 1) 25 mg QD (Phase 1) 50 mg QD (Phase 1) 75 mg QD (Phase 1) 100 mg QD (Phase 1) 150 mg QD (Phase 1) 200 mg QD (Phase 1) 35 mg BID (Phase 1) 75 mg BID (Phase 1) 100 mg BID (Phase 1)
Hide Arm/Group Description:
PF-06463922 10 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 25 mg was orally given once daily (QD) in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. Midazolam 2 mg was orally given QD on Day -7 and Cycle 1 Day 15.
PF-06463922 50 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 75 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 100 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 150 mg was orally given once daily (QD) in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. Midazolam 2 mg was orally given QD on Day -7 and Cycle 1 Day 15.
PF-06463922 200 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 35 mg was orally given twice daily (BID) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 75 mg was orally given twice daily (BID) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 100 mg was orally given twice daily (BID) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Overall Number of Participants Analyzed 3 3 3 12 16 3 3 3 3 3
Median (Full Range)
Unit of Measure: hours
1.00
(1.00 to 1.08)
1.00
(1.00 to 2.00)
2.00
(1.92 to 2.75)
1.03
(0.50 to 2.00)
1.13
(1.00 to 4.00)
1.30
(1.00 to 24.0)
1.61
(1.22 to 2.00)
0.50
(0.50 to 0.50)
0.55
(0.50 to 2.05)
2.00
(1.00 to 2.00)
14.Secondary Outcome
Title Area Under the Plasma Concentration-Time Profile From Time Zero to Time Tau (AUCtau) of PF-06463922 Following Single Oral Doses (Phase 1)
Hide Description Tau refers to the dosing interval, and it equals to 12 or 24 hours for BID or QD dosing, respectively. AUCtau was determined using linear/log trapezoidal method.
Time Frame Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 1 for 25 mg QD and 150 mg QD groups; pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, and 24 hours post-dose on Day -7 for all other groups.
Hide Outcome Measure Data
Hide Analysis Population Description
PK parameter analysis set for PF-06463922 included all enrolled participants who received at least 1 dose of PF-06463922 and had sufficient information to estimate at least one of the PK parameters of interest for PF-06463922.
Arm/Group Title 10 mg QD (Phase 1) 25 mg QD (Phase 1) 50 mg QD (Phase 1) 75 mg QD (Phase 1) 100 mg QD (Phase 1) 150 mg QD (Phase 1) 200 mg QD (Phase 1) 35 mg BID (Phase 1) 75 mg BID (Phase 1) 100 mg BID (Phase 1)
Hide Arm/Group Description:
PF-06463922 10 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 25 mg was orally given once daily (QD) in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. Midazolam 2 mg was orally given QD on Day -7 and Cycle 1 Day 15.
PF-06463922 50 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 75 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 100 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 150 mg was orally given once daily (QD) in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. Midazolam 2 mg was orally given QD on Day -7 and Cycle 1 Day 15.
PF-06463922 200 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 35 mg was orally given twice daily (BID) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 75 mg was orally given twice daily (BID) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 100 mg was orally given twice daily (BID) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Overall Number of Participants Analyzed 3 3 2 12 16 3 3 3 3 4
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: nanogram*hour/milliliter (ng*hr/mL)
488.2
(21%)
1387
(35%)
NA [1] 
(NA%)
3990
(55%)
5110
(28%)
7474
(73%)
11410
(43%)
982.4
(9%)
2996
(20%)
2925
(47%)
[1]
Summary statistics were not calculated when fewer than 3 participants had reportable values. Individual values are 3310 and 3880 ng*hr/mL, respectively.
15.Secondary Outcome
Title Area Under the Plasma Concentration-Time Profile From Time Zero to Time Tau (AUCtau) of PF-06463922 Following Multiple Oral Doses (Phase 1)
Hide Description Tau refers to the dosing interval, and it equals to 12 or 24 hours for BID or QD dosing, respectively. AUCtau was determined using linear/log trapezoidal method.
Time Frame Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24 hours post-dose on Cycle 1 Day 15 (24-hour samples not collected for BID groups)
Hide Outcome Measure Data
Hide Analysis Population Description
PK parameter analysis set for PF-06463922 included all enrolled participants who received at least 1 dose of PF-06463922 and had sufficient information to estimate at least one of the PK parameters of interest for PF-06463922.
Arm/Group Title 10 mg QD (Phase 1) 25 mg QD (Phase 1) 50 mg QD (Phase 1) 75 mg QD (Phase 1) 100 mg QD (Phase 1) 150 mg QD (Phase 1) 200 mg QD (Phase 1) 35 mg BID (Phase 1) 75 mg BID (Phase 1) 100 mg BID (Phase 1)
Hide Arm/Group Description:
PF-06463922 10 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 25 mg was orally given once daily (QD) in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. Midazolam 2 mg was orally given QD on Day -7 and Cycle 1 Day 15.
PF-06463922 50 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 75 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 100 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 150 mg was orally given once daily (QD) in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. Midazolam 2 mg was orally given QD on Day -7 and Cycle 1 Day 15.
PF-06463922 200 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 35 mg was orally given twice daily (BID) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 75 mg was orally given twice daily (BID) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 100 mg was orally given twice daily (BID) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Overall Number of Participants Analyzed 3 3 3 12 16 3 2 1 3 3
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng*hr/mL
752.1
(26%)
1701
(29%)
3367
(39%)
4107
(53%)
5121
(30%)
6157
(9%)
NA [1] 
(NA%)
NA [2] 
(NA%)
3574
(35%)
4058
(33%)
[1]
Summary statistics were not calculated when fewer than 3 participants had reportable values. Individual values are 4480 and 12900 ng*hr/mL, respectively.
[2]
Summary statistics were not calculated when fewer than 3 participants had reportable values. The individual value is 2140 ng*hr/mL.
16.Secondary Outcome
Title Area Under the Plasma Concentration-Time Profile From Time Zero Extrapolated to Infinite Time (AUCinf) of PF-06463922 Following Single Oral Doses (Phase 1)
Hide Description AUCinf was calculated as AUClast + (Clast*/kel), where AUClast was the area under the plasma concentration-time profile from time 0 to the time of the last quantifiable concentration, Clast* was the predicted plasma concentration at the last quantifiable time point estimated from the log-linear regression analysis, and kel was the rate constant for terminal phase.
Time Frame Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 1 for 25 mg QD and 150 mg QD groups; pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24, 48, 72, 96 and 120 hours post-dose on Day -7 for all other groups.
Hide Outcome Measure Data
Hide Analysis Population Description
PK parameter analysis set for PF-06463922 included all enrolled participants who received at least 1 dose of PF-06463922 and had sufficient information to estimate at least one of the PK parameters of interest for PF-06463922.
Arm/Group Title 10 mg QD (Phase 1) 50 mg QD (Phase 1) 75 mg QD (Phase 1) 100 mg QD (Phase 1) 200 mg QD (Phase 1) 35 mg BID (Phase 1) 75 mg BID (Phase 1) 100 mg BID (Phase 1)
Hide Arm/Group Description:
PF-06463922 10 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 50 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 75 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 100 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 200 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 35 mg was orally given twice daily (BID) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 75 mg was orally given twice daily (BID) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 100 mg was orally given twice daily (BID) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Overall Number of Participants Analyzed 1 2 11 15 3 2 1 4
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng*hr/mL
NA [1] 
(NA%)
NA [2] 
(NA%)
7663
(79%)
8236
(25%)
18340
(61%)
NA [3] 
(NA%)
NA [4] 
(NA%)
6318
(56%)
[1]
Summary statistics were not calculated when fewer than 3 participants had reportable values. The individual value is 698 ng*hr/mL.
[2]
Summary statistics were not calculated when fewer than 3 participants had reportable values. Individual values are 7210 and 7240 ng*hr/mL, respectively.
[3]
Summary statistics were not calculated when fewer than 3 participants had reportable values. Individual values are 2630 and 3690 ng*hr/mL.
[4]
Summary statistics were not calculated when fewer than 3 participants had reportable values. The individual value is 6860 ng*hr/mL.
17.Secondary Outcome
Title Apparent Oral Clearance (CL/F) of PF-06463922 Following Single Oral Doses (Phase 1)
Hide Description Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. CL/F was calculated as dose/AUCinf, where AUCinf was the area under the plasma concentration-time profile from time 0 extrapolated to infinite time.
Time Frame Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 1 for 25 mg QD and 150 mg QD groups; pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24, 48, 72, 96 and 120 hours post-dose on Day -7 for all other groups.
Hide Outcome Measure Data
Hide Analysis Population Description
PK parameter analysis set for PF-06463922 included all enrolled participants who received at least 1 dose of PF-06463922 and had sufficient information to estimate at least one of the PK parameters of interest for PF-06463922.
Arm/Group Title 10 mg QD (Phase 1) 50 mg QD (Phase 1) 75 mg QD (Phase 1) 100 mg QD (Phase 1) 200 mg QD (Phase 1) 35 mg BID (Phase 1) 75 mg BID (Phase 1) 100 mg BID (Phase 1)
Hide Arm/Group Description:
PF-06463922 10 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 50 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 75 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 100 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 200 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 35 mg was orally given twice daily (BID) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 75 mg was orally given twice daily (BID) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 100 mg was orally given twice daily (BID) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Overall Number of Participants Analyzed 1 2 11 15 3 2 1 4
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: liter/hour (L/hr)
NA [1] 
(NA%)
NA [2] 
(NA%)
9.788
(79%)
12.14
(25%)
10.90
(61%)
NA [3] 
(NA%)
NA [4] 
(NA%)
15.83
(56%)
[1]
Summary statistics were not calculated when fewer than 3 participants had reportable values. The individual value is 14.3 L/hr.
[2]
Summary statistics were not calculated when fewer than 3 participants had reportable values. Individual values are 6.91 and 6.94 L/hr, respectively.
[3]
Summary statistics were not calculated when fewer than 3 participants had reportable values. Individual values are 9.48 and 13.3 L/hr, respectively.
[4]
Summary statistics were not calculated when fewer than 3 participants had reportable values. The individual value is 10.9 L/hr.
18.Secondary Outcome
Title Apparent Oral Clearance (CL/F) of PF-06463922 Following Multiple Oral Doses (Phase 1)
Hide Description Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. CL/F was calculated as dose/AUCinf, where AUCinf was the area under the plasma concentration-time profile from time 0 extrapolated to infinite time.
Time Frame Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24 hours post-dose on Cycle 1 Day 15 (24-hour samples not collected for BID groups)
Hide Outcome Measure Data
Hide Analysis Population Description
PK parameter analysis set for PF-06463922 included all enrolled participants who received at least 1 dose of PF-06463922 and had sufficient information to estimate at least one of the PK parameters of interest for PF-06463922.
Arm/Group Title 10 mg QD (Phase 1) 25 mg QD (Phase 1) 50 mg QD (Phase 1) 75 mg QD (Phase 1) 100 mg QD (Phase 1) 150 mg QD (Phase 1) 200 mg QD (Phase 1) 35 mg BID (Phase 1) 75 mg BID (Phase 1) 100 mg BID (Phase 1)
Hide Arm/Group Description:
PF-06463922 10 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 25 mg was orally given once daily (QD) in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. Midazolam 2 mg was orally given QD on Day -7 and Cycle 1 Day 15.
PF-06463922 50 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 75 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 100 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 150 mg was orally given once daily (QD) in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. Midazolam 2 mg was orally given QD on Day -7 and Cycle 1 Day 15.
PF-06463922 200 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 35 mg was orally given twice daily (BID) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 75 mg was orally given twice daily (BID) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 100 mg was orally given twice daily (BID) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Overall Number of Participants Analyzed 3 3 3 12 16 3 2 1 3 3
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: L/hr
13.27
(26%)
14.72
(29%)
14.84
(39%)
17.66
(48%)
19.52
(30%)
24.37
(9%)
NA [1] 
(NA%)
NA [2] 
(NA%)
20.99
(35%)
22.37
(47%)
[1]
Summary statistics were not calculated when fewer than 3 participants had reportable values. Individual values are 15.5 and 44.6 L/hr, respectively.
[2]
Summary statistics were not calculated when fewer than 3 participants had reportable values. The individual value is 16.3 L/hr.
19.Secondary Outcome
Title Apparent Volume of Distribution (Vz/F) of PF-06463922 Following Single Oral Doses (Phase 1)
Hide Description Vz/F was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug, and calculated as dose/(AUCinf*kel), where AUCinf was the area under the plasma concentration-time profile from time 0 extrapolated to infinite time, kel was the rate constant for terminal phase.
Time Frame Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9 and 24 hours post-dose on Cycle1 Day 1 for 25 mg QD and 150 mg QD groups; pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24, 48, 72, 96 and 120 hours post-dose on Day -7 for all other groups.
Hide Outcome Measure Data
Hide Analysis Population Description
PK parameter analysis set for PF-06463922 included all enrolled participants who received at least 1 dose of PF-06463922 and had sufficient information to estimate at least one of the PK parameters of interest for PF-06463922.
Arm/Group Title 10 mg QD (Phase 1) 50 mg QD (Phase 1) 75 mg QD (Phase 1) 100 mg QD (Phase 1) 200 mg QD (Phase 1) 35 mg BID (Phase 1) 75 mg BID (Phase 1) 100 mg BID (Phase 1)
Hide Arm/Group Description:
PF-06463922 10 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 50 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 75 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 100 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 200 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 35 mg was orally given twice daily (BID) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 75 mg was orally given twice daily (BID) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 100 mg was orally given twice daily (BID) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Overall Number of Participants Analyzed 1 2 11 15 3 2 1 4
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: liters (L)
NA [1] 
(NA%)
NA [2] 
(NA%)
367.9
(54%)
356.3
(39%)
307.8
(41%)
NA [3] 
(NA%)
NA [4] 
(NA%)
378.3
(54%)
[1]
Summary statistics were not calculated when fewer than 3 participants had reportable values. The individual value is 373 L.
[2]
Summary statistics were not calculated when fewer than 3 participants had reportable values. Individual values are 166 and 307 L, respectively.
[3]
Summary statistics were not calculated when fewer than 3 participants had reportable values. Individual values are 362 and 472 L, respectively.
[4]
Summary statistics were not calculated when fewer than 3 participants had reportable values. The individual value is 410 L.
20.Secondary Outcome
Title Observed Accumulation Ratio (Rac) of PF-06463922 Following Multiple Oral Doses (Phase 1)
Hide Description Rac was calculated as Day 15 AUCtau/Day -7 AUCtau or Day 1 AUCtau, where AUCtau was the area under the plasma concentration-time profile from time 0 to time tau (12 and 24 hours for BID and QD dosing regimen, respectively).
Time Frame Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24 hours post-dose on Cycle 1 Day 15 (24-hour samples not collected for BID groups)
Hide Outcome Measure Data
Hide Analysis Population Description
PK parameter analysis set for PF-06463922 included all enrolled participants who received at least 1 dose of PF-06463922 and had sufficient information to estimate at least one of the PK parameters of interest for PF-06463922.
Arm/Group Title 10 mg QD (Phase 1) 25 mg QD (Phase 1) 50 mg QD (Phase 1) 75 mg QD (Phase 1) 100 mg QD (Phase 1) 150 mg QD (Phase 1) 200 mg QD (Phase 1) 35 mg BID (Phase 1) 75 mg BID (Phase 1) 100 mg BID (Phase 1)
Hide Arm/Group Description:
PF-06463922 10 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 25 mg was orally given once daily (QD) in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. Midazolam 2 mg was orally given QD on Day -7 and Cycle 1 Day 15.
PF-06463922 50 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 75 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 100 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 150 mg was orally given once daily (QD) in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. Midazolam 2 mg was orally given QD on Day -7 and Cycle 1 Day 15.
PF-06463922 200 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 35 mg was orally given twice daily (BID) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 75 mg was orally given twice daily (BID) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 100 mg was orally given twice daily (BID) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Overall Number of Participants Analyzed 3 3 2 12 15 3 2 1 3 3
Mean (Standard Deviation)
Unit of Measure: ratio
1.543  (0.075056) 1.237  (0.20817) 1.105 [1]   (NA) 1.121  (0.44575) 1.071  (0.31138) 1.000  (0.79137) 0.6500 [1]   (NA) NA [2]   (NA) 1.231  (0.35228) 1.523  (0.29569)
[1]
Standard deviation was not calculated when fewer than 3 participants had reportable values.
[2]
These summary statistics were not calculated when fewer than 3 participants had reportable values. The individual value is 2.09.
21.Secondary Outcome
Title Terminal Half-Life of PF-06463922 Following Single Oral Doses (Phase 1)
Hide Description Terminal plasma half-life was defined as the time measured for the plasma concentration to decrease by one half, and calculated as loge(2)/kel, where kel was the rate constant for terminal phase.
Time Frame Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 1 for 25 mg QD and 150 mg QD groups; pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24, 48, 72, 96 and 120 hours post-dose on Day -7 for all other groups.
Hide Outcome Measure Data
Hide Analysis Population Description
PK parameter analysis set for PF-06463922 included all enrolled participants who received at least 1 dose of PF-06463922 and had sufficient information to estimate at least one of the PK parameters of interest for PF-06463922.
Arm/Group Title 10 mg QD (Phase 1) 50 mg QD (Phase 1) 75 mg QD (Phase 1) 100 mg QD (Phase 1) 200 mg QD (Phase 1) 35 mg BID (Phase 1) 75 mg BID (Phase 1) 100 mg BID (Phase 1)
Hide Arm/Group Description:
PF-06463922 10 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 50 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 75 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 100 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 200 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 35 mg was orally given twice daily (BID) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 75 mg was orally given twice daily (BID) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 100 mg was orally given twice daily (BID) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Overall Number of Participants Analyzed 1 2 11 15 3 2 1 4
Mean (Standard Deviation)
Unit of Measure: hours (hr)
NA [1]   (NA) 23.70 [2]   (NA) 27.22  (8.2961) 20.89  (5.0308) 19.80  (3.3045) 25.55 [3]   (NA) NA [4]   (NA) 17.18  (5.1874)
[1]
Summary statistics were not calculated when fewer than 3 participants had reportable values. The individual value is 18.0 hr.
[2]
Standard deviation was not calculated when fewer than 3 participants had reportable values. Individual values are 16.6 and 30.8 hr, respectively.
[3]
Standard deviation was not calculated when fewer than 3 participants had reportable values. Individual values are 24.6 and 26.5 hr, respectively.
[4]
Summary statistics were not calculated when fewer than 3 participants had reportable values. The individual value is 26.0 hr.
22.Secondary Outcome
Title Steady State Accumulation Ratio (Rss) of PF-06463922 Following Multiple Oral Doses (Phase 1)
Hide Description Rss was calculated as Day 15 AUCtau/Day -7 AUCinf, where AUCtau was the area under the plasma concentration-time profile from time 0 to time tau (12 and 24 hours for BID and QD dosing regimen, respectively), and AUCinf was the area under the plasma concentration-time profile from time 0 extrapolated to infinite time.
Time Frame Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24 hours post-dose on Cycle 1 Day 15 (24-hour samples not collected for BID groups)
Hide Outcome Measure Data
Hide Analysis Population Description
PK parameter analysis set for PF-06463922 included all enrolled participants who received at least 1 dose of PF-06463922 and had sufficient information to estimate at least one of the PK parameters of interest for PF-06463922.
Arm/Group Title 10 mg QD (Phase 1) 50 mg QD (Phase 1) 75 mg QD (Phase 1) 100 mg QD (Phase 1) 200 mg QD (Phase 1) 35 mg BID (Phase 1) 75 mg BID (Phase 1) 100 mg BID (Phase 1)
Hide Arm/Group Description:
PF-06463922 10 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 50 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 75 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 100 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 200 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 35 mg was orally given twice daily (BID) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 75 mg was orally given twice daily (BID) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 100 mg was orally given twice daily (BID) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Overall Number of Participants Analyzed 1 2 11 14 2 1 1 3
Mean (Standard Deviation)
Unit of Measure: ratio
NA [1]   (NA) 0.5600 [2]   (NA) 0.6131  (0.29021) 0.6603  (0.18604) 0.3935 [3]   (NA) NA [4]   (NA) NA [5]   (NA) 0.7687  (0.13552)
[1]
These summary statistics were not calculated when fewer than 3 participants had reportable values. The individual value is 0.993.
[2]
Standard deviation was not calculated when fewer than 3 participants had reportable values. Individual values are 0.401 and 0.719, respectively.
[3]
Standard deviation was not calculated when fewer than 3 participants had reportable values. Individual values are 0.384 and 0.403, respectively.
[4]
These summary statistics were not calculated when fewer than 3 participants had reportable values. The individual value is 0.815.
[5]
These summary statistics were not calculated when fewer than 3 participants had reportable values. The individual value is 0.542.
23.Secondary Outcome
Title Renal Clearance (CLr) of PF-06463922 (Phase 1)
Hide Description Renal clearance was calculated as Aetau/AUCtau, where Aetau was the cumulative amount of drug recovered unchanged in urine up to dosing interval tau (24 hours for QD dosing regimen), and AUCtau was the area under the plasma concentration-time profile from time 0 to time tau (24 hours for QD dosing regimen).
Time Frame 0-4 hours, 4-12 hours and 12-24 hours post-dose on Cycle 1 Day 15
Hide Outcome Measure Data
Hide Analysis Population Description
PK parameter analysis set for PF-06463922 included all enrolled participants who received at least 1 dose of PF-06463922 and had sufficient information to estimate at least one of the PK parameters of interest for PF-06463922. As planned, this parameter was only analyzed for 100 mg QD group.
Arm/Group Title 100 mg QD (Phase 1)
Hide Arm/Group Description:
PF-06463922 100 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Overall Number of Participants Analyzed 3
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ml/hour
61.31
(58%)
24.Secondary Outcome
Title Percent of PF-06463922 Recovered Unchanged in Urine up to Dosing Interval (AEtau%) (Phase 1)
Hide Description Dosing interval was 24 hours for QD dosing regimen. Aetau% was calculated as 100*Ae24/dose, where Ae24 was the cumulative amount of drug recovered unchanged in urine up to 24 hours post-dose.
Time Frame 0-4 hours, 4-12 hours and 12-24 hours post-dose on Cycle 1 Day 15
Hide Outcome Measure Data
Hide Analysis Population Description
PK parameter analysis set for PF-06463922 included all enrolled participants who received at least 1 dose of PF-06463922 and had sufficient information to estimate at least one of the PK parameters of interest for PF-06463922. As planned, this parameter was only analyzed for 100 mg QD group.
Arm/Group Title 100 mg QD (Phase 1)
Hide Arm/Group Description:
PF-06463922 100 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Overall Number of Participants Analyzed 3
Mean (Standard Deviation)
Unit of Measure: percentage of recovered PF-06463922
0.4017  (0.11074)
25.Secondary Outcome
Title Maximum Observed Plasma Concentration (Cmax) of Midazolam (Phase 1)
Hide Description Cmax of midazolam was observed directly from data. Only participants in 25 mg and 150 mg QD groups were given midazolam. Day -7 data reflected the PK assessment before administration of PF-06463922, and Cycle 1 Day 15 data reflected the PK assessment after multiple doses of PF-06463922 were administered.
Time Frame Pre-dose, 0.5, 1, 2, 4, 6, 8, 9 and 24 hours post-dose on Day -7 and pre-dose, 0.5, 1, 2, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 15
Hide Outcome Measure Data
Hide Analysis Population Description
PK concentration analysis set for midazolam included all participants treated with midazolam who had at least 1 concentration of midazolam.
Arm/Group Title 25 mg QD (Phase 1) 150 mg QD (Phase 1)
Hide Arm/Group Description:
PF-06463922 25 mg was orally given once daily (QD) in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. Midazolam 2 mg was orally given QD on Day -7 and Cycle 1 Day 15.
PF-06463922 150 mg was orally given once daily (QD) in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. Midazolam 2 mg was orally given QD on Day -7 and Cycle 1 Day 15.
Overall Number of Participants Analyzed 3 3
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng/mL
Day -7
16.06
(42%)
11.56
(48%)
Cycle 1 Day 15
9.697
(40%)
5.734
(43%)
26.Secondary Outcome
Title Time for Cmax (Tmax) of Midazolam (Phase 1)
Hide Description Tmax of midazolam was observed directly from data as time of first occurrence. Only participants in 25 mg and 150 mg QD groups were given midazolam. Day -7 data reflect the PK assessment before administration of PF-06463922, and Cycle 1 Day 15 data reflect the PK assessment after multiple doses of PF-06463922 were administered.
Time Frame Pre-dose, 0.5, 1, 2, 4, 6, 8, 9 and 24 hours post-dose on Day -7 and pre-dose, 0.5, 1, 2, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 15
Hide Outcome Measure Data
Hide Analysis Population Description
PK parameter analysis set for midazolam included all participants who received at least 1 dose of midazolam and for which at least 1 midazolam PK parameter of interest was available.
Arm/Group Title 25 mg QD (Phase 1) 150 mg QD (Phase 1)
Hide Arm/Group Description:
PF-06463922 25 mg was orally given once daily (QD) in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. Midazolam 2 mg was orally given QD on Day -7 and Cycle 1 Day 15.
PF-06463922 150 mg was orally given once daily (QD) in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. Midazolam 2 mg was orally given QD on Day -7 and Cycle 1 Day 15.
Overall Number of Participants Analyzed 3 3
Median (Full Range)
Unit of Measure: hours
Day -7
0.50
(0.50 to 1.00)
0.50
(0.50 to 0.50)
Cycle 1 Day 15
0.50
(0.50 to 1.00)
0.50
(0.50 to 0.533)
27.Secondary Outcome
Title Area Under the Plasma Concentration-Time Profile From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Midazolam (Phase 1)
Hide Description Area under the plasma concentration-time profile from time 0 to the time of the last quantifiable concentration (AUClast) of midazolam was determined using linear/log trapezoidal method. Only participants in 25 mg and 150 mg QD groups were given midazolam. Day -7 data reflect the PK assessment before administration of PF-06463922, and Cycle 1 Day 15 data reflect the PK assessment after multiple doses of PF-06463922 were administered.
Time Frame Pre-dose, 0.5, 1, 2, 4, 6, 8, 9 and 24 hours post-dose on Day -7 and pre-dose, 0.5, 1, 2, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 15
Hide Outcome Measure Data
Hide Analysis Population Description
PK parameter analysis set for midazolam included all participants who received at least 1 dose of midazolam and for which at least 1 midazolam PK parameter of interest was available.
Arm/Group Title 25 mg QD (Phase 1) 150 mg QD (Phase 1)
Hide Arm/Group Description:
PF-06463922 25 mg was orally given once daily (QD) in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. Midazolam 2 mg was orally given QD on Day -7 and Cycle 1 Day 15.
PF-06463922 150 mg was orally given once daily (QD) in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. Midazolam 2 mg was orally given QD on Day -7 and Cycle 1 Day 15.
Overall Number of Participants Analyzed 3 3
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng*hr/mL
Day -7
51.30
(47%)
36.49
(20%)
Cycle 1 Day 15
20.43
(18%)
14.44
(25%)
28.Secondary Outcome
Title Area Under the Plasma Concentration-Time Profile From Time Zero Extrapolated to Infinite Time (AUCinf) of Midazolam (Phase 1)
Hide Description AUCinf was calculated as AUClast + (Clast*/kel), where AUClast was the area under the plasma concentration-time profile from time 0 to the time of the last quantifiable concentration, Clast* was the predicted plasma concentration at the last quantifiable time point estimated from the log-linear regression analysis, and kel was the rate constant for terminal phase. Only participants in 25 mg and 150 mg QD groups were given midazolam. Day -7 data reflect the PK assessment before administration of PF-06463922, and Cycle 1 Day 15 data reflect the PK assessment after multiple doses of PF-06463922 were administered.
Time Frame Pre-dose, 0.5, 1, 2, 4, 6, 8, 9 and 24 hours post-dose on Day -7 and pre-dose, 0.5, 1, 2, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 15
Hide Outcome Measure Data
Hide Analysis Population Description
PK parameter analysis set for midazolam included all participants who received at least 1 dose of midazolam and for which at least 1 midazolam PK parameter of interest was available.
Arm/Group Title 25 mg QD (Phase 1) 150 mg QD (Phase 1)
Hide Arm/Group Description:
PF-06463922 25 mg was orally given once daily (QD) in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. Midazolam 2 mg was orally given QD on Day -7 and Cycle 1 Day 15.
PF-06463922 150 mg was orally given once daily (QD) in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. Midazolam 2 mg was orally given QD on Day -7 and Cycle 1 Day 15.
Overall Number of Participants Analyzed 3 3
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng*hr/mL
Day -7 Number Analyzed 3 participants 2 participants
54.53
(43%)
NA [1] 
(NA%)
Cycle 1 Day 15 Number Analyzed 3 participants 3 participants
21.32
(18%)
16.09
(29%)
[1]
Summary statistics were not calculated when fewer than 3 participants had reportable values. Individual values are 42.2 and 46.8 ng*hr/mL, respectively.
29.Secondary Outcome
Title Apparent Oral Clearance (CL/F) of Midazolam (Phase 1)
Hide Description Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. CL/F was calculated as dose/AUCinf, where AUCinf was the area under the plasma concentration-time profile from time 0 extrapolated to infinite time. Only participants in 25 mg and 150 mg QD groups were given midazolam. Day -7 data reflect the PK assessment before administration of PF-06463922, and Cycle 1 Day 15 data reflect the PK assessment after multiple doses of PF-06463922 were administered.
Time Frame Pre-dose, 0.5, 1, 2, 4, 6, 8, 9 and 24 hours post-dose on Day -7 and pre-dose, 0.5, 1, 2, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 15
Hide Outcome Measure Data
Hide Analysis Population Description
PK parameter analysis set for midazolam included all participants who received at least 1 dose of midazolam and for which at least 1 midazolam PK parameter of interest was available.
Arm/Group Title 25 mg QD (Phase 1) 150 mg QD (Phase 1)
Hide Arm/Group Description:
PF-06463922 25 mg was orally given once daily (QD) in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. Midazolam 2 mg was orally given QD on Day -7 and Cycle 1 Day 15.
PF-06463922 150 mg was orally given once daily (QD) in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. Midazolam 2 mg was orally given QD on Day -7 and Cycle 1 Day 15.
Overall Number of Participants Analyzed 3 3
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: L/hr
Day -7 Number Analyzed 3 participants 2 participants
36.68
(43%)
NA [1] 
(NA%)
Cycle 1 Day 15 Number Analyzed 3 participants 3 participants
93.86
(18%)
124.2
(29%)
[1]
Summary statistics were not calculated when fewer than 3 participants had reportable values. Individual values are 42.7 and 47.4 L/hr, respectively.
30.Secondary Outcome
Title Apparent Volume of Distribution (Vz/F) of Midazolam (Phase 1)
Hide Description Vz/F was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug, and calculated as dose/(AUCinf*kel), where AUCinf was the area under the plasma concentration-time profile from time 0 extrapolated to infinite time, kel was the rate constant for terminal phase. Only participants in 25 mg and 150 mg QD groups were given midazolam. Day -7 data reflect the PK assessment before administration of PF-06463922, and Cycle 1 Day 15 data reflect the PK assessment after multiple doses of PF-06463922 were administered.
Time Frame Pre-dose, 0.5, 1, 2, 4, 6, 8, 9 and 24 hours post-dose on Day -7 and pre-dose, 0.5, 1, 2, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 15
Hide Outcome Measure Data
Hide Analysis Population Description
PK parameter analysis set for midazolam included all participants who received at least 1 dose of midazolam and for which at least 1 midazolam PK parameter of interest was available.
Arm/Group Title 25 mg QD (Phase 1) 150 mg QD (Phase 1)
Hide Arm/Group Description:
PF-06463922 25 mg was orally given once daily (QD) in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. Midazolam 2 mg was orally given QD on Day -7 and Cycle 1 Day 15.
PF-06463922 150 mg was orally given once daily (QD) in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. Midazolam 2 mg was orally given QD on Day -7 and Cycle 1 Day 15.
Overall Number of Participants Analyzed 3 3
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: L
Day -7 Number Analyzed 3 participants 2 participants
229.0
(7%)
NA [1] 
(NA%)
Cycle 1 Day 15 Number Analyzed 3 participants 3 participants
404.4
(51%)
702.2
(100%)
[1]
Summary statistics were not calculated when fewer than 3 participants had reportable values. Individual values are 161 and 486 L, respectively.
31.Secondary Outcome
Title Terminal Half-Life of Midazolam (Phase 1)
Hide Description Terminal plasma half-life was defined as the time measured for the plasma concentration to decrease by one half, and calculated as loge(2)/kel, where kel was the rate constant for terminal phase. Only participants in 25 mg and 150 mg QD groups were given midazolam. Day -7 data reflect the PK assessment before administration of PF-06463922, and Cycle 1 Day 15 data reflect the PK assessment after multiple doses of PF-06463922 were administered.
Time Frame Pre-dose, 0.5, 1, 2, 4, 6, 8, 9 and 24 hours post-dose on Day -7 and pre-dose, 0.5, 1, 2, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 15
Hide Outcome Measure Data
Hide Analysis Population Description
PK parameter analysis set for midazolam included all participants who received at least 1 dose of midazolam and for which at least 1 midazolam PK parameter of interest was available.
Arm/Group Title 25 mg QD (Phase 1) 150 mg QD (Phase 1)
Hide Arm/Group Description:
PF-06463922 25 mg was orally given once daily (QD) in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. Midazolam 2 mg was orally given QD on Day -7 and Cycle 1 Day 15.
PF-06463922 150 mg was orally given once daily (QD) in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. Midazolam 2 mg was orally given QD on Day -7 and Cycle 1 Day 15.
Overall Number of Participants Analyzed 3 3
Mean (Standard Deviation)
Unit of Measure: hr
Day -7 Number Analyzed 3 participants 2 participants
4.620  (1.9328) 5.120 [1]   (NA)
Cycle 1 Day 15 Number Analyzed 3 participants 3 participants
3.343  (2.0358) 5.257  (5.0639)
[1]
Standard deviation was not calculated when fewer than 3 participants had reportable values. Individual values are 2.35 and 7.89 hr, respectively.
32.Secondary Outcome
Title Number of Participants With ALK Mutation Based on Plasma CNA Analysis (Phase 1)
Hide Description Plasma circulating nucleic acid (CNA) samples were analyzed for ALK kinase domain mutations by digital polymerase chain reaction (PCR) BEAMing technology. Number of participants with one or more ALK mutations is presented.
Time Frame Screening
Hide Outcome Measure Data
Hide Analysis Population Description
CNA peripheral blood analysis set included all participants of the ITT analysis set who had at least 1 molecular biomarker assayed.
Arm/Group Title ALK Positive Population (Phase 1)
Hide Arm/Group Description:
This reporting arm includes all Phase 1 participants who had documented ALK rearrangement.
Overall Number of Participants Analyzed 39
Measure Type: Count of Participants
Unit of Measure: Participants
14
  35.9%
33.Secondary Outcome
Title Number of Participants With ALK Mutation Based on Tumor Tissue Analysis (Phase 1)
Hide Description Tumor tissues from archived tissue specimens and/or a de novo biopsy were analyzed for ALK kinase domain mutations. Number of participants with one or more ALK mutations is presented.
Time Frame Screening
Hide Outcome Measure Data
Hide Analysis Population Description
Tumor Tissue analysis set included all participants of the ITT analysis set who had at least 1 molecular tumor biomarker assayed from either the screening archival or screening de novo tumor biopsy sample (or both).
Arm/Group Title ALK Positive Population (Phase 1)
Hide Arm/Group Description:
This reporting arm includes all Phase 1 participants who had documented ALK rearrangement.
Overall Number of Participants Analyzed 30
Measure Type: Count of Participants
Unit of Measure: Participants
7
  23.3%
34.Secondary Outcome
Title Number of Participants Who Improved, Worsened or Remained Stable in EORTC QLQ-C30 (Phase 1)
Hide Description European Organisation for Research and Treatment of Cancer Core Quality of Life Questionaires (EORTC QLQ)-C30 (version 3.0) consists of 30 questions assessing 5 functional domains (physical, role, emotional, cognitive and social), global quality of life (QoL), disease/treatment related symptoms (fatigue, nausea/vomiting, pain, dyspnea, insomnia, appetite loss, constipation and diarrhoea), and the perceived financial impact of disease. Each scale was transformed to a range of 0 to 100 using standard EORTC algorithm. For global QoL and functional scales, higher score indicate better performance, and improvement was defined as an increase of at least 10 points, worsening was defined as a decrease of at least 10 points. For symptom scales, higher score indicates worse symptoms, and improvement was defined as a decrease of at least 10 points, worsening was defined as an increase of at least 10 points. All scales which had not improved nor worsened were considered stable.
Time Frame Baseline, Day 1 of Cycles 2-25, Day 1 of every other cycle after Cycle 25, end of treatment (up to 3 years)
Hide Outcome Measure Data
Hide Analysis Population Description
Patient reported outcome (PRO) evaluable analysis set included all enrolled participants who received at least 1 dose of PF-06463922 and completed a baseline and at least 1 post-baseline PRO assessment.
Arm/Group Title Phase 1 PRO Evaluable Population
Hide Arm/Group Description:
This reporting group includes all Phase 1 participants who received at least 1 dose of PF-06463922 and completed a baseline and at least 1 post-baseline PRO assessment.
Overall Number of Participants Analyzed 43
Measure Type: Count of Participants
Unit of Measure: Participants
Improved in global QoL
20
  46.5%
Stable in global QoL
13
  30.2%
Worsened in global QoL
10
  23.3%
Improved in physical functioning
6
  14.0%
Stable in physical functioning
30
  69.8%
Worsened in physical functioning
7
  16.3%
Improved in role functioning
15
  34.9%
Stable in role functioning
16
  37.2%
Worsened in role functioning
12
  27.9%
Improved in emotional functioning
15
  34.9%
Stable in emotional functioning
20
  46.5%
Worsened in emotional functioning
8
  18.6%
Improved in cognitive functioning
8
  18.6%
Stable in cognitive functioning
21
  48.8%
Worsened in cognitive functioning
14
  32.6%
Improved in social functioning
13
  30.2%
Stable in social functioning
18
  41.9%
Worsened in social functioning
12
  27.9%
Improved in fatigue
18
  41.9%
Stable in fatigue
19
  44.2%
Worsened in fatigue
6
  14.0%
Improved in nausea and vomiting
10
  23.3%
Stable in nausea and vomiting
32
  74.4%
worsened in nausea and vomiting
1
   2.3%
Improved in pain
18
  41.9%
Stable in pain
15
  34.9%
Worsened in pain
10
  23.3%
Improved in dyspnea
13
  30.2%
Stable in dyspnea
19
  44.2%
Worsened in dyspnea
11
  25.6%
Improved in insomnia
19
  44.2%
Stable in insomnia
17
  39.5%
Worsened in insomnia
7
  16.3%
Improved in appetite loss
14
  32.6%
Stable in appetite loss
27
  62.8%
Worsened in appetite loss
2
   4.7%
Improved in constipation
11
  25.6%
Stable in constipation
27
  62.8%
Worsened in constipation
5
  11.6%
Improved in diarrhea
9
  20.9%
Stable in diarrhea
29
  67.4%
Worsened in diarrhea
5
  11.6%
Improved in financial difficulties
7
  16.3%
Stable in financial difficulties
21
  48.8%
Worsened in financial difficulties
15
  34.9%
35.Secondary Outcome
Title Number of Participants Who Improved, Worsened or Remained Stable in EORTC QLQ-LC13 (Phase 1)
Hide Description EORTC QLQ-LC13 is the lung cancer module of EORTC QLQ-C30 and includes questions specific to the disease associated symptoms (dyspnea, cough, hemoptysis, and site specific pain), treatment-related symptoms (sore mouth, dysphagia, neuropathy and alopecia), and analgesic use of lung cancer patients. The scale was transformed to a range of 0 to 100 using standard EORTC algorithm. Higher score indicates worse symptoms, and improvement was defined as a decrease of at least 10 points, worsening was defined as an increase of at least 10 points. All scales which had not improved nor worsened were considered stable.
Time Frame Baseline, Day 1 of Cycles 2-25, Day 1 of every other cycle after Cycle 25, end of treatment (up to 3 years)
Hide Outcome Measure Data
Hide Analysis Population Description
Patient reported outcome (PRO) evaluable analysis set included all enrolled participants who received at least 1 dose of PF-06463922 and completed a baseline and at least 1 post-baseline PRO assessment.
Arm/Group Title Phase 1 PRO Evaluable Population
Hide Arm/Group Description:
This reporting group includes all Phase 1 participants who received at least 1 dose of PF-06463922 and completed a baseline and at least 1 post-baseline PRO assessment.
Overall Number of Participants Analyzed 43
Measure Type: Count of Participants
Unit of Measure: Participants
Improved in dyspnea Number Analyzed 43 participants
10
  23.3%
Stable in dyspnea Number Analyzed 43 participants
22
  51.2%
Worsened in dyspnea Number Analyzed 43 participants
11
  25.6%
Improved in coughing Number Analyzed 43 participants
23
  53.5%
Stable in coughing Number Analyzed 43 participants
12
  27.9%
Worsened in coughing Number Analyzed 43 participants
8
  18.6%
Improved in hemoptysis Number Analyzed 43 participants
1
   2.3%
Stable in hemoptysis Number Analyzed 43 participants
42
  97.7%
Worsened in hemoptysis Number Analyzed 43 participants
0
   0.0%
Improved in sore mouth Number Analyzed 43 participants
0
   0.0%
Stable in sore mouth Number Analyzed 43 participants
40
  93.0%
Worsened in sore mouth Number Analyzed 43 participants
3
   7.0%
Improved in dysphagia Number Analyzed 43 participants
4
   9.3%
Stable in dysphagia Number Analyzed 43 participants
37
  86.0%
Worsened in dysphagia Number Analyzed 43 participants
2
   4.7%
Improved in peripheral neuropathy Number Analyzed 43 participants
6
  14.0%
Stable in peripheral neuropathy Number Analyzed 43 participants
19
  44.2%
Worsened in peripheral neuropathy Number Analyzed 43 participants
18
  41.9%
Improved in alopecia Number Analyzed 42 participants
3
   7.1%
Stable in alopecia Number Analyzed 42 participants
30
  71.4%
Worsened in alopecia Number Analyzed 42 participants
9
  21.4%
Improved in chest pain Number Analyzed 43 participants
16
  37.2%
Stable in chest pain Number Analyzed 43 participants
22
  51.2%
Worsened in chest pain Number Analyzed 43 participants
5
  11.6%
Improved in arm or shoulder pain Number Analyzed 43 participants
10
  23.3%
Stable in arm or shoulder pain Number Analyzed 43 participants
28
  65.1%
Worsened in arm or shoulder pain Number Analyzed 43 participants
5
  11.6%
Improved in pain in other parts Number Analyzed 43 participants
19
  44.2%
Stable in pain in other parts Number Analyzed 43 participants
14
  32.6%
Worsened in pain in other parts Number Analyzed 43 participants
10
  23.3%
36.Secondary Outcome
Title Change From Baseline in Mini Mental State Examination (MMSE) Score (Phase 1)
Hide Description In Phase 1, the MMSE was collected to assess mental status. The MMSE is a 30 item questionnaire that tests 5 areas of cognitive function: orientation, registration, attention and calculation, recall and language. The maximum score is 30. A score of 23 or lower is indicative of cognitive impairment. The MMSE was removed under Amendment 6 of the study protocol, and not required for Phase 2, as the tool was not considered meaningful for assessment of cognitive function.
Time Frame Baseline, Day 1 of each cycle, and end of treatment (up to 3 years)
Hide Outcome Measure Data
Hide Analysis Population Description
MMSE assessment evaluable analysis set included all participants in the safety analysis set (all participants who received at least 1 dose of PF-06463922) who completed a baseline and at least 1 post-baseline assessment.
Arm/Group Title 10 mg QD (Phase 1) 25 mg QD (Phase 1) 50 mg QD (Phase 1) 75 mg QD (Phase 1) 100 mg QD (Phase 1) 150 mg QD (Phase 1) 200 mg QD (Phase 1) 35 mg BID (Phase 1) 75 mg BID (Phase 1) 100 mg BID (Phase 1)
Hide Arm/Group Description:
PF-06463922 10 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 25 mg was orally given once daily (QD) in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. Midazolam 2 mg was orally given QD on Day -7 and Cycle 1 Day 15.
PF-06463922 50 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 75 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 100 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 150 mg was orally given once daily (QD) in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. Midazolam 2 mg was orally given QD on Day -7 and Cycle 1 Day 15.
PF-06463922 200 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 35 mg was orally given twice daily (BID) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 75 mg was orally given twice daily (BID) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 100 mg was orally given twice daily (BID) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Overall Number of Participants Analyzed 2 3 3 9 16 3 2 2 3 4
Mean (Standard Deviation)
Unit of Measure: units on a score
Cycle 1 Day 1 Number Analyzed 2 participants 0 participants 2 participants 7 participants 9 participants 0 participants 0 participants 0 participants 1 participants 1 participants
1.0  (1.41) -0.5  (0.71) -0.9  (2.27) 0.8  (1.39) 0.0 [1]   (NA) 0.0 [1]   (NA)
Cycle 2 Day 1 Number Analyzed 1 participants 3 participants 1 participants 9 participants 16 participants 3 participants 2 participants 2 participants 2 participants 3 participants
2.0 [1]   (NA) -0.3  (0.58) 2.0 [1]   (NA) 0.3  (1.41) 0.0  (1.79) 4.7  (8.08) 4.0  (4.24) 0.0  (0.00) 0.0  (0.00) -0.3  (1.15)
Cycle 3 Day 1 Number Analyzed 2 participants 3 participants 2 participants 8 participants 15 participants 2 participants 2 participants 0 participants 1 participants 3 participants
2.0  (0.00) 0.3  (0.58) -0.5  (0.71) -0.6  (1.85) 0.2  (1.52) 5.0  (8.49) 3.0  (2.83) 0.0 [1]   (NA) -1.0  (1.00)
Cycle 4 Day 1 Number Analyzed 1 participants 2 participants 2 participants 8 participants 14 participants 3 participants 2 participants 0 participants 1 participants 3 participants
5.0 [1]   (NA) 0.5  (0.71) 1.5  (2.12) -1.1  (1.81) 0.0  (1.47) 2.0  (6.24) -0.5  (3.54) 0.0 [1]   (NA) -0.7  (1.15)
Cycle 5 Day 1 Number Analyzed 2 participants 2 participants 2 participants 7 participants 11 participants 3 participants 2 participants 0 participants 1 participants 2 participants
0.5  (3.54) 0.5  (0.71) 1.5  (2.12) 0.3  (1.25) -0.2  (1.72) 4.7  (8.14) 0.5  (6.36) 0.0 [1]   (NA) -0.5  (0.71)
Cycle 6 Day 1 Number Analyzed 2 participants 2 participants 2 participants 7 participants 11 participants 3 participants 2 participants 0 participants 1 participants 3 participants
2.5  (2.12) 0.5  (0.71) 1.0  (1.41) -0.4  (2.70) 0.3  (0.90) 4.3  (5.86) 2.0  (4.24) 0.0 [1]   (NA) -1.3  (2.31)
Cycle 7 Day 1 Number Analyzed 1 participants 2 participants 2 participants 7 participants 12 participants 3 participants 2 participants 0 participants 1 participants 3 participants
2.0 [1]   (NA) 0.5  (0.71) 1.5  (2.12) -0.1  (1.21) 0.4  (0.90) 4.7  (8.33) 3.0  (4.24) 0.0 [1]   (NA) -0.7  (1.15)
Cycle 8 Day 1 Number Analyzed 1 participants 2 participants 2 participants 7 participants 12 participants 3 participants 2 participants 0 participants 1 participants 3 participants
-4.0 [1]   (NA) 0.5  (0.71) 1.5  (2.12) -0.1  (2.34) 0.2  (1.34) 3.0  (7.81) 4.0  (4.24) 0.0 [1]   (NA) 0.0  (0.00)
Cycle 9 Day 1 Number Analyzed 0 participants 2 participants 1 participants 7 participants 11 participants 2 participants 1 participants 0 participants 0 participants 3 participants
0.0  (0.00) 0.0 [1]   (NA) -1.0  (2.31) 0.3  (2.10) 6.0  (8.49) 6.0 [1]   (NA) -0.3  (0.58)
Cycle 10 Day 1 Number Analyzed 1 participants 2 participants 1 participants 5 participants 10 participants 2 participants 1 participants 0 participants 1 participants 3 participants
-5.0 [1]   (NA) 0.5  (0.71) 0.0 [1]   (NA) 0.0  (0.00) -0.1  (0.88) 6.5  (9.19) 6.0 [1]   (NA) 0.0 [1]   (NA) -1.7  (1.53)
Cycle 11 Day 1 Number Analyzed 0 participants 2 participants 1 participants 7 participants 12 participants 2 participants 2 participants 0 participants 1 participants 3 participants
-0.5  (0.71) 0.0 [1]   (NA) 0.3  (1.70) -0.2  (1.53) 7.0  (8.49) 3.5  (3.54) 0.0 [1]   (NA) 0.0  (0.00)
Cycle 12 Day 1 Number Analyzed 0 participants 2 participants 0 participants 5 participants 12 participants 2 participants 2 participants 0 participants 1 participants 3 participants
0.5  (0.71) -0.6  (2.19) -0.2  (2.33) 6.5  (9.19) 3.5  (3.54) 0.0 [1]   (NA) -0.7  (0.58)
Cycle 13 Day 1 Number Analyzed 0 participants 2 participants 0 participants 5 participants 10 participants 2 participants 2 participants 0 participants 1 participants 2 participants
0.5  (0.71) 0.8  (1.79) 0.5  (2.22) 5.5  (7.78) 3.0  (4.24) 0.0 [1]   (NA) -0.5  (0.71)
Cycle 14 Day 1 Number Analyzed 0 participants 2 participants 0 participants 6 participants 11 participants 2 participants 2 participants 0 participants 1 participants 3 participants
0.5  (0.71) -0.3  (3.20) 0.3  (0.79) 6.0  (8.49) 2.5  (3.54) 0.0 [1]   (NA) 0.0  (0.00)
Cycle 15 Day 1 Number Analyzed 0 participants 2 participants 0 participants 6 participants 9 participants 0 participants 2 participants 0 participants 1 participants 3 participants
0.5  (0.71) -1.7  (5.43) 0.1  (1.36) 4.0  (4.24) 0.0 [1]   (NA) -0.3  (0.58)
Cycle 16 Day 1 Number Analyzed 0 participants 2 participants 0 participants 5 participants 9 participants 1 participants 2 participants 0 participants 1 participants 2 participants
0.0  (1.41) -0.2  (2.49) -0.2  (1.99) 1.0 [1]   (NA) 1.5  (6.36) 0.0 [1]   (NA) 0.0  (0.00)
Cycle 17 Day 1 Number Analyzed 0 participants 2 participants 0 participants 5 participants 9 participants 1 participants 2 participants 0 participants 1 participants 3 participants
-2.0  (2.83) 0.6  (1.95) 0.1  (1.17) -3.0 [1]   (NA) 4.0  (4.24) 0.0 [1]   (NA) -1.3  (1.53)
Cycle 18 Day 1 Number Analyzed 0 participants 2 participants 0 participants 5 participants 9 participants 1 participants 2 participants 0 participants 0 participants 2 participants
-0.5  (0.71) 0.8  (1.79) 0.0  (1.73) -2.0 [1]   (NA) 3.0  (4.24) 0.0  (0.00)
Cycle 19 Day 1 Number Analyzed 0 participants 2 participants 0 participants 5 participants 9 participants 1 participants 2 participants 0 participants 1 participants 2 participants
-0.5  (0.71) 0.8  (1.79) -0.6  (2.65) 0.0 [1]   (NA) 3.5  (4.95) 0.0 [1]   (NA) -0.5  (0.71)
Cycle 20 Day 1 Number Analyzed 0 participants 2 participants 0 participants 5 participants 9 participants 1 participants 2 participants 0 participants 1 participants 2 participants
0.0  (0.00) 0.0  (1.41) 0.7  (2.12) 0.0 [1]   (NA) 3.5  (3.54) 0.0 [1]   (NA) -0.5  (0.71)
Cycle 21 Day 1 Number Analyzed 0 participants 2 participants 0 participants 5 participants 9 participants 0 participants 2 participants 0 participants 1 participants 2 participants
-0.5  (0.71) 0.0  (1.41) 0.1  (2.09) 4.0  (4.24) 0.0 [1]   (NA) -0.5  (0.71)
Cycle 22 Day 1 Number Analyzed 0 participants 2 participants 0 participants 5 participants 9 participants 1 participants 2 participants 0 participants 1 participants 3 participants
0.0  (0.00) 0.4  (1.52) 0.1  (1.45) 0.0 [1]   (NA) 3.5  (3.54) -1.0 [1]   (NA) -0.3  (0.58)
Cycle 23 Day 1 Number Analyzed 0 participants 2 participants 0 participants 5 participants 8 participants 1 participants 2 participants 0 participants 1 participants 3 participants
0.5  (0.71) 0.0  (1.41) 0.1  (1.81) -1.0 [1]   (NA) 1.5  (3.54) 0.0 [1]   (NA) -2.3  (4.04)
Cycle 24 Day 1 Number Analyzed 0 participants 2 participants 0 participants 5 participants 8 participants 1 participants 2 participants 0 participants 1 participants 2 participants
0.5  (0.71) -0.4  (0.89) 0.6  (0.74) 1.0 [1]   (NA) 1.5  (4.95) 0.0 [1]   (NA) 0.0  (0.00)
Cycle 25 Day 1 Number Analyzed 0 participants 2 participants 0 participants 5 participants 7 participants 1 participants 2 participants 0 participants 1 participants 2 participants
0.0  (0.00) 0.8  (1.79) -0.9  (2.27) -2.0 [1]   (NA) 2.5  (4.95) 0.0 [1]   (NA) 0.0  (0.00)
Cycle 26 Day 1 Number Analyzed 0 participants 2 participants 0 participants 5 participants 8 participants 1 participants 2 participants 0 participants 1 participants 3 participants
0.5  (0.71) 0.8  (1.79) -0.4  (2.77) -1.0 [1]   (NA) 2.0  (4.24) 0.0 [1]   (NA) -0.3  (0.58)
Cycle 27 Day 1 Number Analyzed 0 participants 2 participants 0 participants 5 participants 7 participants 1 participants 2 participants 0 participants 1 participants 2 participants
0.5  (0.71) 0.8  (1.79) -0.1  (2.67) -1.0 [1]   (NA) 3.5  (3.54) 0.0 [1]   (NA) -1.0  (1.41)
Cycle 28 Day 1 Number Analyzed 0 participants 2 participants 0 participants 4 participants 7 participants 1 participants 2 participants 0 participants 1 participants 3 participants
0.5  (0.71) 1.0  (2.00) 0.7  (0.76) -2.0 [1]   (NA) 3.0  (2.83) 0.0 [1]   (NA) 0.0  (0.00)
Cycle 29 Day 1 Number Analyzed 0 participants 2 participants 0 participants 4 participants 8 participants 1 participants 2 participants 0 participants 1 participants 3 participants
-1.5  (2.12) 0.5  (1.73) 0.1  (1.81) 0.0 [1]   (NA) 3.5  (3.54) 0.0 [1]   (NA) 0.0  (0.00)
Cycle 30 Day 1 Number Analyzed 0 participants 2 participants 0 participants 4 participants 5 participants 1 participants 2 participants 0 participants 1 participants 3 participants
0.0  (0.00) 0.8  (1.50) 0.4  (0.55) 0.0 [1]   (NA) 3.0  (2.83) 0.0 [1]   (NA) -1.0  (1.00)
Cycle 31 Day 1 Number Analyzed 0 participants 2 participants 0 participants 3 participants 6 participants 1 participants 2 participants 0 participants 0 participants 3 participants
0.5  (0.71) 1.0  (2.65) 0.7  (0.82) 0.0 [1]   (NA) 3.0  (4.24) 0.0  (0.00)
Cycle 32 Day 1 Number Analyzed 0 participants 2 participants 0 participants 3 participants 5 participants 0 participants 2 participants 0 participants 1 participants 2 participants
0.0  (0.00) 1.3  (2.31) 0.4  (0.55) 3.5  (3.54) 0.0 [1]   (NA) 0.0  (0.00)
Cycle 33 Day 1 Number Analyzed 0 participants 2 participants 0 participants 3 participants 4 participants 0 participants 2 participants 0 participants 1 participants 2 participants
0.0  (0.00) 1.3  (2.31) 0.5  (0.58) 3.5  (3.54) 0.0 [1]   (NA) 0.0  (0.00)
Cycle 34 Day 1 Number Analyzed 0 participants 2 participants 0 participants 2 participants 4 participants 0 participants 2 participants 0 participants 1 participants 2 participants
0.0  (0.00) 0.0  (0.00) 0.3  (0.50) 4.0  (4.24) 0.0 [1]   (NA) 0.0  (0.00)
Cycle 35 Day 1 Number Analyzed 0 participants 2 participants 0 participants 1 participants 4 participants 0 participants 2 participants 0 participants 1 participants 1 participants
0.5  (0.71) 0.0 [1]   (NA) 0.3  (0.50) 4.0  (4.24) 0.0 [1]   (NA) 0.0 [1]   (NA)
Cycle 36 Day 1 Number Analyzed 0 participants 2 participants 0 participants 1 participants 3 participants 0 participants 2 participants 0 participants 1 participants 1 participants
-0.5  (0.71) 0.0 [1]   (NA) 0.0  (0.00) 4.0  (4.24) 0.0 [1]   (NA) 0.0 [1]   (NA)
Cycle 37 Day 1 Number Analyzed 0 participants 2 participants 0 participants 1 participants 2 participants 0 participants 2 participants 0 participants 0 participants 0 participants
0.0  (0.00) -1.0 [1]   (NA) 0.0  (0.00) 3.5  (4.95)
Cycle 38 Day 1 Number Analyzed 0 participants 2 participants 0 participants 1 participants 2 participants 0 participants 2 participants 0 participants 1 participants 0 participants
0.0  (0.00) 0.0 [1]   (NA) 0.0  (0.00) 3.0  (2.83) 0.0 [1]   (NA)
Cycle 39 Day 1 Number Analyzed 0 participants 1 participants 0 participants 1 participants 2 participants 0 participants 2 participants 0 participants 0 participants 0 participants
0.0 [1]   (NA) 0.0 [1]   (NA) -0.5  (0.71) 3.5  (4.95)
Cycle 40 Day 1 Number Analyzed 0 participants 2 participants 0 participants 1 participants 1 participants 0 participants 2 participants 0 participants 0 participants 0 participants
0.5  (0.71) -1.0 [1]   (NA) 0.0 [1]   (NA) 4.0  (4.24)
Cycle 41 Day 1 Number Analyzed 0 participants 2 participants 0 participants 1 participants 1 participants 0 participants 2 participants 0 participants 0 participants 0 participants
0.5  (0.71) 0.0 [1]   (NA) 0.0 [1]   (NA) 1.5  (6.36)
Cycle 42 Day 1 Number Analyzed 0 participants 2 participants 0 participants 1 participants 1 participants 0 participants 2 participants 0 participants 0 participants 0 participants
-0.5  (0.71) 0.0 [1]   (NA) 0.0 [1]   (NA) 4.0  (4.24)
Cycle 43 Day 1 Number Analyzed 0 participants 2 participants 0 participants 1 participants 0 participants 0 participants 2 participants 0 participants 0 participants 0 participants
0.0  (0.00) 0.0 [1]   (NA) 4.0  (4.24)
Cycle 44 Day 1 Number Analyzed 0 participants 1 participants 0 participants 1 participants 0 participants 0 participants 2 participants 0 participants 0 participants 0 participants
1.0 [1]   (NA) -1.0 [1]   (NA) 3.0  (4.24)
Cycle 45 Day 1 Number Analyzed 0 participants 1 participants 0 participants 1 participants 0 participants 0 participants 1 participants 0 participants 0 participants 0 participants
1.0 [1]   (NA) 0.0 [1]   (NA) 1.0 [1]   (NA)
Cycle 46 Day 1 Number Analyzed 0 participants 1 participants 0 participants 1 participants 0 participants 0 participants 0 participants 0 participants 0 participants 0 participants
0.0 [1]   (NA) -1.0 [1]   (NA)
Cycle 47 Day 1 Number Analyzed 0 participants 1 participants 0 participants 1 participants 0 participants 0 participants 0 participants 0 participants 0 participants 0 participants
0.0 [1]   (NA) 0.0 [1]   (NA)
Cycle 48 Day 1 Number Analyzed 0 participants 1 participants 0 participants 1 participants 0 participants 0 participants 0 participants 0 participants 0 participants 0 participants
-3.0 [1]   (NA) 0.0 [1]   (NA)
Cycle 49 Day 1 Number Analyzed 0 participants 2 participants 0 participants 0 participants 0 participants 0 participants 0 participants 0 participants 0 participants 0 participants
0.5  (0.71)
Cycle 50 Day 1 Number Analyzed 0 participants 1 participants 0 participants 0 participants 0 participants 0 participants 0 participants 0 participants 0 participants 0 participants
-3.0 [1]   (NA)
Cycle 51 Day 1 Number Analyzed 0 participants 2 participants 0 participants 0 participants 0 participants 0 participants 0 participants 0 participants 0 participants 0 participants
-0.5  (0.71)
Cycle 52 Day 1 Number Analyzed 0 participants 1 participants 0 participants 0 participants 0 participants 0 participants 0 participants 0 participants 0 participants 0 participants
1.0 [1]   (NA)
End of treatment Number Analyzed 1 participants 0 participants 3 participants 1 participants 4 participants 0 participants 0 participants 0 participants 1 participants 1 participants
-8.0 [1]   (NA) 0.7  (1.15) -2.0 [1]   (NA) -2.3  (5.19) -15.0 [1]   (NA) 0.0 [1]   (NA)
[1]
Standard deviation was not applicable when only 1 participant had data.
37.Secondary Outcome
Title Time to Tumor Response (TTR) and Intracranial TTR (Phase 2)
Hide Description Time to tumor response (TTR) was defined as the time from the first dose of study treatment to the first documentation of objective tumor response (CR or PR). For participants whose objective response proceeded from PR to CR, the onset of PR was taken as the onset of response. TTR was only calculated for the subgroup of participants with a confirmed objective tumor response. Intracranial TTR was only calculated for participants with confirmed intracranial objective response. Results presented here were based on independent central review.
Time Frame 3 years
Hide Outcome Measure Data
Hide Analysis Population Description
TTR analysis set included all ITT participants who had confirmed objective response; intracranial TTR analysis set included all ITT participants who had CNS metastases and achieved confirmed intracranial objective response.
Arm/Group Title EXP-1 (Phase 2) EXP-2 (Phase 2) EXP-3 (Phase 2) EXP-4 (Phase 2) EXP-5 (Phase 2) EXP-6 (Phase 2)
Hide Arm/Group Description:
Treatment-naïve participants with advanced ALK-positive NSCLC with or without asymptomatic central nervous system (CNS) metastases were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after only crizotinib therapy were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after crizotinib therapy and 1 or 2 prior regimens of chemotherapy given before or after crizotinib therapy, or participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 1 ALK inhibitor therapy other than crizotinib with or without any number of prior chemotherapy regimens in any disease setting were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 2 prior lines of ALK inhibitor therapies were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 3 prior lines of ALK inhibitor therapies were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participant scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ROS1-positive NSCLC who were treatment naïve or had any number of prior cancer therapies with or without asymptomatic CNS metastases were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Overall Number of Participants Analyzed 27 20 30 27 16 17
Median (Full Range)
Unit of Measure: months
TTR Number Analyzed 27 participants 20 participants 30 participants 27 participants 16 participants 17 participants
1.4
(1.2 to 5.4)
1.4
(1.2 to 11.0)
1.4
(1.1 to 5.7)
2.6
(1.2 to 9.9)
1.4
(1.2 to 4.0)
1.4
(1.3 to 4.2)
Intracranial TTR Number Analyzed 6 participants 10 participants 20 participants 25 participants 15 participants 14 participants
2.1
(1.2 to 2.8)
1.4
(1.2 to 1.5)
1.4
(1.1 to 5.7)
1.5
(1.2 to 6.2)
1.4
(1.2 to 3.3)
1.4
(1.2 to 5.5)
38.Secondary Outcome
Title Duration of Response (DOR) and Intracranial DOR (Phase 2)
Hide Description Duration of Response (DOR) was defined as the time from the first documentation of objective tumor response (CR or PR) to the first documentation of disease progression or to death due to any cause, whichever occurred first. DOR was only calculated for the subgroup of participants with a confirmed objective tumor response. Intracranial DOR was only calculated for participants with confirmed intracranial objective response. Results presented here were based on independent central review.
Time Frame 3 years
Hide Outcome Measure Data
Hide Analysis Population Description
DOR analysis set included all ITT participants who had confirmed objective response; intracranial DOR analysis set included all ITT participants who had CNS metastases and achieved confirmed intracranial objective response.
Arm/Group Title EXP-1 (Phase 2) EXP-2 (Phase 2) EXP-3 (Phase 2) EXP-4 (Phase 2) EXP-5 (Phase 2) EXP-6 (Phase 2)
Hide Arm/Group Description:
Treatment-naïve participants with advanced ALK-positive NSCLC with or without asymptomatic central nervous system (CNS) metastases were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after only crizotinib therapy were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after crizotinib therapy and 1 or 2 prior regimens of chemotherapy given before or after crizotinib therapy, or participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 1 ALK inhibitor therapy other than crizotinib with or without any number of prior chemotherapy regimens in any disease setting were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 2 prior lines of ALK inhibitor therapies were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 3 prior lines of ALK inhibitor therapies were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participant scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ROS1-positive NSCLC who were treatment naïve or had any number of prior cancer therapies with or without asymptomatic CNS metastases were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Overall Number of Participants Analyzed 27 20 30 27 16 17
Median (95% Confidence Interval)
Unit of Measure: months
DOR Number Analyzed 27 participants 20 participants 30 participants 27 participants 16 participants 17 participants
NA [1] 
(10.02 to NA)
NA [1] 
(NA to NA)
NA [1] 
(6.80 to NA)
6.93 [1] 
(5.22 to NA)
NA [1] 
(4.17 to NA)
13.83 [1] 
(11.10 to NA)
Intra-cranial DOR Number Analyzed 6 participants 10 participants 20 participants 25 participants 15 participants 14 participants
9.15
(8.28 to 10.02)
NA [2] 
(NA to NA)
NA [2] 
(8.38 to NA)
14.52 [2] 
(NA to NA)
8.31 [2] 
(6.93 to NA)
NA [2] 
(4.99 to NA)
[1]
Majority of the participants with confirmed response had their DOR data censored, therefore, it's impossible to derive such summary statistics.
[2]
Majority of the participants with confirmed intracranial response had their intracranial DOR data censored, therefore, it's impossible to derive such summary statistics.
39.Secondary Outcome
Title Percentage of Participants Achieving Disease Control and Intracranial Disease Control at 12 Weeks (Phase 2)
Hide Description Tumor response was evaluated according to RECIST version 1.1, and disease control was defined as confirmed complete response (CR), confirmed partial response (PR), or stable disease (SD). Intracranial assessment was only performed for participants CNS metastases. Results presented here were based on independent central review.
Time Frame 12 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
The intent-to-treat (ITT) analysis set was used for overall response assessment, and included all enrolled participants with documented ALK or ROS1 rearrangement who received at least 1 dose of PF-06463922; participants with CNS metastases in the ITT analysis set was used for intracranial response assessment.
Arm/Group Title EXP-1 (Phase 2) EXP-2 (Phase 2) EXP-3 (Phase 2) EXP-4 (Phase 2) EXP-5 (Phase 2) EXP-6 (Phase 2)
Hide Arm/Group Description:
Treatment-naïve participants with advanced ALK-positive NSCLC with or without asymptomatic central nervous system (CNS) metastases were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after only crizotinib therapy were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after crizotinib therapy and 1 or 2 prior regimens of chemotherapy given before or after crizotinib therapy, or participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 1 ALK inhibitor therapy other than crizotinib with or without any number of prior chemotherapy regimens in any disease setting were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 2 prior lines of ALK inhibitor therapies were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 3 prior lines of ALK inhibitor therapies were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participant scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ROS1-positive NSCLC who were treatment naïve or had any number of prior cancer therapies with or without asymptomatic CNS metastases were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Overall Number of Participants Analyzed 30 27 59 65 46 47
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
Disease control rate Number Analyzed 30 participants 27 participants 59 participants 65 participants 46 participants 47 participants
93.3
(77.9 to 99.2)
85.2
(66.3 to 95.8)
67.8
(54.4 to 79.4)
63.1
(50.2 to 74.7)
52.2
(36.9 to 67.1)
63.8
(48.5 to 77.3)
Intra-cranial disease control rate Number Analyzed 8 participants 17 participants 32 participants 45 participants 38 participants 25 participants
87.5
(47.3 to 99.7)
94.1
(71.3 to 99.9)
75.0
(56.6 to 88.5)
77.8
(62.9 to 88.8)
68.4
(51.3 to 82.5)
72.0
(50.6 to 87.9)
40.Secondary Outcome
Title Time to Progression (TTP) on the Last Prior Therapy (Phase 2)
Hide Description TTP on the last prior therapy was defined as time from the first dose date of the last prior treatment regimen to the date of progression.
Time Frame 3 years
Hide Outcome Measure Data
Hide Analysis Population Description
The intent-to-treat (ITT) analysis set included all enrolled participants with documented ALK or ROS1 rearrangement who received at least 1 dose of PF-06463922. As planned, this outcome measure was not analyzed for EXP-1 and EXP-6 groups.
Arm/Group Title EXP-2 (Phase 2) EXP-3 (Phase 2) EXP-4 (Phase 2) EXP-5 (Phase 2)
Hide Arm/Group Description:
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after only crizotinib therapy were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after crizotinib therapy and 1 or 2 prior regimens of chemotherapy given before or after crizotinib therapy, or participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 1 ALK inhibitor therapy other than crizotinib with or without any number of prior chemotherapy regimens in any disease setting were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 2 prior lines of ALK inhibitor therapies were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 3 prior lines of ALK inhibitor therapies were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participant scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Overall Number of Participants Analyzed 27 59 65 46
Median (95% Confidence Interval)
Unit of Measure: months
Prior systemic therapy before PF-06463922
11.5
(7.2 to 19.6)
12.8
(9.2 to 16.9)
10.2
(7.6 to 14.9)
3.7
(2.1 to 6.4)
Prior ALK+/ROS1+ TKI treatment
11.5
(7.2 to 19.6)
12.9
(11.2 to 18.1)
12.1
(7.9 to 16.4)
3.7
(2.1 to 6.6)
Prior systemic therapy other than ALK+/ROS1+ TKI
19.6
(16.1 to 30.7)
8.5
(5.0 to 12.6)
5.0
(3.1 to 10.8)
5.6
(4.7 to 11.2)
41.Secondary Outcome
Title Time to Tumor Progression （TTP) and Intracranial TTP (Phase 2)
Hide Description Time to progression (TTP) was defined as the time from the first dose of study treatment to the first documentation of objective disease progression. Intracranial TTP was defined as the time from the first dose of study treatment to the date of the first documentation of objective progression of intracranial disease, based on either new brain metastases or progression of existing brain metastases. Results presented here were based on independent central review.
Time Frame 3 years
Hide Outcome Measure Data
Hide Analysis Population Description
ITT analysis set was used for TTP determination and included all enrolled participants with documented ALK or ROS1 rearrangement who received at least 1 dose of PF-06463922; ITT participants with CNS metastases were analyzed for intracranial TTP.
Arm/Group Title EXP-1 (Phase 2) EXP-2 (Phase 2) EXP-3 (Phase 2) EXP-4 (Phase 2) EXP-5 (Phase 2) EXP-6 (Phase 2)
Hide Arm/Group Description:
Treatment-naïve participants with advanced ALK-positive NSCLC with or without asymptomatic central nervous system (CNS) metastases were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after only crizotinib therapy were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after crizotinib therapy and 1 or 2 prior regimens of chemotherapy given before or after crizotinib therapy, or participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 1 ALK inhibitor therapy other than crizotinib with or without any number of prior chemotherapy regimens in any disease setting were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 2 prior lines of ALK inhibitor therapies were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 3 prior lines of ALK inhibitor therapies were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participant scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ROS1-positive NSCLC who were treatment naïve or had any number of prior cancer therapies with or without asymptomatic CNS metastases were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Overall Number of Participants Analyzed 30 27 59 65 46 47
Median (95% Confidence Interval)
Unit of Measure: months
TTP Number Analyzed 30 participants 27 participants 59 participants 65 participants 46 participants 47 participants
NA [1] 
(11.4 to NA)
NA [1] 
(NA to NA)
9.0 [1] 
(5.5 to NA)
8.4
(5.6 to 13.7)
7.1
(4.1 to 12.5)
12.5 [1] 
(8.2 to NA)
Intracranial Number Analyzed 8 participants 17 participants 32 participants 45 participants 38 participants 25 participants
11.4
(9.6 to 11.4)
NA [2] 
(NA to NA)
NA [2] 
(6.9 to NA)
15.7
(11.0 to 15.7)
NA [2] 
(8.3 to NA)
NA [2] 
(NA to NA)
[1]
Number of participants with progression is too small to provide such summary statistics.
[2]
Number of participants with intracranial progression is too small to provide such summary statistics.
42.Secondary Outcome
Title Probability of First Event Being a Central Nervous System (CNS) Progression, Non CNS Progression, or Death (Phase 2)
Hide Description The probability of the first event being a CNS progression, a non-CNS progression, or death was evaluated with a competing risk approach by estimating cumulative incidence functions (range: 0-1) relative to the analysis set. The time to first event being a Competing Event (either "CNS progression" or "non CNS progression" or "Death") was defined as time from first dose until the date of that specific event. Participants not known to have any of the Competing Events were censored on the date they were last assessed for disease status for PFS. Participants who presented one type of event were counted as a competing cause of failure for the analysis of other type of events. For each type of event, the cumulative incidence function corresponding to the nearest time point preceding 1 year is presented. The results are based on independent central review.
Time Frame 3 years
Hide Outcome Measure Data
Hide Analysis Population Description
The intent-to-treat (ITT) analysis set included all enrolled participants with documented ALK or ROS1 rearrangement who received at least 1 dose of PF-06463922.
Arm/Group Title Phase 2 ITT Population
Hide Arm/Group Description:
This reporting group includes all Phase 2 participants in the ITT analysis set.
Overall Number of Participants Analyzed 274
Measure Type: Number
Unit of Measure: probability
CNS progression 0.179
Non CNS progression 0.325
Death 0.055
43.Secondary Outcome
Title Progression-Free Survival (PFS) (Phase 2)
Hide Description PFS was defined as the time from the first dose of study treatment to the first documentation of objective disease progression or to death on study due to any cause, whichever came first. Results presented here were based on independent central review.
Time Frame 3 years
Hide Outcome Measure Data
Hide Analysis Population Description
PFS analysis set included all participants with documented ALK or ROS1 rearrangement who received at least 1 dose of PF-06463922.
Arm/Group Title EXP-1 (Phase 2) EXP-2 (Phase 2) EXP-3 (Phase 2) EXP-4 (Phase 2) EXP-5 (Phase 2) EXP-6 (Phase 2)
Hide Arm/Group Description:
Treatment-naïve participants with advanced ALK-positive NSCLC with or without asymptomatic central nervous system (CNS) metastases were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after only crizotinib therapy were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after crizotinib therapy and 1 or 2 prior regimens of chemotherapy given before or after crizotinib therapy, or participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 1 ALK inhibitor therapy other than crizotinib with or without any number of prior chemotherapy regimens in any disease setting were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 2 prior lines of ALK inhibitor therapies were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 3 prior lines of ALK inhibitor therapies were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participant scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ROS1-positive NSCLC who were treatment naïve or had any number of prior cancer therapies with or without asymptomatic CNS metastases were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Overall Number of Participants Analyzed 30 27 59 65 46 47
Median (95% Confidence Interval)
Unit of Measure: months
NA [1] 
(11.4 to NA)
NA [1] 
(NA to NA)
8.2 [1] 
(5.5 to NA)
7.3
(5.4 to 11.0)
5.6
(4.0 to 12.5)
9.6 [1] 
(4.7 to NA)
[1]
A large proportion of participants had their PFS data censored, therefore, it is impossible to derive such summary statistics.
44.Secondary Outcome
Title Overall Survival (Phase 2)
Hide Description OS was defined as the time from first dose to the date of death due to any cause. For participants still alive at the time of analysis, the OS time was censored on the last date the participants were known to be alive. Estimates of OS and its 95% confidence interval were determined using Kaplan-Meier method.
Time Frame 3 years
Hide Outcome Measure Data
Hide Analysis Population Description
The intent-to-treat (ITT) analysis set included all enrolled participants with documented ALK or ROS1 rearrangement who received at least 1 dose of PF-06463922.
Arm/Group Title EXP-1 (Phase 2) EXP-2 (Phase 2) EXP-3 (Phase 2) EXP-4 (Phase 2) EXP-5 (Phase 2) EXP-6 (Phase 2)
Hide Arm/Group Description:
Treatment-naïve participants with advanced ALK-positive NSCLC with or without asymptomatic central nervous system (CNS) metastases were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after only crizotinib therapy were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after crizotinib therapy and 1 or 2 prior regimens of chemotherapy given before or after crizotinib therapy, or participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 1 ALK inhibitor therapy other than crizotinib with or without any number of prior chemotherapy regimens in any disease setting were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 2 prior lines of ALK inhibitor therapies were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 3 prior lines of ALK inhibitor therapies were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participant scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ROS1-positive NSCLC who were treatment naïve or had any number of prior cancer therapies with or without asymptomatic CNS metastases were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Overall Number of Participants Analyzed 30 27 59 65 46 47
Median (95% Confidence Interval)
Unit of Measure: months
NA [1] 
(NA to NA)
NA [1] 
(12.1 to NA)
NA [1] 
(14.4 to NA)
NA [1] 
(14.7 to NA)
NA [1] 
(9.7 to NA)
NA [1] 
(NA to NA)
[1]
A large proportion of participants in the analysis set had their OS data censored, and number of participants dead by the cutoff date of this report was small, so it's impossible to derive such summary statistics.
45.Secondary Outcome
Title Maximum Observed Plasma Concentration (Cmax) of PF-06463922 (Phase 2)
Hide Description Maximum observed plasma concentration (Cmax) of PF-06463922 was observed directly from data.
Time Frame Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24, 48, 72, 96 and 120 hours post-dose on Day -7 and pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 15
Hide Outcome Measure Data
Hide Analysis Population Description
PK concentration analysis set of PF-06463922 included all participants treated who had at least 1 concentration of PF-06463922.
Arm/Group Title Phase 2 and Japan LIC PK Analysis Set
Hide Arm/Group Description:
PK parameters of PF-06463922 were determined for a small subset of Phase 2 participants and Japan LIC. These participants received PF-06463922 100 mg orally QD and were combined into 1 reporting group for PK analysis. Japan LIC was not included in single-dose PK analysis, ie, they did not contribute to Day -7 data.
Overall Number of Participants Analyzed 22
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng/mL
Day -7 Number Analyzed 19 participants
695.2
(40%)
Cycle 1 Day 15 Number Analyzed 22 participants
576.5
(42%)
46.Secondary Outcome
Title Time for Cmax (Tmax) of PF-06463922 (Phase 2)
Hide Description Tmax of PF-06463922 was observed directly from data as time of first occurrence.
Time Frame Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24, 48, 72, 96 and 120 hours post-dose on Day -7 and pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 15
Hide Outcome Measure Data
Hide Analysis Population Description
PK parameter analysis set for PF-06463922 included all enrolled participants who received at least 1 dose of PF-06463922 and had sufficient information to estimate at least one of the PK parameters of interest for PF-06463922.
Arm/Group Title Phase 2 and Japan LIC PK Analysis Set
Hide Arm/Group Description:
PK parameters of PF-06463922 were determined for a small subset of Phase 2 participants and Japan LIC. These participants received PF-06463922 100 mg orally QD and were combined into 1 reporting group for PK analysis. Japan LIC was not included in single-dose PK analysis, ie, they did not contribute to Day -7 data.
Overall Number of Participants Analyzed 22
Median (Full Range)
Unit of Measure: hours
Day -7 Number Analyzed 19 participants
1.15
(0.50 to 4.02)
Cycle 1 Day 15 Number Analyzed 22 participants
1.96
(0.50 to 22.7)
47.Secondary Outcome
Title Area Under the Plasma Concentration-Time Profile From Time Zero Extrapolated to Infinite Time (AUCinf) of PF-06463922 (Phase 2)
Hide Description AUCinf was calculated as AUClast + (Clast*/kel), where AUClast was the area under the plasma concentration-time profile from time 0 to the time of the last quantifiable concentration, Clast* was the predicted plasma concentration at the last quantifiable time point estimated from the log-linear regression analysis, and kel was the rate constant for terminal phase.
Time Frame Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24, 48, 72, 96 and 120 hours post-dose on Day -7
Hide Outcome Measure Data
Hide Analysis Population Description
PK parameter analysis set for PF-06463922 included all enrolled participants who received at least 1 dose of PF-06463922 and had sufficient information to estimate at least one of the PK parameters of interest for PF-06463922.
Arm/Group Title Phase 2 and Japan LIC PK Analysis Set
Hide Arm/Group Description:
PK parameters of PF-06463922 were determined for a small subset of Phase 2 participants and Japan LIC. These participants received PF-06463922 100 mg orally QD and were combined into 1 reporting group for PK analysis. Japan LIC was not included in single-dose PK analysis, ie, they did not contribute to Day -7 data.
Overall Number of Participants Analyzed 16
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng*hour/mL
9088
(35%)
48.Secondary Outcome
Title Area Under the Plasma Concentration-Time Profile From Time Zero to Time Tau (AUCtau) of PF-06463922 (Phase 2)
Hide Description Tau refers to the dosing interval, and it equals to 24 hours for QD dosing which was adopted in Phase 2. AUCtau was determined using linear/log trapezoidal method.
Time Frame Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9 and 24 hours post-dose on Day -7 and pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 15
Hide Outcome Measure Data
Hide Analysis Population Description
PK parameter analysis set for PF-06463922 included all enrolled participants who received at least 1 dose of PF-06463922 and had sufficient information to estimate at least one of the PK parameters of interest for PF-06463922.
Arm/Group Title Phase 2 and Japan LIC PK Analysis Set
Hide Arm/Group Description:
PK parameters of PF-06463922 were determined for a small subset of Phase 2 participants and Japan LIC. These participants received PF-06463922 100 mg orally QD and were combined into 1 reporting group for PK analysis. Japan LIC was not included in single-dose PK analysis, ie, they did not contribute to Day -7 data.
Overall Number of Participants Analyzed 22
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng*hour/mL
Day -7 Number Analyzed 19 participants
5308
(36%)
Cycle 1 Day 15 Number Analyzed 22 participants
5650
(39%)
49.Secondary Outcome
Title Apparent Oral Clearance (CL/F) of PF-06463922 (Phase 2)
Hide Description Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. CL/F was calculated as dose/AUCinf, where AUCinf was the area under the plasma concentration-time profile from time 0 extrapolated to infinite time.
Time Frame Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24, 48, 72, 96 and 120 hours post-dose on Day -7 and pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 15
Hide Outcome Measure Data
Hide Analysis Population Description
PK parameter analysis set for PF-06463922 included all enrolled participants who received at least 1 dose of PF-06463922 and had sufficient information to estimate at least one of the PK parameters of interest for PF-06463922.
Arm/Group Title Phase 2 and Japan LIC PK Analysis Set
Hide Arm/Group Description:
PK parameters of PF-06463922 were determined for a small subset of Phase 2 participants and Japan LIC. These participants received PF-06463922 100 mg orally QD and were combined into 1 reporting group for PK analysis. Japan LIC was not included in single-dose PK analysis, ie, they did not contribute to Day -7 data.
Overall Number of Participants Analyzed 22
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: liter/hour
Day -7 Number Analyzed 16 participants
11.01
(35%)
Cycle 1 Day 15 Number Analyzed 22 participants
17.70
(39%)
50.Secondary Outcome
Title Apparent Volume of Distribution (Vz/F) of PF-06463922 (Phase 2)
Hide Description Vz/F was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug, and calculated as dose/(AUCinf*kel), where AUCinf was the area under the plasma concentration-time profile from time 0 extrapolated to infinite time, kel was the rate constant for terminal phase.
Time Frame Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24, 48, 72, 96 and 120 hours post-dose on Day -7
Hide Outcome Measure Data
Hide Analysis Population Description
PK parameter analysis set for PF-06463922 included all enrolled participants who received at least 1 dose of PF-06463922 and had sufficient information to estimate at least one of the PK parameters of interest for PF-06463922.
Arm/Group Title Phase 2 and Japan LIC PK Analysis Set
Hide Arm/Group Description:
PK parameters of PF-06463922 were determined for a small subset of Phase 2 participants and Japan LIC. These participants received PF-06463922 100 mg orally QD and were combined into 1 reporting group for PK analysis. Japan LIC was not included in single-dose PK analysis, ie, they did not contribute to Day -7 data.
Overall Number of Participants Analyzed 16
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: liters
351.5
(37%)
51.Secondary Outcome
Title Terminal Half-Life of PF-06463922 (Phase 2)
Hide Description Terminal plasma half-life was defined as the time measured for the plasma concentration to decrease by one half, and calculated as loge(2)/kel, where kel was the rate constant for terminal phase.
Time Frame Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24, 48, 72, 96 and 120 hours post-dose on Day -7
Hide Outcome Measure Data
Hide Analysis Population Description
PK parameter analysis set for PF-06463922 included all enrolled participants who received at least 1 dose of PF-06463922 and had sufficient information to estimate at least one of the PK parameters of interest for PF-06463922.
Arm/Group Title Phase 2 and Japan LIC PK Analysis Set
Hide Arm/Group Description:
PK parameters of PF-06463922 were determined for a small subset of Phase 2 participants and Japan LIC. These participants received PF-06463922 100 mg orally QD and were combined into 1 reporting group for PK analysis. Japan LIC was not included in single-dose PK analysis, ie, they did not contribute to Day -7 data.
Overall Number of Participants Analyzed 16
Mean (Standard Deviation)
Unit of Measure: hours
23.58  (9.3743)
52.Secondary Outcome
Title Observed Accumulation Ratio (Rac) of PF-06463922 Following Multiple Oral Doses (Phase 2)
Hide Description Rac was calculated as Day 15 AUCtau/Day -7 AUCtau, where AUCtau was the area under the plasma concentration-time profile from time 0 to time tau (24 hours for QD dosing regimen which was adopted in Phase 2).
Time Frame Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 15
Hide Outcome Measure Data
Hide Analysis Population Description
PK parameter analysis set for PF-06463922 included all enrolled participants who received at least 1 dose of PF-06463922 and had sufficient information to estimate at least one of the PK parameters of interest for PF-06463922.
Arm/Group Title Phase 2 and Japan LIC PK Analysis Set
Hide Arm/Group Description:
PK parameters of PF-06463922 were determined for a small subset of Phase 2 participants and Japan LIC. These participants received PF-06463922 100 mg orally QD and were combined into 1 reporting group for PK analysis. Japan LIC was not included in single-dose PK analysis, ie, they did not contribute to Day -7 data.
Overall Number of Participants Analyzed 20
Mean (Standard Deviation)
Unit of Measure: ratio
1.082  (0.42701)
53.Secondary Outcome
Title Steady State Accumulation Ratio (Rss) of PF-06463922 Following Multiple Oral Doses (Phase 2)
Hide Description Rss was calculated as Day 15 AUCtau/Day -7 AUCinf, where AUCtau was the area under the plasma concentration-time profile from time 0 to time tau (24 hours for QD dosing regimen which was adopted in Phase 2), and AUCinf was the area under the plasma concentration-time profile from time 0 extrapolated to infinite time.
Time Frame Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 15
Hide Outcome Measure Data
Hide Analysis Population Description
PK parameter analysis set for PF-06463922 included all enrolled participants who received at least 1 dose of PF-06463922 and had sufficient information to estimate at least one of the PK parameters of interest for PF-06463922.
Arm/Group Title Phase 2 and Japan LIC PK Analysis Set
Hide Arm/Group Description:
PK parameters of PF-06463922 were determined for a small subset of Phase 2 participants and Japan LIC. These participants received PF-06463922 100 mg orally QD and were combined into 1 reporting group for PK analysis. Japan LIC was not included in single-dose PK analysis, ie, they did not contribute to Day -7 data.
Overall Number of Participants Analyzed 14
Mean (Standard Deviation)
Unit of Measure: ratio
0.6577  (0.28627)
54.Secondary Outcome
Title Number of Participants With ALK Mutation Based on Plasma CNA Analysis (Phase 2)
Hide Description Plasma CNA samples were analyzed for ALK kinase domain mutations by Next Generation Sequencing (NGS). Number of participants with one or more ALK mutations is presented.
Time Frame Screening
Hide Outcome Measure Data
Hide Analysis Population Description
CNA peripheral blood analysis set included all participants of the ITT analysis set who had at least 1 molecular biomarker assayed.
Arm/Group Title EXP-1 (Phase 2) EXP-2 (Phase 2) EXP-3 (Phase 2) EXP-4 (Phase 2) EXP-5 (Phase 2)
Hide Arm/Group Description:
Treatment-naïve participants with advanced ALK-positive NSCLC with or without asymptomatic central nervous system (CNS) metastases were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after only crizotinib therapy were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after crizotinib therapy and 1 or 2 prior regimens of chemotherapy given before or after crizotinib therapy, or participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 1 ALK inhibitor therapy other than crizotinib with or without any number of prior chemotherapy regimens in any disease setting were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 2 prior lines of ALK inhibitor therapies were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 3 prior lines of ALK inhibitor therapies were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participant scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Overall Number of Participants Analyzed 30 26 58 61 45
Measure Type: Count of Participants
Unit of Measure: Participants
1
   3.3%
6
  23.1%
8
  13.8%
17
  27.9%
14
  31.1%
55.Secondary Outcome
Title Number of Participants With ALK Mutation Based on Tumor Tissue Analysis (Phase 2)
Hide Description Tumor tissues from archived tissue specimens and/or a de novo biopsy were analyzed for ALK kinase domain mutations. Number of participants with one or more ALK mutations is presented.
Time Frame Screening
Hide Outcome Measure Data
Hide Analysis Population Description
Tumor Tissue analysis set included all participants of the ITT analysis set who had at least 1 molecular tumor biomarker assayed from either the screening archival or screening de novo tumor biopsy sample (or both).
Arm/Group Title EXP-1 (Phase 2) EXP-2 (Phase 2) EXP-3 (Phase 2) EXP-4 (Phase 2) EXP-5 (Phase 2)
Hide Arm/Group Description:
Treatment-naïve participants with advanced ALK-positive NSCLC with or without asymptomatic central nervous system (CNS) metastases were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after only crizotinib therapy were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after crizotinib therapy and 1 or 2 prior regimens of chemotherapy given before or after crizotinib therapy, or participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 1 ALK inhibitor therapy other than crizotinib with or without any number of prior chemotherapy regimens in any disease setting were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 2 prior lines of ALK inhibitor therapies were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 3 prior lines of ALK inhibitor therapies were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participant scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Overall Number of Participants Analyzed 26 26 52 48 33
Measure Type: Count of Participants
Unit of Measure: Participants
0
   0.0%
7
  26.9%
8
  15.4%
11
  22.9%
13
  39.4%
56.Secondary Outcome
Title Number of Participants Who Improved, Worsened or Remained Stable in EORTC QLQ-C30 (Phase 2)
Hide Description European Organisation for Research and Treatment of Cancer Core Quality of Life Questionaires (EORTC QLQ)-C30 (version 3.0) consists of 30 questions assessing 5 functional domains (physical, role, emotional, cognitive and social), global quality of life (QoL), disease/treatment related symptoms (fatigue, nausea/vomiting, pain, dyspnea, insomnia, appetite loss, constipation and diarrhoea), and the perceived financial impact of disease. Each scale was transformed to a range of 0 to 100 using standard EORTC algorithm. For global QoL and functional scales, higher score indicate better performance, and improvement was defined as an increase of at least 10 points, worsening was defined as a decrease of at least 10 points. For symptom scales, higher score indicates worse symptoms, and improvement was defined as a decrease of at least 10 points, worsening was defined as an increase of at least 10 points. All scales which had not improved nor worsened were considered stable.
Time Frame 3 years
Hide Outcome Measure Data
Hide Analysis Population Description
Patient reported outcome (PRO) evaluable analysis set included all enrolled participants who received at least 1 dose of PF-06463922 and completed a baseline and at least 1 post-baseline PRO assessment.
Arm/Group Title EXP-1 (Phase 2) EXP-2 (Phase 2) EXP-3 (Phase 2) EXP-4 (Phase 2) EXP-5 (Phase 2) EXP-6 (Phase 2)
Hide Arm/Group Description:
Treatment-naïve participants with advanced ALK-positive NSCLC with or without asymptomatic central nervous system (CNS) metastases were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after only crizotinib therapy were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after crizotinib therapy and 1 or 2 prior regimens of chemotherapy given before or after crizotinib therapy, or participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 1 ALK inhibitor therapy other than crizotinib with or without any number of prior chemotherapy regimens in any disease setting were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 2 prior lines of ALK inhibitor therapies were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 3 prior lines of ALK inhibitor therapies were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participant scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ROS1-positive NSCLC who were treatment naïve or had any number of prior cancer therapies with or without asymptomatic CNS metastases were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Overall Number of Participants Analyzed 30 26 55 60 43 40
Measure Type: Count of Participants
Unit of Measure: Participants
Improved in global QoL Number Analyzed 30 participants 26 participants 55 participants 60 participants 43 participants 40 participants
17
  56.7%
11
  42.3%
18
  32.7%
25
  41.7%
18
  41.9%
20
  50.0%
Stable in global QoL Number Analyzed 30 participants 26 participants 55 participants 60 participants 43 participants 40 participants
10
  33.3%
13
  50.0%
26
  47.3%
22
  36.7%
17
  39.5%
13
  32.5%
Worsened in global QoL Number Analyzed 30 participants 26 participants 55 participants 60 participants 43 participants 40 participants
3
  10.0%
2
   7.7%
11
  20.0%
13
  21.7%
8
  18.6%
7
  17.5%
Improved in physical functioning Number Analyzed 30 participants 26 participants 55 participants 60 participants 43 participants 40 participants
10
  33.3%
7
  26.9%
14
  25.5%
23
  38.3%
8
  18.6%
11
  27.5%
Stable in physical functioning Number Analyzed 30 participants 26 participants 55 participants 60 participants 43 participants 40 participants
14
  46.7%
19
  73.1%
37
  67.3%
27
  45.0%
25
  58.1%
24
  60.0%
Worsened in physical functioning Number Analyzed 30 participants 26 participants 55 participants 60 participants 43 participants 40 participants
6
  20.0%
0
   0.0%
4
   7.3%
10
  16.7%
10
  23.3%
5
  12.5%
Improved in role functioning Number Analyzed 30 participants 26 participants 55 participants 60 participants 43 participants 39 participants
12
  40.0%
8
  30.8%
18
  32.7%
25
  41.7%
16
  37.2%
17
  43.6%
Stable in role functioning Number Analyzed 30 participants 26 participants 55 participants 60 participants 43 participants 39 participants
11
  36.7%
15
  57.7%
31
  56.4%
19
  31.7%
16
  37.2%
19
  48.7%
Worsened in role functioning Number Analyzed 30 participants 26 participants 55 participants 60 participants 43 participants 39 participants
7
  23.3%
3
  11.5%
6
  10.9%
16
  26.7%
11
  25.6%
3
   7.7%
Improved in emotional functioning Number Analyzed 30 participants 26 participants 55 participants 60 participants 43 participants 40 participants
12
  40.0%
12
  46.2%
18
  32.7%
21
  35.0%
18
  41.9%
17
  42.5%
Stable in emotional functioning Number Analyzed 30 participants 26 participants 55 participants 60 participants 43 participants 40 participants
14
  46.7%
14
  53.8%
29
  52.7%
32
  53.3%
20
  46.5%
20
  50.0%
Worsened in emotional functioning Number Analyzed 30 participants 26 participants 55 participants 60 participants 43 participants 40 participants
4
  13.3%
0
   0.0%
8
  14.5%
7
  11.7%
5
  11.6%
3
   7.5%
Improved in cognitive functioning Number Analyzed 30 participants 26 participants 55 participants 60 participants 43 participants 40 participants
10
  33.3%
3
  11.5%
11
  20.0%
13
  21.7%
13
  30.2%
12
  30.0%
Stable in cognitive functioning Number Analyzed 30 participants 26 participants 55 participants 60 participants 43 participants 40 participants
12
  40.0%
15
  57.7%
31
  56.4%
35
  58.3%
16
  37.2%
22
  55.0%
Worsened in cognitive functioning Number Analyzed 30 participants 26 participants 55 participants 60 participants 43 participants 40 participants
8
  26.7%
8
  30.8%
13
  23.6%
12
  20.0%
14
  32.6%
6
  15.0%
Improved in social functioning Number Analyzed 30 participants 26 participants 55 participants 60 participants 43 participants 40 participants
14
  46.7%
7
  26.9%
18
  32.7%
22
  36.7%
12
  27.9%
13
  32.5%
Stable in social functioning Number Analyzed 30 participants 26 participants 55 participants 60 participants 43 participants 40 participants
13
  43.3%
17
  65.4%
32
  58.2%
28
  46.7%
23
  53.5%
22
  55.0%
Worsened in social functioning Number Analyzed 30 participants 26 participants 55 participants 60 participants 43 participants 40 participants
3
  10.0%
2
   7.7%
5
   9.1%
10
  16.7%
8
  18.6%
5
  12.5%
Improved in fatigue Number Analyzed 30 participants 26 participants 55 participants 60 participants 43 participants 40 participants
17
  56.7%
14
  53.8%
22
  40.0%
29
  48.3%
26
  60.5%
17
  42.5%
Stable in fatigue Number Analyzed 30 participants 26 participants 55 participants 60 participants 43 participants 40 participants
9
  30.0%
11
  42.3%
25
  45.5%
22
  36.7%
11
  25.6%
19
  47.5%
Worsened in fatigue Number Analyzed 30 participants 26 participants 55 participants 60 participants 43 participants 40 participants
4
  13.3%
1
   3.8%
8
  14.5%
9
  15.0%
6
  14.0%
4
  10.0%
Improved in nausea and vomiting Number Analyzed 30 participants 26 participants 55 participants 60 participants 43 participants 40 participants
8
  26.7%
4
  15.4%
11
  20.0%
16
  26.7%
14
  32.6%
10
  25.0%
Stable in nausea and vomiting Number Analyzed 30 participants 26 participants 55 participants 60 participants 43 participants 40 participants
22
  73.3%
22
  84.6%
43
  78.2%
38
  63.3%
28
  65.1%
28
  70.0%
Worsened in nausea and vomiting Number Analyzed 30 participants 26 participants 55 participants 60 participants 43 participants 40 participants
0
   0.0%
0
   0.0%
1
   1.8%
6
  10.0%
1
   2.3%
2
   5.0%
Improved in pain Number Analyzed 30 participants 26 participants 55 participants 60 participants 43 participants 40 participants
14
  46.7%
9
  34.6%
19
  34.5%
23
  38.3%
18
  41.9%
21
  52.5%
Stable in pain Number Analyzed 30 participants 26 participants 55 participants 60 participants 43 participants 40 participants
11
  36.7%
15
  57.7%
27
  49.1%
26
  43.3%
20
  46.5%
12
  30.0%
Worsened in pain Number Analyzed 30 participants 26 participants 55 participants 60 participants 43 participants 40 participants
5
  16.7%
2
   7.7%
9
  16.4%
11
  18.3%
5
  11.6%
7
  17.5%
Improved in dyspnea Number Analyzed 30 participants 26 participants 55 participants 60 participants 43 participants 40 participants
15
  50.0%
9
  34.6%
10
  18.2%
21
  35.0%
14
  32.6%
13
  32.5%
Stable in dyspnea Number Analyzed 30 participants 26 participants 55 participants 60 participants 43 participants 40 participants
11
  36.7%
14
  53.8%
34
  61.8%
22
  36.7%
21
  48.8%
19
  47.5%
Worsened in dyspnea Number Analyzed 30 participants 26 participants 55 participants 60 participants 43 participants 40 participants
4
  13.3%
3
  11.5%
11
  20.0%
17
  28.3%
8
  18.6%
8
  20.0%
Improved in insomnia Number Analyzed 30 participants 26 participants 55 participants 60 participants 43 participants 40 participants
19
  63.3%
8
  30.8%
19
  34.5%
28
  46.7%
22
  51.2%
19
  47.5%
Stable in insomnia Number Analyzed 30 participants 26 participants 55 participants 60 participants 43 participants 40 participants
10
  33.3%
14
  53.8%
28
  50.9%
23
  38.3%
14
  32.6%
18
  45.0%
Worsened in insomnia Number Analyzed 30 participants 26 participants 55 participants 60 participants 43 participants 40 participants
1
   3.3%
4
  15.4%
8
  14.5%
9
  15.0%
7
  16.3%
3
   7.5%
Improved in appetite loss Number Analyzed 30 participants 26 participants 55 participants 60 participants 43 participants 40 participants
14
  46.7%
4
  15.4%
17
  30.9%
29
  48.3%
22
  51.2%
20
  50.0%
Stable in appetite loss Number Analyzed 30 participants 26 participants 55 participants 60 participants 43 participants 40 participants
16
  53.3%
22
  84.6%
37
  67.3%
26
  43.3%
21
  48.8%
20
  50.0%
Worsened in appetite loss Number Analyzed 30 participants 26 participants 55 participants 60 participants 43 participants 40 participants
0
   0.0%
0
   0.0%
1
   1.8%
5
   8.3%
0
   0.0%
0
   0.0%
Improved in constipation Number Analyzed 30 participants 26 participants 55 participants 60 participants 43 participants 40 participants
10
  33.3%
6
  23.1%
9
  16.4%
15
  25.0%
11
  25.6%
13
  32.5%
Stable in constipation Number Analyzed 30 participants 26 participants 55 participants 60 participants 43 participants 40 participants
13
  43.3%
18
  69.2%
36
  65.5%
33
  55.0%
28
  65.1%
23
  57.5%
Worsened in constipation Number Analyzed 30 participants 26 participants 55 participants 60 participants 43 participants 40 participants
7
  23.3%
2
   7.7%
10
  18.2%
12
  20.0%
4
   9.3%
4
  10.0%
Improved in diarrhea Number Analyzed 30 participants 26 participants 55 participants 60 participants 43 participants 40 participants
5
  16.7%
3
  11.5%
8
  14.5%
9
  15.0%
11
  25.6%
8
  20.0%
Stable in diarrhea Number Analyzed 30 participants 26 participants 55 participants 60 participants 43 participants 40 participants
19
  63.3%
22
  84.6%
42
  76.4%
40
  66.7%
26
  60.5%
28
  70.0%
Worsened in diarrhea Number Analyzed 30 participants 26 participants 55 participants 60 participants 43 participants 40 participants
6
  20.0%
1
   3.8%
5
   9.1%
11
  18.3%
6
  14.0%
4
  10.0%
Improved in financial difficulties Number Analyzed 30 participants 26 participants 55 participants 60 participants 43 participants 40 participants
10
  33.3%
6
  23.1%
11
  20.0%
13
  21.7%
11
  25.6%
10
  25.0%
Stable in financial difficulties Number Analyzed 30 participants 26 participants 55 participants 60 participants 43 participants 40 participants
18
  60.0%
18
  69.2%
33
  60.0%
38
  63.3%
22
  51.2%
26
  65.0%
Worsened in financial difficulties Number Analyzed 30 participants 26 participants 55 participants 60 participants 43 participants 40 participants
2
   6.7%
2
   7.7%
11
  20.0%
9
  15.0%
10
  23.3%
4
  10.0%
57.Secondary Outcome
Title Number of Participants Who Improved, Worsened or Remained Stable in EORTC QLQ-LC13 (Phase 2)
Hide Description EORTC QLQ-LC13 is the lung cancer module of EORTC QLQ-C30 and includes questions specific to the disease associated symptoms (dyspnea, cough, hemoptysis, and site specific pain), treatment-related symptoms (sore mouth, dysphagia, neuropathy and alopecia), and analgesic use of lung cancer patients. The scale was transformed to a range of 0 to 100 using standard EORTC algorithm. Higher score indicates worse symptoms, and improvement was defined as a decrease of at least 10 points, worsening was defined as an increase of at least 10 points. All scales which had not improved nor worsened were considered stable.
Time Frame 3 years
Hide Outcome Measure Data
Hide Analysis Population Description
Patient reported outcome (PRO) evaluable analysis set included all enrolled participants who received at least 1 dose of PF-06463922 and completed a baseline and at least 1 post-baseline PRO assessment.
Arm/Group Title EXP-1 (Phase 2) EXP-2 (Phase 2) EXP-3 (Phase 2) EXP-4 (Phase 2) EXP-5 (Phase 2) EXP-6 (Phase 2)
Hide Arm/Group Description:
Treatment-naïve participants with advanced ALK-positive NSCLC with or without asymptomatic central nervous system (CNS) metastases were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after only crizotinib therapy were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after crizotinib therapy and 1 or 2 prior regimens of chemotherapy given before or after crizotinib therapy, or participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 1 ALK inhibitor therapy other than crizotinib with or without any number of prior chemotherapy regimens in any disease setting were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 2 prior lines of ALK inhibitor therapies were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 3 prior lines of ALK inhibitor therapies were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participant scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ROS1-positive NSCLC who were treatment naïve or had any number of prior cancer therapies with or without asymptomatic CNS metastases were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Overall Number of Participants Analyzed 30 26 55 60 42 41
Measure Type: Count of Participants
Unit of Measure: Participants
Improved in dyspnea Number Analyzed 30 participants 26 participants 55 participants 60 participants 42 participants 41 participants
11
  36.7%
5
  19.2%
11
  20.0%
20
  33.3%
12
  28.6%
13
  31.7%
Stable in dyspnea Number Analyzed 30 participants 26 participants 55 participants 60 participants 42 participants 41 participants
16
  53.3%
19
  73.1%
36
  65.5%
26
  43.3%
22
  52.4%
22
  53.7%
Worsened in dyspnea Number Analyzed 30 participants 26 participants 55 participants 60 participants 42 participants 41 participants
3
  10.0%
2
   7.7%
8
  14.5%
14
  23.3%
8
  19.0%
6
  14.6%
Improved in coughing Number Analyzed 30 participants 26 participants 55 participants 60 participants 42 participants 41 participants
18
  60.0%
9
  34.6%
22
  40.0%
27
  45.0%
18
  42.9%
17
  41.5%
Stable in coughing Number Analyzed 30 participants 26 participants 55 participants 60 participants 42 participants 41 participants
9
  30.0%
14
  53.8%
26
  47.3%
27
  45.0%
15
  35.7%
17
  41.5%
Worsened in coughing Number Analyzed 30 participants 26 participants 55 participants 60 participants 42 participants 41 participants
3
  10.0%
3
  11.5%
7
  12.7%
6
  10.0%
9
  21.4%
7
  17.1%
Improved in hemoptysis Number Analyzed 30 participants 26 participants 55 participants 60 participants 42 participants 41 participants
4
  13.3%
0
   0.0%
7
  12.7%
5
   8.3%
5
  11.9%
4
   9.8%
Stable in hemoptysis Number Analyzed 30 participants 26 participants 55 participants 60 participants 42 participants 41 participants
24
  80.0%
26
 100.0%
47
  85.5%
53
  88.3%
34
  81.0%
36
  87.8%
Worsened in hemoptysis Number Analyzed 30 participants 26 participants 55 participants 60 participants 42 participants 41 participants
2
   6.7%
0
   0.0%
1
   1.8%
2
   3.3%
3
   7.1%
1
   2.4%
Improved in sore mouth Number Analyzed 30 participants 26 participants 55 participants 60 participants 42 participants 41 participants
0
   0.0%
2
   7.7%
4
   7.3%
10
  16.7%
2
   4.8%
5
  12.2%
Stable in sore mouth Number Analyzed 30 participants 26 participants 55 participants 60 participants 42 participants 41 participants
24
  80.0%
21
  80.8%
45
  81.8%
39
  65.0%
32
  76.2%
28
  68.3%
Worsened in sore mouth Number Analyzed 30 participants 26 participants 55 participants 60 participants 42 participants 41 participants
6
  20.0%
3
  11.5%
6
  10.9%
11
  18.3%
8
  19.0%
8
  19.5%
Improved in dysphagia Number Analyzed 30 participants 26 participants 55 participants 60 participants 42 participants 41 participants
3
  10.0%
1
   3.8%
5
   9.1%
7
  11.7%
4
   9.5%
5
  12.2%
Stable in dysphagia Number Analyzed 30 participants 26 participants 55 participants 60 participants 42 participants 41 participants
24
  80.0%
25
  96.2%
44
  80.0%
47
  78.3%
33
  78.6%
30
  73.2%
Worsened in dysphagia Number Analyzed 30 participants 26 participants 55 participants 60 participants 42 participants 41 participants
3
  10.0%
0
   0.0%
6
  10.9%
6
  10.0%
5
  11.9%
6
  14.6%
Improved in peripheral neuropathy Number Analyzed 30 participants 26 participants 55 participants 60 participants 42 participants 41 participants
2
   6.7%
4
  15.4%
9
  16.4%
5
   8.3%
6
  14.3%
8
  19.5%
Stable in peripheral neuropathy Number Analyzed 30 participants 26 participants 55 participants 60 participants 42 participants 41 participants
10
  33.3%
13
  50.0%
25
  45.5%
32
  53.3%
23
  54.8%
19
  46.3%
Worsened in peripheral neuropathy Number Analyzed 30 participants 26 participants 55 participants 60 participants 42 participants 41 participants
18
  60.0%
9
  34.6%
21
  38.2%
23
  38.3%
13
  31.0%
14
  34.1%
Improved in alopecia Number Analyzed 30 participants 26 participants 55 participants 60 participants 42 participants 41 participants
1
   3.3%
1
   3.8%
2
   3.6%
10
  16.7%
8
  19.0%
9
  22.0%
Stable in alopecia Number Analyzed 30 participants 26 participants 55 participants 60 participants 42 participants 41 participants
19
  63.3%
22
  84.6%
41
  74.5%
38
  63.3%
27
  64.3%
26
  63.4%
Worsened in alopecia Number Analyzed 30 participants 26 participants 55 participants 60 participants 42 participants 41 participants
10
  33.3%
3
  11.5%
12
  21.8%
12
  20.0%
7
  16.7%
6
  14.6%
Improved in chest pain Number Analyzed 30 participants 26 participants 54 participants 60 participants 42 participants 41 participants
11
  36.7%
5
  19.2%
14
  25.9%
18
  30.0%
14
  33.3%
14
  34.1%
Stable in chest pain Number Analyzed 30 participants 26 participants 54 participants 60 participants 42 participants 41 participants
15
  50.0%
19
  73.1%
36
  66.7%
33
  55.0%
25
  59.5%
22
  53.7%
Worsened in chest pain Number Analyzed 30 participants 26 participants 54 participants 60 participants 42 participants 41 participants
4
  13.3%
2
   7.7%
4
   7.4%
9
  15.0%
3
   7.1%
5
  12.2%
Improved in arm or shoulder pain Number Analyzed 30 participants 26 participants 55 participants 60 participants 42 participants 41 participants
9
  30.0%
4
  15.4%
13
  23.6%
14
  23.3%
12
  28.6%
12
  29.3%
Stable in arm or shoulder pain Number Analyzed 30 participants 26 participants 55 participants 60 participants 42 participants 41 participants
16
  53.3%
18
  69.2%
33
  60.0%
37
  61.7%
21
  50.0%
21
  51.2%
Worsened in arm or shoulder pain Number Analyzed 30 participants 26 participants 55 participants 60 participants 42 participants 41 participants
5
  16.7%
4
  15.4%
9
  16.4%
9
  15.0%
9
  21.4%
8
  19.5%
Improved in pain in other parts Number Analyzed 30 participants 26 participants 55 participants 60 participants 41 participants 41 participants
10
  33.3%
5
  19.2%
18
  32.7%
19
  31.7%
14
  34.1%
17
  41.5%
Stable in pain in other parts Number Analyzed 30 participants 26 participants 55 participants 60 participants 41 participants 41 participants
14
  46.7%
12
  46.2%
23
  41.8%
25
  41.7%
11
  26.8%
17
  41.5%
Worsened in pain in other parts Number Analyzed 30 participants 26 participants 55 participants 60 participants 41 participants 41 participants
6
  20.0%
9
  34.6%
14
  25.5%
16
  26.7%
16
  39.0%
7
  17.1%
58.Secondary Outcome
Title Number of Participants With Treatment-Emergent Adverse Events (Phase 1 and Phase 2)
Hide Description AE was defined as any untoward medical occurrence in a clinical investigation participant administered a product or medical device, regardless of the causal relationship to study treatment. Treatment-emergent AEs (TEAEs) were defined as AEs which occurred for the first time during the effective duration of treatment or AEs that increased in severity during treatment. Serious AEs (SAEs) were defined as any untoward medical occurrence at any dose that resulted in death; was life-threatening (immediate risk of death); required inpatient hospitalization or caused prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity (substantial disruption of the ability to conduction normal life functions). AEs included SAEs and non-serious AEs. Causality to study treatment was determined by the investigator. Severity was graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.
Time Frame 3 years
Hide Outcome Measure Data
Hide Analysis Population Description
The safety analysis set included all enrolled participants who received at least 1 dose of PF-06463922.
Arm/Group Title 10 mg QD (Phase 1) 25 mg QD (Phase 1) 50 mg QD (Phase 1) 75 mg QD (Phase 1) 100 mg QD (Phase 1) 150 mg QD (Phase 1) 200 mg QD (Phase 1) 35 mg BID (Phase 1) 75 mg BID (Phase 1) 100 mg BID (Phase 1) EXP-1 (Phase 2) EXP-2 (Phase 2) EXP-3 (Phase 2) EXP-4 (Phase 2) EXP-5 (Phase 2) EXP-6 (Phase 2)
Hide Arm/Group Description:
PF-06463922 10 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 25 mg was orally given once daily (QD) in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. Midazolam 2 mg was orally given QD on Day -7 and Cycle 1 Day 15.
PF-06463922 50 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 75 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 100 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 150 mg was orally given once daily (QD) in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. Midazolam 2 mg was orally given QD on Day -7 and Cycle 1 Day 15.
PF-06463922 200 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 35 mg was orally given twice daily (BID) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 75 mg was orally given twice daily (BID) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 100 mg was orally given twice daily (BID) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Treatment-naïve participants with advanced ALK-positive NSCLC with or without asymptomatic central nervous system (CNS) metastases were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after only crizotinib therapy were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after crizotinib therapy and 1 or 2 prior regimens of chemotherapy given before or after crizotinib therapy, or participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 1 ALK inhibitor therapy other than crizotinib with or without any number of prior chemotherapy regimens in any disease setting were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 2 prior lines of ALK inhibitor therapies were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 3 prior lines of ALK inhibitor therapies were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participant scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ROS1-positive NSCLC who were treatment naïve or had any number of prior cancer therapies with or without asymptomatic CNS metastases were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Overall Number of Participants Analyzed 3 3 3 12 17 3 3 3 3 4 30 27 60 65 46 47
Measure Type: Count of Participants
Unit of Measure: Participants
AEs (all causality)
3
 100.0%
3
 100.0%
3
 100.0%
12
 100.0%
17
 100.0%
3
 100.0%
3
 100.0%
3
 100.0%
3
 100.0%
4
 100.0%
30
 100.0%
27
 100.0%
59
  98.3%
65
 100.0%
46
 100.0%
47
 100.0%
AEs (treatment-related)
3
 100.0%
3
 100.0%
3
 100.0%
11
  91.7%
16
  94.1%
3
 100.0%
3
 100.0%
1
  33.3%
3
 100.0%
4
 100.0%
30
 100.0%
27
 100.0%
55
  91.7%
61
  93.8%
43
  93.5%
45
  95.7%
SAEs (all causality)
3
 100.0%
1
  33.3%
1
  33.3%
4
  33.3%
9
  52.9%
3
 100.0%
1
  33.3%
2
  66.7%
2
  66.7%
2
  50.0%
8
  26.7%
5
  18.5%
18
  30.0%
24
  36.9%
18
  39.1%
16
  34.0%
SAEs (treatment-related)
1
  33.3%
0
   0.0%
0
   0.0%
1
   8.3%
1
   5.9%
3
 100.0%
0
   0.0%
0
   0.0%
0
   0.0%
1
  25.0%
3
  10.0%
0
   0.0%
5
   8.3%
4
   6.2%
5
  10.9%
2
   4.3%
Grade 1 (all causality)
0
   0.0%
0
   0.0%
1
  33.3%
1
   8.3%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
3
  10.0%
0
   0.0%
5
   8.3%
3
   4.6%
3
   6.5%
0
   0.0%
Grade 2 (all causality)
0
   0.0%
1
  33.3%
2
  66.7%
4
  33.3%
5
  29.4%
0
   0.0%
1
  33.3%
1
  33.3%
1
  33.3%
0
   0.0%
12
  40.0%
11
  40.7%
20
  33.3%
19
  29.2%
11
  23.9%
12
  25.5%
Grade 3 (all causality)
2
  66.7%
0
   0.0%
0
   0.0%
5
  41.7%
8
  47.1%
0
   0.0%
2
  66.7%
1
  33.3%
0
   0.0%
1
  25.0%
12
  40.0%
12
  44.4%
24
  40.0%
28
  43.1%
20
  43.5%
26
  55.3%
Grade 4 (all causality)
0
   0.0%
1
  33.3%
0
   0.0%
1
   8.3%
1
   5.9%
1
  33.3%
0
   0.0%
1
  33.3%
1
  33.3%
3
  75.0%
3
  10.0%
3
  11.1%
3
   5.0%
7
  10.8%
4
   8.7%
3
   6.4%
Grade 5 (all causality)
1
  33.3%
1
  33.3%
0
   0.0%
1
   8.3%
3
  17.6%
2
  66.7%
0
   0.0%
0
   0.0%
1
  33.3%
0
   0.0%
0
   0.0%
1
   3.7%
7
  11.7%
8
  12.3%
8
  17.4%
6
  12.8%
59.Secondary Outcome
Title Number of Participants With Laboratory Abnormalities (Phase 1 and Phase 2) - Hematology
Hide Description Hematology evaluation included hemoglobin, platelets, white blood cell, absolute neutrophils, absolute lymphocytes, absolute monocytes, absolute eosinophils and absolute basophils.
Time Frame 3 years
Hide Outcome Measure Data
Hide Analysis Population Description
The safety analysis set included all enrolled participants who received at least 1 dose of PF-06463922.
Arm/Group Title 10 mg QD (Phase 1) 25 mg QD (Phase 1) 50 mg QD (Phase 1) 75 mg QD (Phase 1) 100 mg QD (Phase 1) 150 mg QD (Phase 1) 200 mg QD (Phase 1) 35 mg BID (Phase 1) 75 mg BID (Phase 1) 100 mg BID (Phase 1) EXP-1 (Phase 2) EXP-2 (Phase 2) EXP-3 (Phase 2) EXP-4 (Phase 2) EXP-5 (Phase 2) EXP-6 (Phase 2)
Hide Arm/Group Description:
PF-06463922 10 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 25 mg was orally given once daily (QD) in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. Midazolam 2 mg was orally given QD on Day -7 and Cycle 1 Day 15.
PF-06463922 50 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 75 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 100 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 150 mg was orally given once daily (QD) in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. Midazolam 2 mg was orally given QD on Day -7 and Cycle 1 Day 15.
PF-06463922 200 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 35 mg was orally given twice daily (BID) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 75 mg was orally given twice daily (BID) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 100 mg was orally given twice daily (BID) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Treatment-naïve participants with advanced ALK-positive NSCLC with or without asymptomatic central nervous system (CNS) metastases were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after only crizotinib therapy were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after crizotinib therapy and 1 or 2 prior regimens of chemotherapy given before or after crizotinib therapy, or participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 1 ALK inhibitor therapy other than crizotinib with or without any number of prior chemotherapy regimens in any disease setting were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 2 prior lines of ALK inhibitor therapies were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 3 prior lines of ALK inhibitor therapies were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participant scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ROS1-positive NSCLC who were treatment naïve or had any number of prior cancer therapies with or without asymptomatic CNS metastases were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Overall Number of Participants Analyzed 3 3 3 12 17 3 3 3 3 4 30 27 60 64 45 47
Measure Type: Count of Participants
Unit of Measure: Participants
Anemia Number Analyzed 3 participants 3 participants 3 participants 12 participants 17 participants 3 participants 3 participants 3 participants 3 participants 4 participants 30 participants 27 participants 60 participants 64 participants 45 participants 47 participants
3
 100.0%
3
 100.0%
3
 100.0%
8
  66.7%
16
  94.1%
3
 100.0%
3
 100.0%
3
 100.0%
3
 100.0%
4
 100.0%
20
  66.7%
14
  51.9%
50
  83.3%
48
  75.0%
35
  77.8%
32
  68.1%
Hemoglobin increased Number Analyzed 3 participants 3 participants 3 participants 12 participants 17 participants 3 participants 3 participants 3 participants 3 participants 4 participants 30 participants 27 participants 60 participants 64 participants 45 participants 47 participants
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
1
   1.7%
3
   4.7%
1
   2.2%
1
   2.1%
Lymphocyte count decreased Number Analyzed 3 participants 3 participants 3 participants 12 participants 17 participants 3 participants 3 participants 3 participants 3 participants 4 participants 30 participants 27 participants 60 participants 64 participants 45 participants 46 participants
2
  66.7%
2
  66.7%
2
  66.7%
6
  50.0%
4
  23.5%
3
 100.0%
3
 100.0%
0
   0.0%
0
   0.0%
2
  50.0%
9
  30.0%
9
  33.3%
21
  35.0%
29
  45.3%
18
  40.0%
21
  45.7%
Lymphocyte count increased Number Analyzed 3 participants 3 participants 3 participants 12 participants 17 participants 3 participants 3 participants 3 participants 3 participants 4 participants 30 participants 27 participants 60 participants 64 participants 45 participants 46 participants
1
  33.3%
0
   0.0%
0
   0.0%
0
   0.0%
3
  17.6%
1
  33.3%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
3
  10.0%
3
  11.1%
6
  10.0%
4
   6.3%
2
   4.4%
1
   2.2%
Neutrophil count decreased Number Analyzed 3 participants 3 participants 3 participants 12 participants 17 participants 3 participants 3 participants 3 participants 3 participants 4 participants 30 participants 27 participants 60 participants 64 participants 45 participants 46 participants
1
  33.3%
0
   0.0%
0
   0.0%
4
  33.3%
2
  11.8%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
1
  25.0%
5
  16.7%
2
   7.4%
7
  11.7%
6
   9.4%
1
   2.2%
5
  10.9%
Platelet count decreased Number Analyzed 3 participants 3 participants 3 participants 12 participants 17 participants 3 participants 3 participants 3 participants 3 participants 4 participants 30 participants 27 participants 60 participants 64 participants 45 participants 47 participants
2
  66.7%
2
  66.7%
0
   0.0%
4
  33.3%
5
  29.4%
1
  33.3%
0
   0.0%
0
   0.0%
0
   0.0%
1
  25.0%
6
  20.0%
9
  33.3%
13
  21.7%
9
  14.1%
10
  22.2%
11
  23.4%
White blood cell decreased Number Analyzed 3 participants 3 participants 3 participants 12 participants 17 participants 3 participants 3 participants 3 participants 3 participants 4 participants 30 participants 27 participants 60 participants 64 participants 45 participants 47 participants
2
  66.7%
0
   0.0%
0
   0.0%
4
  33.3%
2
  11.8%
2
  66.7%
1
  33.3%
0
   0.0%
0
   0.0%
1
  25.0%
6
  20.0%
3
  11.1%
6
  10.0%
9
  14.1%
5
  11.1%
8
  17.0%
60.Secondary Outcome
Title Number of Participants With Laboratory Abnormalities (Phase 1 and Phase 2) - Chemistry
Hide Description Chemistry evaluation included alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, sodium, potassium, magnesium, chloride, total calcium, total bilirubin, blood urea nitrogen (BUN) or urea, creatinine, uric acid, glucose (non-fasted), albumin, phosphorus or phosphate, serum total amylase and serum lipase.
Time Frame 3 years
Hide Outcome Measure Data
Hide Analysis Population Description
The safety analysis set included all enrolled participants who received at least 1 dose of PF-06463922.
Arm/Group Title 10 mg QD (Phase 1) 25 mg QD (Phase 1) 50 mg QD (Phase 1) 75 mg QD (Phase 1) 100 mg QD (Phase 1) 150 mg QD (Phase 1) 200 mg QD (Phase 1) 35 mg BID (Phase 1) 75 mg BID (Phase 1) 100 mg BID (Phase 1) EXP-1 (Phase 2) EXP-2 (Phase 2) EXP-3 (Phase 2) EXP-4 (Phase 2) EXP-5 (Phase 2) EXP-6 (Phase 2)
Hide Arm/Group Description:
PF-06463922 10 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 25 mg was orally given once daily (QD) in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. Midazolam 2 mg was orally given QD on Day -7 and Cycle 1 Day 15.
PF-06463922 50 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 75 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 100 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 150 mg was orally given once daily (QD) in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. Midazolam 2 mg was orally given QD on Day -7 and Cycle 1 Day 15.
PF-06463922 200 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 35 mg was orally given twice daily (BID) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 75 mg was orally given twice daily (BID) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 100 mg was orally given twice daily (BID) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Treatment-naïve participants with advanced ALK-positive NSCLC with or without asymptomatic central nervous system (CNS) metastases were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after only crizotinib therapy were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after crizotinib therapy and 1 or 2 prior regimens of chemotherapy given before or after crizotinib therapy, or participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 1 ALK inhibitor therapy other than crizotinib with or without any number of prior chemotherapy regimens in any disease setting were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 2 prior lines of ALK inhibitor therapies were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 3 prior lines of ALK inhibitor therapies were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participant scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ROS1-positive NSCLC who were treatment naïve or had any number of prior cancer therapies with or without asymptomatic CNS metastases were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Overall Number of Participants Analyzed 3 3 3 12 17 3 3 3 3 4 30 27 60 65 45 47
Measure Type: Count of Participants
Unit of Measure: Participants
ALT increased Number Analyzed 3 participants 3 participants 3 participants 12 participants 17 participants 3 participants 3 participants 3 participants 3 participants 4 participants 30 participants 27 participants 60 participants 63 participants 45 participants 47 participants
2
  66.7%
1
  33.3%
1
  33.3%
4
  33.3%
7
  41.2%
2
  66.7%
2
  66.7%
0
   0.0%
0
   0.0%
3
  75.0%
11
  36.7%
11
  40.7%
23
  38.3%
17
  27.0%
12
  26.7%
13
  27.7%
Alkaline phosphatase increased Number Analyzed 3 participants 3 participants 3 participants 12 participants 17 participants 3 participants 3 participants 3 participants 3 participants 4 participants 30 participants 27 participants 60 participants 63 participants 45 participants 47 participants
1
  33.3%
1
  33.3%
3
 100.0%
4
  33.3%
9
  52.9%
3
 100.0%
1
  33.3%
0
   0.0%
2
  66.7%
3
  75.0%
6
  20.0%
8
  29.6%
21
  35.0%
21
  33.3%
21
  46.7%
14
  29.8%
AST increased Number Analyzed 3 participants 3 participants 3 participants 12 participants 17 participants 3 participants 3 participants 3 participants 3 participants 4 participants 30 participants 27 participants 60 participants 63 participants 45 participants 47 participants
2
  66.7%
2
  66.7%
2
  66.7%
3
  25.0%
7
  41.2%
2
  66.7%
2
  66.7%
0
   0.0%
1
  33.3%
3
  75.0%
15
  50.0%
12
  44.4%
31
  51.7%
27
  42.9%
17
  37.8%
17
  36.2%
Blood bilirubin increased Number Analyzed 3 participants 3 participants 3 participants 12 participants 17 participants 3 participants 3 participants 3 participants 3 participants 4 participants 30 participants 27 participants 60 participants 63 participants 45 participants 47 participants
1
  33.3%
0
   0.0%
0
   0.0%
1
   8.3%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
1
  25.0%
0
   0.0%
0
   0.0%
2
   3.3%
0
   0.0%
1
   2.2%
1
   2.1%
CPK increased Number Analyzed 0 participants 0 participants 0 participants 0 participants 3 participants 1 participants 0 participants 0 participants 1 participants 0 participants 1 participants 1 participants 4 participants 2 participants 0 participants 5 participants
1
  33.3%
1
 100.0%
1
 100.0%
0
   0.0%
0
   0.0%
3
  75.0%
0
   0.0%
2
  40.0%
Creatinine increased Number Analyzed 3 participants 3 participants 3 participants 12 participants 17 participants 3 participants 3 participants 3 participants 3 participants 4 participants 30 participants 27 participants 60 participants 64 participants 45 participants 47 participants
3
 100.0%
2
  66.7%
3
 100.0%
9
  75.0%
13
  76.5%
3
 100.0%
3
 100.0%
2
  66.7%
2
  66.7%
3
  75.0%
26
  86.7%
21
  77.8%
37
  61.7%
44
  68.8%
32
  71.1%
34
  72.3%
GGT increased Number Analyzed 1 participants 0 participants 0 participants 0 participants 4 participants 1 participants 1 participants 0 participants 1 participants 2 participants 0 participants 2 participants 3 participants 1 participants 0 participants 2 participants
0
   0.0%
1
  25.0%
0
   0.0%
1
 100.0%
0
   0.0%
2
 100.0%
1
  50.0%
2
  66.7%
1
 100.0%
1
  50.0%
Hypercalcemia Number Analyzed 3 participants 3 participants 3 participants 12 participants 17 participants 3 participants 3 participants 3 participants 3 participants 4 participants 30 participants 27 participants 60 participants 64 participants 45 participants 47 participants
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
1
   5.9%
1
  33.3%
0
   0.0%
0
   0.0%
0
   0.0%
1
  25.0%
4
  13.3%
3
  11.1%
4
   6.7%
4
   6.3%
3
   6.7%
1
   2.1%
Hyperglycemia Number Analyzed 3 participants 3 participants 3 participants 12 participants 17 participants 3 participants 3 participants 3 participants 3 participants 4 participants 30 participants 27 participants 60 participants 64 participants 45 participants 47 participants
3
 100.0%
2
  66.7%
2
  66.7%
6
  50.0%
8
  47.1%
2
  66.7%
1
  33.3%
1
  33.3%
2
  66.7%
0
   0.0%
11
  36.7%
16
  59.3%
30
  50.0%
41
  64.1%
31
  68.9%
29
  61.7%
Hyperkalemia Number Analyzed 3 participants 3 participants 3 participants 12 participants 17 participants 3 participants 3 participants 3 participants 3 participants 4 participants 30 participants 27 participants 60 participants 64 participants 45 participants 47 participants
0
   0.0%
1
  33.3%
2
  66.7%
2
  16.7%
6
  35.3%
1
  33.3%
1
  33.3%
1
  33.3%
1
  33.3%
2
  50.0%
8
  26.7%
7
  25.9%
14
  23.3%
11
  17.2%
5
  11.1%
5
  10.6%
Hypermagnesemia Number Analyzed 3 participants 3 participants 3 participants 12 participants 17 participants 3 participants 3 participants 3 participants 3 participants 4 participants 30 participants 27 participants 59 participants 64 participants 45 participants 47 participants
2
  66.7%
0
   0.0%
0
   0.0%
1
   8.3%
2
  11.8%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
2
   6.7%
1
   3.7%
2
   3.4%
2
   3.1%
1
   2.2%
3
   6.4%
Hypernatremia Number Analyzed 3 participants 3 participants 3 participants 12 participants 17 participants 3 participants 3 participants 3 participants 3 participants 4 participants 30 participants 27 participants 60 participants 64 participants 45 participants 47 participants
0
   0.0%
1
  33.3%
0
   0.0%
0
   0.0%
4
  23.5%
2
  66.7%
0
   0.0%
0
   0.0%
0
   0.0%
1
  25.0%
3
  10.0%
1
   3.7%
2
   3.3%
4
   6.3%
2
   4.4%
4
   8.5%
Hypoalbuminemia Number Analyzed 3 participants 3 participants 3 participants 12 participants 17 participants 3 participants 3 participants 3 participants 3 participants 4 participants 30 participants 27 participants 60 participants 63 participants 45 participants 46 participants
2
  66.7%
1
  33.3%
3
 100.0%
4
  33.3%
6
  35.3%
3
 100.0%
1
  33.3%
1
  33.3%
3
 100.0%
1
  25.0%
16
  53.3%
15
  55.6%
34
  56.7%
42
  66.7%
29
  64.4%
27
  58.7%
Hypocalcemia Number Analyzed 3 participants 3 participants 3 participants 12 participants 17 participants 3 participants 3 participants 3 participants 3 participants 4 participants 30 participants 27 participants 60 participants 64 participants 45 participants 47 participants
1
  33.3%
0
   0.0%
1
  33.3%
3
  25.0%
3
  17.6%
2
  66.7%
1
  33.3%
0
   0.0%
0
   0.0%
1
  25.0%
2
   6.7%
4
  14.8%
11
  18.3%
9
  14.1%
3
   6.7%
9
  19.1%
Hypoglycemia Number Analyzed 3 participants 3 participants 3 participants 12 participants 17 participants 3 participants 3 participants 3 participants 3 participants 4 participants 30 participants 27 participants 60 participants 64 participants 45 participants 47 participants
0
   0.0%
0
   0.0%
1
  33.3%
3
  25.0%
4
  23.5%
0
   0.0%
1
  33.3%
0
   0.0%
1
  33.3%
0
   0.0%
1
   3.3%
2
   7.4%
8
  13.3%
7
  10.9%
5
  11.1%
3
   6.4%
Hypokalemia Number Analyzed 3 participants 3 participants 3 participants 12 participants 17 participants 3 participants 3 participants 3 participants 3 participants 4 participants 30 participants 27 participants 60 participants 64 participants 45 participants 47 participants
0
   0.0%
0
   0.0%
2
  66.7%
3
  25.0%
3
  17.6%
3
 100.0%
1
  33.3%
1
  33.3%
0
   0.0%
2
  50.0%
6
  20.0%
1
   3.7%
9
  15.0%
9
  14.1%
6
  13.3%
13
  27.7%
Hypomagnesemia Number Analyzed 3 participants 3 participants 3 participants 12 participants 17 participants 3 participants 3 participants 3 participants 3 participants 4 participants 30 participants 27 participants 59 participants 64 participants 45 participants 47 participants
0
   0.0%
1
  33.3%
2
  66.7%
4
  33.3%
1
   5.9%
3
 100.0%
0
   0.0%
1
  33.3%
1
  33.3%
3
  75.0%
4
  13.3%
8
  29.6%
20
  33.9%
17
  26.6%
13
  28.9%
11
  23.4%
Hyponatremia Number Analyzed 3 participants 3 participants 3 participants 12 participants 17 participants 3 participants 3 participants 3 participants 3 participants 4 participants 30 participants 27 participants 60 participants 64 participants 45 participants 47 participants
2
  66.7%
1
  33.3%
1
  33.3%
1
   8.3%
4
  23.5%
1
  33.3%
1
  33.3%
0
   0.0%
2
  66.7%
2
  50.0%
8
  26.7%
6
  22.2%
10
  16.7%
19
  29.7%
9
  20.0%
6
  12.8%
Hypophosphatemia Number Analyzed 3 participants 3 participants 3 participants 12 participants 17 participants 3 participants 3 participants 3 participants 3 participants 4 participants 30 participants 27 participants 59 participants 64 participants 45 participants 47 participants
1
  33.3%
2
  66.7%
0
   0.0%
3
  25.0%
3
  17.6%
2
  66.7%
1
  33.3%
1
  33.3%
2
  66.7%
1
  25.0%
3
  10.0%
6
  22.2%
17
  28.8%
14
  21.9%
7
  15.6%
14
  29.8%
Lipase increased Number Analyzed 3 participants 3 participants 3 participants 12 participants 17 participants 3 participants 3 participants 3 participants 3 participants 4 participants 30 participants 27 participants 59 participants 63 participants 45 participants 46 participants
3
 100.0%
1
  33.3%
0
   0.0%
8
  66.7%
6
  35.3%
0
   0.0%
1
  33.3%
0
   0.0%
2
  66.7%
2
  50.0%
9
  30.0%
5
  18.5%
11
  18.6%
15
  23.8%
14
  31.1%
16
  34.8%
Serum amylase increased Number Analyzed 3 participants 3 participants 1 participants 11 participants 16 participants 3 participants 3 participants 3 participants 2 participants 4 participants 30 participants 25 participants 57 participants 63 participants 45 participants 45 participants
3
 100.0%
0
   0.0%
0
   0.0%
2
  18.2%
5
  31.3%
0
   0.0%
1
  33.3%
0
   0.0%
0
   0.0%
2
  50.0%
9
  30.0%
5
  20.0%
14
  24.6%
18
  28.6%
10
  22.2%
13
  28.9%
61.Secondary Outcome
Title Number of Participants With Laboratory Abnormalities (Phase 1 and Phase 2) - Coagulation, Lipids and Urinalysis
Hide Description Coagulation evaluation included activated partial thromboplastin time, international normalized ratio (INR), and prothrombin time. Lipid evaluation included total cholesterol, low density lipoprotein (LDL), high density lipoprotein (HDL) and triglycerides. Urinalysis included urine protein and urine blood.
Time Frame 3 years
Hide Outcome Measure Data
Hide Analysis Population Description
The safety analysis set included all enrolled participants who received at least 1 dose of PF-06463922.
Arm/Group Title 10 mg QD (Phase 1) 25 mg QD (Phase 1) 50 mg QD (Phase 1) 75 mg QD (Phase 1) 100 mg QD (Phase 1) 150 mg QD (Phase 1) 200 mg QD (Phase 1) 35 mg BID (Phase 1) 75 mg BID (Phase 1) 100 mg BID (Phase 1) EXP-1 (Phase 2) EXP-2 (Phase 2) EXP-3 (Phase 2) EXP-4 (Phase 2) EXP-5 (Phase 2) EXP-6 (Phase 2)
Hide Arm/Group Description:
PF-06463922 10 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 25 mg was orally given once daily (QD) in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. Midazolam 2 mg was orally given QD on Day -7 and Cycle 1 Day 15.
PF-06463922 50 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 75 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 100 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 150 mg was orally given once daily (QD) in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. Midazolam 2 mg was orally given QD on Day -7 and Cycle 1 Day 15.
PF-06463922 200 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 35 mg was orally given twice daily (BID) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 75 mg was orally given twice daily (BID) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 100 mg was orally given twice daily (BID) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Treatment-naïve participants with advanced ALK-positive NSCLC with or without asymptomatic central nervous system (CNS) metastases were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after only crizotinib therapy were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after crizotinib therapy and 1 or 2 prior regimens of chemotherapy given before or after crizotinib therapy, or participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 1 ALK inhibitor therapy other than crizotinib with or without any number of prior chemotherapy regimens in any disease setting were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 2 prior lines of ALK inhibitor therapies were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 3 prior lines of ALK inhibitor therapies were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participant scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ROS1-positive NSCLC who were treatment naïve or had any number of prior cancer therapies with or without asymptomatic CNS metastases were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Overall Number of Participants Analyzed 3 3 3 12 17 3 3 3 3 4 30 27 60 65 46 47
Measure Type: Count of Participants
Unit of Measure: Participants
Activated partial thromboplastin time prolonged Number Analyzed 3 participants 3 participants 3 participants 11 participants 14 participants 3 participants 3 participants 3 participants 3 participants 3 participants 4 participants 2 participants 11 participants 14 participants 9 participants 15 participants
1
  33.3%
0
   0.0%
1
  33.3%
3
  27.3%
2
  14.3%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
1
  25.0%
0
   0.0%
1
   9.1%
0
   0.0%
1
  11.1%
4
  26.7%
Cholesterol high Number Analyzed 2 participants 2 participants 2 participants 12 participants 17 participants 2 participants 3 participants 3 participants 3 participants 4 participants 30 participants 27 participants 60 participants 64 participants 45 participants 46 participants
2
 100.0%
2
 100.0%
2
 100.0%
10
  83.3%
16
  94.1%
2
 100.0%
3
 100.0%
3
 100.0%
2
  66.7%
3
  75.0%
30
 100.0%
26
  96.3%
57
  95.0%
64
 100.0%
45
 100.0%
44
  95.7%
Hypertriglyceridemia Number Analyzed 1 participants 2 participants 2 participants 12 participants 17 participants 2 participants 3 participants 3 participants 3 participants 4 participants 30 participants 27 participants 60 participants 64 participants 45 participants 46 participants
0
   0.0%
2
 100.0%
2
 100.0%
10
  83.3%
16
  94.1%
2
 100.0%
3
 100.0%
2
  66.7%
1
  33.3%
3
  75.0%
30
 100.0%
25
  92.6%
56
  93.3%
60
  93.8%
45
 100.0%
42
  91.3%
INR increased Number Analyzed 3 participants 3 participants 3 participants 11 participants 14 participants 3 participants 3 participants 3 participants 3 participants 3 participants 4 participants 5 participants 14 participants 22 participants 11 participants 18 participants
2
  66.7%
0
   0.0%
1
  33.3%
2
  18.2%
2
  14.3%
1
  33.3%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
1
   7.1%
4
  18.2%
0
   0.0%
6
  33.3%
Proteinuria Number Analyzed 3 participants 3 participants 3 participants 9 participants 14 participants 3 participants 3 participants 3 participants 3 participants 3 participants 3 participants 5 participants 11 participants 22 participants 12 participants 14 participants
2
  66.7%
0
   0.0%
0
   0.0%
0
   0.0%
4
  28.6%
3
 100.0%
0
   0.0%
0
   0.0%
1
  33.3%
0
   0.0%
1
  33.3%
0
   0.0%
2
  18.2%
2
   9.1%
2
  16.7%
4
  28.6%
Prothrombin time Number Analyzed 3 participants 3 participants 3 participants 11 participants 14 participants 3 participants 3 participants 3 participants 3 participants 3 participants 4 participants 5 participants 11 participants 21 participants 11 participants 14 participants
2
  66.7%
0
   0.0%
1
  33.3%
3
  27.3%
3
  21.4%
1
  33.3%
0
   0.0%
0
   0.0%
1
  33.3%
1
  33.3%
0
   0.0%
1
  20.0%
4
  36.4%
4
  19.0%
2
  18.2%
5
  35.7%
62.Secondary Outcome
Title Number of Participants With Vital Signs Data Meeting Pre-defined Criteria (Phase 1 and Phase 2)
Hide Description Blood pressure (BP), including systolic BP (SBP) and diastolic BP (DBP), and pulse rate were recorded in sitting position. Body weight was also measured.
Time Frame Baseline, Days 1, 8 and 15 of Cycle 1, Day 1 of Cycles 2-25 for Phase 1 (Cycles 2-38 for Phase 2), Day 1 of every other cycle thereafter, end of treatment (up to 3 years)
Hide Outcome Measure Data
Hide Analysis Population Description
The safety analysis set included all enrolled participants who received at least 1 dose of PF-06463922.
Arm/Group Title 10 mg QD (Phase 1) 25 mg QD (Phase 1) 50 mg QD (Phase 1) 75 mg QD (Phase 1) 100 mg QD (Phase 1) 150 mg QD (Phase 1) 200 mg QD (Phase 1) 35 mg BID (Phase 1) 75 mg BID (Phase 1) 100 mg BID (Phase 1) EXP-1 (Phase 2) EXP-2 (Phase 2) EXP-3 (Phase 2) EXP-4 (Phase 2) EXP-5 (Phase 2) EXP-6 (Phase 2)
Hide Arm/Group Description:
PF-06463922 10 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 25 mg was orally given once daily (QD) in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. Midazolam 2 mg was orally given QD on Day -7 and Cycle 1 Day 15.
PF-06463922 50 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 75 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 100 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 150 mg was orally given once daily (QD) in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. Midazolam 2 mg was orally given QD on Day -7 and Cycle 1 Day 15.
PF-06463922 200 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 35 mg was orally given twice daily (BID) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 75 mg was orally given twice daily (BID) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 100 mg was orally given twice daily (BID) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Treatment-naïve participants with advanced ALK-positive NSCLC with or without asymptomatic central nervous system (CNS) metastases were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after only crizotinib therapy were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after crizotinib therapy and 1 or 2 prior regimens of chemotherapy given before or after crizotinib therapy, or participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 1 ALK inhibitor therapy other than crizotinib with or without any number of prior chemotherapy regimens in any disease setting were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 2 prior lines of ALK inhibitor therapies were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 3 prior lines of ALK inhibitor therapies were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participant scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ROS1-positive NSCLC who were treatment naïve or had any number of prior cancer therapies with or without asymptomatic CNS metastases were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Overall Number of Participants Analyzed 3 3 3 12 17 3 3 3 3 4 30 27 60 65 45 46
Measure Type: Count of Participants
Unit of Measure: Participants
Sitting pulse rate <50 bpm Number Analyzed 3 participants 3 participants 3 participants 12 participants 17 participants 3 participants 3 participants 3 participants 3 participants 4 participants 30 participants 27 participants 60 participants 65 participants 45 participants 46 participants
0
   0.0%
1
  33.3%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
3
   5.0%
1
   1.5%
0
   0.0%
2
   4.3%
Sitting pulse rate >120 bpm Number Analyzed 3 participants 3 participants 3 participants 12 participants 17 participants 3 participants 3 participants 3 participants 3 participants 4 participants 30 participants 27 participants 60 participants 65 participants 45 participants 46 participants
0
   0.0%
0
   0.0%
1
  33.3%
1
   8.3%
2
  11.8%
2
  66.7%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
4
   6.7%
8
  12.3%
3
   6.7%
2
   4.3%
Increase in weight: 10% to <20% Number Analyzed 3 participants 3 participants 3 participants 12 participants 17 participants 3 participants 3 participants 3 participants 3 participants 4 participants 30 participants 26 participants 58 participants 61 participants 44 participants 43 participants
1
  33.3%
1
  33.3%
0
   0.0%
6
  50.0%
6
  35.3%
2
  66.7%
2
  66.7%
0
   0.0%
1
  33.3%
0
   0.0%
9
  30.0%
12
  46.2%
14
  24.1%
18
  29.5%
15
  34.1%
12
  27.9%
Increase in weight: >=20% Number Analyzed 3 participants 3 participants 3 participants 12 participants 17 participants 3 participants 3 participants 3 participants 3 participants 4 participants 30 participants 26 participants 58 participants 61 participants 44 participants 43 participants
0
   0.0%
1
  33.3%
1
  33.3%
1
   8.3%
4
  23.5%
1
  33.3%
0
   0.0%
0
   0.0%
0
   0.0%
1
  25.0%
8
  26.7%
1
   3.8%
4
   6.9%
9
  14.8%
3
   6.8%
8
  18.6%
Increase in sitting SBP >=40 mmHg Number Analyzed 3 participants 3 participants 3 participants 12 participants 17 participants 3 participants 3 participants 3 participants 3 participants 4 participants 30 participants 26 participants 60 participants 65 participants 45 participants 44 participants
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
1
   5.9%
2
  66.7%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
5
  16.7%
3
  11.5%
4
   6.7%
5
   7.7%
5
  11.1%
3
   6.8%
Increase in sitting SBP >=60 mmHg Number Analyzed 3 participants 3 participants 3 participants 12 participants 17 participants 3 participants 3 participants 3 participants 3 participants 4 participants 30 participants 26 participants 60 participants 65 participants 45 participants 44 participants
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
1
   1.5%
0
   0.0%
0
   0.0%
Increase in sitting DBP >=20 mmHg Number Analyzed 3 participants 3 participants 3 participants 12 participants 17 participants 3 participants 3 participants 3 participants 3 participants 4 participants 30 participants 26 participants 60 participants 65 participants 45 participants 44 participants
0
   0.0%
2
  66.7%
0
   0.0%
0
   0.0%
7
  41.2%
3
 100.0%
1
  33.3%
0
   0.0%
0
   0.0%
0
   0.0%
9
  30.0%
9
  34.6%
16
  26.7%
12
  18.5%
10
  22.2%
11
  25.0%
Increase in sitting DBP >=40 mmHg Number Analyzed 3 participants 3 participants 3 participants 12 participants 17 participants 3 participants 3 participants 3 participants 3 participants 4 participants 30 participants 26 participants 60 participants 65 participants 45 participants 44 participants
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
1
   3.8%
0
   0.0%
0
   0.0%
0
   0.0%
2
   4.5%
Increase in sitting pulse rate >=30 bpm Number Analyzed 3 participants 3 participants 3 participants 12 participants 17 participants 3 participants 3 participants 3 participants 3 participants 4 participants 30 participants 26 participants 60 participants 65 participants 44 participants 44 participants
0
   0.0%
1
  33.3%
0
   0.0%
1
   8.3%
3
  17.6%
1
  33.3%
0
   0.0%
0
   0.0%
0
   0.0%
1
  25.0%
0
   0.0%
2
   7.7%
10
  16.7%
15
  23.1%
12
  27.3%
13
  29.5%
Decrease in weight >=10% Number Analyzed 3 participants 3 participants 3 participants 12 participants 17 participants 3 participants 3 participants 3 participants 3 participants 4 participants 30 participants 26 participants 58 participants 61 participants 44 participants 43 participants
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
1
  25.0%
1
   3.3%
0
   0.0%
6
  10.3%
4
   6.6%
1
   2.3%
1
   2.3%
Decrease in SBP >=40 mmHg Number Analyzed 3 participants 3 participants 3 participants 12 participants 17 participants 3 participants 3 participants 3 participants 3 participants 4 participants 30 participants 26 participants 60 participants 65 participants 45 participants 44 participants
0
   0.0%
0
   0.0%
0
   0.0%
3
  25.0%
2
  11.8%
1
  33.3%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
1
   3.8%
2
   3.3%
1
   1.5%
1
   2.2%
3
   6.8%
Decrease in SBP >=60 mmHg Number Analyzed 3 participants 3 participants 3 participants 12 participants 17 participants 3 participants 3 participants 3 participants 3 participants 4 participants 30 participants 26 participants 60 participants 65 participants 45 participants 44 participants
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Decrease in DBP >=20 mmHg Number Analyzed 3 participants 3 participants 3 participants 12 participants 17 participants 3 participants 3 participants 3 participants 3 participants 4 participants 30 participants 26 participants 60 participants 65 participants 45 participants 44 participants
2
  66.7%
1
  33.3%
0
   0.0%
4
  33.3%
3
  17.6%
2
  66.7%
2
  66.7%
0
   0.0%
1
  33.3%
2
  50.0%
5
  16.7%
3
  11.5%
12
  20.0%
8
  12.3%
5
  11.1%
6
  13.6%
Decrease in DBP >=40 mmHg Number Analyzed 3 participants 3 participants 3 participants 12 participants 17 participants 3 participants 3 participants 3 participants 3 participants 4 participants 30 participants 26 participants 60 participants 65 participants 45 participants 44 participants
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Decrease in sitting pulse rate >=30 bpm Number Analyzed 3 participants 3 participants 3 participants 12 participants 17 participants 3 participants 3 participants 3 participants 3 participants 4 participants 30 participants 26 participants 60 participants 65 participants 44 participants 44 participants
0
   0.0%
0
   0.0%
1
  33.3%
2
  16.7%
0
   0.0%
1
  33.3%
0
   0.0%
1
  33.3%
1
  33.3%
1
  25.0%
7
  23.3%
2
   7.7%
4
   6.7%
5
   7.7%
3
   6.8%
5
  11.4%
63.Secondary Outcome
Title Number of Participants With Maximum Decrease From Baseline Greater Than or Equal to 20 Percent in Left Ventricular Ejection Fraction (LVEF) (Phase 1 and Phase 2)
Hide Description Left Ventricular Ejection Fraction (LVEF) was determined by electrocardiogram (ECG) measurement. Baseline was defined as the measurement prior to the first dose of study treatment.
Time Frame Baseline, Day 1 of Cycles 2-3, Day 1 of every other cycle from Cycle 5 up to 18 months for Phase 1 (up to 30 months for Phase 2), every 4 cycles thereafter, and end of treatment (up to 3 years)
Hide Outcome Measure Data
Hide Analysis Population Description
The safety analysis set included all enrolled participants who received at least 1 dose of PF-06463922.
Arm/Group Title 10 mg QD (Phase 1) 25 mg QD (Phase 1) 50 mg QD (Phase 1) 75 mg QD (Phase 1) 100 mg QD (Phase 1) 150 mg QD (Phase 1) 200 mg QD (Phase 1) 35 mg BID (Phase 1) 75 mg BID (Phase 1) 100 mg BID (Phase 1) EXP-1 (Phase 2) EXP-2 (Phase 2) EXP-3 (Phase 2) EXP-4 (Phase 2) EXP-5 (Phase 2) EXP-6 (Phase 2)
Hide Arm/Group Description:
PF-06463922 10 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 25 mg was orally given once daily (QD) in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. Midazolam 2 mg was orally given QD on Day -7 and Cycle 1 Day 15.
PF-06463922 50 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 75 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 100 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 150 mg was orally given once daily (QD) in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. Midazolam 2 mg was orally given QD on Day -7 and Cycle 1 Day 15.
PF-06463922 200 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 35 mg was orally given twice daily (BID) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 75 mg was orally given twice daily (BID) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 100 mg was orally given twice daily (BID) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Treatment-naïve participants with advanced ALK-positive NSCLC with or without asymptomatic central nervous system (CNS) metastases were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after only crizotinib therapy were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after crizotinib therapy and 1 or 2 prior regimens of chemotherapy given before or after crizotinib therapy, or participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 1 ALK inhibitor therapy other than crizotinib with or without any number of prior chemotherapy regimens in any disease setting were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 2 prior lines of ALK inhibitor therapies were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 3 prior lines of ALK inhibitor therapies were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participant scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ROS1-positive NSCLC who were treatment naïve or had any number of prior cancer therapies with or without asymptomatic CNS metastases were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Overall Number of Participants Analyzed 3 3 3 12 17 3 3 3 3 4 30 27 60 65 46 47
Measure Type: Count of Participants
Unit of Measure: Participants
1
  33.3%
0
   0.0%
1
  33.3%
3
  25.0%
4
  23.5%
2
  66.7%
1
  33.3%
0
   0.0%
0
   0.0%
2
  50.0%
3
  10.0%
1
   3.7%
9
  15.0%
11
  16.9%
3
   6.5%
4
   8.5%
64.Secondary Outcome
Title Number of Participants With Absolute Values and Change From Baseline in QTcF Meeting Pre-defined Criteria (Phase 1 and Phase 2)
Hide Description Triplicate 12-lead electrocardiograms (ECGs) were performed approximately 2 minutes apart to determine mean QTc interval (QT interval corrected for heart rate). QT interval was corrected for heart rate using Fridericia's formula to provide QTcF. Absolute values and changes from baseline were summarized according to pre-defined criteria. Baseline was defined as the last evaluation on or prior to the first dose of study treatment.
Time Frame Phase 1: baseline, Days 1, 8 and 15 of Cycle 1, Day 1 of Cycles 2-25, end of treatment (up to 3 years); Phase 2: baseline, Days 1, 8 and 15 of Cycle 1, Day 1 of Cycles 2-5, end of treatment (up to 3 years)
Hide Outcome Measure Data
Hide Analysis Population Description
The safety analysis set included all enrolled participants who received at least 1 dose of PF-06463922.
Arm/Group Title 10 mg QD (Phase 1) 25 mg QD (Phase 1) 50 mg QD (Phase 1) 75 mg QD (Phase 1) 100 mg QD (Phase 1) 150 mg QD (Phase 1) 200 mg QD (Phase 1) 35 mg BID (Phase 1) 75 mg BID (Phase 1) 100 mg BID (Phase 1) EXP-1 (Phase 2) EXP-2 (Phase 2) EXP-3 (Phase 2) EXP-4 (Phase 2) EXP-5 (Phase 2) EXP-6 (Phase 2)
Hide Arm/Group Description:
PF-06463922 10 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 25 mg was orally given once daily (QD) in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. Midazolam 2 mg was orally given QD on Day -7 and Cycle 1 Day 15.
PF-06463922 50 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 75 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 100 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 150 mg was orally given once daily (QD) in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. Midazolam 2 mg was orally given QD on Day -7 and Cycle 1 Day 15.
PF-06463922 200 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 35 mg was orally given twice daily (BID) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 75 mg was orally given twice daily (BID) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
PF-06463922 100 mg was orally given twice daily (BID) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Treatment-naïve participants with advanced ALK-positive NSCLC with or without asymptomatic central nervous system (CNS) metastases were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after only crizotinib therapy were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after crizotinib therapy and 1 or 2 prior regimens of chemotherapy given before or after crizotinib therapy, or participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 1 ALK inhibitor therapy other than crizotinib with or without any number of prior chemotherapy regimens in any disease setting were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 2 prior lines of ALK inhibitor therapies were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 3 prior lines of ALK inhibitor therapies were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participant scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ROS1-positive NSCLC who were treatment naïve or had any number of prior cancer therapies with or without asymptomatic CNS metastases were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Overall Number of Participants Analyzed 3 3 3 12 17 3 3 3 3 4 30 27 60 65 46 47
Measure Type: Count of Participants
Unit of Measure: Participants
QTcF: 450 to <480 ms
1
  33.3%
0
   0.0%
0
   0.0%
2
  16.7%
1
   5.9%
1
  33.3%
0
   0.0%
2
  66.7%
0
   0.0%
0
   0.0%
4
  13.3%
7
  25.9%
11
  18.3%
9
  13.8%
13
  28.3%
8
  17.0%
QTcF: 480 to <500 ms
1
  33.3%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
1
  25.0%
1
   3.3%
1
   3.7%
3
   5.0%
0
   0.0%
1
   2.2%
1
   2.1%
QTcF: >=500 ms
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
1
   1.5%
1
   2.2%
0
   0.0%
QTcF Increase: 30 to <60 ms
0
   0.0%
0
   0.0%
1
  33.3%
3
  25.0%
3
  17.6%
0
   0.0%
0
   0.0%
1
  33.3%
0
   0.0%
0
   0.0%
8
  26.7%
8
  29.6%
17
  28.3%
20
  30.8%
7
  15.2%
11
  23.4%
QTcF: >=60 ms
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
1
  25.0%
0
   0.0%
0
   0.0%
0
   0.0%
1
   1.5%
3
   6.5%
1
   2.1%
65.Secondary Outcome
Title Number of Participants With Suicidal Ideation and Suicidal Behavior (Phase 2)
Hide Description The Columbia Suicide Severity Rating Scale (C-SSRS) was used to analyze participants' suicidal ideation and behavior, and it is a unique, simple and short method of assessing both behavior and ideation that tracks all suicidal events and provides a summary of suicidality. It assesses the lethality of attempts and other features of ideation (frequency, duration, controllability, reasons for ideation and deterrents), all of which are significantly predictive of completed suicide.
Time Frame 3 years
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis set included all enrolled participants who received study treatment, had a baseline test assessment and at least 1 on-study test assessment.
Arm/Group Title EXP-1 (Phase 2) EXP-2 (Phase 2) EXP-3 (Phase 2) EXP-4 (Phase 2) EXP-5 (Phase 2) EXP-6 (Phase 2)
Hide Arm/Group Description:
Treatment-naïve participants with advanced ALK-positive NSCLC with or without asymptomatic central nervous system (CNS) metastases were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after only crizotinib therapy were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after crizotinib therapy and 1 or 2 prior regimens of chemotherapy given before or after crizotinib therapy, or participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 1 ALK inhibitor therapy other than crizotinib with or without any number of prior chemotherapy regimens in any disease setting were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 2 prior lines of ALK inhibitor therapies were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 3 prior lines of ALK inhibitor therapies were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participant scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ROS1-positive NSCLC who were treatment naïve or had any number of prior cancer therapies with or without asymptomatic CNS metastases were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Overall Number of Participants Analyzed 26 24 52 43 30 25
Measure Type: Count of Participants
Unit of Measure: Participants
Suicidal ideation
1
   3.8%
0
   0.0%
2
   3.8%
1
   2.3%
1
   3.3%
2
   8.0%
Suicidal behavior
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
1
   4.0%
66.Secondary Outcome
Title Change From Baseline in Total Scores for Beck Depression Inventory (BDI)-II (Mood Assessment) (Phase 2)
Hide Description The Beck Depression Inventory (BDI)-II is a 21-item self-report scale, with each item rated by participants on a 4-point scale (ranging from 0-3). The scale includes items capturing mood, (loss of pleasure, sadness, and irritability), suicidal ideation, and cognitive signs (punitive thoughts, self-criticism, self-dislike, pessimism, and poor concentration) as well as somatic signs (appetite, sleep, fatigue and libido). Scores were obtained by adding up the total points from the series of answers. Higher total scores indicate more severe depressive symptoms. The standardized cutoffs are as follows: 0-13: minimal depression; 14-19: mild depression; 20-28: moderate depression; 29-63: severe depression.
Time Frame Baseline, Day 1 of Cycles 2-5, Day 1 of every other cycle from Cycle 6, and end of treatment (up to 3 years)
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis set included all enrolled participants who received study treatment, had a baseline test assessment and at least 1 on-study test assessment.
Arm/Group Title EXP-1 (Phase 2) EXP-2 (Phase 2) EXP-3 (Phase 2) EXP-4 (Phase 2) EXP-5 (Phase 2) EXP-6 (Phase 2)
Hide Arm/Group Description:
Treatment-naïve participants with advanced ALK-positive NSCLC with or without asymptomatic central nervous system (CNS) metastases were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after only crizotinib therapy were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after crizotinib therapy and 1 or 2 prior regimens of chemotherapy given before or after crizotinib therapy, or participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 1 ALK inhibitor therapy other than crizotinib with or without any number of prior chemotherapy regimens in any disease setting were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 2 prior lines of ALK inhibitor therapies were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 3 prior lines of ALK inhibitor therapies were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participant scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ROS1-positive NSCLC who were treatment naïve or had any number of prior cancer therapies with or without asymptomatic CNS metastases were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Overall Number of Participants Analyzed 24 24 53 41 28 26
Least Squares Mean (95% Confidence Interval)
Unit of Measure: units on score
Cycle 2 Day 1 Number Analyzed 24 participants 24 participants 53 participants 41 participants 28 participants 26 participants
-2.59
(-4.82 to -0.37)
-3.27
(-5.52 to -1.01)
-2.26
(-3.77 to -0.76)
-2.17
(-3.89 to -0.46)
-1.52
(-3.60 to 0.56)
-2.43
(-4.57 to -0.29)
Cycle 3 Day 1 Number Analyzed 24 participants 24 participants 53 participants 41 participants 28 participants 26 participants
-3.34
(-5.57 to -1.12)
-3.18
(-5.43 to -0.93)
-3.03
(-4.55 to -1.51)
-3.10
(-4.85 to -1.35)
-0.46
(-2.61 to 1.69)
-1.24
(-3.37 to 0.90)
Cycle 4 Day 1 Number Analyzed 24 participants 24 participants 53 participants 41 participants 28 participants 26 participants
-3.84
(-6.07 to -1.62)
-4.10
(-6.38 to -1.82)
-2.59
(-4.14 to -1.05)
-1.95
(-3.72 to -0.19)
-1.19
(-3.38 to 1.01)
-1.94
(-4.12 to 0.24)
Cycle 5 Day 1 Number Analyzed 24 participants 24 participants 53 participants 41 participants 28 participants 26 participants
-4.47
(-6.69 to -2.24)
-3.96
(-6.27 to -1.66)
-2.75
(-4.33 to -1.16)
-3.03
(-4.82 to -1.25)
-1.51
(-3.74 to 0.72)
-1.25
(-3.46 to 0.95)
Cycle 6 Day 1 Number Analyzed 24 participants 24 participants 53 participants 41 participants 28 participants 26 participants
-3.51
(-5.73 to -1.28)
-4.25
(-6.56 to -1.94)
-3.31
(-4.90 to -1.72)
-3.79
(-5.61 to -1.98)
-0.42
(-2.64 to 1.81)
-0.29
(-2.54 to 1.96)
Cycle 8 Day 1 Number Analyzed 24 participants 24 participants 53 participants 41 participants 28 participants 26 participants
-4.17
(-6.41 to -1.92)
-4.86
(-7.23 to -2.50)
-2.26
(-3.86 to -0.66)
-4.06
(-5.90 to -2.22)
-1.09
(-3.34 to 1.17)
0.17
(-2.10 to 2.45)
Cycle 10 Day 1 Number Analyzed 24 participants 24 participants 53 participants 41 participants 28 participants 26 participants
-3.09
(-5.38 to -0.80)
-4.92
(-7.28 to -2.55)
-1.94
(-3.54 to -0.34)
-4.27
(-6.14 to -2.39)
-2.97
(-5.29 to -0.66)
-0.19
(-2.60 to 2.22)
Cycle 12 Day 1 Number Analyzed 24 participants 24 participants 53 participants 41 participants 28 participants 26 participants
-3.95
(-6.30 to -1.61)
-5.60
(-7.97 to -3.24)
-0.72
(-2.40 to 0.95)
-4.80
(-6.83 to -2.77)
-1.94
(-4.29 to 0.42)
-1.40
(-3.81 to 1.01)
Cycle 14 Day 1 Number Analyzed 24 participants 24 participants 53 participants 41 participants 28 participants 26 participants
-3.81
(-6.18 to -1.43)
-5.80
(-8.35 to -3.25)
-2.58
(-4.41 to -0.76)
-4.29
(-6.41 to -2.17)
-1.73
(-4.40 to 0.94)
-0.08
(-2.59 to 2.42)
Cycle 16 Day 1 Number Analyzed 24 participants 24 participants 53 participants 41 participants 28 participants 26 participants
-1.75
(-4.40 to 0.89)
-4.61
(-7.51 to -1.71)
-2.15
(-4.35 to 0.06)
-4.65
(-6.90 to -2.41)
-2.22
(-5.50 to 1.07)
0.03
(-2.65 to 2.71)
Cycle 18 Day 1 Number Analyzed 24 participants 24 participants 53 participants 41 participants 28 participants 26 participants
-4.49
(-7.49 to -1.49)
-7.02
(-10.59 to -3.46)
-1.96
(-4.22 to 0.31)
-2.86
(-5.21 to -0.51)
-1.11
(-8.25 to 6.03)
1.88
(-1.66 to 5.41)
Cycle 20 Day 1 Number Analyzed 24 participants 24 participants 53 participants 41 participants 0 participants 26 participants
-5.01
(-8.55 to -1.46)
-5.17
(-9.06 to -1.29)
-1.82
(-4.70 to 1.06)
-3.63
(-6.31 to -0.95)
1.88
(-1.66 to 5.41)
Cycle 22 Day 1 Number Analyzed 24 participants 24 participants 53 participants 41 participants 0 participants 26 participants
-2.93
(-6.79 to 0.94)
-4.63
(-9.00 to -0.26)
-2.36
(-5.68 to 0.96)
-5.50
(-8.87 to -2.12)
-2.39
(-6.73 to 1.94)
Cycle 24 Day 1 Number Analyzed 24 participants 24 participants 53 participants 41 participants 0 participants 26 participants
-7.31
(-11.66 to -2.96)
-5.63
(-10.00 to -1.26)
-2.88
(-7.04 to 1.28)
-3.89
(-8.10 to 0.32)
2.27
(-2.06 to 6.61)
Cycle 26 Day 1 Number Analyzed 24 participants 0 participants 53 participants 41 participants 0 participants 0 participants
-5.50
(-10.67 to -0.33)
-3.03
(-10.01 to 3.95)
-4.30
(-11.31 to 2.70)
End of treatment Number Analyzed 24 participants 24 participants 53 participants 41 participants 28 participants 26 participants
-4.77
(-9.23 to -0.32)
-0.73
(-5.61 to 4.15)
-2.55
(-5.28 to 0.18)
-3.22
(-5.49 to -0.95)
0.74
(-2.70 to 4.17)
-2.08
(-5.65 to 1.50)
67.Secondary Outcome
Title Change From Baseline in Total Scores for Detection Test (Cognitive Function Assessment) (Phase 2)
Hide Description The Detection Test is a measure of psychomotor function and uses a well validated simple reaction time paradigm with playing card stimuli. In this test, the on-screen instructions ask: "Has the card turned over?". A playing card is presented face down in the center of the screen. The card flips over so it is face up. As soon as the card flips over the participant must press "Yes". The participant is encouraged to work as quickly as they can and be as accurate as possible. The speed and accuracy of each response are recorded and mean of the log10 transformed reaction times for correct responses is calculated. Lower values of least square mean change from baseline indicate performance decline. Upper limit of 95% confidence interval of -0.00 or lower indicate statistically significant decline of performance over baseline at that cycle.
Time Frame Baseline, Day 1 of Cycles 2-5, Day 1 of every other cycle from Cycle 6, and end of treatment (up to 3 years)
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis set included all enrolled participants who received study treatment, had a baseline test assessment and at least 1 on-study test assessment.
Arm/Group Title EXP-1 (Phase 2) EXP-2 (Phase 2) EXP-3 (Phase 2) EXP-4 (Phase 2) EXP-5 (Phase 2) EXP-6 (Phase 2)
Hide Arm/Group Description:
Treatment-naïve participants with advanced ALK-positive NSCLC with or without asymptomatic central nervous system (CNS) metastases were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after only crizotinib therapy were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after crizotinib therapy and 1 or 2 prior regimens of chemotherapy given before or after crizotinib therapy, or participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 1 ALK inhibitor therapy other than crizotinib with or without any number of prior chemotherapy regimens in any disease setting were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 2 prior lines of ALK inhibitor therapies were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 3 prior lines of ALK inhibitor therapies were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participant scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ROS1-positive NSCLC who were treatment naïve or had any number of prior cancer therapies with or without asymptomatic CNS metastases were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Overall Number of Participants Analyzed 24 26 50 46 38 29
Least Squares Mean (95% Confidence Interval)
Unit of Measure: units on a score
Cycle 2 Day 1 Number Analyzed 24 participants 26 participants 50 participants 46 participants 38 participants 29 participants
0.01
(-0.04 to 0.05)
0.04
(-0.01 to 0.08)
-0.01
(-0.04 to 0.02)
0.02
(-0.01 to 0.05)
-0.02
(-0.05 to 0.02)
0.01
(-0.03 to 0.05)
Cycle 3 Day 1 Number Analyzed 24 participants 26 participants 50 participants 46 participants 38 participants 29 participants
-0.01
(-0.05 to 0.03)
0.01
(-0.03 to 0.05)
0.01
(-0.02 to 0.04)
-0.01
(-0.04 to 0.02)
-0.01
(-0.05 to 0.02)
-0.01
(-0.05 to 0.03)
Cycle 4 Day 1 Number Analyzed 24 participants 26 participants 50 participants 46 participants 38 participants 29 participants
0.03
(-0.02 to 0.07)
0.00
(-0.04 to 0.04)
-0.03
(-0.06 to 0.00)
-0.02
(-0.05 to 0.01)
-0.04
(-0.07 to -0.00)
-0.01
(-0.06 to 0.03)
Cycle 5 Day 1 Number Analyzed 24 participants 26 participants 50 participants 46 participants 38 participants 29 participants
-0.01
(-0.05 to 0.03)
-0.01
(-0.06 to 0.03)
-0.00
(-0.03 to 0.03)
0.00
(-0.03 to 0.03)
-0.04
(-0.08 to -0.01)
-0.04
(-0.08 to 0.00)
Cycle 6 Day 1 Number Analyzed 24 participants 26 participants 50 participants 46 participants 38 participants 29 participants
-0.03
(-0.07 to 0.01)
0.01
(-0.03 to 0.06)
-0.02
(-0.05 to 0.01)
-0.00
(-0.04 to 0.03)
-0.01
(-0.05 to 0.02)
-0.02
(-0.07 to 0.02)
Cycle 8 Day 1 Number Analyzed 24 participants 26 participants 50 participants 46 participants 38 participants 29 participants
-0.02
(-0.06 to 0.02)
0.00
(-0.04 to 0.05)
-0.02
(-0.05 to 0.01)
-0.03
(-0.06 to 0.01)
-0.04
(-0.07 to 0.00)
0.00
(-0.04 to 0.05)
Cycle 10 Day 1 Number Analyzed 24 participants 26 participants 50 participants 46 participants 38 participants 29 participants
-0.02
(-0.06 to 0.02)
0.03
(-0.01 to 0.08)
-0.02
(-0.06 to 0.01)
-0.01
(-0.05 to 0.02)
-0.05
(-0.09 to -0.01)
-0.04
(-0.08 to 0.01)
Cycle 12 Day 1 Number Analyzed 24 participants 26 participants 50 participants 46 participants 38 participants 29 participants
-0.04
(-0.08 to 0.01)
-0.00
(-0.05 to 0.04)
-0.02
(-0.06 to 0.02)
-0.03
(-0.06 to 0.01)
-0.08
(-0.13 to -0.04)
-0.01
(-0.05 to 0.04)
Cycle 14 Day 1 Number Analyzed 24 participants 26 participants 50 participants 46 participants 38 participants 29 participants
0.02
(-0.04 to 0.07)
0.02
(-0.03 to 0.08)
-0.05
(-0.09 to -0.01)
-0.04
(-0.08 to -0.00)
-0.02
(-0.07 to 0.04)
0.01
(-0.05 to 0.06)
Cycle 16 Day 1 Number Analyzed 24 participants 26 participants 50 participants 46 participants 38 participants 29 participants
-0.03
(-0.09 to 0.03)
0.01
(-0.05 to 0.07)
0.02
(-0.03 to 0.07)
-0.03
(-0.08 to 0.01)
-0.04
(-0.14 to 0.06)
-0.01
(-0.07 to 0.06)
Cycle 18 Day 1 Number Analyzed 24 participants 26 participants 50 participants 46 participants 38 participants 29 participants
0.09
(0.01 to 0.18)
-0.02
(-0.09 to 0.05)
-0.03
(-0.09 to 0.02)
-0.06
(-0.11 to -0.01)
-0.09
(-0.23 to 0.04)
-0.01
(-0.08 to 0.05)
Cycle 20 Day 1 Number Analyzed 24 participants 26 participants 50 participants 46 participants 0 participants 29 participants
0.07
(-0.03 to 0.17)
0.02
(-0.06 to 0.09)
0.01
(-0.06 to 0.08)
-0.09
(-0.16 to -0.03)
-0.03
(-0.11 to 0.04)
Cycle 22 Day 1 Number Analyzed 24 participants 26 participants 50 participants 46 participants 0 participants 29 participants
-0.02
(-0.12 to 0.08)
-0.02
(-0.10 to 0.07)
0.00
(-0.08 to 0.08)
-0.08
(-0.16 to 0.00)
-0.05
(-0.13 to 0.03)
Cycle 24 Day 1 Number Analyzed 24 participants 0 participants 0 participants 46 participants 0 participants 0 participants
0.03
(-0.11 to 0.16)
-0.06
(-0.20 to 0.07)
End of treatment Number Analyzed 24 participants 26 participants 50 participants 46 participants 38 participants 29 participants
-0.04
(-0.13 to 0.04)
-0.01
(-0.10 to 0.08)
-0.02
(-0.08 to 0.04)
-0.05
(-0.10 to -0.00)
-0.07
(-0.14 to -0.01)
-0.05
(-0.12 to 0.03)
68.Secondary Outcome
Title Change From Baseline in Total Scores for Identification Test (Cognitive Function Assessment) (Phase 2)
Hide Description The Identification Test is a measure of visual attention and uses a well validated choice reaction time paradigm with playing card stimuli. In this task, the playing cards are all red or black jokers. The on-screen instructions ask: "Is the card red?". A playing card is presented face down in the center of the screen. The card flips over so it is face up. As soon as it flips over the participant must decide whether the card is red or not. If it is red the participant should press "Yes", and if it is not red the participant should press "No". The participant is encouraged to work as quickly and accurately as possible. The speed and accuracy of each response are recorded and mean of the log10 transformed reaction times for correct responses is calculated. Lower values of least square mean change from baseline indicate performance decline. Upper limit of 95% confidence interval of -0.00 or lower indicate statistically significant decline of performance over baseline at that cycle.
Time Frame Baseline, Day 1 of Cycles 2-5, Day 1 of every other cycle from Cycle 6, and end of treatment (up to 3 years)
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis set included all enrolled participants who received study treatment, had a baseline test assessment and at least 1 on-study test assessment.
Arm/Group Title EXP-1 (Phase 2) EXP-2 (Phase 2) EXP-3 (Phase 2) EXP-4 (Phase 2) EXP-5 (Phase 2) EXP-6 (Phase 2)
Hide Arm/Group Description:
Treatment-naïve participants with advanced ALK-positive NSCLC with or without asymptomatic central nervous system (CNS) metastases were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after only crizotinib therapy were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after crizotinib therapy and 1 or 2 prior regimens of chemotherapy given before or after crizotinib therapy, or participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 1 ALK inhibitor therapy other than crizotinib with or without any number of prior chemotherapy regimens in any disease setting were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 2 prior lines of ALK inhibitor therapies were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 3 prior lines of ALK inhibitor therapies were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participant scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ROS1-positive NSCLC who were treatment naïve or had any number of prior cancer therapies with or without asymptomatic CNS metastases were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Overall Number of Participants Analyzed 24 26 50 46 38 29
Least Squares Mean (95% Confidence Interval)
Unit of Measure: units on a score
Cycle 2 Day 1 Number Analyzed 24 participants 26 participants 50 participants 46 participants 38 participants 29 participants
-0.02
(-0.05 to 0.01)
-0.02
(-0.05 to 0.01)
-0.01
(-0.03 to 0.00)
-0.01
(-0.03 to 0.01)
-0.02
(-0.04 to 0.01)
-0.01
(-0.04 to 0.02)
Cycle 3 Day 1 Number Analyzed 24 participants 26 participants 50 participants 46 participants 38 participants 29 participants
-0.01
(-0.04 to 0.02)
-0.01
(-0.04 to 0.02)
-0.02
(-0.04 to 0.00)
-0.02
(-0.04 to 0.00)
-0.02
(-0.05 to 0.00)
-0.01
(-0.04 to 0.02)
Cycle 4 Day 1 Number Analyzed 24 participants 26 participants 50 participants 46 participants 38 participants 29 participants
-0.02
(-0.05 to 0.01)
-0.01
(-0.04 to 0.01)
-0.02
(-0.04 to 0.00)
-0.03
(-0.05 to -0.01)
-0.05
(-0.08 to -0.03)
-0.02
(-0.04 to 0.01)
Cycle 5 Day 1 Number Analyzed 24 participants 26 participants 50 participants 46 participants 38 participants 29 participants
-0.03
(-0.06 to -0.00)
-0.02
(-0.05 to 0.01)
-0.03
(-0.05 to -0.00)
-0.02
(-0.04 to 0.01)
-0.05
(-0.07 to -0.02)
-0.02
(-0.05 to 0.00)
Cycle 6 Day 1 Number Analyzed 24 participants 26 participants 50 participants 46 participants 38 participants 29 participants
-0.04
(-0.07 to -0.01)
-0.02
(-0.05 to 0.01)
-0.02
(-0.04 to 0.00)
-0.03
(-0.06 to -0.01)
-0.03
(-0.06 to -0.01)
-0.03
(-0.06 to -0.00)
Cycle 8 Day 1 Number Analyzed 24 participants 26 participants 50 participants 46 participants 38 participants 29 participants
-0.03
(-0.06 to -0.00)
-0.02
(-0.05 to 0.01)
-0.03
(-0.05 to -0.01)
-0.03
(-0.05 to -0.01)
-0.05
(-0.07 to -0.02)
-0.03
(-0.06 to 0.00)
Cycle 10 Day 1 Number Analyzed 24 participants 26 participants 50 participants 46 participants 38 participants 29 participants
-0.03
(-0.06 to 0.00)
-0.01
(-0.04 to 0.02)
-0.03
(-0.05 to -0.01)
-0.02
(-0.05 to 0.00)
-0.05
(-0.08 to -0.02)
-0.03
(-0.06 to 0.00)
Cycle 12 Day 1 Number Analyzed 24 participants 26 participants 50 participants 46 participants 38 participants 29 participants
-0.05
(-0.08 to -0.02)
-0.04
(-0.07 to -0.01)
-0.04
(-0.06 to -0.01)
-0.04
(-0.07 to -0.01)
-0.06
(-0.09 to -0.03)
-0.03
(-0.06 to 0.00)
Cycle 14 Day 1 Number Analyzed 24 participants 26 participants 50 participants 46 participants 38 participants 29 participants
-0.04
(-0.08 to 0.00)
-0.04
(-0.07 to -0.00)
-0.03
(-0.06 to -0.00)
-0.04
(-0.07 to -0.01)
-0.04
(-0.08 to -0.00)
-0.02
(-0.06 to 0.02)
Cycle 16 Day 1 Number Analyzed 24 participants 26 participants 50 participants 46 participants 38 participants 29 participants
-0.09
(-0.13 to -0.05)
-0.00
(-0.04 to 0.04)
-0.03
(-0.07 to 0.01)
-0.03
(-0.06 to 0.01)
-0.07
(-0.13 to 0.00)
-0.06
(-0.10 to -0.01)
Cycle 18 Day 1 Number Analyzed 24 participants 26 participants 50 participants 46 participants 38 participants 29 participants
-0.01
(-0.06 to 0.05)
-0.05
(-0.09 to 0.00)
-0.04
(-0.08 to 0.00)
-0.07
(-0.10 to -0.03)
-0.19
(-0.29 to -0.09)
-0.01
(-0.05 to 0.04)
Cycle 20 Day 1 Number Analyzed 24 participants 26 participants 50 participants 46 participants 0 participants 29 participants
-0.03
(-0.10 to 0.04)
-0.01
(-0.06 to 0.04)
-0.03
(-0.08 to 0.02)
-0.10
(-0.15 to -0.06)
-0.03
(-0.08 to 0.02)
Cycle 22 Day 1 Number Analyzed 24 participants 26 participants 50 participants 46 participants 0 participants 29 participants
0.04
(-0.03 to 0.11)
-0.01
(-0.07 to 0.05)
-0.06
(-0.11 to 0.00)
-0.05
(-0.11 to 0.00)
-0.08
(-0.14 to -0.03)
Cycle 24 Day 1 Number Analyzed 24 participants 0 participants 0 participants 46 participants 0 participants 0 participants
0.08
(-0.01 to 0.18)
-0.06
(-0.15 to 0.04)
End of treatment Number Analyzed 24 participants 26 participants 50 participants 46 participants 38 participants 29 participants
-0.07
(-0.13 to -0.02)
-0.03
(-0.10 to 0.03)
-0.02
(-0.06 to 0.02)
-0.03
(-0.06 to 0.01)
-0.09
(-0.14 to -0.05)
-0.06
(-0.11 to -0.01)
69.Secondary Outcome
Title Change From Baseline in Total Scores for One Back Test (Cognitive Function Assessment) (Phase 2)
Hide Description The One Back Test is a measure of working memory and uses a well validated n back paradigm with playing cards. In this task, the on-screen instructions ask: "Is the previous card the same?". A playing card is presented in the center of the screen. The participant must decide whether the card is the same as the previous card. If it is the same the participant should press "Yes", and if not press "No". The participant is encouraged to work as quickly and accurately as possible. The speed and accuracy of each response are recorded, mean of the log10 transformed reaction times for correct responses is used to demonstrate speed of performance, and the arcsine transformation of the square root of the proportion of correct responses is used to demonstrate accuracy. Lower values of least square mean change from baseline indicate performance decline. Upper limit of 95% confidence interval of -0.00 or lower indicate statistically significant decline of performance over baseline at that cycle.
Time Frame Baseline, Day 1 of Cycles 2-5, Day 1 of every other cycle from Cycle 6, and end of treatment (up to 3 years)
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis set included all enrolled participants who received study treatment, had a baseline test assessment and at least 1 on-study test assessment.
Arm/Group Title EXP-1 (Phase 2) EXP-2 (Phase 2) EXP-3 (Phase 2) EXP-4 (Phase 2) EXP-5 (Phase 2) EXP-6 (Phase 2)
Hide Arm/Group Description:
Treatment-naïve participants with advanced ALK-positive NSCLC with or without asymptomatic central nervous system (CNS) metastases were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after only crizotinib therapy were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after crizotinib therapy and 1 or 2 prior regimens of chemotherapy given before or after crizotinib therapy, or participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 1 ALK inhibitor therapy other than crizotinib with or without any number of prior chemotherapy regimens in any disease setting were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 2 prior lines of ALK inhibitor therapies were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 3 prior lines of ALK inhibitor therapies were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participant scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ROS1-positive NSCLC who were treatment naïve or had any number of prior cancer therapies with or without asymptomatic CNS metastases were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Overall Number of Participants Analyzed 24 26 50 46 38 29
Least Squares Mean (95% Confidence Interval)
Unit of Measure: units on a score
Cycle 2 Day 1 Number Analyzed 24 participants 26 participants 50 participants 46 participants 38 participants 29 participants
0.01
(-0.02 to 0.05)
0.02
(-0.01 to 0.05)
0.02
(0.00 to 0.05)
0.01
(-0.01 to 0.04)
0.02
(-0.01 to 0.05)
0.01
(-0.02 to 0.04)
Cycle 3 Day 1 Number Analyzed 24 participants 26 participants 50 participants 46 participants 38 participants 29 participants
0.06
(0.02 to 0.09)
0.01
(-0.02 to 0.05)
0.01
(-0.01 to 0.04)
0.01
(-0.02 to 0.03)
-0.01
(-0.04 to 0.02)
-0.00
(-0.04 to 0.03)
Cycle 4 Day 1 Number Analyzed 24 participants 26 participants 50 participants 46 participants 38 participants 29 participants
0.04
(0.01 to 0.08)
0.03
(-0.00 to 0.06)
0.02
(-0.01 to 0.04)
-0.01
(-0.04 to 0.01)
-0.02
(-0.05 to 0.01)
-0.01
(-0.05 to 0.02)
Cycle 5 Day 1 Number Analyzed 24 participants 26 participants 50 participants 46 participants 38 participants 29 participants
0.02
(-0.01 to 0.06)
0.03
(-0.00 to 0.07)
0.03
(0.00 to 0.05)
-0.01
(-0.04 to 0.02)
-0.02
(-0.05 to 0.01)
0.02
(-0.01 to 0.05)
Cycle 6 Day 1 Number Analyzed 24 participants 26 participants 50 participants 46 participants 38 participants 29 participants
0.03
(-0.01 to 0.06)
0.03
(-0.00 to 0.07)
0.03
(0.01 to 0.06)
0.01
(-0.02 to 0.04)
-0.00
(-0.03 to 0.03)
0.01
(-0.03 to 0.04)
Cycle 8 Day 1 Number Analyzed 24 participants 26 participants 50 participants 46 participants 38 participants 29 participants
0.03
(-0.01 to 0.06)
0.02
(-0.02 to 0.06)
0.03
(0.00 to 0.05)
0.01
(-0.02 to 0.03)
-0.01
(-0.04 to 0.02)
0.01
(-0.02 to 0.05)
Cycle 10 Day 1 Number Analyzed 24 participants 26 participants 50 participants 46 participants 38 participants 29 participants
0.07
(0.03 to 0.11)
0.03
(-0.00 to 0.07)
0.03
(0.00 to 0.05)
0.02
(-0.01 to 0.05)
-0.01
(-0.05 to 0.02)
0.01
(-0.02 to 0.05)
Cycle 12 Day 1 Number Analyzed 24 participants 26 participants 50 participants 46 participants 38 participants 29 participants
0.05
(0.01 to 0.08)
0.01
(-0.03 to 0.05)
0.02
(-0.01 to 0.05)
0.01
(-0.02 to 0.04)
-0.00
(-0.04 to 0.03)
0.03
(-0.01 to 0.07)
Cycle 14 Day 1 Number Analyzed 24 participants 26 participants 50 participants 46 participants 38 participants 29 participants
0.00
(-0.05 to 0.05)
0.03
(-0.01 to 0.07)
0.03
(-0.01 to 0.07)
-0.00
(-0.04 to 0.03)
0.01
(-0.04 to 0.06)
0.02
(-0.03 to 0.07)
Cycle 16 Day 1 Number Analyzed 24 participants 26 participants 50 participants 46 participants 38 participants 29 participants
0.03
(-0.03 to 0.08)
0.05
(-0.01 to 0.10)
0.05
(0.00 to 0.09)
-0.02
(-0.05 to 0.02)
-0.01
(-0.10 to 0.08)
0.03
(-0.03 to 0.08)
Cycle 18 Day 1 Number Analyzed 24 participants 26 participants 50 participants 46 participants 38 participants 29 participants
0.02
(-0.06 to 0.09)
0.01
(-0.04 to 0.07)
0.06
(0.02 to 0.11)
-0.02
(-0.06 to 0.03)
-0.18
(-0.30 to -0.06)
0.05
(-0.01 to 0.10)
Cycle 20 Day 1 Number Analyzed 24 participants 26 participants 50 participants 46 participants 0 participants 29 participants
-0.06
(-0.15 to 0.03)
0.07
(0.00 to 0.13)
0.02
(-0.05 to 0.08)
-0.01
(-0.06 to 0.05)
0.02
(-0.04 to 0.09)
Cycle 22 Day 1 Number Analyzed 24 participants 26 participants 50 participants 46 participants 0 participants 29 participants
0.02
(-0.07 to 0.11)
0.05
(-0.02 to 0.12)
0.04
(-0.03 to 0.11)
-0.07
(-0.14 to 0.00)
0.03
(-0.04 to 0.11)
Cycle 24 Day 1 Number Analyzed 24 participants 0 participants 0 participants 46 participants 0 participants 0 participants
0.09
(-0.03 to 0.21)
0.01
(-0.11 to 0.13)
End of treatment Number Analyzed 24 participants 26 participants 50 participants 46 participants 38 participants 29 participants
-0.03
(-0.10 to 0.05)
0.03
(-0.05 to 0.11)
0.03
(-0.02 to 0.07)
0.01
(-0.04 to 0.05)
-0.03
(-0.08 to 0.02)
0.02
(-0.05 to 0.08)
70.Secondary Outcome
Title Change From Baseline in Total Scores for International Shopping List Test (Cognitive Function Assessment) (Phase 2)
Hide Description The International Shopping List task is a measure of verbal learning and uses a well validated list learning paradigm administered using a computer. High frequencies, high imagery, concrete nouns (items from a shopping list) were read to the participant at the rate of one word every 2 seconds. Once all 12 words had been read, the participant was asked to recall as many of the words as quickly as possible. The words recalled by the participant were marked on the computer screen. When the participant could recall no more words, the same list was read again. The words recalled by the participant were recorded. This was then repeated a third time. Total number of correct responses on 3 consecutive trials at a single assessment was recorded. Lower values of least square mean change from baseline indicate performance decline. Upper limit of 95% confidence interval of -0.00 or lower indicate statistically significant decline of performance over baseline at that cycle.
Time Frame Baseline, Day 1 of Cycles 2-5, Day 1 of every other cycle from Cycle 6, and end of treatment (up to 3 years)
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis set included all enrolled participants who received study treatment, had a baseline test assessment and at least 1 on-study test assessment.
Arm/Group Title EXP-1 (Phase 2) EXP-2 (Phase 2) EXP-3 (Phase 2) EXP-4 (Phase 2) EXP-5 (Phase 2) EXP-6 (Phase 2)
Hide Arm/Group Description:
Treatment-naïve participants with advanced ALK-positive NSCLC with or without asymptomatic central nervous system (CNS) metastases were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after only crizotinib therapy were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after crizotinib therapy and 1 or 2 prior regimens of chemotherapy given before or after crizotinib therapy, or participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 1 ALK inhibitor therapy other than crizotinib with or without any number of prior chemotherapy regimens in any disease setting were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 2 prior lines of ALK inhibitor therapies were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 3 prior lines of ALK inhibitor therapies were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participant scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ROS1-positive NSCLC who were treatment naïve or had any number of prior cancer therapies with or without asymptomatic CNS metastases were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Overall Number of Participants Analyzed 24 26 50 46 38 29
Least Squares Mean (95% Confidence Interval)
Unit of Measure: units on a score
Cycle 2 Day 1 Number Analyzed 24 participants 26 participants 50 participants 46 participants 38 participants 29 participants
-0.02
(-1.89 to 1.84)
-1.13
(-2.90 to 0.64)
0.25
(-1.01 to 1.52)
-0.45
(-1.76 to 0.86)
0.96
(-0.50 to 2.43)
0.16
(-1.51 to 1.83)
Cycle 3 Day 1 Number Analyzed 24 participants 26 participants 50 participants 46 participants 38 participants 29 participants
0.19
(-1.66 to 2.03)
-0.81
(-2.58 to 0.96)
0.14
(-1.15 to 1.43)
-1.04
(-2.36 to 0.29)
-0.08
(-1.59 to 1.44)
-0.56
(-2.21 to 1.09)
Cycle 4 Day 1 Number Analyzed 24 participants 26 participants 50 participants 46 participants 38 participants 29 participants
0.58
(-1.26 to 2.42)
0.26
(-1.54 to 2.05)
0.28
(-1.05 to 1.61)
0.24
(-1.12 to 1.60)
1.30
(-0.26 to 2.86)
-0.87
(-2.59 to 0.84)
Cycle 5 Day 1 Number Analyzed 24 participants 26 participants 50 participants 46 participants 38 participants 29 participants
1.30
(-0.51 to 3.12)
-0.66
(-2.53 to 1.21)
0.59
(-0.77 to 1.95)
-0.94
(-2.33 to 0.45)
1.23
(-0.36 to 2.82)
0.74
(-0.97 to 2.45)
Cycle 6 Day 1 Number Analyzed 24 participants 26 participants 50 participants 46 participants 38 participants 29 participants
0.18
(-1.64 to 1.99)
0.81
(-1.06 to 2.68)
0.50
(-0.87 to 1.87)
0.08
(-1.31 to 1.47)
0.82
(-0.83 to 2.46)
-0.51
(-2.31 to 1.29)
Cycle 8 Day 1 Number Analyzed 24 participants 26 participants 50 participants 46 participants 38 participants 29 participants
0.84
(-1.00 to 2.68)
0.60
(-1.30 to 2.50)
1.69
(0.29 to 3.08)
0.15
(-1.27 to 1.57)
0.44
(-1.23 to 2.11)
1.70
(-0.11 to 3.50)
Cycle 10 Day 1 Number Analyzed 24 participants 26 participants 50 participants 46 participants 38 participants 29 participants
0.26
(-1.68 to 2.21)
2.59
(0.65 to 4.52)
0.86
(-0.56 to 2.27)
0.13
(-1.46 to 1.72)
2.29
(0.53 to 4.05)
0.97
(-0.99 to 2.93)
Cycle 12 Day 1 Number Analyzed 24 participants 26 participants 50 participants 46 participants 38 participants 29 participants
2.87
(0.86 to 4.88)
0.02
(-2.06 to 2.10)
0.11
(-1.52 to 1.73)
0.69
(-0.98 to 2.35)
1.74
(-0.25 to 3.72)
3.10
(1.06 to 5.14)
Cycle 14 Day 1 Number Analyzed 24 participants 26 participants 50 participants 46 participants 38 participants 29 participants
1.91
(-0.71 to 4.53)
1.46
(-0.85 to 3.78)
2.27
(0.36 to 4.17)
0.94
(-0.86 to 2.73)
-4.43
(-7.11 to -1.75)
2.67
(0.09 to 5.25)
Cycle 16 Day 1 Number Analyzed 24 participants 26 participants 50 participants 46 participants 38 participants 29 participants
4.52
(1.58 to 7.46)
0.87
(-2.06 to 3.79)
1.36
(-1.11 to 3.84)
1.04
(-0.99 to 3.07)
3.46
(-1.26 to 8.18)
1.97
(-0.93 to 4.87)
Cycle 18 Day 1 Number Analyzed 24 participants 26 participants 50 participants 46 participants 38 participants 29 participants
4.77
(0.82 to 8.73)
0.66
(-2.50 to 3.81)
-0.27
(-2.89 to 2.36)
-0.52
(-2.77 to 1.73)
-0.35
(-6.90 to 6.21)
3.13
(0.00 to 6.27)
Cycle 20 Day 1 Number Analyzed 24 participants 26 participants 50 participants 46 participants 0 participants 29 participants
-2.72
(-7.47 to 2.03)
-1.44
(-4.91 to 2.03)
0.56
(-2.81 to 3.92)
1.20
(-1.84 to 4.24)
0.56
(-2.89 to 4.01)
Cycle 22 Day 1 Number Analyzed 24 participants 26 participants 50 participants 46 participants 0 participants 29 participants
-5.72
(-10.47 to -0.97)
-0.28
(-4.22 to 3.66)
2.17
(-1.68 to 6.01)
-0.36
(-4.21 to 3.48)
3.99
(0.07 to 7.91)
Cycle 24 Day 1 Number Analyzed 24 participants 0 participants 0 participants 46 participants 0 participants 0 participants
-8.49
(-15.06 to -1.92)
-3.35
(-9.86 to 3.16)
End of treatment Number Analyzed 24 participants 26 participants 50 participants 46 participants 38 participants 29 participants
1.02
(-2.99 to 5.04)
-1.62
(-5.95 to 2.71)
0.80
(-1.80 to 3.40)
-0.27
(-2.47 to 1.92)
2.37
(-0.54 to 5.27)
-0.60
(-4.09 to 2.89)
71.Secondary Outcome
Title Change From Baseline in Total Scores for International Shopping List Test-Delayed Recall (Cognitive Function Assessment) (Phase 2)
Hide Description This test was performed in the same way as the International Shopping List Test, with the exception that, the delayed recall condition required the participant to recall the words from the list 15 30 minutes later without having the list read again. During the recognition condition, the qualified personnel read a shopping list item that may or may not have been on the original list and the participant had to respond either affirmatively (if the item was on the original list) or negatively (if it was not). Total number of correct responses made in remembering the word list after a delay was recorded. Lower values of least square mean change from baseline indicate performance decline. Upper limit of 95% confidence interval of -0.00 or lower indicate statistically significant decline of performance over baseline at that cycle.
Time Frame Baseline, Day 1 of Cycles 2-5, Day 1 of every other cycle from Cycle 6, and end of treatment (up to 3 years)
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis set included all enrolled participants who received study treatment, had a baseline test assessment and at least 1 on-study test assessment.
Arm/Group Title EXP-1 (Phase 2) EXP-2 (Phase 2) EXP-3 (Phase 2) EXP-4 (Phase 2) EXP-5 (Phase 2) EXP-6 (Phase 2)
Hide Arm/Group Description:
Treatment-naïve participants with advanced ALK-positive NSCLC with or without asymptomatic central nervous system (CNS) metastases were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after only crizotinib therapy were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after crizotinib therapy and 1 or 2 prior regimens of chemotherapy given before or after crizotinib therapy, or participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 1 ALK inhibitor therapy other than crizotinib with or without any number of prior chemotherapy regimens in any disease setting were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 2 prior lines of ALK inhibitor therapies were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 3 prior lines of ALK inhibitor therapies were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participant scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Participants with advanced ROS1-positive NSCLC who were treatment naïve or had any number of prior cancer therapies with or without asymptomatic CNS metastases were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.
Overall Number of Participants Analyzed 24 26 50 46 38 29
Least Squares Mean (95% Confidence Interval)
Unit of Measure: units on a score
Cycle 2 Day 1 Number Analyzed 24 participants 26 participants 50 participants 46 participants 38 participants 29 participants
0.10
(-0.85 to 1.06)
-0.84
(-1.76 to 0.08)
-0.12
(-0.77 to 0.53)
-0.59
(-1.28 to 0.09)
-0.22
(-0.96 to 0.53)
-0.25
(-1.11 to 0.62)
Cycle 3 Day 1 Number Analyzed 24 participants 26 participants 50 participants 46 participants 38 participants 29 participants
-0.33
(-1.28 to 0.62)
-1.32
(-2.24 to -0.40)
-0.14
(-0.81 to 0.52)
-0.77
(-1.46 to -0.07)
-0.87
(-1.64 to -0.10)
-0.30
(-1.15 to 0.56)
Cycle 4 Day 1 Number Analyzed 24 participants 26 participants 50 participants 46 participants 38 participants 29 participants
-0.44
(-1.38 to 0.50)
-0.91
(-1.86 to 0.03)
0.03
(-0.66 to 0.72)
-0.25
(-0.97 to 0.47)
-0.02
(-0.82 to 0.78)
-1.06
(-1.95 to -0.18)
Cycle 5 Day 1 Number Analyzed 24 participants 26 participants 50 participants 46 participants 38 participants 29 participants
-0.35
(-1.29 to 0.59)
-0.57
(-1.54 to 0.40)
0.02
(-0.69 to 0.73)
-0.46
(-1.20 to 0.27)
0.09
(-0.74 to 0.92)
0.17
(-0.72 to 1.05)
Cycle 6 Day 1 Number Analyzed 24 participants 26 participants 50 participants 46 participants 38 participants 29 participants
0.48
(-0.46 to 1.42)
-0.38
(-1.35 to 0.59)
0.12
(-0.59 to 0.84)
-0.22
(-0.95 to 0.52)
0.30
(-0.55 to 1.15)
-0.28
(-1.21 to 0.66)
Cycle 8 Day 1 Number Analyzed 24 participants 26 participants 50 participants 46 participants 38 participants 29 participants
0.56
(-0.38 to 1.50)
-0.24
(-1.23 to 0.75)
0.02
(-0.70 to 0.74)
-0.49
(-1.24 to 0.25)
-1.08
(-1.94 to -0.22)
-0.16
(-1.10 to 0.77)
Cycle 10 Day 1 Number Analyzed 24 participants 26 participants 50 participants 46 participants 38 participants 29 participants
0.29
(-0.74 to 1.31)
0.80
(-0.22 to 1.82)
0.54
(-0.20 to 1.28)
0.23
(-0.61 to 1.08)
0.25
(-0.67 to 1.16)
-0.00
(-1.02 to 1.02)
Cycle 12 Day 1 Number Analyzed 24 participants 26 participants 50 participants 46 participants 38 participants 29 participants
0.90
(-0.15 to 1.95)
0.13
(-0.95 to 1.21)
0.22
(-0.63 to 1.07)
0.19
(-0.70 to 1.07)
0.60
(-0.43 to 1.64)
0.42
(-0.64 to 1.49)
Cycle 14 Day 1 Number Analyzed 24 participants 26 participants 50 participants 46 participants 38 participants 29 participants
0.38
(-0.99 to 1.75)
0.06
(-1.15 to 1.27)
1.06
(0.06 to 2.06)
0.11
(-0.85 to 1.07)
-1.80
(-3.31 to -0.30)
0.35
(-1.00 to 1.71)
Cycle 16 Day 1 Number Analyzed 24 participants 26 participants 50 participants 46 participants 38 participants 29 participants
0.89
(-0.66 to 2.43)
0.52
(-1.02 to 2.05)
0.68
(-0.62 to 1.98)
-0.12
(-1.22 to 0.98)
0.40
(-2.09 to 2.88)
-0.22
(-1.75 to 1.30)
Cycle 18 Day 1 Number Analyzed 24 participants 26 participants 50 participants 46 participants 38 participants 29 participants
1.06
(-1.02 to 3.14)
0.68
(-0.98 to 2.34)
0.38
(-1.00 to 1.76)
-0.24
(-1.54 to 1.07)
-0.39
(-3.85 to 3.07)
-0.33
(-1.97 to 1.32)
Cycle 20 Day 1 Number Analyzed 24 participants 26 participants 50 participants 46 participants 0 participants 29 participants
-1.22
(-3.73 to 1.28)
0.16
(-1.67 to 1.98)
-0.24
(-2.01 to 1.53)
-0.18
(-1.78 to 1.43)
-0.70
(-2.52 to 1.11)
Cycle 22 Day 1 Number Analyzed 24 participants 26 participants 50 participants 46 participants 0 participants 29 participants
-3.22
(-5.73 to -0.72)
0.68
(-1.40 to 2.76)
0.80
(-1.23 to 2.83)
-0.64
(-2.67 to 1.39)
0.37
(-1.70 to 2.43)
Cycle 24 Day 1 Number Analyzed 24 participants 0 participants 0 participants 46 participants 0 participants 0 participants
-2.43
(-5.89 to 1.04)
-0.80
(-4.25 to 2.64)
End of treatment Number Analyzed 24 participants 26 participants 50 participants 46 participants 38 participants 29 participants
-0.87
(-2.99 to 1.24)
-2.31
(-4.58 to -0.04)
0.52
(-0.84 to 1.89)
-0.85
(-2.06 to 0.35)
-0.19
(-1.71 to 1.34)
0.11
(-1.72 to 1.95)
Time Frame 3 years
Adverse Event Reporting Description The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
 
Arm/Group Title 10 mg QD (Phase 1) 25 mg QD (Phase 1) 50 mg QD (Phase 1) 75 mg QD (Phase 1) 100 mg QD (Phase 1) 150 mg QD (Phase 1) 200 mg QD (Phase 1) 35 mg BID (Phase 1) 75 mg BID (Phase 1) 100 mg BID (Phase 1) EXP-1 (Phase 2) EXP-2 (Phase 2) EXP-3 (Phase 2) EXP-4 (Phase 2) EXP-5 (Phase 2) EXP-6 (Phase 2) Japan Lead-In Cohort (LIC)
Hide Arm/Group Description PF-06463922 10 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. PF-06463922 25 mg was orally given once daily (QD) in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. Midazolam 2 mg was orally given QD on Day -7 and Cycle 1 Day 15. PF-06463922 50 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. PF-06463922 75 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. PF-06463922 100 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. PF-06463922 150 mg was orally given once daily (QD) in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. Midazolam 2 mg was orally given QD on Day -7 and Cycle 1 Day 15. PF-06463922 200 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. PF-06463922 35 mg was orally given twice daily (BID) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. PF-06463922 75 mg was orally given twice daily (BID) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. PF-06463922 100 mg was orally given twice daily (BID) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. Treatment-naïve participants with advanced ALK-positive NSCLC with or without asymptomatic central nervous system (CNS) metastases were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after only crizotinib therapy were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after crizotinib therapy and 1 or 2 prior regimens of chemotherapy given before or after crizotinib therapy, or participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 1 ALK inhibitor therapy other than crizotinib with or without any number of prior chemotherapy regimens in any disease setting were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 2 prior lines of ALK inhibitor therapies were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 3 prior lines of ALK inhibitor therapies were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participant scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. Participants with advanced ROS1-positive NSCLC who were treatment naïve or had any number of prior cancer therapies with or without asymptomatic CNS metastases were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. Few Japanese participants were given PF-06463922 100 mg orally once daily (QD) in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal to evaluate safety of PF-06463922 in Japanese participants, in order to support inclusion of Japanese participants in Phase 2.
All-Cause Mortality
10 mg QD (Phase 1) 25 mg QD (Phase 1) 50 mg QD (Phase 1) 75 mg QD (Phase 1) 100 mg QD (Phase 1) 150 mg QD (Phase 1) 200 mg QD (Phase 1) 35 mg BID (Phase 1) 75 mg BID (Phase 1) 100 mg BID (Phase 1) EXP-1 (Phase 2) EXP-2 (Phase 2) EXP-3 (Phase 2) EXP-4 (Phase 2) EXP-5 (Phase 2) EXP-6 (Phase 2) Japan Lead-In Cohort (LIC)
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   1/3 (33.33%)      1/3 (33.33%)      0/3 (0.00%)      1/12 (8.33%)      3/17 (17.65%)      3/3 (100.00%)      0/3 (0.00%)      0/3 (0.00%)      1/3 (33.33%)      0/4 (0.00%)      0/30 (0.00%)      1/27 (3.70%)      4/60 (6.67%)      8/65 (12.31%)      4/46 (8.70%)      5/47 (10.64%)      0/3 (0.00%)    
Hide Serious Adverse Events
10 mg QD (Phase 1) 25 mg QD (Phase 1) 50 mg QD (Phase 1) 75 mg QD (Phase 1) 100 mg QD (Phase 1) 150 mg QD (Phase 1) 200 mg QD (Phase 1) 35 mg BID (Phase 1) 75 mg BID (Phase 1) 100 mg BID (Phase 1) EXP-1 (Phase 2) EXP-2 (Phase 2) EXP-3 (Phase 2) EXP-4 (Phase 2) EXP-5 (Phase 2) EXP-6 (Phase 2) Japan Lead-In Cohort (LIC)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   3/3 (100.00%)      1/3 (33.33%)      1/3 (33.33%)      4/12 (33.33%)      9/17 (52.94%)      3/3 (100.00%)      1/3 (33.33%)      2/3 (66.67%)      2/3 (66.67%)      2/4 (50.00%)      8/30 (26.67%)      5/27 (18.52%)      18/60 (30.00%)      24/65 (36.92%)      18/46 (39.13%)      16/47 (34.04%)      0/3 (0.00%)    
Cardiac disorders                                   
Cardiac arrest * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 1/47 (2.13%)  1 0/3 (0.00%)  0
Pericardial effusion * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  2 1/3 (33.33%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 1/30 (3.33%)  1 0/27 (0.00%)  0 0/60 (0.00%)  0 1/65 (1.54%)  1 1/46 (2.17%)  1 0/47 (0.00%)  0 0/3 (0.00%)  0
Atrial fibrillation * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 2/65 (3.08%)  2 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Atrioventricular block complete * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 1/47 (2.13%)  1 0/3 (0.00%)  0
Myocardial infarction * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 1/47 (2.13%)  1 0/3 (0.00%)  0
Sinus node dysfunction * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 1/65 (1.54%)  1 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Supraventricular tachycardia * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 1/65 (1.54%)  1 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Ear and labyrinth disorders                                   
Vertigo * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 1/30 (3.33%)  2 0/27 (0.00%)  0 0/60 (0.00%)  0 1/65 (1.54%)  1 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Eye disorders                                   
Cataract * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Eye pain * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/4 (25.00%)  1 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Blepharitis * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 1/65 (1.54%)  1 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Gastrointestinal disorders                                   
Abdominal pain * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Crohn's disease * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/4 (25.00%)  2 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Ileus * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/4 (25.00%)  1 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Intestinal perforation * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Large intestinal obstruction * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Abdominal pain upper * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 1/46 (2.17%)  1 0/47 (0.00%)  0 0/3 (0.00%)  0
Abdominal wall haematoma * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 1/47 (2.13%)  1 0/3 (0.00%)  0
Gastric volvulus * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 1/30 (3.33%)  1 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Gastritis * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 1/46 (2.17%)  1 0/47 (0.00%)  0 0/3 (0.00%)  0
Glossitis * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 1/30 (3.33%)  1 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Intestinal obstruction * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 1/30 (3.33%)  1 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Nausea * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 1/30 (3.33%)  1 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Pancreatitis * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 1/65 (1.54%)  1 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Vomiting * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 2/65 (3.08%)  2 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
General disorders                                   
Disease progression * 1  1/3 (33.33%)  1 1/3 (33.33%)  1 0/3 (0.00%)  0 1/12 (8.33%)  1 3/17 (17.65%)  3 1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 6/60 (10.00%)  6 6/65 (9.23%)  6 5/46 (10.87%)  5 5/47 (10.64%)  5 0/3 (0.00%)  0
Pyrexia * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 3/30 (10.00%)  3 0/27 (0.00%)  0 1/60 (1.67%)  1 1/65 (1.54%)  1 0/46 (0.00%)  0 1/47 (2.13%)  1 0/3 (0.00%)  0
Asthenia * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Chest pain * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 1/60 (1.67%)  1 0/65 (0.00%)  0 1/46 (2.17%)  1 0/47 (0.00%)  0 0/3 (0.00%)  0
Fatigue * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 1/30 (3.33%)  1 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
General physical health deterioration * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 1/46 (2.17%)  1 0/47 (0.00%)  0 0/3 (0.00%)  0
Generalised oedema * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 1/60 (1.67%)  1 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Pain * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 1/46 (2.17%)  1 0/47 (0.00%)  0 0/3 (0.00%)  0
Peripheral swelling * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 1/60 (1.67%)  1 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Hepatobiliary disorders                                   
Biloma * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/17 (5.88%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Jaundice * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 1/60 (1.67%)  1 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Infections and infestations                                   
Influenza * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 1/60 (1.67%)  1 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Lower respiratory tract infection * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/4 (25.00%)  1 1/30 (3.33%)  2 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Lung infection * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 1/27 (3.70%)  1 0/60 (0.00%)  0 0/65 (0.00%)  0 1/46 (2.17%)  1 0/47 (0.00%)  0 0/3 (0.00%)  0
Pneumonia * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 1/30 (3.33%)  2 1/27 (3.70%)  1 0/60 (0.00%)  0 3/65 (4.62%)  6 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Respiratory tract infection * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 1/30 (3.33%)  1 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Bronchitis * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/17 (5.88%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Pyelonephritis * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Urinary tract infection * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/17 (5.88%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Diverticulitis * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 1/65 (1.54%)  1 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Erysipelas * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 1/60 (1.67%)  1 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Lung abscess * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 1/60 (1.67%)  1 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Sepsis * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 1/60 (1.67%)  1 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Septic shock * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 1/60 (1.67%)  1 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Upper respiratory tract infection * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 1/60 (1.67%)  1 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Vestibular neuronitis * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 1/65 (1.54%)  1 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Injury, poisoning and procedural complications                                   
Subdural haematoma * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/17 (5.88%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Fall * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 1/65 (1.54%)  1 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Femoral neck fracture * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 1/60 (1.67%)  1 1/65 (1.54%)  1 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Hip fracture * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 1/65 (1.54%)  1 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Humerus fracture * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 1/47 (2.13%)  1 0/3 (0.00%)  0
Pelvic fracture * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 1/65 (1.54%)  2 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Post procedural haemorrhage * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 1/46 (2.17%)  1 0/47 (0.00%)  0 0/3 (0.00%)  0
Rib fracture * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 1/47 (2.13%)  1 0/3 (0.00%)  0
Road traffic accident * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 1/27 (3.70%)  1 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Toxicity to various agents * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 1/65 (1.54%)  1 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Investigations                                   
Aspartate aminotransferase increased * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/4 (25.00%)  1 1/30 (3.33%)  1 0/27 (0.00%)  0 0/60 (0.00%)  0 1/65 (1.54%)  1 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Lipase increased * 1  1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/0  0 0/0  0 0/0  0 0/0  0 0/0  0 0/0  0 0/3 (0.00%)  0
Alanine aminotransferase increased * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 1/30 (3.33%)  1 0/27 (0.00%)  0 0/60 (0.00%)  0 1/65 (1.54%)  1 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Blood cholesterol increased * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 1/60 (1.67%)  1 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Blood creatine phosphokinase increased * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 1/60 (1.67%)  1 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Ejection fraction decreased * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 1/47 (2.13%)  1 0/3 (0.00%)  0
Metabolism and nutrition disorders                                   
Decreased appetite * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/4 (25.00%)  1 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Hypercalcaemia * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Hyperuricaemia * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Hypertriglyceridaemia * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 1/46 (2.17%)  1 0/47 (0.00%)  0 0/3 (0.00%)  0
Musculoskeletal and connective tissue disorders                                   
Back pain * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 1/65 (1.54%)  2 1/46 (2.17%)  1 0/47 (0.00%)  0 0/3 (0.00%)  0
Intervertebral disc protrusion * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 1/27 (3.70%)  1 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Spinal pain * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 1/60 (1.67%)  1 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Nervous system disorders                                   
Haemorrhage intracranial * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 1/46 (2.17%)  1 0/47 (0.00%)  0 0/3 (0.00%)  0
Headache * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/4 (25.00%)  3 0/30 (0.00%)  0 0/27 (0.00%)  0 1/60 (1.67%)  1 1/65 (1.54%)  1 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Presyncope * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 1/47 (2.13%)  1 0/3 (0.00%)  0
Cerebrovascular accident * 1  0/3 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Seizure * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/4 (25.00%)  1 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Brain compression * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 1/47 (2.13%)  1 0/3 (0.00%)  0
Brain oedema * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 1/46 (2.17%)  1 0/47 (0.00%)  0 0/3 (0.00%)  0
Cognitive disorder * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 1/60 (1.67%)  1 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Hydrocephalus * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 1/65 (1.54%)  1 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Ischaemic stroke * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 1/47 (2.13%)  1 0/3 (0.00%)  0
Lacunar stroke * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 1/65 (1.54%)  1 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Partial seizures * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 1/47 (2.13%)  1 0/3 (0.00%)  0
Peripheral sensory neuropathy * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 1/46 (2.17%)  1 0/47 (0.00%)  0 0/3 (0.00%)  0
Syncope * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 1/60 (1.67%)  1 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Vagus nerve disorder * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 1/65 (1.54%)  1 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Psychiatric disorders                                   
Confusional state * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 1/30 (3.33%)  1 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Mental status changes * 1  1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/17 (5.88%)  1 1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 1/65 (1.54%)  1 1/46 (2.17%)  1 1/47 (2.13%)  1 0/3 (0.00%)  0
Delirium * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/17 (5.88%)  2 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Hallucination * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 1/3 (33.33%)  2 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Respiratory, thoracic and mediastinal disorders                                   
Dyspnoea * 1  1/3 (33.33%)  3 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/17 (5.88%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/4 (25.00%)  1 1/30 (3.33%)  1 0/27 (0.00%)  0 1/60 (1.67%)  1 3/65 (4.62%)  3 1/46 (2.17%)  2 0/47 (0.00%)  0 0/3 (0.00%)  0
Hypoxia * 1  1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 1/65 (1.54%)  1 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Pleural effusion * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/17 (5.88%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 1/60 (1.67%)  2 1/65 (1.54%)  1 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Haemoptysis * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1 0/12 (0.00%)  0 1/17 (5.88%)  1 0/3 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Acute pulmonary oedema * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 1/60 (1.67%)  1 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Acute respiratory failure * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 1/60 (1.67%)  1 1/65 (1.54%)  1 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Asthma * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 1/30 (3.33%)  1 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Chronic obstructive pulmonary disease * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 1/60 (1.67%)  1 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Dyspnoea exertional * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 1/60 (1.67%)  1 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Epistaxis * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 1/30 (3.33%)  1 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Interstitial lung disease * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 1/46 (2.17%)  1 0/47 (0.00%)  0 0/3 (0.00%)  0
Lung disorder * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 1/65 (1.54%)  1 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Pleuritic pain * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 1/46 (2.17%)  1 0/47 (0.00%)  0 0/3 (0.00%)  0
Pneumonitis * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 2/65 (3.08%)  2 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Pulmonary congestion * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 1/60 (1.67%)  1 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Pulmonary embolism * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 2/65 (3.08%)  2 1/46 (2.17%)  1 0/47 (0.00%)  0 0/3 (0.00%)  0
Pulmonary hypertension * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 1/27 (3.70%)  1 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Respiratory distress * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 1/27 (3.70%)  1 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Respiratory failure * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 1/60 (1.67%)  1 1/65 (1.54%)  1 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Skin and subcutaneous tissue disorders                                   
Dermatomyositis * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 1/3 (33.33%)  2 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Vascular disorders                                   
Embolism * 1  0/3 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 1/65 (1.54%)  1 1/46 (2.17%)  1 0/47 (0.00%)  0 0/3 (0.00%)  0
Embolism venous * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Aortic dissection * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 1/47 (2.13%)  1 0/3 (0.00%)  0
Deep vein thrombosis * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 1/65 (1.54%)  1 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Hypertensive crisis * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 1/65 (1.54%)  1 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Peripheral artery occlusion * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 1/65 (1.54%)  2 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Superior vena cava syndrome * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 2/65 (3.08%)  2 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Thrombosis * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 2/46 (4.35%)  2 0/47 (0.00%)  0 0/3 (0.00%)  0
1
Term from vocabulary, MedDRA 20.0
*
Indicates events were collected by non-systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
10 mg QD (Phase 1) 25 mg QD (Phase 1) 50 mg QD (Phase 1) 75 mg QD (Phase 1) 100 mg QD (Phase 1) 150 mg QD (Phase 1) 200 mg QD (Phase 1) 35 mg BID (Phase 1) 75 mg BID (Phase 1) 100 mg BID (Phase 1) EXP-1 (Phase 2) EXP-2 (Phase 2) EXP-3 (Phase 2) EXP-4 (Phase 2) EXP-5 (Phase 2) EXP-6 (Phase 2) Japan Lead-In Cohort (LIC)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   3/3 (100.00%)      3/3 (100.00%)      3/3 (100.00%)      12/12 (100.00%)      17/17 (100.00%)      3/3 (100.00%)      3/3 (100.00%)      3/3 (100.00%)      3/3 (100.00%)      4/4 (100.00%)      30/30 (100.00%)      27/27 (100.00%)      59/60 (98.33%)      65/65 (100.00%)      45/46 (97.83%)      47/47 (100.00%)      3/3 (100.00%)    
Blood and lymphatic system disorders                                   
Anaemia * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 2/12 (16.67%)  3 6/17 (35.29%)  14 3/3 (100.00%)  5 1/3 (33.33%)  1 1/3 (33.33%)  1 2/3 (66.67%)  4 2/4 (50.00%)  2 5/30 (16.67%)  9 1/27 (3.70%)  1 3/60 (5.00%)  3 12/65 (18.46%)  18 7/46 (15.22%)  8 3/47 (6.38%)  8 0/3 (0.00%)  0
Thrombocytopenia * 1  1/3 (33.33%)  1 1/3 (33.33%)  1 0/3 (0.00%)  0 1/12 (8.33%)  1 2/17 (11.76%)  2 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 1/27 (3.70%)  1 1/60 (1.67%)  1 1/65 (1.54%)  1 0/46 (0.00%)  0 3/47 (6.38%)  8 0/3 (0.00%)  0
Febrile neutropenia * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/4 (25.00%)  1 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Haemorrhagic diathesis * 1  1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Iron deficiency anaemia * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Leukocytosis * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 2/12 (16.67%)  2 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Neutropenia * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/17 (5.88%)  2 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Thrombocytosis * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/17 (5.88%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Cardiac disorders                                   
Tachycardia * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 1/27 (3.70%)  1 0/60 (0.00%)  0 5/65 (7.69%)  6 2/46 (4.35%)  2 3/47 (6.38%)  3 0/3 (0.00%)  0
Atrial fibrillation * 1  0/3 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Ventricular dysfunction * 1  1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Pericardial effusion * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 2/30 (6.67%)  2 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 3/46 (6.52%)  4 0/47 (0.00%)  0 0/3 (0.00%)  0
Ear and labyrinth disorders                                   
Tinnitus * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  3 3/12 (25.00%)  4 3/17 (17.65%)  3 1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/4 (25.00%)  1 2/30 (6.67%)  2 2/27 (7.41%)  8 3/60 (5.00%)  3 7/65 (10.77%)  10 4/46 (8.70%)  4 1/47 (2.13%)  1 0/3 (0.00%)  0
Ear discomfort * 1  0/3 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Hypoacusis * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  2 1/17 (5.88%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Vertigo * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Vertigo positional * 1  0/3 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Endocrine disorders                                   
Cushingoid * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/17 (5.88%)  2 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Hyperparathyroidism * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Hypothyroidism * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Eye disorders                                   
Vision blurred * 1  1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 2/17 (11.76%)  2 0/3 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 3/30 (10.00%)  3 2/27 (7.41%)  2 0/60 (0.00%)  0 3/65 (4.62%)  3 3/46 (6.52%)  3 2/47 (4.26%)  2 0/3 (0.00%)  0
Visual impairment * 1  0/3 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 1/12 (8.33%)  1 0/17 (0.00%)  0 1/3 (33.33%)  3 1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 1/27 (3.70%)  1 1/60 (1.67%)  1 3/65 (4.62%)  3 3/46 (6.52%)  3 2/47 (4.26%)  4 0/3 (0.00%)  0
Asthenopia * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Astigmatism * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/17 (5.88%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Conjunctival oedema * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/17 (5.88%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Diplopia * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Dry eye * 1  1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Photophobia * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Photopsia * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/17 (5.88%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 1/3 (33.33%)  1
Presbyopia * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/17 (5.88%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Retinal vein occlusion * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Visual acuity reduced * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 1/17 (5.88%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Eye irritation * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 2/30 (6.67%)  2 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Gastrointestinal disorders                                   
Abdominal distension * 1  1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/17 (5.88%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 2/30 (6.67%)  2 1/27 (3.70%)  1 0/60 (0.00%)  0 4/65 (6.15%)  4 3/46 (6.52%)  6 5/47 (10.64%)  5 0/3 (0.00%)  0
Abdominal pain * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 2/12 (16.67%)  2 1/17 (5.88%)  1 0/3 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 1/4 (25.00%)  3 0/30 (0.00%)  0 1/27 (3.70%)  1 2/60 (3.33%)  2 4/65 (6.15%)  4 3/46 (6.52%)  4 1/47 (2.13%)  1 0/3 (0.00%)  0
Constipation * 1  0/3 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 3/12 (25.00%)  3 3/17 (17.65%)  4 0/3 (0.00%)  0 2/3 (66.67%)  2 1/3 (33.33%)  1 1/3 (33.33%)  1 0/4 (0.00%)  0 8/30 (26.67%)  9 5/27 (18.52%)  6 8/60 (13.33%)  10 8/65 (12.31%)  8 5/46 (10.87%)  5 5/47 (10.64%)  5 0/3 (0.00%)  0
Diarrhoea * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1 3/12 (25.00%)  6 3/17 (17.65%)  4 1/3 (33.33%)  1 2/3 (66.67%)  4 0/3 (0.00%)  0 0/3 (0.00%)  0 3/4 (75.00%)  5 7/30 (23.33%)  13 4/27 (14.81%)  6 7/60 (11.67%)  14 16/65 (24.62%)  22 8/46 (17.39%)  9 7/47 (14.89%)  7 0/3 (0.00%)  0
Dyspepsia * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 1/30 (3.33%)  1 1/27 (3.70%)  1 2/60 (3.33%)  2 5/65 (7.69%)  5 0/46 (0.00%)  0 1/47 (2.13%)  1 0/3 (0.00%)  0
Dysphagia * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 1/27 (3.70%)  1 3/60 (5.00%)  3 4/65 (6.15%)  4 2/46 (4.35%)  2 0/47 (0.00%)  0 0/3 (0.00%)  0
Gastrooesophageal reflux disease * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 2/17 (11.76%)  2 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 1/30 (3.33%)  1 0/27 (0.00%)  0 4/60 (6.67%)  4 1/65 (1.54%)  1 2/46 (4.35%)  4 3/47 (6.38%)  3 0/3 (0.00%)  0
Nausea * 1  1/3 (33.33%)  1 1/3 (33.33%)  1 0/3 (0.00%)  0 2/12 (16.67%)  2 2/17 (11.76%)  3 0/3 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 1/3 (33.33%)  1 2/4 (50.00%)  4 4/30 (13.33%)  4 3/27 (11.11%)  4 4/60 (6.67%)  4 15/65 (23.08%)  16 7/46 (15.22%)  9 6/47 (12.77%)  8 1/3 (33.33%)  1
Vomiting * 1  0/3 (0.00%)  0 2/3 (66.67%)  2 1/3 (33.33%)  1 1/12 (8.33%)  1 3/17 (17.65%)  4 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 2/4 (50.00%)  6 4/30 (13.33%)  7 0/27 (0.00%)  0 5/60 (8.33%)  5 7/65 (10.77%)  10 3/46 (6.52%)  3 5/47 (10.64%)  5 0/3 (0.00%)  0
Abdominal discomfort * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Abdominal pain upper * 1  1/3 (33.33%)  1 0/3 (0.00%)  0 1/3 (33.33%)  1 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1 1/3 (33.33%)  1 2/4 (50.00%)  2 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Ascites * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Crohn's disease * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/4 (25.00%)  1 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Dry mouth * 1  1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/17 (5.88%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Faeces discoloured * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Gastrointestinal disorder * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Intestinal obstruction * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/17 (5.88%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Swollen tongue * 1  1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Odynophagia * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 2/27 (7.41%)  2 1/60 (1.67%)  1 0/65 (0.00%)  0 1/46 (2.17%)  1 0/47 (0.00%)  0 0/3 (0.00%)  0
Stomatitis * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 1/30 (3.33%)  1 2/27 (7.41%)  3 2/60 (3.33%)  2 2/65 (3.08%)  2 1/46 (2.17%)  1 2/47 (4.26%)  2 0/3 (0.00%)  0
Toothache * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 2/30 (6.67%)  2 0/27 (0.00%)  0 1/60 (1.67%)  1 0/65 (0.00%)  0 1/46 (2.17%)  1 1/47 (2.13%)  1 0/3 (0.00%)  0
General disorders                                   
Asthenia * 1  1/3 (33.33%)  1 0/3 (0.00%)  0 2/3 (66.67%)  2 3/12 (25.00%)  7 3/17 (17.65%)  3 0/3 (0.00%)  0 1/3 (33.33%)  2 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 3/30 (10.00%)  3 2/27 (7.41%)  3 8/60 (13.33%)  10 6/65 (9.23%)  12 5/46 (10.87%)  7 2/47 (4.26%)  2 0/3 (0.00%)  0
Chest pain * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/17 (5.88%)  2 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 1/27 (3.70%)  2 2/60 (3.33%)  2 6/65 (9.23%)  6 5/46 (10.87%)  6 2/47 (4.26%)  2 0/3 (0.00%)  0
Face oedema * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 2/30 (6.67%)  2 0/27 (0.00%)  0 2/60 (3.33%)  2 1/65 (1.54%)  1 1/46 (2.17%)  1 1/47 (2.13%)  1 0/3 (0.00%)  0
Fatigue * 1  1/3 (33.33%)  1 1/3 (33.33%)  1 0/3 (0.00%)  0 4/12 (33.33%)  4 4/17 (23.53%)  5 2/3 (66.67%)  4 1/3 (33.33%)  2 0/3 (0.00%)  0 1/3 (33.33%)  1 3/4 (75.00%)  5 8/30 (26.67%)  11 4/27 (14.81%)  7 3/60 (5.00%)  4 11/65 (16.92%)  22 4/46 (8.70%)  4 7/47 (14.89%)  9 0/3 (0.00%)  0
Gait disturbance * 1  1/3 (33.33%)  1 1/3 (33.33%)  2 1/3 (33.33%)  2 1/12 (8.33%)  1 1/17 (5.88%)  1 0/3 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 5/65 (7.69%)  5 3/46 (6.52%)  5 0/47 (0.00%)  0 0/3 (0.00%)  0
Mucosal inflammation * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  2 0/4 (0.00%)  0 3/30 (10.00%)  3 0/27 (0.00%)  0 1/60 (1.67%)  1 2/65 (3.08%)  2 1/46 (2.17%)  1 0/47 (0.00%)  0 0/3 (0.00%)  0
Oedema * 1  0/3 (0.00%)  0 1/3 (33.33%)  1 1/3 (33.33%)  1 2/12 (16.67%)  3 0/17 (0.00%)  0 0/3 (0.00%)  0 2/3 (66.67%)  2 0/3 (0.00%)  0 0/3 (0.00%)  0 1/4 (25.00%)  1 4/30 (13.33%)  6 1/27 (3.70%)  6 4/60 (6.67%)  4 6/65 (9.23%)  7 4/46 (8.70%)  4 3/47 (6.38%)  3 0/3 (0.00%)  0
Oedema peripheral * 1  3/3 (100.00%)  3 1/3 (33.33%)  1 1/3 (33.33%)  1 3/12 (25.00%)  4 9/17 (52.94%)  16 3/3 (100.00%)  7 1/3 (33.33%)  1 0/3 (0.00%)  0 2/3 (66.67%)  3 3/4 (75.00%)  7 12/30 (40.00%)  17 12/27 (44.44%)  18 29/60 (48.33%)  43 21/65 (32.31%)  37 15/46 (32.61%)  24 24/47 (51.06%)  30 1/3 (33.33%)  1
Pain * 1  1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 2/30 (6.67%)  2 0/27 (0.00%)  0 1/60 (1.67%)  1 4/65 (6.15%)  8 2/46 (4.35%)  2 2/47 (4.26%)  2 0/3 (0.00%)  0
Peripheral swelling * 1  1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 2/12 (16.67%)  4 0/17 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 2/27 (7.41%)  2 1/60 (1.67%)  1 7/65 (10.77%)  12 4/46 (8.70%)  5 3/47 (6.38%)  3 0/3 (0.00%)  0
Pyrexia * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1 0/12 (0.00%)  0 3/17 (17.65%)  3 1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 2/30 (6.67%)  4 1/27 (3.70%)  2 5/60 (8.33%)  6 7/65 (10.77%)  7 1/46 (2.17%)  1 5/47 (10.64%)  5 0/3 (0.00%)  0
Axillary pain * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Catheter site extravasation * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Chest discomfort * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Chills * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Disease progression * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Generalised oedema * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Non-cardiac chest pain * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Performance status decreased * 1  1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Swelling * 1  1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Hepatobiliary disorders                                   
Hepatocellular injury * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/4 (25.00%)  1 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Immune system disorders                                   
Hypersensitivity * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Infections and infestations                                   
Bronchitis * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 2/17 (11.76%)  3 1/3 (33.33%)  1 1/3 (33.33%)  1 0/3 (0.00%)  0 1/3 (33.33%)  3 1/4 (25.00%)  1 1/30 (3.33%)  1 2/27 (7.41%)  2 1/60 (1.67%)  1 3/65 (4.62%)  4 0/46 (0.00%)  0 1/47 (2.13%)  2 0/3 (0.00%)  0
Influenza * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/17 (5.88%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 2/30 (6.67%)  2 1/27 (3.70%)  1 1/60 (1.67%)  1 3/65 (4.62%)  3 0/46 (0.00%)  0 1/47 (2.13%)  1 0/3 (0.00%)  0
Lung infection * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 2/27 (7.41%)  2 3/60 (5.00%)  3 2/65 (3.08%)  2 0/46 (0.00%)  0 1/47 (2.13%)  1 0/3 (0.00%)  0
Pneumonia * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/4 (25.00%)  1 0/30 (0.00%)  0 1/27 (3.70%)  1 0/60 (0.00%)  0 8/65 (12.31%)  8 1/46 (2.17%)  1 0/47 (0.00%)  0 0/3 (0.00%)  0
Rhinitis * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  2 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 1/27 (3.70%)  1 5/60 (8.33%)  7 2/65 (3.08%)  3 0/46 (0.00%)  0 3/47 (6.38%)  3 0/3 (0.00%)  0
Sinusitis * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  2 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 2/60 (3.33%)  3 0/65 (0.00%)  0 1/46 (2.17%)  1 3/47 (6.38%)  3 0/3 (0.00%)  0
Upper respiratory tract infection * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  2 2/12 (16.67%)  6 4/17 (23.53%)  6 1/3 (33.33%)  1 2/3 (66.67%)  2 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 5/30 (16.67%)  6 2/27 (7.41%)  2 2/60 (3.33%)  3 6/65 (9.23%)  7 1/46 (2.17%)  1 3/47 (6.38%)  3 0/3 (0.00%)  0
Viral upper respiratory tract infection * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/17 (5.88%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 1/30 (3.33%)  1 3/27 (11.11%)  4 2/60 (3.33%)  4 2/65 (3.08%)  2 2/46 (4.35%)  3 3/47 (6.38%)  3 0/3 (0.00%)  0
Bacterial infection * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/17 (5.88%)  2 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Candida infection * 1  1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Cellulitis * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Chronic sinusitis * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/4 (25.00%)  1 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Clostridium difficile colitis * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/17 (5.88%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Enteritis infectious * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Enterococcal bacteraemia * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Gastroenteritis * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Helicobacter infection * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/17 (5.88%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Herpes virus infection * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Laryngitis * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/17 (5.88%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Lower respiratory tract infection * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/4 (25.00%)  1 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Nasopharyngitis * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/4 (25.00%)  1 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Oral candidiasis * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/17 (5.88%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Periodontitis * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/17 (5.88%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Pharyngitis * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/17 (5.88%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 1/3 (33.33%)  2
Respiratory tract infection * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 2/17 (11.76%)  3 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Soft tissue infection * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Tooth abscess * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/4 (25.00%)  1 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Urinary tract infection * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 2/17 (11.76%)  3 0/3 (0.00%)  0 2/3 (66.67%)  3 0/3 (0.00%)  0 0/3 (0.00%)  0 1/4 (25.00%)  1 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Viral rhinitis * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/4 (25.00%)  1 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Conjunctivitis * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 1/3 (33.33%)  1
Herpes zoster * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 1/3 (33.33%)  1
Injury, poisoning and procedural complications                                   
Fall * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/17 (5.88%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 5/65 (7.69%)  11 2/46 (4.35%)  5 2/47 (4.26%)  3 0/3 (0.00%)  0
Contusion * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/17 (5.88%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Incision site pain * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Joint dislocation * 1  0/3 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Laceration * 1  0/3 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/12 (0.00%)  0 1/17 (5.88%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Ligament sprain * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/17 (5.88%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Limb injury * 1  0/3 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Toxicity to various agents * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/17 (5.88%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Procedural pain * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 1/65 (1.54%)  1 0/46 (0.00%)  0 3/47 (6.38%)  4 0/3 (0.00%)  0
Investigations                                   
Alanine aminotransferase increased * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 2/12 (16.67%)  4 2/17 (11.76%)  3 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/4 (25.00%)  5 5/30 (16.67%)  6 1/27 (3.70%)  1 6/60 (10.00%)  12 5/65 (7.69%)  13 5/46 (10.87%)  7 7/47 (14.89%)  7 2/3 (66.67%)  2
Amylase increased * 1  2/3 (66.67%)  3 0/3 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  3 4/17 (23.53%)  11 0/3 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 1/30 (3.33%)  2 0/27 (0.00%)  0 4/60 (6.67%)  5 7/65 (10.77%)  17 2/46 (4.35%)  3 7/47 (14.89%)  11 0/3 (0.00%)  0
Aspartate aminotransferase increased * 1  0/3 (0.00%)  0 1/3 (33.33%)  1 1/3 (33.33%)  1 2/12 (16.67%)  5 2/17 (11.76%)  3 0/3 (0.00%)  0 2/3 (66.67%)  2 0/3 (0.00%)  0 0/3 (0.00%)  0 1/4 (25.00%)  7 7/30 (23.33%)  9 1/27 (3.70%)  1 7/60 (11.67%)  11 7/65 (10.77%)  9 6/46 (13.04%)  8 4/47 (8.51%)  4 1/3 (33.33%)  1
Blood cholesterol increased * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 6/12 (50.00%)  9 3/17 (17.65%)  8 1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/4 (25.00%)  3 13/30 (43.33%)  41 13/27 (48.15%)  55 18/60 (30.00%)  67 17/65 (26.15%)  44 16/46 (34.78%)  42 18/47 (38.30%)  49 3/3 (100.00%)  10
Blood creatine phosphokinase increased * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/17 (5.88%)  4 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1 0/4 (0.00%)  0 1/30 (3.33%)  3 1/27 (3.70%)  1 5/60 (8.33%)  10 0/65 (0.00%)  0 0/46 (0.00%)  0 2/47 (4.26%)  2 2/3 (66.67%)  16
Blood triglycerides increased * 1  0/3 (0.00%)  0 1/3 (33.33%)  2 0/3 (0.00%)  0 2/12 (16.67%)  3 3/17 (17.65%)  8 1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/4 (25.00%)  6 2/30 (6.67%)  2 2/27 (7.41%)  4 4/60 (6.67%)  8 3/65 (4.62%)  3 3/46 (6.52%)  4 3/47 (6.38%)  8 0/3 (0.00%)  0
Electrocardiogram QT prolonged * 1  2/3 (66.67%)  2 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/4 (25.00%)  1 0/30 (0.00%)  0 1/27 (3.70%)  2 3/60 (5.00%)  7 4/65 (6.15%)  4 9/46 (19.57%)  10 2/47 (4.26%)  2 0/3 (0.00%)  0
Lipase increased * 1  2/3 (66.67%)  2 0/3 (0.00%)  0 0/3 (0.00%)  0 2/12 (16.67%)  5 5/17 (29.41%)  20 0/3 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 1/4 (25.00%)  2 3/30 (10.00%)  5 4/27 (14.81%)  6 1/60 (1.67%)  1 7/65 (10.77%)  14 5/46 (10.87%)  6 6/47 (12.77%)  12 1/3 (33.33%)  4
Weight increased * 1  0/3 (0.00%)  0 1/3 (33.33%)  1 1/3 (33.33%)  1 3/12 (25.00%)  7 3/17 (17.65%)  5 1/3 (33.33%)  1 1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 2/4 (50.00%)  3 4/30 (13.33%)  11 4/27 (14.81%)  6 11/60 (18.33%)  18 18/65 (27.69%)  23 10/46 (21.74%)  12 10/47 (21.28%)  17 1/3 (33.33%)  2
Blood alkaline phosphatase increased * 1  1/3 (33.33%)  1 1/3 (33.33%)  1 0/3 (0.00%)  0 1/12 (8.33%)  1 1/17 (5.88%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Blood creatinine increased * 1  1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  3 0/17 (0.00%)  0 2/3 (66.67%)  2 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Blood phosphorus decreased * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Candida test positive * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Ejection fraction decreased * 1  1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 2/3 (66.67%)  2 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/4 (25.00%)  2 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Gamma-glutamyltransferase increased * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  3 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 2/4 (50.00%)  12 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Glucose urine present * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/17 (5.88%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
International normalised ratio increased * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/17 (5.88%)  2 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Lipids increased * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/17 (5.88%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/4 (25.00%)  1 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Liver function test increased * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/17 (5.88%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Transaminases increased * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/17 (5.88%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Weight decreased * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Electrocardiogram PR prolongation * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 1/3 (33.33%)  1
Metabolism and nutrition disorders                                   
Decreased appetite * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 2/4 (50.00%)  3 4/30 (13.33%)  4 1/27 (3.70%)  1 0/60 (0.00%)  0 5/65 (7.69%)  5 2/46 (4.35%)  2 2/47 (4.26%)  2 0/3 (0.00%)  0
Hypercholesterolaemia * 1  1/3 (33.33%)  1 2/3 (66.67%)  6 1/3 (33.33%)  2 7/12 (58.33%)  25 12/17 (70.59%)  38 2/3 (66.67%)  4 3/3 (100.00%)  18 1/3 (33.33%)  1 1/3 (33.33%)  5 1/4 (25.00%)  5 14/30 (46.67%)  61 11/27 (40.74%)  39 33/60 (55.00%)  126 37/65 (56.92%)  102 25/46 (54.35%)  62 25/47 (53.19%)  60 0/3 (0.00%)  0
Hyperglycaemia * 1  0/3 (0.00%)  0 1/3 (33.33%)  5 0/3 (0.00%)  0 0/12 (0.00%)  0 1/17 (5.88%)  6 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 3/30 (10.00%)  7 1/27 (3.70%)  1 2/60 (3.33%)  7 3/65 (4.62%)  9 6/46 (13.04%)  23 5/47 (10.64%)  8 3/3 (100.00%)  11
Hyperlipidaemia * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 2/17 (11.76%)  4 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 2/30 (6.67%)  2 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 2/46 (4.35%)  2 0/47 (0.00%)  0 0/3 (0.00%)  0
Hypertriglyceridaemia * 1  0/3 (0.00%)  0 1/3 (33.33%)  9 1/3 (33.33%)  4 4/12 (33.33%)  9 6/17 (35.29%)  27 1/3 (33.33%)  1 2/3 (66.67%)  10 0/3 (0.00%)  0 1/3 (33.33%)  2 1/4 (25.00%)  3 20/30 (66.67%)  106 12/27 (44.44%)  34 27/60 (45.00%)  99 44/65 (67.69%)  135 29/46 (63.04%)  100 23/47 (48.94%)  78 0/3 (0.00%)  0
Hyperuricaemia * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/4 (25.00%)  1 2/30 (6.67%)  2 1/27 (3.70%)  1 2/60 (3.33%)  2 1/65 (1.54%)  1 3/46 (6.52%)  3 3/47 (6.38%)  3 0/3 (0.00%)  0
Hypokalaemia * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1 0/12 (0.00%)  0 1/17 (5.88%)  1 2/3 (66.67%)  7 1/3 (33.33%)  11 1/3 (33.33%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 2/30 (6.67%)  4 0/27 (0.00%)  0 4/60 (6.67%)  4 4/65 (6.15%)  6 2/46 (4.35%)  2 3/47 (6.38%)  3 0/3 (0.00%)  0
Hypomagnesaemia * 1  0/3 (0.00%)  0 1/3 (33.33%)  2 1/3 (33.33%)  1 0/12 (0.00%)  0 0/17 (0.00%)  0 3/3 (100.00%)  5 0/3 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 2/30 (6.67%)  3 0/27 (0.00%)  0 2/60 (3.33%)  2 1/65 (1.54%)  1 3/46 (6.52%)  3 3/47 (6.38%)  4 0/3 (0.00%)  0
Hypophosphataemia * 1  1/3 (33.33%)  1 2/3 (66.67%)  5 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 1/3 (33.33%)  4 1/3 (33.33%)  2 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 2/27 (7.41%)  2 2/60 (3.33%)  2 1/65 (1.54%)  1 3/46 (6.52%)  4 3/47 (6.38%)  5 0/3 (0.00%)  0
Dehydration * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 1/17 (5.88%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Fluid retention * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 2/12 (16.67%)  2 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Hypercalcaemia * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Hypocalcaemia * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 1/3 (33.33%)  4 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Hypocholesterolaemia * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/17 (5.88%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Hypoalbuminaemia * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 3/30 (10.00%)  5 0/27 (0.00%)  0 3/60 (5.00%)  6 4/65 (6.15%)  5 4/46 (8.70%)  6 2/47 (4.26%)  2 0/3 (0.00%)  0
Increased appetite * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 1/3 (33.33%)  1
Musculoskeletal and connective tissue disorders                                   
Arthralgia * 1  1/3 (33.33%)  2 1/3 (33.33%)  1 0/3 (0.00%)  0 2/12 (16.67%)  3 4/17 (23.53%)  5 0/3 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 1/3 (33.33%)  1 1/4 (25.00%)  1 5/30 (16.67%)  9 4/27 (14.81%)  4 9/60 (15.00%)  12 11/65 (16.92%)  18 11/46 (23.91%)  13 14/47 (29.79%)  17 0/3 (0.00%)  0
Back pain * 1  0/3 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 2/12 (16.67%)  2 6/17 (35.29%)  7 0/3 (0.00%)  0 2/3 (66.67%)  4 0/3 (0.00%)  0 1/3 (33.33%)  1 2/4 (50.00%)  2 2/30 (6.67%)  2 5/27 (18.52%)  6 2/60 (3.33%)  2 10/65 (15.38%)  10 5/46 (10.87%)  5 3/47 (6.38%)  3 1/3 (33.33%)  1
Bone pain * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 1/17 (5.88%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 1/30 (3.33%)  1 0/27 (0.00%)  0 1/60 (1.67%)  1 0/65 (0.00%)  0 3/46 (6.52%)  3 0/47 (0.00%)  0 0/3 (0.00%)  0
Joint swelling * 1  1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/17 (5.88%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 1/27 (3.70%)  3 0/60 (0.00%)  0 2/65 (3.08%)  3 0/46 (0.00%)  0 3/47 (6.38%)  3 0/3 (0.00%)  0
Muscle spasms * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1 1/4 (25.00%)  1 0/30 (0.00%)  0 0/27 (0.00%)  0 3/60 (5.00%)  3 1/65 (1.54%)  2 3/46 (6.52%)  3 5/47 (10.64%)  5 0/3 (0.00%)  0
Muscular weakness * 1  1/3 (33.33%)  1 1/3 (33.33%)  1 0/3 (0.00%)  0 1/12 (8.33%)  1 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 2/30 (6.67%)  2 0/27 (0.00%)  0 6/60 (10.00%)  6 3/65 (4.62%)  5 1/46 (2.17%)  1 3/47 (6.38%)  3 0/3 (0.00%)  0
Musculoskeletal chest pain * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/17 (5.88%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 3/60 (5.00%)  3 0/65 (0.00%)  0 1/46 (2.17%)  1 4/47 (8.51%)  4 0/3 (0.00%)  0
Musculoskeletal pain * 1  1/3 (33.33%)  1 0/3 (0.00%)  0 1/3 (33.33%)  1 0/12 (0.00%)  0 2/17 (11.76%)  2 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 4/30 (13.33%)  5 2/27 (7.41%)  3 3/60 (5.00%)  4 3/65 (4.62%)  3 2/46 (4.35%)  2 2/47 (4.26%)  2 1/3 (33.33%)  1
Myalgia * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 2/17 (11.76%)  2 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/4 (25.00%)  1 3/30 (10.00%)  3 2/27 (7.41%)  2 5/60 (8.33%)  5 6/65 (9.23%)  7 5/46 (10.87%)  5 6/47 (12.77%)  7 2/3 (66.67%)  2
Pain in extremity * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 1/17 (5.88%)  1 1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  2 0/4 (0.00%)  0 2/30 (6.67%)  4 8/27 (29.63%)  10 4/60 (6.67%)  8 6/65 (9.23%)  6 4/46 (8.70%)  4 8/47 (17.02%)  9 0/3 (0.00%)  0
Arthritis * 1  0/3 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 1/12 (8.33%)  1 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Bone lesion * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/17 (5.88%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Flank pain * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 2/17 (11.76%)  2 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Limb discomfort * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Musculoskeletal discomfort * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/17 (5.88%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Neck pain * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 2/17 (11.76%)  2 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Osteoarthritis * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Osteoporosis * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/4 (25.00%)  1 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Pain in jaw * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 2/17 (11.76%)  2 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Plantar fasciitis * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/17 (5.88%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Torticollis * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Musculoskeletal stiffness * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 1/30 (3.33%)  1 0/27 (0.00%)  0 0/60 (0.00%)  0 3/65 (4.62%)  3 1/46 (2.17%)  1 4/47 (8.51%)  4 0/3 (0.00%)  0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)                                   
Melanocytic naevus * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/17 (5.88%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Tumour pain * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 1/3 (33.33%)  1
Nervous system disorders                                   
Amnesia * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 1/3 (33.33%)  1 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 6/60 (10.00%)  6 6/65 (9.23%)  10 2/46 (4.35%)  4 2/47 (4.26%)  2 0/3 (0.00%)  0
Aphasia * 1  2/3 (66.67%)  2 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 1/3 (33.33%)  1 0/4 (0.00%)  0 0/30 (0.00%)  0 2/27 (7.41%)  2 0/60 (0.00%)  0 2/65 (3.08%)  2 2/46 (4.35%)  2 1/47 (2.13%)  1 0/3 (0.00%)  0
Cognitive disorder * 1  1/3 (33.33%)  1 1/3 (33.33%)  1 0/3 (0.00%)  0 2/12 (16.67%)  2 0/17 (0.00%)  0 2/3 (66.67%)  2 1/3 (33.33%)  3 0/3 (0.00%)  0 0/3 (0.00%)  0 1/4 (25.00%)  1 1/30 (3.33%)  1 1/27 (3.70%)  3 5/60 (8.33%)  5 6/65 (9.23%)  7 2/46 (4.35%)  2 3/47 (6.38%)  6 0/3 (0.00%)  0
Disturbance in attention * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 2/12 (16.67%)  2 0/17 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 1/60 (1.67%)  1 2/65 (3.08%)  13 1/46 (2.17%)  1 3/47 (6.38%)  3 0/3 (0.00%)  0
Dizziness * 1  1/3 (33.33%)  1 1/3 (33.33%)  2 0/3 (0.00%)  0 1/12 (8.33%)  1 2/17 (11.76%)  2 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/4 (25.00%)  1 6/30 (20.00%)  12 4/27 (14.81%)  12 5/60 (8.33%)  5 9/65 (13.85%)  12 7/46 (15.22%)  8 11/47 (23.40%)  20 0/3 (0.00%)  0
Dysgeusia * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 2/12 (16.67%)  2 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/4 (25.00%)  1 2/30 (6.67%)  2 0/27 (0.00%)  0 1/60 (1.67%)  1 6/65 (9.23%)  6 2/46 (4.35%)  2 1/47 (2.13%)  1 0/3 (0.00%)  0
Headache * 1  1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 3/12 (25.00%)  3 1/17 (5.88%)  2 1/3 (33.33%)  1 1/3 (33.33%)  1 1/3 (33.33%)  1 1/3 (33.33%)  1 2/4 (50.00%)  3 5/30 (16.67%)  8 6/27 (22.22%)  7 8/60 (13.33%)  10 11/65 (16.92%)  15 10/46 (21.74%)  11 2/47 (4.26%)  2 1/3 (33.33%)  1
Memory impairment * 1  0/3 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 1/12 (8.33%)  1 2/17 (11.76%)  2 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/4 (25.00%)  2 2/30 (6.67%)  2 3/27 (11.11%)  3 4/60 (6.67%)  5 6/65 (9.23%)  12 2/46 (4.35%)  2 7/47 (14.89%)  16 0/3 (0.00%)  0
Neuropathy peripheral * 1  2/3 (66.67%)  2 0/3 (0.00%)  0 1/3 (33.33%)  1 5/12 (41.67%)  7 2/17 (11.76%)  2 1/3 (33.33%)  3 2/3 (66.67%)  4 0/3 (0.00%)  0 1/3 (33.33%)  1 0/4 (0.00%)  0 5/30 (16.67%)  6 3/27 (11.11%)  4 6/60 (10.00%)  7 7/65 (10.77%)  7 5/46 (10.87%)  5 5/47 (10.64%)  8 0/3 (0.00%)  0
Paraesthesia * 1  0/3 (0.00%)  0 2/3 (66.67%)  2 0/3 (0.00%)  0 1/12 (8.33%)  4 2/17 (11.76%)  2 0/3 (0.00%)  0 1/3 (33.33%)  1 1/3 (33.33%)  1 1/3 (33.33%)  1 2/4 (50.00%)  4 3/30 (10.00%)  5 4/27 (14.81%)  7 11/60 (18.33%)  13 9/65 (13.85%)  9 5/46 (10.87%)  6 5/47 (10.64%)  6 0/3 (0.00%)  0
Peripheral sensory neuropathy * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 1/17 (5.88%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 3/30 (10.00%)  3 3/27 (11.11%)  4 7/60 (11.67%)  14 3/65 (4.62%)  3 4/46 (8.70%)  4 2/47 (4.26%)  2 2/3 (66.67%)  2
Presyncope * 1  1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/4 (25.00%)  1 0/30 (0.00%)  0 0/27 (0.00%)  0 1/60 (1.67%)  1 0/65 (0.00%)  0 0/46 (0.00%)  0 3/47 (6.38%)  3 0/3 (0.00%)  0
Slow speech * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  2 1/12 (8.33%)  1 3/17 (17.65%)  4 0/3 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 5/60 (8.33%)  9 2/65 (3.08%)  2 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Ataxia * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Balance disorder * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/4 (25.00%)  1 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Carpal tunnel syndrome * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Dysaesthesia * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/17 (5.88%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Dysarthria * 1  0/3 (0.00%)  0 1/3 (33.33%)  4 0/3 (0.00%)  0 1/12 (8.33%)  1 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 1/3 (33.33%)  1
Formication * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Hemiparesis * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Hypoaesthesia * 1  0/3 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 3/12 (25.00%)  3 1/17 (5.88%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Mental impairment * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Migraine * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Nervous system disorder * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/17 (5.88%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Neuralgia * 1  0/3 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Neurotoxicity * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/17 (5.88%)  5 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Partial seizures * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Peroneal nerve palsy * 1  1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Psychomotor hyperactivity * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/17 (5.88%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Seizure * 1  0/3 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Sensory disturbance * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Speech disorder * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 2/12 (16.67%)  2 1/17 (5.88%)  1 0/3 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 1/3 (33.33%)  1 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Tremor * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Psychiatric disorders                                   
Affect lability * 1  1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 3/12 (25.00%)  5 0/17 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 2/60 (3.33%)  4 2/65 (3.08%)  3 0/46 (0.00%)  0 3/47 (6.38%)  3 0/3 (0.00%)  0
Anxiety * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 2/12 (16.67%)  2 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  2 0/3 (0.00%)  0 1/4 (25.00%)  1 0/30 (0.00%)  0 2/27 (7.41%)  2 1/60 (1.67%)  1 7/65 (10.77%)  7 1/46 (2.17%)  1 4/47 (8.51%)  6 0/3 (0.00%)  0
Insomnia * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 0/17 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 4/30 (13.33%)  5 3/27 (11.11%)  3 5/60 (8.33%)  6 3/65 (4.62%)  3 3/46 (6.52%)  3 4/47 (8.51%)  4 0/3 (0.00%)  0
Irritability * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 2/17 (11.76%)  2 0/3 (0.00%)  0 1/3 (33.33%)  2 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 3/30 (10.00%)  3 1/27 (3.70%)  1 3/60 (5.00%)  4 2/65 (3.08%)  2 6/46 (13.04%)  6 1/47 (2.13%)  1 0/3 (0.00%)  0
Abnormal dreams * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 1/3 (33.33%)  1 1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Agitation * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  2 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Attention deficit/hyperactivity disorder * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/17 (5.88%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Bradyphrenia * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Confusional state * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 2/17 (11.76%)  2 1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Depressed mood * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Hallucination * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 1/3 (33.33%)  2 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Mental status changes * 1  1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Nightmare * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Reading disorder * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/17 (5.88%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Sleep disorder * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Depression * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 1/30 (3.33%)  1 2/27 (7.41%)  5 6/60 (10.00%)  7 1/65 (1.54%)  1 1/46 (2.17%)  1 1/47 (2.13%)  1 0/3 (0.00%)  0
Mood swings * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 2/30 (6.67%)  2 1/27 (3.70%)  1 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Hallucination, auditory * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 1/3 (33.33%)  1
Renal and urinary disorders                                   
Haematuria * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 2/17 (11.76%)  2 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 2/30 (6.67%)  2 0/27 (0.00%)  0 1/60 (1.67%)  1 1/65 (1.54%)  1 0/46 (0.00%)  0 2/47 (4.26%)  3 0/3 (0.00%)  0
Chronic kidney disease * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Hydronephrosis * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/17 (5.88%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Micturition urgency * 1  1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/17 (5.88%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Pollakiuria * 1  1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/17 (5.88%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Proteinuria * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/17 (5.88%)  1 1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 1/3 (33.33%)  1
Urinary incontinence * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/17 (5.88%)  1 1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/4 (25.00%)  1 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Reproductive system and breast disorders                                   
Menstruation irregular * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/17 (5.88%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Vaginal haemorrhage * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Respiratory, thoracic and mediastinal disorders                                   
Cough * 1  1/3 (33.33%)  1 2/3 (66.67%)  2 1/3 (33.33%)  1 1/12 (8.33%)  1 1/17 (5.88%)  1 0/3 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 2/4 (50.00%)  2 9/30 (30.00%)  13 3/27 (11.11%)  5 7/60 (11.67%)  10 11/65 (16.92%)  14 8/46 (17.39%)  12 9/47 (19.15%)  12 0/3 (0.00%)  0
Dysphonia * 1  1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/4 (25.00%)  1 1/30 (3.33%)  1 0/27 (0.00%)  0 4/60 (6.67%)  4 2/65 (3.08%)  2 2/46 (4.35%)  2 0/47 (0.00%)  0 0/3 (0.00%)  0
Dyspnoea * 1  1/3 (33.33%)  1 1/3 (33.33%)  1 1/3 (33.33%)  1 0/12 (0.00%)  0 3/17 (17.65%)  3 0/3 (0.00%)  0 0/3 (0.00%)  0 2/3 (66.67%)  3 1/3 (33.33%)  3 2/4 (50.00%)  5 7/30 (23.33%)  8 3/27 (11.11%)  3 14/60 (23.33%)  16 13/65 (20.00%)  14 9/46 (19.57%)  11 14/47 (29.79%)  20 1/3 (33.33%)  1
Dyspnoea exertional * 1  0/3 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/12 (0.00%)  0 1/17 (5.88%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 1/30 (3.33%)  1 1/27 (3.70%)  1 3/60 (5.00%)  6 6/65 (9.23%)  8 3/46 (6.52%)  5 1/47 (2.13%)  2 0/3 (0.00%)  0
Epistaxis * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/17 (5.88%)  1 1/3 (33.33%)  1 0/3 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 2/27 (7.41%)  2 3/60 (5.00%)  3 3/65 (4.62%)  4 0/46 (0.00%)  0 1/47 (2.13%)  1 0/3 (0.00%)  0
Haemoptysis * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 2/3 (66.67%)  2 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 2/30 (6.67%)  3 0/27 (0.00%)  0 2/60 (3.33%)  2 5/65 (7.69%)  6 1/46 (2.17%)  1 0/47 (0.00%)  0 0/3 (0.00%)  0
Hypoxia * 1  1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 1/65 (1.54%)  1 5/46 (10.87%)  10 1/47 (2.13%)  2 0/3 (0.00%)  0
Pleural effusion * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 1/30 (3.33%)  1 0/27 (0.00%)  0 0/60 (0.00%)  0 5/65 (7.69%)  5 1/46 (2.17%)  1 4/47 (8.51%)  4 0/3 (0.00%)  0
Wheezing * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 1/30 (3.33%)  1 0/27 (0.00%)  0 1/60 (1.67%)  1 2/65 (3.08%)  2 3/46 (6.52%)  3 2/47 (4.26%)  2 0/3 (0.00%)  0
Acute respiratory failure * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Bronchitis chronic * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/17 (5.88%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Laryngeal inflammation * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Nasal congestion * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Oropharyngeal pain * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/17 (5.88%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/4 (25.00%)  1 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Pleuritic pain * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/17 (5.88%)  2 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Productive cough * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Pulmonary embolism * 1  1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Pulmonary hypertension * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/4 (25.00%)  2 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Pulmonary oedema * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Rales * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Respiratory tract congestion * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Rhinorrhoea * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/4 (25.00%)  1 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Sinus congestion * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Skin and subcutaneous tissue disorders                                   
Alopecia * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 0/17 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  2 0/3 (0.00%)  0 0/3 (0.00%)  0 1/4 (25.00%)  1 2/30 (6.67%)  2 2/27 (7.41%)  2 2/60 (3.33%)  2 2/65 (3.08%)  2 3/46 (6.52%)  3 2/47 (4.26%)  2 1/3 (33.33%)  1
Dry skin * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/17 (5.88%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1 1/4 (25.00%)  1 3/30 (10.00%)  3 1/27 (3.70%)  1 2/60 (3.33%)  2 0/65 (0.00%)  0 0/46 (0.00%)  0 1/47 (2.13%)  1 1/3 (33.33%)  1
Hyperhidrosis * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 2/12 (16.67%)  2 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 1/27 (3.70%)  1 2/60 (3.33%)  2 5/65 (7.69%)  5 1/46 (2.17%)  1 4/47 (8.51%)  4 0/3 (0.00%)  0
Pruritus * 1  1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 1/65 (1.54%)  1 4/46 (8.70%)  4 1/47 (2.13%)  1 0/3 (0.00%)  0
Rash * 1  1/3 (33.33%)  1 1/3 (33.33%)  1 0/3 (0.00%)  0 3/12 (25.00%)  4 1/17 (5.88%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 5/30 (16.67%)  9 3/27 (11.11%)  4 2/60 (3.33%)  2 7/65 (10.77%)  7 2/46 (4.35%)  2 4/47 (8.51%)  4 0/3 (0.00%)  0
Dermatitis acneiform * 1  0/3 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Dermatitis contact * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/17 (5.88%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Dermatomyositis * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 1/3 (33.33%)  2 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Night sweats * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Photosensitivity reaction * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Rash erythematous * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Rash maculo-papular * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/17 (5.88%)  2 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 1/3 (33.33%)  1
Rash pruritic * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Rosacea * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/4 (25.00%)  1 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Seborrhoeic dermatitis * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Skin lesion * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Swelling face * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/4 (25.00%)  1 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Erythema * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 2/27 (7.41%)  2 1/60 (1.67%)  1 1/65 (1.54%)  1 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Vascular disorders                                   
Hypertension * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 2/12 (16.67%)  3 1/17 (5.88%)  1 1/3 (33.33%)  1 0/3 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 2/30 (6.67%)  2 1/27 (3.70%)  1 2/60 (3.33%)  6 8/65 (12.31%)  17 4/46 (8.70%)  11 3/47 (6.38%)  6 0/3 (0.00%)  0
Deep vein thrombosis * 1  1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/4 (25.00%)  1 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Haematoma * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/4 (25.00%)  1 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Haemorrhage * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Hot flush * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1 1/4 (25.00%)  1 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Hypotension * 1  1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
Shock * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/17 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 0/30 (0.00%)  0 0/27 (0.00%)  0 0/60 (0.00%)  0 0/65 (0.00%)  0 0/46 (0.00%)  0 0/47 (0.00%)  0 0/3 (0.00%)  0
1
Term from vocabulary, MedDRA 20.0
*
Indicates events were collected by non-systematic assessment
The study is still ongoing. This report reflects data collected up to 15 Mar 2017, and will be updated after completion of the whole study.
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Pfizer ClinicalTrials.gov Call Center
Organization: Pfizer, Inc.
Phone: 1-800-718-1021
EMail: ClinicalTrials.gov_Inquiries@pfizer.com
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Layout table for additonal information
Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT01970865    
Other Study ID Numbers: B7461001
2013-002620-17 ( EudraCT Number )
First Submitted: October 16, 2013
First Posted: October 28, 2013
Results First Submitted: March 5, 2018
Results First Posted: May 29, 2018
Last Update Posted: June 7, 2023