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History of Changes for Study: NCT01970865
A Study Of PF-06463922 An ALK/ROS1 Inhibitor In Patients With Advanced Non Small Cell Lung Cancer With Specific Molecular Alterations
Latest version (submitted June 5, 2023) on ClinicalTrials.gov
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Study Record Versions
Version A B Submitted Date Changes
1 October 22, 2013 None (earliest Version on record)
2 November 20, 2013 Study Status
3 December 16, 2013 Study Status
4 January 14, 2014 Study Status
5 January 24, 2014 Recruitment Status, Study Status and Contacts/Locations
6 February 24, 2014 Study Status and Contacts/Locations
7 March 25, 2014 Study Status
8 April 29, 2014 Outcome Measures, Study Status, Contacts/Locations and Eligibility
9 May 28, 2014 Study Status and Contacts/Locations
10 June 24, 2014 Study Status
11 July 11, 2014 Study Status
12 August 7, 2014 Study Status
13 September 9, 2014 Study Status
14 October 30, 2014 Study Status, Contacts/Locations, Study Design and Study Identification
15 November 4, 2014 Study Status
16 November 17, 2014 Outcome Measures, Contacts/Locations, Eligibility, Study Design, Study Status and Study Identification
17 December 12, 2014 Contacts/Locations, Study Status and Study Identification
18 January 9, 2015 Study Status and Contacts/Locations
19 February 9, 2015 Study Status, Contacts/Locations and Study Design
20 March 13, 2015 Study Status, Contacts/Locations and Study Design
21 March 19, 2015 Study Design and Study Status
22 April 13, 2015 Contacts/Locations and Study Status
23 May 13, 2015 Study Status and Contacts/Locations
24 June 8, 2015 Contacts/Locations and Study Status
25 July 1, 2015 Study Status, Contacts/Locations and Study Identification
26 July 29, 2015 Contacts/Locations and Study Status
27 August 20, 2015 Contacts/Locations, Outcome Measures, Study Status, Study Design, Arms and Interventions, Eligibility, Conditions and Study Identification
28 September 18, 2015 Contacts/Locations, Study Status, Eligibility and Outcome Measures
29 October 5, 2015 Contacts/Locations, Study Status, Eligibility and Study Design
30 November 4, 2015 Contacts/Locations, Study Design, Study Status and Eligibility
31 December 1, 2015 Contacts/Locations, Study Status and Outcome Measures
32 December 10, 2015 Contacts/Locations, Study Status and Study Identification
33 January 20, 2016 Contacts/Locations, Study Status and Study Identification
34 February 6, 2016 Contacts/Locations, Study Status and Study Identification
35 March 9, 2016 Contacts/Locations, Study Status and Study Identification
36 March 25, 2016 Contacts/Locations, Study Design, Study Status and Study Identification
37 April 1, 2016 Contacts/Locations, Study Status and Eligibility
38 May 1, 2016 Contacts/Locations and Study Status
39 May 26, 2016 Study Status and Contacts/Locations
40 June 15, 2016 Contacts/Locations and Study Status
41 July 7, 2016 Contacts/Locations and Study Status
42 July 26, 2016 Contacts/Locations, Study Design, Study Status and Study Identification
43 August 12, 2016 Contacts/Locations, Study Design, Study Status and Study Identification
44 September 12, 2016 Contacts/Locations and Study Status
45 October 5, 2016 Study Status and Study Identification
46 November 3, 2016 Study Status and Study Identification
47 November 20, 2016 Study Design, Study Status and Study Identification
48 December 12, 2016 Study Status
49 January 12, 2017 Contacts/Locations, Study Design, Study Status and Study Identification
50 January 14, 2017 Contacts/Locations, Study Status and Study Identification
51 January 30, 2017 Contacts/Locations and Study Status
52 February 23, 2017 Contacts/Locations and Study Status
53 March 14, 2017 Study Status and Contacts/Locations
54 April 4, 2017 Study Status and Contacts/Locations
55 April 10, 2017 Study Status
56 May 1, 2017 Contacts/Locations and Study Status
57 May 18, 2017 Study Status and Contacts/Locations
58 June 6, 2017 Study Status and Contacts/Locations
59 June 29, 2017 Contacts/Locations and Study Status
60 July 24, 2017 Study Status and Contacts/Locations
61 August 17, 2017 Study Status
62 September 11, 2017 Study Status
63 September 28, 2017 Study Status
64 October 25, 2017 Recruitment Status, Study Status, Contacts/Locations and Study Design
65 November 6, 2017 Contacts/Locations, Study Status and Study Design
66 November 21, 2017 Study Status
67 January 29, 2018 Study Status and Study Design
68 February 12, 2018 Study Status and Study Design
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Results Submission Events
69 May 8, 2018 Study Status, Outcome Measures, Document Section, Results and Contacts/Locations
70 May 30, 2018 Study Status and Contacts/Locations
71 August 22, 2018 Study Status
72 November 29, 2018 Study Status and Study Design
73 January 1, 2019 Study Status
74 April 29, 2019 Study Status, Contacts/Locations, IPDSharing and Study Identification
75 October 23, 2019 Contacts/Locations and Study Status
76 July 2, 2020 Study Status, Outcome Measures
77 February 18, 2021 Study Status, Contacts/Locations and Study Design
78 November 4, 2021 Study Status
79 February 16, 2022 Study Status
80 October 24, 2022 Study Status
81 January 9, 2023 Study Status, Contacts/Locations and Study Design
82 March 16, 2023 Study Status and Contacts/Locations
83 June 5, 2023 Recruitment Status, Study Status and Study Design
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Study NCT01970865
Submitted Date:  March 16, 2023 (v82)
Open or close this module Study Identification
Unique Protocol ID: B7461001
Brief Title: A Study Of PF-06463922 An ALK/ROS1 Inhibitor In Patients With Advanced Non Small Cell Lung Cancer With Specific Molecular Alterations
Official Title: PHASE 1/2 STUDY OF PF-06463922 (AN ALK/ROS1 TYROSINE KINASE INHIBITOR) IN PATIENTS WITH ADVANCED NON-SMALL CELL LUNG CANCER HARBORING SPECIFIC MOLECULAR ALTERATIONS
Secondary IDs: 2013-002620-17 [EudraCT Number]
Open or close this module Study Status
Record Verification: March 2023
Overall Status: Active, not recruiting
Study Start: January 8, 2014
Primary Completion: March 15, 2017 [Actual]
Study Completion: May 31, 2023 [Anticipated]
First Submitted: October 16, 2013
First Submitted that
Met QC Criteria:		 October 22, 2013
First Posted: October 28, 2013 [Estimate]
Results First Submitted: March 5, 2018
Results First Submitted that
Met QC Criteria:		 May 8, 2018
Results First Posted: May 29, 2018 [Actual]
Last Update Submitted that
Met QC Criteria:		 March 16, 2023
Last Update Posted: March 20, 2023 [Actual]
Open or close this module Sponsor/Collaborators
Sponsor: Pfizer
Responsible Party: Sponsor
Collaborators:
Open or close this module Oversight
U.S. FDA-regulated Drug:
U.S. FDA-regulated Device:
Data Monitoring: No
Open or close this module Study Description
Brief Summary: Phase 1 and 2 trial to study the safety, pharmacokinetics, pharmacodynamics, patient reported outcomes and efficacy of PF-06463922 in ALK + advanced non-small cell lung cancer patients and ROS1+ advanced non small cell lung cancer patients .
Detailed Description:
Open or close this module Conditions
Conditions: ALK-positive Non Small Cell Lung Cancer (NSCLC) and ROS1-positive NSCLC
Keywords: Phase 1
Phase 2
safety
pharmacokinetic
pharmacodynamic
efficacy
Open or close this module Study Design
Study Type: Interventional
Primary Purpose: Treatment
Study Phase: Phase 2
Interventional Study Model:
Number of Arms: 2
Masking: None (Open Label)
Allocation: Non-Randomized
Enrollment: 334 [Actual]
Open or close this module Arms and Interventions
Arms Assigned Interventions
Experimental: PF-06463922 Drug: PF-06463922
Oral, starting dose 10mg once a day, dose escalation in Phase 1 until recommended Phase 2 dose determined, continuous daily dosing, cycles lasting 21 days
Crizotinib
ALK+ NSCLC patients who are treatment naïve may be eligible to receive crizotinib following PF-06463922 as a substudy to the main study.
 Drug: Crizotinib
Oral, starting dose of 250 mg BID continuous daily dosing every 21 days
Other Names:
  • Xalkori
Open or close this module Outcome Measures
[See Results Section.]
Primary Outcome Measures:
1. Number of Participants With Cycle 1 Dose-Limiting Toxicities (DLTs) in Phase 1
[ Time Frame: Cycle 1 (21 days) ]

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.
2. Percentage of Participants With Overall and Intracranial Objective Response (Phase 2)
[ Time Frame: 3 years ]

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.
Secondary Outcome Measures:
1. Percentage of Participants With Overall and Intracranial Objective Response (Phase 1)
[ Time Frame: 3 years ]

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.
2. Time to Tumor Response (TTR) and Intracranial TTR (Phase 1)
[ Time Frame: 3 years ]

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.
3. Duration of Response (DOR) and Intracranial DOR (Phase 1)
[ Time Frame: 3 years ]

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.
4. Percentage of Participants Achieving Disease Control and Intracranial Disease Control at 12 Weeks (Phase 1)
[ Time Frame: 12 weeks ]

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.
5. Probability of First Event Being a Central Nervous System (CNS) Progression, Non CNS Progression, or Death (Phase 1)
[ Time Frame: 3 years ]

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.
6. Progression-Free Survival (PFS) (Phase 1)
[ Time Frame: 3 years ]

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.
7. Overall Survival (OS) (Phase 1)
[ Time Frame: 3 years ]

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.
8. Maximum Observed Plasma Concentration (Cmax) of PF-06463922 Following Single Oral Doses (Phase 1)
[ 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. ]

Maximum observed plasma concentration (Cmax) of PF-06463922 was observed directly from data.
9. Maximum Observed Plasma Concentration (Cmax) of PF-06463922 Following Multiple Oral Doses (Phase 1)
[ 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). ]

Maximum Observed Plasma Concentration (Cmax) of PF-06463922 was observed directly from data.
10. Time for Cmax (Tmax) of PF-06463922 Following Single Oral Doses (Phase 1)
[ 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. ]

Tmax of PF-06463922 was observed directly from data as time of first occurrence.
11. Time for Cmax (Tmax) of PF-06463922 Following Multiple Oral Doses (Phase 1)
[ 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). ]

Tmax of PF-06463922 was observed directly from data as time of first occurrence.
12. Area Under the Plasma Concentration-Time Profile From Time Zero to Time Tau (AUCtau) of PF-06463922 Following Single Oral Doses (Phase 1)
[ 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. ]

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.
13. Area Under the Plasma Concentration-Time Profile From Time Zero to Time Tau (AUCtau) of PF-06463922 Following Multiple Oral Doses (Phase 1)
[ 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) ]

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.
14. Area Under the Plasma Concentration-Time Profile From Time Zero Extrapolated to Infinite Time (AUCinf) of PF-06463922 Following Single Oral Doses (Phase 1)
[ 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. ]

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.
15. Apparent Oral Clearance (CL/F) of PF-06463922 Following Single Oral Doses (Phase 1)
[ 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. ]

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.
16. Apparent Oral Clearance (CL/F) of PF-06463922 Following Multiple Oral Doses (Phase 1)
[ 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) ]

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.
17. Apparent Volume of Distribution (Vz/F) of PF-06463922 Following Single Oral Doses (Phase 1)
[ 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. ]

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.
18. Observed Accumulation Ratio (Rac) of PF-06463922 Following Multiple Oral Doses (Phase 1)
[ 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) ]

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).
19. Terminal Half-Life of PF-06463922 Following Single Oral Doses (Phase 1)
[ 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. ]

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.
20. Steady State Accumulation Ratio (Rss) of PF-06463922 Following Multiple Oral Doses (Phase 1)
[ 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) ]

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.
21. Renal Clearance (CLr) of PF-06463922 (Phase 1)
[ Time Frame: 0-4 hours, 4-12 hours and 12-24 hours post-dose on Cycle 1 Day 15 ]

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).
22. Percent of PF-06463922 Recovered Unchanged in Urine up to Dosing Interval (AEtau%) (Phase 1)
[ Time Frame: 0-4 hours, 4-12 hours and 12-24 hours post-dose on Cycle 1 Day 15 ]

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.
23. Maximum Observed Plasma Concentration (Cmax) of Midazolam (Phase 1)
[ 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 ]

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.
24. Time for Cmax (Tmax) of Midazolam (Phase 1)
[ 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 ]

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.
25. Area Under the Plasma Concentration-Time Profile From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Midazolam (Phase 1)
[ 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 ]

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.
26. Area Under the Plasma Concentration-Time Profile From Time Zero Extrapolated to Infinite Time (AUCinf) of Midazolam (Phase 1)
[ 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 ]

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.
27. Apparent Oral Clearance (CL/F) of Midazolam (Phase 1)
[ 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 ]

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.
28. Apparent Volume of Distribution (Vz/F) of Midazolam (Phase 1)
[ 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 ]

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.
29. Terminal Half-Life of Midazolam (Phase 1)
[ 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 ]

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.
30. Number of Participants With ALK Mutation Based on Plasma CNA Analysis (Phase 1)
[ Time Frame: Screening ]

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.
31. Number of Participants With ALK Mutation Based on Tumor Tissue Analysis (Phase 1)
[ Time Frame: Screening ]

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.
32. Number of Participants Who Improved, Worsened or Remained Stable in EORTC QLQ-C30 (Phase 1)
[ 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) ]

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.
33. Number of Participants Who Improved, Worsened or Remained Stable in EORTC QLQ-LC13 (Phase 1)
[ 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) ]

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.
34. Change From Baseline in Mini Mental State Examination (MMSE) Score (Phase 1)
[ Time Frame: Baseline, Day 1 of each cycle, and end of treatment (up to 3 years) ]

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.
35. Time to Tumor Response (TTR) and Intracranial TTR (Phase 2)
[ Time Frame: 3 years ]

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.
36. Duration of Response (DOR) and Intracranial DOR (Phase 2)
[ Time Frame: 3 years ]

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.
37. Percentage of Participants Achieving Disease Control and Intracranial Disease Control at 12 Weeks (Phase 2)
[ Time Frame: 12 weeks ]

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.
38. Time to Progression (TTP) on the Last Prior Therapy (Phase 2)
[ Time Frame: 3 years ]

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.
39. Time to Tumor Progression （TTP) and Intracranial TTP (Phase 2)
[ Time Frame: 3 years ]

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.
40. Probability of First Event Being a Central Nervous System (CNS) Progression, Non CNS Progression, or Death (Phase 2)
[ Time Frame: 3 years ]

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.
41. Progression-Free Survival (PFS) (Phase 2)
[ Time Frame: 3 years ]

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.
42. Overall Survival (Phase 2)
[ Time Frame: 3 years ]

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.
43. Maximum Observed Plasma Concentration (Cmax) of PF-06463922 (Phase 2)
[ 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 ]

Maximum observed plasma concentration (Cmax) of PF-06463922 was observed directly from data.
44. Time for Cmax (Tmax) of PF-06463922 (Phase 2)
[ 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 ]

Tmax of PF-06463922 was observed directly from data as time of first occurrence.
45. Area Under the Plasma Concentration-Time Profile From Time Zero Extrapolated to Infinite Time (AUCinf) of PF-06463922 (Phase 2)
[ 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 ]

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.
46. Area Under the Plasma Concentration-Time Profile From Time Zero to Time Tau (AUCtau) of PF-06463922 (Phase 2)
[ 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 ]

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.
47. Apparent Oral Clearance (CL/F) of PF-06463922 (Phase 2)
[ 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 ]

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.
48. Apparent Volume of Distribution (Vz/F) of PF-06463922 (Phase 2)
[ 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 ]

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.
49. Terminal Half-Life of PF-06463922 (Phase 2)
[ 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 ]

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.
50. Observed Accumulation Ratio (Rac) of PF-06463922 Following Multiple Oral Doses (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 ]

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).
51. Steady State Accumulation Ratio (Rss) of PF-06463922 Following Multiple Oral Doses (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 ]

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.
52. Number of Participants With ALK Mutation Based on Plasma CNA Analysis (Phase 2)
[ Time Frame: Screening ]

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.
53. Number of Participants With ALK Mutation Based on Tumor Tissue Analysis (Phase 2)
[ Time Frame: Screening ]

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.
54. Number of Participants Who Improved, Worsened or Remained Stable in EORTC QLQ-C30 (Phase 2)
[ Time Frame: 3 years ]

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.
55. Number of Participants Who Improved, Worsened or Remained Stable in EORTC QLQ-LC13 (Phase 2)
[ Time Frame: 3 years ]

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.
56. Number of Participants With Treatment-Emergent Adverse Events (Phase 1 and Phase 2)
[ Time Frame: 3 years ]

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.
57. Number of Participants With Laboratory Abnormalities (Phase 1 and Phase 2) - Hematology
[ Time Frame: 3 years ]

Hematology evaluation included hemoglobin, platelets, white blood cell, absolute neutrophils, absolute lymphocytes, absolute monocytes, absolute eosinophils and absolute basophils.
58. Number of Participants With Laboratory Abnormalities (Phase 1 and Phase 2) - Chemistry
[ Time Frame: 3 years ]

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.
59. Number of Participants With Laboratory Abnormalities (Phase 1 and Phase 2) - Coagulation, Lipids and Urinalysis
[ Time Frame: 3 years ]

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.
60. Number of Participants With Vital Signs Data Meeting Pre-defined Criteria (Phase 1 and Phase 2)
[ 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) ]

Blood pressure (BP), including systolic BP (SBP) and diastolic BP (DBP), and pulse rate were recorded in sitting position. Body weight was also measured.
61. 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)
[ 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) ]

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.
62. Number of Participants With Absolute Values and Change From Baseline in QTcF Meeting Pre-defined Criteria (Phase 1 and Phase 2)
[ 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) ]

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.
63. Number of Participants With Suicidal Ideation and Suicidal Behavior (Phase 2)
[ Time Frame: 3 years ]

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.
64. Change From Baseline in Total Scores for Beck Depression Inventory (BDI)-II (Mood Assessment) (Phase 2)
[ 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) ]

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.
65. Change From Baseline in Total Scores for Detection Test (Cognitive Function Assessment) (Phase 2)
[ 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) ]

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.
66. Change From Baseline in Total Scores for Identification Test (Cognitive Function Assessment) (Phase 2)
[ 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) ]

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.
67. Change From Baseline in Total Scores for One Back Test (Cognitive Function Assessment) (Phase 2)
[ 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) ]

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.
68. Change From Baseline in Total Scores for International Shopping List Test (Cognitive Function Assessment) (Phase 2)
[ 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) ]

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.
69. Change From Baseline in Total Scores for International Shopping List Test-Delayed Recall (Cognitive Function Assessment) (Phase 2)
[ 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) ]

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.
Open or close this module Eligibility
Minimum Age: 18 Years
Maximum Age:
Sex: All
Gender Based:
Accepts Healthy Volunteers: No
Criteria:

Inclusion Criteria

  • Evidence of histologically or cytologically confirmed diagnosis of metastatic NSCLC (Stage IV, AJCC v7.0) that carries an ALK rearrangement, as determined by the Food and Drug Administration (FDA) approved FISH assay (Abbott Molecular Inc) or by Immunohistochemistry (IHC) (Ventana Inc), or a ROS1 rearrangement as determined by FISH or RT PCR or Next Generation Sequencing (NGS) via a local diagnostic test (LDT). All patients (ALK positive and ROS1 positive) must have archival tissue sample available and collected prior to enrollment.
  • Disease Status Requirements:

Phase 1: ALK-positive NSCLC and ROS1-positive patients must either be treatment naïve in the advanced setting or have had disease progression after at least 1 previous ALK/ROS1 inhibitor therapy(ies).

Phase 2:

ALK-positive NSCLC patients must either be or have had:

  • Treatment naïve (ie, no prior chemotherapy in the metastatic disease setting and no prior ALK inhibitor therapy allowed).
  • Disease progression after crizotinib only. No prior chemotherapy is allowed in the metastatic disease setting.
  • Disease progression after crizotinib and 1 or 2 prior regimens of chemotherapy in the metastatic disease setting.
  • Disease progression after 1 prior ALK inhibitor therapy other than crizotinib. Patients may have had any number of prior chemotherapy regimens in any disease setting.
  • Disease progression after 2 prior ALK inhibitor therapies. Patients may have had any number of prior chemotherapy regimens in any disease setting.
  • Disease progression after 3 prior ALK inhibitor therapies. Patients may have had any number of prior chemotherapy regimens in any disease setting.

ROS1-positive NSCLC patients may be:

  • Treatment naïve (ie, no prior chemotherapy in the metastatic disease setting and no prior ROS inhibitor therapy).
  • Any number of prior therapies (ie, chemotherapy and/or ROS inhibitor therapies).
    • Tumor Requirements:

All Patients must have at least one measurable target extracranial lesion according to RECIST v1.1. In addition patients with asymptomatic CNS metastases (including patients asymptomatic by means of stable or decreasing doses of steroids within the last 2 weeks prior to study entry) will be eligible. Patients who have leptomeningeal disease (LM) or carcinomatous meningitis (CM) are eligible.

  • Adequate Bone Marrow, Pancreatic Function, Renal Function and Liver Function.
  • Negative Serum pregnancy test for females of childbearing potential Exclusion Criteria
  • Radiation therapy (except palliative to relieve bone pain) within 2 weeks of study entry. Whole brain radiation must have completed at least 4 weeks prior to study entry.
  • Systemic anti cancer therapy completed within a minimum of 5 half lives of study entry.
  • Prior therapy with an antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways, including, but not limited to, anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-cytotoxic T lymphocyte associated antigen 4 (anti-CTLA-4) antibody.
  • Active and clinically significant bacterial, fungal, or viral infection including hepatitis B (HBV), hepatitis C (HCV), known human immunodeficiency virus (HIV), or acquired immunodeficiency syndrome (AIDS) related illness.
  • Clinically significant cardiovascular disease (that is, active or <3 months prior to enrollment): cerebral vascular accident/stroke, myocardial infarction, unstable angina, congestive heart failure (New York Heart Association Classification Class ≥ II), second-degree or third-degree AV block (unless paced) or any AV block with PR >220 msec. Ongoing cardiac dysrhythmias of NCI CTCAE Grade ≥2, uncontrolled atrial fibrillation of any grade, bradycardia defined as <50 bpm (unless patient is otherwise healthy such as long-distance runners, etc.), machine-read ECG with QTc >470 msec, or congenital long QT syndrome.
  • History of extensive, disseminated, bilateral or presence of Grade 3 or 4 interstitial fibrosis or interstitial lung disease including a history of pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, interstitial lung disease, obliterative bronchiolitis and pulmonary fibrosis.
  • Current use or anticipated need for food or drugs that are known strong or moderate CYP3A4 inhibitors, inducers and substrates; drugs that are CYP2C9 substrates; drugs that are sensitive CYP2B6 substrates; drugs that are strong CYP2C19 inhibitors; drugs that are strong CYP2C8 inhibitors; and drugs that are P-gp substrates.
Open or close this module Contacts/Locations
Study Officials: Pfizer CT.gov Call Center
Study Director
Pfizer
Locations: United States, Arkansas
Highlands Oncology Group/Research
Fayetteville, Arkansas, United States, 72703
Highlands Oncology Group
Rogers, Arkansas, United States, 72758
United States, California
Chao Family Comprehensive Cancer Center
Orange, California, United States, 92868-3201
UC Irvine Medical Center
Orange, California, United States, 92868-3201
United States, Colorado
University of Colorado Cancer Center
Aurora, Colorado, United States, 80045
University of Colorado Hospital
Aurora, Colorado, United States, 80045
United States, Connecticut
MDZ: Yale-New Haven Hospital
New Haven, Connecticut, United States, 06504
Smilow Cancer Hospital at Yale-New Haven
New Haven, Connecticut, United States, 06510
United States, District of Columbia
Georgetown University Medical Center
Washington, District of Columbia, United States, 20007
United States, Massachusetts
Massachusetts General Hospital
Boston, Massachusetts, United States, 02114
Brigham and Women's Hospital
Boston, Massachusetts, United States, 02115
Dana Farber Cancer Institute
Boston, Massachusetts, United States, 02215
United States, Michigan
Karmanos Cancer Institute
Detroit, Michigan, United States, 48201
Karmanos Center Institute
Detroit, Michigan, United States, 48201
Karmanos Cancer Institute
Farmington Hills, Michigan, United States, 48334
United States, Missouri
Siteman Cancer Center-West County
Creve Coeur, Missouri, United States, 63141
Barnes-Jewish Hospital
Saint Louis, Missouri, United States, 63110
Washington University School of Medicine
Saint Louis, Missouri, United States, 63110
Siteman Cancer Center-South County
Saint Louis, Missouri, United States, 63129
United States, New York
Rockefeller Patient Pavilion - Memorial Sloan Kettering
New York, New York, United States, 10022
Memorial Sloan Kettering Cancer Center
New York, New York, United States, 10065
Rochester Regional Health System
Rochester, New York, United States, 14621
SUNY Upstate Medical University
Syracuse, New York, United States, 13210
United States, Ohio
The Ohio State University
Columbus, Ohio, United States, 43205
The Ohio State University
Columbus, Ohio, United States, 43210
The Ohio State University
Columbus, Ohio, United States, 43221
United States, Pennsylvania
Fox Chase Cancer Center
Philadelphia, Pennsylvania, United States, 19111
United States, Tennessee
Sarah Cannon Research Institute (Pharmacy)
Nashville, Tennessee, United States, 37203
Australia, New South Wales
Chris O'Brien Lifehouse
Sydney, New South Wales, Australia, 2050
Royal Prince Alfred Hospital
Sydney, New South Wales, Australia, 2050
Chris O'Brien Lifehouse
Sydney Local Health District [rpa], New South Wales, Australia, 2050
Australia, Victoria
Peter MacCallum Cancer Centre
Melbourne, Victoria, Australia, 3000
Royal Melbourne Hospital
Parkville, Victoria, Australia, 3050
Belgium
University Hospital Antwerp
Edegem, Belgium, 2650
Canada, British Columbia
British Columbia Cancer Agency-Vancouver Centre
Vancouver, British Columbia, Canada, V5Z 4E6
Canada, Ontario
The Ottawa Hospital Cancer Centre
Ottawa, Ontario, Canada, K1H 8L6
Princess Margaret Cancer Centre
Toronto, Ontario, Canada, M5G 2M9
France
CHU Grenoble/ Hôpital Albert Michallon
Grenoble Cedex 9, France, 38043
CHU de Rennes - Hôpital Pontchaillou - CIC Inserm
Rennes Cedex 9, France, 35033
CHU de Rennes - Hôpital Pontchaillou
Rennes Cedex 9, France, 35033
Institut Universitaire du Cancer de Toulouse (IUCT-O)
Toulouse Cedex 9, France, 31059
Institut Gustave Roussy- Pharmacie-Unite Essais Cliniques
Villejuif, France, 94805
Institut Gustave Roussy (comite poumon-pneumologie)
Villejuif Cedex, France, 94805
Germany
Universitaetsklinik Koeln
Cologne, Germany, 50937
Hong Kong
Department of Clinical Oncology, Prince of Wales Hospital
Shatin, Hong Kong
Italy
Struttura Operativa Complessa Oncologia
Aviano (PN), Italy, 33081
Dipartimento di Oncologia Medica, UO Medicina 1Q A, Unita' Nuovi Farmaci e Terapie Innovative
Milano, Italy, 20132
Unita di Farmacologia Clinica e Nuovi Farmaci
Milano, Italy, 20141
Oncologia Medica
Perugia, Italy, 06132
Japan
National Hospital Organization Kyushu Cancer Center
Fukuoka, Japan, 811-1395
The Cancer Institute Hospital of JFCR
Koto-ku, Tokyo, Japan, 135-8550
Japan, Aichi
Aichi Cancer Center Hospital
Nagoya, Aichi, Japan, 464-8681
Nagoya University Hospital
Nagoya, Aichi, Japan, 466-8560
Japan, Chiba
National Cancer Center Hospital East
Kashiwa, Chiba, Japan, 277-8577
Japan, Ehime
National Hospital Organization Shikoku Cancer Center
Matsuyama, Ehime, Japan, 791-0280
Japan, Hokkaido
Hokkaido University Hospital
Sapporo, Hokkaido, Japan, 060-8648
Japan, Hyogo
Hyogo Cancer Center
Akashi, Hyogo, Japan, 673-8558
Japan, Osaka
Kindai University Hospital
Osakasayama, Osaka, Japan, 589-8511
Japan, Shizuoka
Shizuoka Cancer Center
Sunto-gun, Shizuoka, Japan, 411-8777
Japan, Tokyo
National Cancer Center Hospital
Chuo-ku, Tokyo, Japan, 104-0045
Korea, Republic of
Seoul National University Hospital / Department of Internal Medicine
Seoul, Korea, Republic of, 03080
Singapore
National University Hospital
Singapore, Singapore, 119074
National University Hospital Medical Centre
Singapore, Singapore, 119082
National Cancer Center
Singapore, Singapore, 168583
National Cancer Center
Singapore, Singapore, 169610
Spain
Hospital Universitario Quiron Dexeus
Barcelona, Spain, 08028
Hospital Universitari de la Vall D'Hebron Edificio General. Planta Baja. UITM. Servicio de Oncologia
Barcelona, Spain, 08035
Spain, Madrid
Hospital Universitario Quiron Madrid
Pozuelo de Alarcón, Madrid, Spain, 28223
Spain, Navarra
Clinica Universidad De Navarra
Pamplona, Navarra, Spain, 31008
Switzerland
Hospital of Lausanne (CHUV)
Lausanne, Switzerland, 1011
Kantonsspital Winterthur
Winterthur, Switzerland, 8401
Taiwan
National Taiwan University Hospital
Taipei, Taiwan, 100
Open or close this module IPDSharing
Plan to Share IPD: Yes
Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.
Supporting Information:
Time Frame:
Access Criteria:
URL: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests
Open or close this module References
Open or close this module Document Section
Study Protocol
Document Date: July 15, 2016
Uploaded: 03/05/2018 15:06
File Name: Prot_000.pdf
Statistical Analysis Plan
Document Date: April 6, 2017
Uploaded: 03/05/2018 15:06
File Name: SAP_001.pdf
Study Results
Open or close this module Participant Flow
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)
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
Open or close this module Baseline Characteristics
Arm/Group Title10 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
Arm/Group DescriptionPF-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
Baseline Analysis Population Description
Age, Continuous
Mean (Standard Deviation)
Unit of measure: years
Number Analyzed3 Participants3 Participants3 Participants12 Participants17 Participants3 Participants3 Participants3 Participants3 Participants4 Participants30 Participants27 Participants60 Participants65 Participants46 Participants47 Participants3 Participants332 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]
 
[1]Demographic data were not summarized for the whole study population.
Sex: Female, Male
Measure Type: Count of Participants
Unit of measure: Participants
Number Analyzed3 Participants3 Participants3 Participants12 Participants17 Participants3 Participants3 Participants3 Participants3 Participants4 Participants30 Participants27 Participants60 Participants65 Participants46 Participants47 Participants3 Participants332 Participants
Female
2
66.67%
0
0%
1
33.33%
7
58.33%
11
64.71%
2
66.67%
2
66.67%
2
66.67%
3
100%
2
50%
13
43.33%
17
62.96%
38
63.33%
37
56.92%
25
54.35%
27
57.45%
2
66.67%
191
57.53%
Male
1
33.33%
3
100%
2
66.67%
5
41.67%
6
35.29%
1
33.33%
1
33.33%
1
33.33%
0
0%
2
50%
17
56.67%
10
37.04%
22
36.67%
28
43.08%
21
45.65%
20
42.55%
1
33.33%
141
42.47%
Race/Ethnicity, Customized
Measure Type: Count of Participants
Unit of measure: Participants
Number Analyzed3 Participants3 Participants3 Participants12 Participants17 Participants3 Participants3 Participants3 Participants3 Participants4 Participants30 Participants27 Participants60 Participants65 Participants46 Participants47 Participants3 Participants332 Participants
White
2
66.67%
2
66.67%
3
100%
7
58.33%
13
76.47%
2
66.67%
2
66.67%
1
33.33%
2
66.67%
3
75%
10
33.33%
13
48.15%
25
41.67%
32
49.23%
27
58.7%
25
53.19%
0
0%
169
50.9%
Black
1
33.33%
0
0%
0
0%
0
0%
0
0%
1
33.33%
0
0%
1
33.33%
0
0%
0
0%
1
3.33%
0
0%
1
1.67%
0
0%
0
0%
1
2.13%
0
0%
6
1.81%
Asian
0
0%
1
33.33%
0
0%
3
25%
2
11.76%
0
0%
1
33.33%
0
0%
0
0%
0
0%
17
56.67%
10
37.04%
23
38.33%
23
35.38%
14
30.43%
16
34.04%
3
100%
113
34.04%
Other
0
0%
0
0%
0
0%
0
0%
1
5.88%
0
0%
0
0%
0
0%
0
0%
0
0%
1
3.33%
2
7.41%
1
1.67%
3
4.62%
2
4.35%
3
6.38%
0
0%
13
3.92%
Unspecified
0
0%
0
0%
0
0%
2
16.67%
1
5.88%
0
0%
0
0%
1
33.33%
1
33.33%
1
25%
1
3.33%
2
7.41%
10
16.67%
7
10.77%
3
6.52%
2
4.26%
0
0%
31
9.34%
Open or close this module Outcome Measures
1. Primary Outcome:
Title Number of Participants With Cycle 1 Dose-Limiting Toxicities (DLTs) in Phase 1
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)
Outcome Measure Data
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 Title10 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)
Arm/Group DescriptionPF-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 Analyzed3 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%
1
33.3%
0
0%
0
0%
0
0%
No DLT
3
100%
2
66.7%
3
100%
6
54.5%
8
50%
2
66.7%
1
33.3%
2
100%
3
100%
2
66.7%
Data missing
0
0%
1
33.3%
0
0%
5
45.5%
8
50%
1
33.3%
1
33.3%
0
0%
0
0%
1
33.3%
2. Primary Outcome:
Title Percentage of Participants With Overall and Intracranial Objective Response (Phase 2)
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
Outcome Measure Data
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 TitleEXP-1 (Phase 2)EXP-2 (Phase 2)EXP-3 (Phase 2)EXP-4 (Phase 2)EXP-5 (Phase 2)EXP-6 (Phase 2)
Arm/Group DescriptionTreatment-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 Analyzed30 27 59 65 46 47
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
Objective response
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
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)
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
Outcome Measure Data
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 TitleALK Positive Population (Phase 1)ROS1 Positive Population (Phase 1)
Arm/Group DescriptionThis 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 Analyzed41 12
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
Objective response
39.0(24.2 to 55.5) 50.0(21.1 to 78.9)
Intracranial objective response
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)
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
Outcome Measure Data
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 TitleALK Positive Population (Phase 1)ROS1 Positive Population (Phase 1)
Arm/Group DescriptionThis 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 Analyzed16 6
Median (Full Range)
Unit of Measure: months
TTR
1.4(1.2 to 15.2) 1.4(1.2 to 2.8)
Intracranial TTR
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)
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
Outcome Measure Data
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 TitleALK Positive Population (Phase 1)ROS1 Positive Population (Phase 1)
Arm/Group DescriptionThis 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 Analyzed16 6
Median (95% Confidence Interval)
Unit of Measure: months
DOR
14.06(4.17 to NA) [1] NA(9.69 to NA) [1]
Intra-cranial DOR
NA(14.06 to NA) [2] NA(NA to NA) [2]
[1]NA Explanation: Number of participants with confirmed objective response was too small to provide such summary statistics.
[2]NA Explanation: 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)
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
Outcome Measure Data
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 TitleALK Positive Population (Phase 1)ROS1 Positive Population (Phase 1)
Arm/Group DescriptionThis 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 Analyzed41 12
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
Disease control rate
53.7(37.4 to 69.3) 58.3(27.7 to 84.8)
Intra-cranial disease control rate
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)
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
Outcome Measure Data
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 TitlePhase 1 ITT Population
Arm/Group DescriptionThis reporting group includes all Phase 1 participants in the ITT analysis set.
Overall Number of Participants Analyzed53
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)
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
Outcome Measure Data
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 TitleALK Positive Population (Phase 1)ROS1 Positive Population (Phase 1)
Arm/Group DescriptionThis 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 Analyzed41 12
Median (95% Confidence Interval)
Unit of Measure: months
5.3(2.5 to 11.8) 10.1(1.6 to NA) [1]
[1]NA Explanation: 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)
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
Outcome Measure Data
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 TitleALK Positive Population (Phase 1)ROS1 Positive Population (Phase 1)
Arm/Group DescriptionThis 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 Analyzed41 12
Median (95% Confidence Interval)
Unit of Measure: months
22.3(11.4 to NA) [1] NA(4.7 to NA) [1]
[1]NA Explanation: 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)
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.
Outcome Measure Data
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 Title10 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)
Arm/Group DescriptionPF-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 Analyzed3 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(NA) [1] 489.1(45) 595.5(37) 760.0(58) 1201(19) 202.2(57) 594.9(27) 507.2(51)
[1]NA Explanation: 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)
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).
Outcome Measure Data
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 Title10 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)
Arm/Group DescriptionPF-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 Analyzed3 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(NA) [1] NA(NA) [2] 550.0(23) 600.5(27)
[1]NA Explanation: Summary statistics were not calculated when fewer than 3 participants had reportable values. Individual values are 760 and 1430 ng/mL, respectively.
[2]NA Explanation: 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)
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.
Outcome Measure Data
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 Title10 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)
Arm/Group DescriptionPF-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 Analyzed3 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)
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).
Outcome Measure Data
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 Title10 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)
Arm/Group DescriptionPF-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 Analyzed3 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)
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.
Outcome Measure Data
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 Title10 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)
Arm/Group DescriptionPF-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 Analyzed3 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(NA) [1] 3990(55) 5110(28) 7474(73) 11410(43) 982.4(9) 2996(20) 2925(47)
[1]NA Explanation: 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)
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)
Outcome Measure Data
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 Title10 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)
Arm/Group DescriptionPF-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 Analyzed3 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(NA) [1] NA(NA) [2] 3574(35) 4058(33)
[1]NA Explanation: Summary statistics were not calculated when fewer than 3 participants had reportable values. Individual values are 4480 and 12900 ng*hr/mL, respectively.
[2]NA Explanation: 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)
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.
Outcome Measure Data
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 Title10 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)
Arm/Group DescriptionPF-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 Analyzed1 2 11 15 3 2 1 4
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng*hr/mL
NA(NA) [1] NA(NA) [2] 7663(79) 8236(25) 18340(61) NA(NA) [3] NA(NA) [4] 6318(56)
[1]NA Explanation: Summary statistics were not calculated when fewer than 3 participants had reportable values. The individual value is 698 ng*hr/mL.
[2]NA Explanation: Summary statistics were not calculated when fewer than 3 participants had reportable values. Individual values are 7210 and 7240 ng*hr/mL, respectively.
[3]NA Explanation: Summary statistics were not calculated when fewer than 3 participants had reportable values. Individual values are 2630 and 3690 ng*hr/mL.
[4]NA Explanation: 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)
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.
Outcome Measure Data
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 Title10 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)
Arm/Group DescriptionPF-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 Analyzed1 2 11 15 3 2 1 4
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: liter/hour (L/hr)
NA(NA) [1] NA(NA) [2] 9.788(79) 12.14(25) 10.90(61) NA(NA) [3] NA(NA) [4] 15.83(56)
[1]NA Explanation: Summary statistics were not calculated when fewer than 3 participants had reportable values. The individual value is 14.3 L/hr.
[2]NA Explanation: 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]NA Explanation: 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]NA Explanation: 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)
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)
Outcome Measure Data
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 Title10 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)
Arm/Group DescriptionPF-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 Analyzed3 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(NA) [1] NA(NA) [2] 20.99(35) 22.37(47)
[1]NA Explanation: 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]NA Explanation: 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)
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.
Outcome Measure Data
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 Title10 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)
Arm/Group DescriptionPF-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 Analyzed1 2 11 15 3 2 1 4
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: liters (L)
NA(NA) [1] NA(NA) [2] 367.9(54) 356.3(39) 307.8(41) NA(NA) [3] NA(NA) [4] 378.3(54)
[1]NA Explanation: Summary statistics were not calculated when fewer than 3 participants had reportable values. The individual value is 373 L.
[2]NA Explanation: Summary statistics were not calculated when fewer than 3 participants had reportable values. Individual values are 166 and 307 L, respectively.
[3]NA Explanation: Summary statistics were not calculated when fewer than 3 participants had reportable values. Individual values are 362 and 472 L, respectively.
[4]NA Explanation: 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)
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)
Outcome Measure Data
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 Title10 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)
Arm/Group DescriptionPF-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 Analyzed3 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(NA) [1] 1.121(0.44575) 1.071(0.31138) 1.000(0.79137) 0.6500(NA) [1] NA(NA) [2] 1.231(0.35228) 1.523(0.29569)
[1]NA Explanation: Standard deviation was not calculated when fewer than 3 participants had reportable values.
[2]NA Explanation: 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)
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.
Outcome Measure Data
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 Title10 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)
Arm/Group DescriptionPF-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 Analyzed1 2 11 15 3 2 1 4
Mean (Standard Deviation)
Unit of Measure: hours (hr)
NA(NA) [1] 23.70(NA) [2] 27.22(8.2961) 20.89(5.0308) 19.80(3.3045) 25.55(NA) [3] NA(NA) [4] 17.18(5.1874)
[1]NA Explanation: Summary statistics were not calculated when fewer than 3 participants had reportable values. The individual value is 18.0 hr.
[2]NA Explanation: Standard deviation was not calculated when fewer than 3 participants had reportable values. Individual values are 16.6 and 30.8 hr, respectively.
[3]NA Explanation: Standard deviation was not calculated when fewer than 3 participants had reportable values. Individual values are 24.6 and 26.5 hr, respectively.
[4]NA Explanation: 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)
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)
Outcome Measure Data
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 Title10 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)
Arm/Group DescriptionPF-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 Analyzed1 2 11 14 2 1 1 3
Mean (Standard Deviation)
Unit of Measure: ratio
NA(NA) [1] 0.5600(NA) [2] 0.6131(0.29021) 0.6603(0.18604) 0.3935(NA) [3] NA(NA) [4] NA(NA) [5] 0.7687(0.13552)
[1]NA Explanation: These summary statistics were not calculated when fewer than 3 participants had reportable values. The individual value is 0.993.
[2]NA Explanation: Standard deviation was not calculated when fewer than 3 participants had reportable values. Individual values are 0.401 and 0.719, respectively.
[3]NA Explanation: Standard deviation was not calculated when fewer than 3 participants had reportable values. Individual values are 0.384 and 0.403, respectively.
[4]NA Explanation: These summary statistics were not calculated when fewer than 3 participants had reportable values. The individual value is 0.815.
[5]NA Explanation: 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)
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
Outcome Measure Data
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 Title100 mg QD (Phase 1)
Arm/Group DescriptionPF-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 Analyzed3
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)
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
Outcome Measure Data
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 Title100 mg QD (Phase 1)
Arm/Group DescriptionPF-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 Analyzed3
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)
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
Outcome Measure Data
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 Title25 mg QD (Phase 1)150 mg QD (Phase 1)
Arm/Group DescriptionPF-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 Analyzed3 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)
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
Outcome Measure Data
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 Title25 mg QD (Phase 1)150 mg QD (Phase 1)
Arm/Group DescriptionPF-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 Analyzed3 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)
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
Outcome Measure Data
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 Title25 mg QD (Phase 1)150 mg QD (Phase 1)
Arm/Group DescriptionPF-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 Analyzed3 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)
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
Outcome Measure Data
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 Title25 mg QD (Phase 1)150 mg QD (Phase 1)
Arm/Group DescriptionPF-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 Analyzed3 3
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng*hr/mL
 
Day -7
Number Analyzed Participants Participants
54.53(43) NA(NA) [1]
Cycle 1 Day 15
Number Analyzed Participants Participants
21.32(18) 16.09(29)
[1]NA Explanation: 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)
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
Outcome Measure Data
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 Title25 mg QD (Phase 1)150 mg QD (Phase 1)
Arm/Group DescriptionPF-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 Analyzed3 3
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: L/hr
 
Day -7
Number Analyzed Participants Participants
36.68(43) NA(NA) [1]
Cycle 1 Day 15
Number Analyzed Participants Participants
93.86(18) 124.2(29)
[1]NA Explanation: 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)
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
Outcome Measure Data
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 Title25 mg QD (Phase 1)150 mg QD (Phase 1)
Arm/Group DescriptionPF-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 Analyzed3 3
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: L
 
Day -7
Number Analyzed Participants Participants
229.0(7) NA(NA) [1]
Cycle 1 Day 15
Number Analyzed Participants Participants
404.4(51) 702.2(100)
[1]NA Explanation: 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)
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
Outcome Measure Data
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 Title25 mg QD (Phase 1)150 mg QD (Phase 1)
Arm/Group DescriptionPF-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 Analyzed3 3
Mean (Standard Deviation)
Unit of Measure: hr
 
Day -7
Number Analyzed Participants Participants
4.620(1.9328) 5.120(NA) [1]
Cycle 1 Day 15
Number Analyzed Participants Participants
3.343(2.0358) 5.257(5.0639)
[1]NA Explanation: 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)
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
Outcome Measure Data
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 TitleALK Positive Population (Phase 1)
Arm/Group DescriptionThis reporting arm includes all Phase 1 participants who had documented ALK rearrangement.
Overall Number of Participants Analyzed39
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)
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
Outcome Measure Data
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 TitleALK Positive Population (Phase 1)
Arm/Group DescriptionThis reporting arm includes all Phase 1 participants who had documented ALK rearrangement.
Overall Number of Participants Analyzed30
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)
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)
Outcome Measure Data
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 TitlePhase 1 PRO Evaluable Population
Arm/Group DescriptionThis 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 Analyzed43
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%
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%
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)
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)
Outcome Measure Data
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 TitlePhase 1 PRO Evaluable Population
Arm/Group DescriptionThis 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 Analyzed43
Measure Type: Count of Participants
Unit of Measure: Participants
Improved in dyspnea
10
23.3%
Stable in dyspnea
22
51.2%
Worsened in dyspnea
11
25.6%
Improved in coughing
23
53.5%
Stable in coughing
12
27.9%
Worsened in coughing
8
18.6%
Improved in hemoptysis
1
2.3%
Stable in hemoptysis
42
97.7%
Worsened in hemoptysis
0
0%
Improved in sore mouth
0
0%
Stable in sore mouth
40
93%
Worsened in sore mouth
3
7%
Improved in dysphagia
4
9.3%
Stable in dysphagia
37
86%
Worsened in dysphagia
2
4.7%
Improved in peripheral neuropathy
6
14%
Stable in peripheral neuropathy
19
44.2%
Worsened in peripheral neuropathy
18
41.9%
Improved in alopecia
3
7%
Stable in alopecia
30
69.8%
Worsened in alopecia
9
20.9%
Improved in chest pain
16
37.2%
Stable in chest pain
22
51.2%
Worsened in chest pain
5
11.6%
Improved in arm or shoulder pain
10
23.3%
Stable in arm or shoulder pain
28
65.1%
Worsened in arm or shoulder pain
5
11.6%
Improved in pain in other parts
19
44.2%
Stable in pain in other parts
14
32.6%
Worsened in pain in other parts
10
23.3%
36. Secondary Outcome:
Title Change From Baseline in Mini Mental State Examination (MMSE) Score (Phase 1)
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)
Outcome Measure Data
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 Title10 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)
Arm/Group DescriptionPF-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 Analyzed2 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 Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants
1.0(1.41) -0.5(0.71) -0.9(2.27) 0.8(1.39) 0.0(NA) [1] 0.0(NA) [1]
Cycle 2 Day 1
Number Analyzed Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants
2.0(NA) [1] -0.3(0.58) 2.0(NA) [1] 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 Participants Participants Participants Participants Participants Participants Participants Participants Participants 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(NA) [1] -1.0(1.00)
Cycle 4 Day 1
Number Analyzed Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants
5.0(NA) [1] 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(NA) [1] -0.7(1.15)
Cycle 5 Day 1
Number Analyzed Participants Participants Participants Participants Participants Participants Participants Participants Participants 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(NA) [1] -0.5(0.71)
Cycle 6 Day 1
Number Analyzed Participants Participants Participants Participants Participants Participants Participants Participants Participants 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(NA) [1] -1.3(2.31)
Cycle 7 Day 1
Number Analyzed Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants
2.0(NA) [1] 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(NA) [1] -0.7(1.15)
Cycle 8 Day 1
Number Analyzed Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants
-4.0(NA) [1] 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(NA) [1] 0.0(0.00)
Cycle 9 Day 1
Number Analyzed Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants
0.0(0.00) 0.0(NA) [1] -1.0(2.31) 0.3(2.10) 6.0(8.49) 6.0(NA) [1] -0.3(0.58)
Cycle 10 Day 1
Number Analyzed Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants
-5.0(NA) [1] 0.5(0.71) 0.0(NA) [1] 0.0(0.00) -0.1(0.88) 6.5(9.19) 6.0(NA) [1] 0.0(NA) [1] -1.7(1.53)
Cycle 11 Day 1
Number Analyzed Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants
-0.5(0.71) 0.0(NA) [1] 0.3(1.70) -0.2(1.53) 7.0(8.49) 3.5(3.54) 0.0(NA) [1] 0.0(0.00)
Cycle 12 Day 1
Number Analyzed Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants
0.5(0.71) -0.6(2.19) -0.2(2.33) 6.5(9.19) 3.5(3.54) 0.0(NA) [1] -0.7(0.58)
Cycle 13 Day 1
Number Analyzed Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants
0.5(0.71) 0.8(1.79) 0.5(2.22) 5.5(7.78) 3.0(4.24) 0.0(NA) [1] -0.5(0.71)
Cycle 14 Day 1
Number Analyzed Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants
0.5(0.71) -0.3(3.20) 0.3(0.79) 6.0(8.49) 2.5(3.54) 0.0(NA) [1] 0.0(0.00)
Cycle 15 Day 1
Number Analyzed Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants
0.5(0.71) -1.7(5.43) 0.1(1.36) 4.0(4.24) 0.0(NA) [1] -0.3(0.58)
Cycle 16 Day 1
Number Analyzed Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants
0.0(1.41) -0.2(2.49) -0.2(1.99) 1.0(NA) [1] 1.5(6.36) 0.0(NA) [1] 0.0(0.00)
Cycle 17 Day 1
Number Analyzed Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants
-2.0(2.83) 0.6(1.95) 0.1(1.17) -3.0(NA) [1] 4.0(4.24) 0.0(NA) [1] -1.3(1.53)
Cycle 18 Day 1
Number Analyzed Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants
-0.5(0.71) 0.8(1.79) 0.0(1.73) -2.0(NA) [1] 3.0(4.24) 0.0(0.00)
Cycle 19 Day 1
Number Analyzed Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants
-0.5(0.71) 0.8(1.79) -0.6(2.65) 0.0(NA) [1] 3.5(4.95) 0.0(NA) [1] -0.5(0.71)
Cycle 20 Day 1
Number Analyzed Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants
0.0(0.00) 0.0(1.41) 0.7(2.12) 0.0(NA) [1] 3.5(3.54) 0.0(NA) [1] -0.5(0.71)
Cycle 21 Day 1
Number Analyzed Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants
-0.5(0.71) 0.0(1.41) 0.1(2.09) 4.0(4.24) 0.0(NA) [1] -0.5(0.71)
Cycle 22 Day 1
Number Analyzed Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants
0.0(0.00) 0.4(1.52) 0.1(1.45) 0.0(NA) [1] 3.5(3.54) -1.0(NA) [1] -0.3(0.58)
Cycle 23 Day 1
Number Analyzed Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants
0.5(0.71) 0.0(1.41) 0.1(1.81) -1.0(NA) [1] 1.5(3.54) 0.0(NA) [1] -2.3(4.04)
Cycle 24 Day 1
Number Analyzed Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants
0.5(0.71) -0.4(0.89) 0.6(0.74) 1.0(NA) [1] 1.5(4.95) 0.0(NA) [1] 0.0(0.00)
Cycle 25 Day 1
Number Analyzed Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants
0.0(0.00) 0.8(1.79) -0.9(2.27) -2.0(NA) [1] 2.5(4.95) 0.0(NA) [1] 0.0(0.00)
Cycle 26 Day 1
Number Analyzed Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants
0.5(0.71) 0.8(1.79) -0.4(2.77) -1.0(NA) [1] 2.0(4.24) 0.0(NA) [1] -0.3(0.58)
Cycle 27 Day 1
Number Analyzed Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants
0.5(0.71) 0.8(1.79) -0.1(2.67) -1.0(NA) [1] 3.5(3.54) 0.0(NA) [1] -1.0(1.41)
Cycle 28 Day 1
Number Analyzed Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants
0.5(0.71) 1.0(2.00) 0.7(0.76) -2.0(NA) [1] 3.0(2.83) 0.0(NA) [1] 0.0(0.00)
Cycle 29 Day 1
Number Analyzed Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants
-1.5(2.12) 0.5(1.73) 0.1(1.81) 0.0(NA) [1] 3.5(3.54) 0.0(NA) [1] 0.0(0.00)
Cycle 30 Day 1
Number Analyzed Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants
0.0(0.00) 0.8(1.50) 0.4(0.55) 0.0(NA) [1] 3.0(2.83) 0.0(NA) [1] -1.0(1.00)
Cycle 31 Day 1
Number Analyzed Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants
0.5(0.71) 1.0(2.65) 0.7(0.82) 0.0(NA) [1] 3.0(4.24) 0.0(0.00)
Cycle 32 Day 1
Number Analyzed Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants
0.0(0.00) 1.3(2.31) 0.4(0.55) 3.5(3.54) 0.0(NA) [1] 0.0(0.00)
Cycle 33 Day 1
Number Analyzed Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants
0.0(0.00) 1.3(2.31) 0.5(0.58) 3.5(3.54) 0.0(NA) [1] 0.0(0.00)
Cycle 34 Day 1
Number Analyzed Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants
0.0(0.00) 0.0(0.00) 0.3(0.50) 4.0(4.24) 0.0(NA) [1] 0.0(0.00)
Cycle 35 Day 1
Number Analyzed Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants
0.5(0.71) 0.0(NA) [1] 0.3(0.50) 4.0(4.24) 0.0(NA) [1] 0.0(NA) [1]
Cycle 36 Day 1
Number Analyzed Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants
-0.5(0.71) 0.0(NA) [1] 0.0(0.00) 4.0(4.24) 0.0(NA) [1] 0.0(NA) [1]
Cycle 37 Day 1
Number Analyzed Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants
0.0(0.00) -1.0(NA) [1] 0.0(0.00) 3.5(4.95)
Cycle 38 Day 1
Number Analyzed Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants
0.0(0.00) 0.0(NA) [1] 0.0(0.00) 3.0(2.83) 0.0(NA) [1]
Cycle 39 Day 1
Number Analyzed Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants
0.0(NA) [1] 0.0(NA) [1] -0.5(0.71) 3.5(4.95)
Cycle 40 Day 1
Number Analyzed Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants
0.5(0.71) -1.0(NA) [1] 0.0(NA) [1] 4.0(4.24)
Cycle 41 Day 1
Number Analyzed Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants
0.5(0.71) 0.0(NA) [1] 0.0(NA) [1] 1.5(6.36)
Cycle 42 Day 1
Number Analyzed Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants
-0.5(0.71) 0.0(NA) [1] 0.0(NA) [1] 4.0(4.24)
Cycle 43 Day 1
Number Analyzed Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants
0.0(0.00) 0.0(NA) [1] 4.0(4.24)
Cycle 44 Day 1
Number Analyzed Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants
1.0(NA) [1] -1.0(NA) [1] 3.0(4.24)
Cycle 45 Day 1
Number Analyzed Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants
1.0(NA) [1] 0.0(NA) [1] 1.0(NA) [1]
Cycle 46 Day 1
Number Analyzed Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants
0.0(NA) [1] -1.0(NA) [1]
Cycle 47 Day 1
Number Analyzed Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants
0.0(NA) [1] 0.0(NA) [1]
Cycle 48 Day 1
Number Analyzed Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants
-3.0(NA) [1] 0.0(NA) [1]
Cycle 49 Day 1
Number Analyzed Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants
0.5(0.71)
Cycle 50 Day 1
Number Analyzed Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants
-3.0(NA) [1]
Cycle 51 Day 1
Number Analyzed Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants
-0.5(0.71)
Cycle 52 Day 1
Number Analyzed Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants
1.0(NA) [1]
End of treatment
Number Analyzed Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants
-8.0(NA) [1] 0.7(1.15) -2.0(NA) [1] -2.3(5.19) -15.0(NA) [1] 0.0(NA) [1]
[1]NA Explanation: 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)
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
Outcome Measure Data
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 TitleEXP-1 (Phase 2)EXP-2 (Phase 2)EXP-3 (Phase 2)EXP-4 (Phase 2)EXP-5 (Phase 2)EXP-6 (Phase 2)
Arm/Group DescriptionTreatment-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 Analyzed27 20 30 27 16 17
Median (Full Range)
Unit of Measure: months
TTR
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
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)
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
Outcome Measure Data
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 TitleEXP-1 (Phase 2)EXP-2 (Phase 2)EXP-3 (Phase 2)EXP-4 (Phase 2)EXP-5 (Phase 2)EXP-6 (Phase 2)
Arm/Group DescriptionTreatment-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 Analyzed27 20 30 27 16 17
Median (95% Confidence Interval)
Unit of Measure: months
DOR
NA(10.02 to NA) [1] NA(NA to NA) [1] NA(6.80 to NA) [1] 6.93(5.22 to NA) [1] NA(4.17 to NA) [1] 13.83(11.10 to NA) [1]
Intra-cranial DOR
9.15(8.28 to 10.02) NA(NA to NA) [2] NA(8.38 to NA) [2] 14.52(NA to NA) [2] 8.31(6.93 to NA) [2] NA(4.99 to NA) [2]
[1]NA Explanation: Majority of the participants with confirmed response had their DOR data censored, therefore, it's impossible to derive such summary statistics.
[2]NA Explanation: 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)
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
Outcome Measure Data
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 TitleEXP-1 (Phase 2)EXP-2 (Phase 2)EXP-3 (Phase 2)EXP-4 (Phase 2)EXP-5 (Phase 2)EXP-6 (Phase 2)
Arm/Group DescriptionTreatment-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 Analyzed30 27 59 65 46 47
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
Disease control rate
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
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)
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
Outcome Measure Data
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 TitleEXP-2 (Phase 2)EXP-3 (Phase 2)EXP-4 (Phase 2)EXP-5 (Phase 2)
Arm/Group DescriptionParticipants 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 Analyzed27 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)
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
Outcome Measure Data
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 TitleEXP-1 (Phase 2)EXP-2 (Phase 2)EXP-3 (Phase 2)EXP-4 (Phase 2)EXP-5 (Phase 2)EXP-6 (Phase 2)
Arm/Group DescriptionTreatment-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 Analyzed30 27 59 65 46 47
Median (95% Confidence Interval)
Unit of Measure: months
TTP
NA(11.4 to NA) [1] NA(NA to NA) [1] 9.0(5.5 to NA) [1] 8.4(5.6 to 13.7) 7.1(4.1 to 12.5) 12.5(8.2 to NA) [1]
Intracranial
11.4(9.6 to 11.4) NA(NA to NA) [2] NA(6.9 to NA) [2] 15.7(11.0 to 15.7) NA(8.3 to NA) [2] NA(NA to NA) [2]
[1]NA Explanation: Number of participants with progression is too small to provide such summary statistics.
[2]NA Explanation: 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)
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
Outcome Measure Data
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 TitlePhase 2 ITT Population
Arm/Group DescriptionThis reporting group includes all Phase 2 participants in the ITT analysis set.
Overall Number of Participants Analyzed274
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)
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
Outcome Measure Data
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 TitleEXP-1 (Phase 2)EXP-2 (Phase 2)EXP-3 (Phase 2)EXP-4 (Phase 2)EXP-5 (Phase 2)EXP-6 (Phase 2)
Arm/Group DescriptionTreatment-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 Analyzed30 27 59 65 46 47
Median (95% Confidence Interval)
Unit of Measure: months
NA(11.4 to NA) [1] NA(NA to NA) [1] 8.2(5.5 to NA) [1] 7.3(5.4 to 11.0) 5.6(4.0 to 12.5) 9.6(4.7 to NA) [1]
[1]NA Explanation: 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)
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
Outcome Measure Data
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 TitleEXP-1 (Phase 2)EXP-2 (Phase 2)EXP-3 (Phase 2)EXP-4 (Phase 2)EXP-5 (Phase 2)EXP-6 (Phase 2)
Arm/Group DescriptionTreatment-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 Analyzed30 27 59 65 46 47
Median (95% Confidence Interval)
Unit of Measure: months
NA(NA to NA) [1] NA(12.1 to NA) [1] NA(14.4 to NA) [1] NA(14.7 to NA) [1] NA(9.7 to NA) [1] NA(NA to NA) [1]
[1]NA Explanation: 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)
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
Outcome Measure Data
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 TitlePhase 2 and Japan LIC PK Analysis Set
Arm/Group DescriptionPK 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 Analyzed22
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng/mL
 
Day -7
Number Analyzed Participants
695.2(40)
Cycle 1 Day 15
Number Analyzed Participants
576.5(42)
46. Secondary Outcome:
Title Time for Cmax (Tmax) of PF-06463922 (Phase 2)
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
Outcome Measure Data
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 TitlePhase 2 and Japan LIC PK Analysis Set
Arm/Group DescriptionPK 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 Analyzed22
Median (Full Range)
Unit of Measure: hours
 
Day -7
Number Analyzed Participants
1.15(0.50 to 4.02)
Cycle 1 Day 15
Number Analyzed 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)
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
Outcome Measure Data
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 TitlePhase 2 and Japan LIC PK Analysis Set
Arm/Group DescriptionPK 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 Analyzed16
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)
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
Outcome Measure Data
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 TitlePhase 2 and Japan LIC PK Analysis Set
Arm/Group DescriptionPK 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 Analyzed22
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng*hour/mL
 
Day -7
Number Analyzed Participants
5308(36)
Cycle 1 Day 15
Number Analyzed Participants
5650(39)
49. Secondary Outcome:
Title Apparent Oral Clearance (CL/F) of PF-06463922 (Phase 2)
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
Outcome Measure Data
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 TitlePhase 2 and Japan LIC PK Analysis Set
Arm/Group DescriptionPK 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 Analyzed22
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: liter/hour
 
Day -7
Number Analyzed Participants
11.01(35)
Cycle 1 Day 15
Number Analyzed Participants
17.70(39)
50. Secondary Outcome:
Title Apparent Volume of Distribution (Vz/F) of PF-06463922 (Phase 2)
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
Outcome Measure Data
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 TitlePhase 2 and Japan LIC PK Analysis Set
Arm/Group DescriptionPK 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 Analyzed16
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)
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
Outcome Measure Data
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 TitlePhase 2 and Japan LIC PK Analysis Set
Arm/Group DescriptionPK 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 Analyzed16
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)
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
Outcome Measure Data
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 TitlePhase 2 and Japan LIC PK Analysis Set
Arm/Group DescriptionPK 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 Analyzed20
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)
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
Outcome Measure Data
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 TitlePhase 2 and Japan LIC PK Analysis Set
Arm/Group DescriptionPK 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 Analyzed14
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)
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
Outcome Measure Data
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 TitleEXP-1 (Phase 2)EXP-2 (Phase 2)EXP-3 (Phase 2)EXP-4 (Phase 2)EXP-5 (Phase 2)
Arm/Group DescriptionTreatment-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 Analyzed30 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)
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
Outcome Measure Data
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 TitleEXP-1 (Phase 2)EXP-2 (Phase 2)EXP-3 (Phase 2)EXP-4 (Phase 2)EXP-5 (Phase 2)
Arm/Group DescriptionTreatment-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 Analyzed26 26 52 48 33
Measure Type: Count of Participants
Unit of Measure: Participants
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)
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
Outcome Measure Data
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 TitleEXP-1 (Phase 2)EXP-2 (Phase 2)EXP-3 (Phase 2)EXP-4 (Phase 2)EXP-5 (Phase 2)EXP-6 (Phase 2)
Arm/Group DescriptionTreatment-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 Analyzed30 26 55 60 43 40
Measure Type: Count of Participants
Unit of Measure: Participants
Improved in global QoL
17
56.7%
11
42.3%
18
32.7%
25
41.7%
18
41.9%
20
50%
Stable in global QoL
10
33.3%
13
50%
26
47.3%
22
36.7%
17
39.5%
13
32.5%
Worsened in global QoL
3
10%
2
7.7%
11
20%
13
21.7%
8
18.6%
7
17.5%
Improved in physical functioning
10
33.3%
7
26.9%
14
25.5%
23
38.3%
8
18.6%
11
27.5%
Stable in physical functioning
14
46.7%
19
73.1%
37
67.3%
27
45%
25
58.1%
24
60%
Worsened in physical functioning
6
20%
0
0%
4
7.3%
10
16.7%
10
23.3%
5
12.5%
Improved in role functioning
12
40%
8
30.8%
18
32.7%
25
41.7%
16
37.2%
17
42.5%
Stable in role functioning
11
36.7%
15
57.7%
31
56.4%
19
31.7%
16
37.2%
19
47.5%
Worsened in role functioning
7
23.3%
3
11.5%
6
10.9%
16
26.7%
11
25.6%
3
7.5%
Improved in emotional functioning
12
40%
12
46.2%
18
32.7%
21
35%
18
41.9%
17
42.5%
Stable in emotional functioning
14
46.7%
14
53.8%
29
52.7%
32
53.3%
20
46.5%
20
50%
Worsened in emotional functioning
4
13.3%
0
0%
8
14.5%
7
11.7%
5
11.6%
3
7.5%
Improved in cognitive functioning
10
33.3%
3
11.5%
11
20%
13
21.7%
13
30.2%
12
30%
Stable in cognitive functioning
12
40%
15
57.7%
31
56.4%
35
58.3%
16
37.2%
22
55%
Worsened in cognitive functioning
8
26.7%
8
30.8%
13
23.6%
12
20%
14
32.6%
6
15%
Improved in social functioning
14
46.7%
7
26.9%
18
32.7%
22
36.7%
12
27.9%
13
32.5%
Stable in social functioning
13
43.3%
17
65.4%
32
58.2%
28
46.7%
23
53.5%
22
55%
Worsened in social functioning
3
10%
2
7.7%
5
9.1%
10
16.7%
8
18.6%
5
12.5%
Improved in fatigue
17
56.7%
14
53.8%
22
40%
29
48.3%
26
60.5%
17
42.5%
Stable in fatigue
9
30%
11
42.3%
25
45.5%
22
36.7%
11
25.6%
19
47.5%
Worsened in fatigue
4
13.3%
1
3.8%
8
14.5%
9
15%
6
14%
4
10%
Improved in nausea and vomiting
8
26.7%
4
15.4%
11
20%
16
26.7%
14
32.6%
10
25%
Stable in nausea and vomiting
22
73.3%
22
84.6%
43
78.2%
38
63.3%
28
65.1%
28
70%
Worsened in nausea and vomiting
0
0%
0
0%
1
1.8%
6
10%
1
2.3%
2
5%
Improved in pain
14
46.7%
9
34.6%
19
34.5%
23
38.3%
18
41.9%
21
52.5%
Stable in pain
11
36.7%
15
57.7%
27
49.1%
26
43.3%
20
46.5%
12
30%
Worsened in pain
5
16.7%
2
7.7%
9
16.4%
11
18.3%
5
11.6%
7
17.5%
Improved in dyspnea
15
50%
9
34.6%
10
18.2%
21
35%
14
32.6%
13
32.5%
Stable in dyspnea
11
36.7%
14
53.8%
34
61.8%
22
36.7%
21
48.8%
19
47.5%
Worsened in dyspnea
4
13.3%
3
11.5%
11
20%
17
28.3%
8
18.6%
8
20%
Improved in insomnia
19
63.3%
8
30.8%
19
34.5%
28
46.7%
22
51.2%
19
47.5%
Stable in insomnia
10
33.3%
14
53.8%
28
50.9%
23
38.3%
14
32.6%
18
45%
Worsened in insomnia
1
3.3%
4
15.4%
8
14.5%
9
15%
7
16.3%
3
7.5%
Improved in appetite loss
14
46.7%
4
15.4%
17
30.9%
29
48.3%
22
51.2%
20
50%
Stable in appetite loss
16
53.3%
22
84.6%
37
67.3%
26
43.3%
21
48.8%
20
50%
Worsened in appetite loss
0
0%
0
0%
1
1.8%
5
8.3%
0
0%
0
0%
Improved in constipation
10
33.3%
6
23.1%
9
16.4%
15
25%
11
25.6%
13
32.5%
Stable in constipation
13
43.3%
18
69.2%
36
65.5%
33
55%
28
65.1%
23
57.5%
Worsened in constipation
7
23.3%
2
7.7%
10
18.2%
12
20%
4
9.3%
4
10%
Improved in diarrhea
5
16.7%
3
11.5%
8
14.5%
9
15%
11
25.6%
8
20%
Stable in diarrhea
19
63.3%
22
84.6%
42
76.4%
40
66.7%
26
60.5%
28
70%
Worsened in diarrhea
6
20%
1
3.8%
5
9.1%
11
18.3%
6
14%
4
10%
Improved in financial difficulties
10
33.3%
6
23.1%
11
20%
13
21.7%
11
25.6%
10
25%
Stable in financial difficulties
18
60%
18
69.2%
33
60%
38
63.3%
22
51.2%
26
65%
Worsened in financial difficulties
2
6.7%
2
7.7%
11
20%
9
15%
10
23.3%
4
10%
57. Secondary Outcome:
Title Number of Participants Who Improved, Worsened or Remained Stable in EORTC QLQ-LC13 (Phase 2)
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
Outcome Measure Data
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 TitleEXP-1 (Phase 2)EXP-2 (Phase 2)EXP-3 (Phase 2)EXP-4 (Phase 2)EXP-5 (Phase 2)EXP-6 (Phase 2)
Arm/Group DescriptionTreatment-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 Analyzed30 26 55 60 42 41
Measure Type: Count of Participants
Unit of Measure: Participants
Improved in dyspnea
11
36.7%
5
19.2%
11
20%
20
33.3%
12
28.6%
13
31.7%
Stable in dyspnea
16
53.3%
19
73.1%
36
65.5%
26
43.3%
22
52.4%
22
53.7%
Worsened in dyspnea
3
10%
2
7.7%
8
14.5%
14
23.3%
8
19%
6
14.6%
Improved in coughing
18
60%
9
34.6%
22
40%
27
45%
18
42.9%
17
41.5%
Stable in coughing
9
30%
14
53.8%
26
47.3%
27
45%
15
35.7%
17
41.5%
Worsened in coughing
3
10%
3
11.5%
7
12.7%
6
10%
9
21.4%
7
17.1%
Improved in hemoptysis
4
13.3%
0
0%
7
12.7%
5
8.3%
5
11.9%
4
9.8%
Stable in hemoptysis
24
80%
26
100%
47
85.5%
53
88.3%
34
81%
36
87.8%
Worsened in hemoptysis
2
6.7%
0
0%
1
1.8%
2
3.3%
3
7.1%
1
2.4%
Improved in sore mouth
0
0%
2
7.7%
4
7.3%
10
16.7%
2
4.8%
5
12.2%
Stable in sore mouth
24
80%
21
80.8%
45
81.8%
39
65%
32
76.2%
28
68.3%
Worsened in sore mouth
6
20%
3
11.5%
6
10.9%
11
18.3%
8
19%
8
19.5%
Improved in dysphagia
3
10%
1
3.8%
5
9.1%
7
11.7%
4
9.5%
5
12.2%
Stable in dysphagia
24
80%
25
96.2%
44
80%
47
78.3%
33
78.6%
30
73.2%
Worsened in dysphagia
3
10%
0
0%
6
10.9%
6
10%
5
11.9%
6
14.6%
Improved in peripheral neuropathy
2
6.7%
4
15.4%
9
16.4%
5
8.3%
6
14.3%
8
19.5%
Stable in peripheral neuropathy
10
33.3%
13
50%
25
45.5%
32
53.3%
23
54.8%
19
46.3%
Worsened in peripheral neuropathy
18
60%
9
34.6%
21
38.2%
23
38.3%
13
31%
14
34.1%
Improved in alopecia
1
3.3%
1
3.8%
2
3.6%
10
16.7%
8
19%
9
22%
Stable in alopecia
19
63.3%
22
84.6%
41
74.5%
38
63.3%
27
64.3%
26
63.4%
Worsened in alopecia
10
33.3%
3
11.5%
12
21.8%
12
20%
7
16.7%
6
14.6%
Improved in chest pain
11
36.7%
5
19.2%
14
25.5%
18
30%
14
33.3%
14
34.1%
Stable in chest pain
15
50%
19
73.1%
36
65.5%
33
55%
25
59.5%
22
53.7%
Worsened in chest pain
4
13.3%
2
7.7%
4
7.3%
9
15%
3
7.1%
5
12.2%
Improved in arm or shoulder pain
9
30%
4
15.4%
13
23.6%
14
23.3%
12
28.6%
12
29.3%
Stable in arm or shoulder pain
16
53.3%
18
69.2%
33
60%
37
61.7%
21
50%
21
51.2%
Worsened in arm or shoulder pain
5
16.7%
4
15.4%
9
16.4%
9
15%
9
21.4%
8
19.5%
Improved in pain in other parts
10
33.3%
5
19.2%
18
32.7%
19
31.7%
14
33.3%
17
41.5%
Stable in pain in other parts
14
46.7%
12
46.2%
23
41.8%
25
41.7%
11
26.2%
17
41.5%
Worsened in pain in other parts
6
20%
9
34.6%
14
25.5%
16
26.7%
16
38.1%
7
17.1%
58. Secondary Outcome:
Title Number of Participants With Treatment-Emergent Adverse Events (Phase 1 and Phase 2)
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
Outcome Measure Data
Analysis Population Description
The safety analysis set included all enrolled participants who received at least 1 dose of PF-06463922.
 
Arm/Group Title10 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)
Arm/Group DescriptionPF-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 Analyzed3 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%
3
100%
3
100%
12
100%
17
100%
3
100%
3
100%
3
100%
3
100%
4
100%
30
100%
27
100%
59
98.3%
65
100%
46
100%
47
100%
AEs (treatment-related)
3
100%
3
100%
3
100%
11
91.7%
16
94.1%
3
100%
3
100%
1
33.3%
3
100%
4
100%
30
100%
27
100%
55
91.7%
61
93.8%
43
93.5%
45
95.7%
SAEs (all causality)
3
100%
1
33.3%
1
33.3%
4
33.3%
9
52.9%
3
100%
1
33.3%
2
66.7%
2
66.7%
2
50%
8
26.7%
5
18.5%
18
30%
24
36.9%
18
39.1%
16
34%
SAEs (treatment-related)
1
33.3%
0
0%
0
0%
1
8.3%
1
5.9%
3
100%
0
0%
0
0%
0
0%
1
25%
3
10%
0
0%
5
8.3%
4
6.2%
5
10.9%
2
4.3%
Grade 1 (all causality)
0
0%
0
0%
1
33.3%
1
8.3%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
3
10%
0
0%
5
8.3%
3
4.6%
3
6.5%
0
0%
Grade 2 (all causality)
0
0%
1
33.3%
2
66.7%
4
33.3%
5
29.4%
0
0%
1
33.3%
1
33.3%
1
33.3%
0
0%
12
40%
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%
5
41.7%
8
47.1%
0
0%
2
66.7%
1
33.3%
0
0%
1
25%
12
40%
12
44.4%
24
40%
28
43.1%
20
43.5%
26
55.3%
Grade 4 (all causality)
0
0%
1
33.3%
0
0%
1
8.3%
1
5.9%
1
33.3%
0
0%
1
33.3%
1
33.3%
3
75%
3
10%
3
11.1%
3
5%
7
10.8%
4
8.7%
3
6.4%
Grade 5 (all causality)
1
33.3%
1
33.3%
0
0%
1
8.3%
3
17.6%
2
66.7%
0
0%
0
0%
1
33.3%
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
Description Hematology evaluation included hemoglobin, platelets, white blood cell, absolute neutrophils, absolute lymphocytes, absolute monocytes, absolute eosinophils and absolute basophils.
Time Frame 3 years
Outcome Measure Data
Analysis Population Description
The safety analysis set included all enrolled participants who received at least 1 dose of PF-06463922.
 
Arm/Group Title10 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)
Arm/Group DescriptionPF-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 Analyzed3 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
3
100%
3
100%
3
100%
8
66.7%
16
94.1%
3
100%
3
100%
3
100%
3
100%
4
100%
20
66.7%
14
51.9%
50
83.3%
48
75%
35
77.8%
32
68.1%
Hemoglobin increased
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
2
66.7%
2
66.7%
2
66.7%
6
50%
4
23.5%
3
100%
3
100%
0
0%
0
0%
2
50%
9
30%
9
33.3%
21
35%
29
45.3%
18
40%
21
44.7%
Lymphocyte count increased
1
33.3%
0
0%
0
0%
0
0%
3
17.6%
1
33.3%
0
0%
0
0%
0
0%
0
0%
3
10%
3
11.1%
6
10%
4
6.2%
2
4.4%
1
2.1%
Neutrophil count decreased
1
33.3%
0
0%
0
0%
4
33.3%
2
11.8%
0
0%
0
0%
0
0%
0
0%
1
25%
5
16.7%
2
7.4%
7
11.7%
6
9.4%
1
2.2%
5
10.6%
Platelet count decreased
2
66.7%
2
66.7%
0
0%
4
33.3%
5
29.4%
1
33.3%
0
0%
0
0%
0
0%
1
25%
6
20%
9
33.3%
13
21.7%
9
14.1%
10
22.2%
11
23.4%
White blood cell decreased
2
66.7%
0
0%
0
0%
4
33.3%
2
11.8%
2
66.7%
1
33.3%
0
0%
0
0%
1
25%
6
20%
3
11.1%
6
10%
9
14.1%
5
11.1%
8
17%
60. Secondary Outcome:
Title Number of Participants With Laboratory Abnormalities (Phase 1 and Phase 2) - Chemistry
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
Outcome Measure Data
Analysis Population Description
The safety analysis set included all enrolled participants who received at least 1 dose of PF-06463922.
   
Arm/Group Title10 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)
Arm/Group DescriptionPF-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 Analyzed3 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 Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants 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%
3
75%
11
36.7%
11
40.7%
23
38.3%
17
26.2%
12
26.7%
13
27.7%
Alkaline phosphatase increased
Number Analyzed Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants
1
33.3%
1
33.3%
3
100%
4
33.3%
9
52.9%
3
100%
1
33.3%
0
0%
2
66.7%
3
75%
6
20%
8
29.6%
21
35%
21
32.3%
21
46.7%
14
29.8%
AST increased
Number Analyzed Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants
2
66.7%
2
66.7%
2
66.7%
3
25%
7
41.2%
2
66.7%
2
66.7%
0
0%
1
33.3%
3
75%
15
50%
12
44.4%
31
51.7%
27
41.5%
17
37.8%
17
36.2%
Blood bilirubin increased
Number Analyzed Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants
1
33.3%
0
0%
0
0%
1
8.3%
0
0%
0
0%
0
0%
0
0%
0
0%
1
25%
0
0%
0
0%
2
3.3%
0
0%
1
2.2%
1
2.1%
CPK increased
Number Analyzed Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants
1
5.9%
1
33.3%
1
33.3%
0
0%
0
0%
3
5%
0
0%
2
4.3%
Creatinine increased
Number Analyzed Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants
3
100%
2
66.7%
3
100%
9
75%
13
76.5%
3
100%
3
100%
2
66.7%
2
66.7%
3
75%
26
86.7%
21
77.8%
37
61.7%
44
67.7%
32
71.1%
34
72.3%
GGT increased
Number Analyzed Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants
0
0%
1
5.9%
0
0%
1
33.3%
0
0%
2
50%
1
3.7%
2
3.3%
1
1.5%
1
2.1%
Hypercalcemia
Number Analyzed Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants
0
0%
0
0%
0
0%
0
0%
1
5.9%
1
33.3%
0
0%
0
0%
0
0%
1
25%
4
13.3%
3
11.1%
4
6.7%
4
6.2%
3
6.7%
1
2.1%
Hyperglycemia
Number Analyzed Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants
3
100%
2
66.7%
2
66.7%
6
50%
8
47.1%
2
66.7%
1
33.3%
1
33.3%
2
66.7%
0
0%
11
36.7%
16
59.3%
30
50%
41
63.1%
31
68.9%
29
61.7%
Hyperkalemia
Number Analyzed Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants
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%
8
26.7%
7
25.9%
14
23.3%
11
16.9%
5
11.1%
5
10.6%
Hypermagnesemia
Number Analyzed Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants
2
66.7%
0
0%
0
0%
1
8.3%
2
11.8%
0
0%
0
0%
0
0%
0
0%
0
0%
2
6.7%
1
3.7%
2
3.3%
2
3.1%
1
2.2%
3
6.4%
Hypernatremia
Number Analyzed Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants
0
0%
1
33.3%
0
0%
0
0%
4
23.5%
2
66.7%
0
0%
0
0%
0
0%
1
25%
3
10%
1
3.7%
2
3.3%
4
6.2%
2
4.4%
4
8.5%
Hypoalbuminemia
Number Analyzed Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants
2
66.7%
1
33.3%
3
100%
4
33.3%
6
35.3%
3
100%
1
33.3%
1
33.3%
3
100%
1
25%
16
53.3%
15
55.6%
34
56.7%
42
64.6%
29
64.4%
27
57.4%
Hypocalcemia
Number Analyzed Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants
1
33.3%
0
0%
1
33.3%
3
25%
3
17.6%
2
66.7%
1
33.3%
0
0%
0
0%
1
25%
2
6.7%
4
14.8%
11
18.3%
9
13.8%
3
6.7%
9
19.1%
Hypoglycemia
Number Analyzed Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants
0
0%
0
0%
1
33.3%
3
25%
4
23.5%
0
0%
1
33.3%
0
0%
1
33.3%
0
0%
1
3.3%
2
7.4%
8
13.3%
7
10.8%
5
11.1%
3
6.4%
Hypokalemia
Number Analyzed Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants
0
0%
0
0%
2
66.7%
3
25%
3
17.6%
3
100%
1
33.3%
1
33.3%
0
0%
2
50%
6
20%
1
3.7%
9
15%
9
13.8%
6
13.3%
13
27.7%
Hypomagnesemia
Number Analyzed Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants
0
0%
1
33.3%
2
66.7%
4
33.3%
1
5.9%
3
100%
0
0%
1
33.3%
1
33.3%
3
75%
4
13.3%
8
29.6%
20
33.3%
17
26.2%
13
28.9%
11
23.4%
Hyponatremia
Number Analyzed Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants
2
66.7%
1
33.3%
1
33.3%
1
8.3%
4
23.5%
1
33.3%
1
33.3%
0
0%
2
66.7%
2
50%
8
26.7%
6
22.2%
10
16.7%
19
29.2%
9
20%
6
12.8%
Hypophosphatemia
Number Analyzed Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants
1
33.3%
2
66.7%
0
0%
3
25%
3
17.6%
2
66.7%
1
33.3%
1
33.3%
2
66.7%
1
25%
3
10%
6
22.2%
17
28.3%
14
21.5%
7
15.6%
14
29.8%
Lipase increased
Number Analyzed Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants
3
100%
1
33.3%
0
0%
8
66.7%
6
35.3%
0
0%
1
33.3%
0
0%
2
66.7%
2
50%
9
30%
5
18.5%
11
18.3%
15
23.1%
14
31.1%
16
34%
Serum amylase increased
Number Analyzed Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants
3
100%
0
0%
0
0%
2
16.7%
5
29.4%
0
0%
1
33.3%
0
0%
0
0%
2
50%
9
30%
5
18.5%
14
23.3%
18
27.7%
10
22.2%
13
27.7%
61. Secondary Outcome:
Title Number of Participants With Laboratory Abnormalities (Phase 1 and Phase 2) - Coagulation, Lipids and Urinalysis
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
Outcome Measure Data
Analysis Population Description
The safety analysis set included all enrolled participants who received at least 1 dose of PF-06463922.
   
Arm/Group Title10 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)
Arm/Group DescriptionPF-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 Analyzed3 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 Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants
1
33.3%
0
0%
1
33.3%
3
25%
2
11.8%
0
0%
0
0%
0
0%
0
0%
0
0%
1
3.3%
0
0%
1
1.7%
0
0%
1
2.2%
4
8.5%
Cholesterol high
Number Analyzed Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants
2
66.7%
2
66.7%
2
66.7%
10
83.3%
16
94.1%
2
66.7%
3
100%
3
100%
2
66.7%
3
75%
30
100%
26
96.3%
57
95%
64
98.5%
45
97.8%
44
93.6%
Hypertriglyceridemia
Number Analyzed Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants
0
0%
2
66.7%
2
66.7%
10
83.3%
16
94.1%
2
66.7%
3
100%
2
66.7%
1
33.3%
3
75%
30
100%
25
92.6%
56
93.3%
60
92.3%
45
97.8%
42
89.4%
INR increased
Number Analyzed Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants
2
66.7%
0
0%
1
33.3%
2
16.7%
2
11.8%
1
33.3%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
1
1.7%
4
6.2%
0
0%
6
12.8%
Proteinuria
Number Analyzed Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants
2
66.7%
0
0%
0
0%
0
0%
4
23.5%
3
100%
0
0%
0
0%
1
33.3%
0
0%
1
3.3%
0
0%
2
3.3%
2
3.1%
2
4.3%
4
8.5%
Prothrombin time
Number Analyzed Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants Participants
2
66.7%
0
0%
1
33.3%
3
25%
3
17.6%
1
33.3%
0
0%
0
0%
1
33.3%
1
25%
0
0%
1
3.7%
4
6.7%
4
6.2%
2
4.3%
5
10.6%
62. Secondary Outcome:
Title Number of Participants With Vital Signs Data Meeting Pre-defined Criteria (Phase 1 and Phase 2)
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)
Outcome Measure Data
Analysis Population Description
The safety analysis set included all enrolled participants who received at least 1 dose of PF-06463922.
 
Arm/Group Title10 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)
Arm/Group DescriptionPF-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 Analyzed3 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
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%
3
5%
1
1.5%
0
0%
2
4.3%
Sitting pulse rate >120 bpm
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%
4
6.7%
8
12.3%
3
6.7%
2
4.3%
Increase in weight: 10% to <20%
1
33.3%
1
33.3%
0
0%
6
50%
6
35.3%
2
66.7%
2
66.7%
0
0%
1
33.3%
0
0%
9
30%
12
44.4%
14
23.3%
18
27.7%
15
33.3%
12
26.1%
Increase in weight: >=20%
0
0%
1
33.3%
1
33.3%
1
8.3%
4
23.5%
1
33.3%
0
0%
0
0%
0
0%
1
25%
8
26.7%
1
3.7%
4
6.7%
9
13.8%
3
6.7%
8
17.4%
Increase in sitting SBP >=40 mmHg
0
0%
0
0%
0
0%
0
0%
1
5.9%
2
66.7%
0
0%
0
0%
0
0%
0
0%
5
16.7%
3
11.1%
4
6.7%
5
7.7%
5
11.1%
3
6.5%
Increase in sitting SBP >=60 mmHg
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%
Increase in sitting DBP >=20 mmHg
0
0%
2
66.7%
0
0%
0
0%
7
41.2%
3
100%
1
33.3%
0
0%
0
0%
0
0%
9
30%
9
33.3%
16
26.7%
12
18.5%
10
22.2%
11
23.9%
Increase in sitting DBP >=40 mmHg
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
1
3.7%
0
0%
0
0%
0
0%
2
4.3%
Increase in sitting pulse rate >=30 bpm
0
0%
1
33.3%
0
0%
1
8.3%
3
17.6%
1
33.3%
0
0%
0
0%
0
0%
1
25%
0
0%
2
7.4%
10
16.7%
15
23.1%
12
26.7%
13
28.3%
Decrease in weight >=10%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
1
25%
1
3.3%
0
0%
6
10%
4
6.2%
1
2.2%
1
2.2%
Decrease in SBP >=40 mmHg
0
0%
0
0%
0
0%
3
25%
2
11.8%
1
33.3%
0
0%
0
0%
0
0%
0
0%
0
0%
1
3.7%
2
3.3%
1
1.5%
1
2.2%
3
6.5%
Decrease in SBP >=60 mmHg
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
2
66.7%
1
33.3%
0
0%
4
33.3%
3
17.6%
2
66.7%
2
66.7%
0
0%
1
33.3%
2
50%
5
16.7%
3
11.1%
12
20%
8
12.3%
5
11.1%
6
13%
Decrease in DBP >=40 mmHg
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
0
0%
0
0%
1
33.3%
2
16.7%
0
0%
1
33.3%
0
0%
1
33.3%
1
33.3%
1
25%
7
23.3%
2
7.4%
4
6.7%
5
7.7%
3
6.7%
5
10.9%
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)
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)
Outcome Measure Data
Analysis Population Description
The safety analysis set included all enrolled participants who received at least 1 dose of PF-06463922.
 
Arm/Group Title10 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)
Arm/Group DescriptionPF-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 Analyzed3 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%
1
33.3%
3
25%
4
23.5%
2
66.7%
1
33.3%
0
0%
0
0%
2
50%
3
10%
1
3.7%
9
15%
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)
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)
Outcome Measure Data
Analysis Population Description
The safety analysis set included all enrolled participants who received at least 1 dose of PF-06463922.
 
Arm/Group Title10 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)
Arm/Group DescriptionPF-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 Analyzed3 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%
2
16.7%
1
5.9%
1
33.3%
0
0%
2
66.7%
0
0%
0
0%
4
13.3%
7
25.9%
11
18.3%
9
13.8%
13
28.3%
8
17%
QTcF: 480 to <500 ms
1
33.3%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
1
25%
1
3.3%
1
3.7%
3
5%
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%
1
1.5%
1
2.2%
0
0%
QTcF Increase: 30 to <60 ms
0
0%
0
0%
1
33.3%
3
25%
3
17.6%
0
0%
0
0%
1
33.3%
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%
1
25%
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)
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
Outcome Measure Data
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 TitleEXP-1 (Phase 2)EXP-2 (Phase 2)EXP-3 (Phase 2)EXP-4 (Phase 2)EXP-5 (Phase 2)EXP-6 (Phase 2)
Arm/Group DescriptionTreatment-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 Analyzed26 24 52 43 30 25
Measure Type: Count of Participants
Unit of Measure: Participants
Suicidal ideation
1
3.8%
0
0%
2
3.8%
1
2.3%
1
3.3%
2
8%
Suicidal behavior
0
0%
0
0%
0
0%
0
0%
0
0%
1
4%
66. Secondary Outcome:
Title Change From Baseline in Total Scores for Beck Depression Inventory (BDI)-II (Mood Assessment) (Phase 2)
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)
Outcome Measure Data
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 TitleEXP-1 (Phase 2)EXP-2 (Phase 2)EXP-3 (Phase 2)EXP-4 (Phase 2)EXP-5 (Phase 2)EXP-6 (Phase 2)
Arm/Group DescriptionTreatment-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 Analyzed24 24 53 41 28 26
Least Squares Mean (95% Confidence Interval)
Unit of Measure: units on score
Cycle 2 Day 1
-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
-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
-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
-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
-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
-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
-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
-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
-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
-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
-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
-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
-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
-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
-5.50(-10.67 to -0.33) -3.03(-10.01 to 3.95) -4.30(-11.31 to 2.70)
End of treatment
-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)
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)
Outcome Measure Data
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 TitleEXP-1 (Phase 2)EXP-2 (Phase 2)EXP-3 (Phase 2)EXP-4 (Phase 2)EXP-5 (Phase 2)EXP-6 (Phase 2)
Arm/Group DescriptionTreatment-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 Analyzed24 26 50 46 38 29
Least Squares Mean (95% Confidence Interval)
Unit of Measure: units on a score
Cycle 2 Day 1
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
-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
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
-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
-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
-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
-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
-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
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
-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
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
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
-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
0.03(-0.11 to 0.16) -0.06(-0.20 to 0.07)
End of treatment
-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)
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)
Outcome Measure Data
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 TitleEXP-1 (Phase 2)EXP-2 (Phase 2)EXP-3 (Phase 2)EXP-4 (Phase 2)EXP-5 (Phase 2)EXP-6 (Phase 2)
Arm/Group DescriptionTreatment-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 Analyzed24 26 50 46 38 29
Least Squares Mean (95% Confidence Interval)
Unit of Measure: units on a score
Cycle 2 Day 1
-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
-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
-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
-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
-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
-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
-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
-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
-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
-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
-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
-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
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
0.08(-0.01 to 0.18) -0.06(-0.15 to 0.04)
End of treatment
-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)
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)
Outcome Measure Data
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 TitleEXP-1 (Phase 2)EXP-2 (Phase 2)EXP-3 (Phase 2)EXP-4 (Phase 2)EXP-5 (Phase 2)EXP-6 (Phase 2)
Arm/Group DescriptionTreatment-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 Analyzed24 26 50 46 38 29
Least Squares Mean (95% Confidence Interval)
Unit of Measure: units on a score
Cycle 2 Day 1
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
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
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
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
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
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
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
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
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
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
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
-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
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
0.09(-0.03 to 0.21) 0.01(-0.11 to 0.13)
End of treatment
-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)
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)
Outcome Measure Data
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 TitleEXP-1 (Phase 2)EXP-2 (Phase 2)EXP-3 (Phase 2)EXP-4 (Phase 2)EXP-5 (Phase 2)EXP-6 (Phase 2)
Arm/Group DescriptionTreatment-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 Analyzed24 26 50 46 38 29
Least Squares Mean (95% Confidence Interval)
Unit of Measure: units on a score
Cycle 2 Day 1
-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
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
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
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
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
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
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
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
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
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
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
-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
-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
-8.49(-15.06 to -1.92) -3.35(-9.86 to 3.16)
End of treatment
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)
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)
Outcome Measure Data
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 TitleEXP-1 (Phase 2)EXP-2 (Phase 2)EXP-3 (Phase 2)EXP-4 (Phase 2)EXP-5 (Phase 2)EXP-6 (Phase 2)
Arm/Group DescriptionTreatment-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 Analyzed24 26 50 46 38 29
Least Squares Mean (95% Confidence Interval)
Unit of Measure: units on a score
Cycle 2 Day 1
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
-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
-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
-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
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
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
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
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
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
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
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
-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
-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
-2.43(-5.89 to 1.04) -0.80(-4.25 to 2.64)
End of treatment
-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)
Open or close this module Adverse Events
 
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)
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 (%)# 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 1 / 3 (33.33%)1 / 3 (33.33%)0 / 3 (0%)1 / 12 (8.33%)3 / 17 (17.65%)3 / 3 (100%)0 / 3 (0%)0 / 3 (0%)1 / 3 (33.33%)0 / 4 (0%)0 / 30 (0%)1 / 27 (3.7%)4 / 60 (6.67%)8 / 65 (12.31%)4 / 46 (8.7%)5 / 47 (10.64%)0 / 3 (0%)
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%)1 / 3 (33.33%)1 / 3 (33.33%)4 / 12 (33.33%)9 / 17 (52.94%)3 / 3 (100%)1 / 3 (33.33%)2 / 3 (66.67%)2 / 3 (66.67%)2 / 4 (50%)8 / 30 (26.67%)5 / 27 (18.52%)18 / 60 (30%)24 / 65 (36.92%)18 / 46 (39.13%)16 / 47 (34.04%)0 / 3 (0%)
Cardiac disorders
Atrial fibrillation ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)02 / 65 (3.08%)20 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Atrioventricular block complete ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)01 / 47 (2.13%)10 / 3 (0%)0
Cardiac arrest ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)01 / 3 (33.33%)10 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)01 / 47 (2.13%)10 / 3 (0%)0
Myocardial infarction ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)01 / 47 (2.13%)10 / 3 (0%)0
Pericardial effusion ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)01 / 3 (33.33%)21 / 3 (33.33%)10 / 3 (0%)00 / 4 (0%)01 / 30 (3.33%)10 / 27 (0%)00 / 60 (0%)01 / 65 (1.54%)11 / 46 (2.17%)10 / 47 (0%)00 / 3 (0%)0
Sinus node dysfunction ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)01 / 65 (1.54%)10 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Supraventricular tachycardia ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)01 / 65 (1.54%)10 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Ear and labyrinth disorders
Vertigo ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)01 / 30 (3.33%)20 / 27 (0%)00 / 60 (0%)01 / 65 (1.54%)10 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Eye disorders
Blepharitis ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)01 / 65 (1.54%)10 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Cataract ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 12 (8.33%)10 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Eye pain ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 4 (25%)10 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Gastrointestinal disorders
Abdominal pain ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 3 (33.33%)10 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Abdominal pain upper ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)01 / 46 (2.17%)10 / 47 (0%)00 / 3 (0%)0
Abdominal wall haematoma ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)01 / 47 (2.13%)10 / 3 (0%)0
Crohn's disease ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 4 (25%)20 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Gastric volvulus ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)01 / 30 (3.33%)10 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Gastritis ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)01 / 46 (2.17%)10 / 47 (0%)00 / 3 (0%)0
Glossitis ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)01 / 30 (3.33%)10 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Ileus ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 4 (25%)10 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Intestinal obstruction ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)01 / 30 (3.33%)10 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Intestinal perforation ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 12 (8.33%)10 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Large intestinal obstruction ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 12 (8.33%)10 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Nausea ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)01 / 30 (3.33%)10 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Pancreatitis ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)01 / 65 (1.54%)10 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Vomiting ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)02 / 65 (3.08%)20 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
General disorders
Asthenia ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 12 (8.33%)10 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Chest pain ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)01 / 60 (1.67%)10 / 65 (0%)01 / 46 (2.17%)10 / 47 (0%)00 / 3 (0%)0
Disease progression ∗ A 1 / 3 (33.33%)11 / 3 (33.33%)10 / 3 (0%)01 / 12 (8.33%)13 / 17 (17.65%)31 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)01 / 3 (33.33%)10 / 4 (0%)00 / 30 (0%)00 / 27 (0%)06 / 60 (10%)66 / 65 (9.23%)65 / 46 (10.87%)55 / 47 (10.64%)50 / 3 (0%)0
Fatigue ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)01 / 30 (3.33%)10 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
General physical health deterioration ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)01 / 46 (2.17%)10 / 47 (0%)00 / 3 (0%)0
Generalised oedema ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)01 / 60 (1.67%)10 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Pain ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)01 / 46 (2.17%)10 / 47 (0%)00 / 3 (0%)0
Peripheral swelling ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)01 / 60 (1.67%)10 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Pyrexia ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 12 (8.33%)10 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)03 / 30 (10%)30 / 27 (0%)01 / 60 (1.67%)11 / 65 (1.54%)10 / 46 (0%)01 / 47 (2.13%)10 / 3 (0%)0
Hepatobiliary disorders
Biloma ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)01 / 17 (5.88%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Jaundice ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)01 / 60 (1.67%)10 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Infections and infestations
Bronchitis ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)01 / 17 (5.88%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Diverticulitis ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)01 / 65 (1.54%)10 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Erysipelas ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)01 / 60 (1.67%)10 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Influenza ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 12 (8.33%)10 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)01 / 60 (1.67%)10 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Lower respiratory tract infection ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 4 (25%)11 / 30 (3.33%)20 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Lung abscess ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)01 / 60 (1.67%)10 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Lung infection ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)01 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)01 / 27 (3.7%)10 / 60 (0%)00 / 65 (0%)01 / 46 (2.17%)10 / 47 (0%)00 / 3 (0%)0
Pneumonia ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)01 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)01 / 30 (3.33%)21 / 27 (3.7%)10 / 60 (0%)03 / 65 (4.62%)60 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Pyelonephritis ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)01 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Respiratory tract infection ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)01 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 4 (0%)01 / 30 (3.33%)10 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Sepsis ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)01 / 60 (1.67%)10 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Septic shock ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)01 / 60 (1.67%)10 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Upper respiratory tract infection ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)01 / 60 (1.67%)10 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Urinary tract infection ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)01 / 17 (5.88%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Vestibular neuronitis ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)01 / 65 (1.54%)10 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Injury, poisoning and procedural complications
Fall ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)01 / 65 (1.54%)10 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Femoral neck fracture ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)01 / 60 (1.67%)11 / 65 (1.54%)10 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Hip fracture ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)01 / 65 (1.54%)10 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Humerus fracture ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)01 / 47 (2.13%)10 / 3 (0%)0
Pelvic fracture ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)01 / 65 (1.54%)20 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Post procedural haemorrhage ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)01 / 46 (2.17%)10 / 47 (0%)00 / 3 (0%)0
Rib fracture ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)01 / 47 (2.13%)10 / 3 (0%)0
Road traffic accident ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)01 / 27 (3.7%)10 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Subdural haematoma ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)01 / 17 (5.88%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Toxicity to various agents ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)01 / 65 (1.54%)10 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Investigations
Alanine aminotransferase increased ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)01 / 30 (3.33%)10 / 27 (0%)00 / 60 (0%)01 / 65 (1.54%)10 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Aspartate aminotransferase increased ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 4 (25%)11 / 30 (3.33%)10 / 27 (0%)00 / 60 (0%)01 / 65 (1.54%)10 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Blood cholesterol increased ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)01 / 60 (1.67%)10 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Blood creatine phosphokinase increased ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)01 / 60 (1.67%)10 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Ejection fraction decreased ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)01 / 47 (2.13%)10 / 3 (0%)0
Lipase increased ∗ A 1 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 000 / 000 / 000 / 000 / 000 / 000 / 3 (0%)0
Metabolism and nutrition disorders
Decreased appetite ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 4 (25%)10 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Hypercalcaemia ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)01 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Hypertriglyceridaemia ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)01 / 46 (2.17%)10 / 47 (0%)00 / 3 (0%)0
Hyperuricaemia ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)01 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Musculoskeletal and connective tissue disorders
Back pain ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)01 / 65 (1.54%)21 / 46 (2.17%)10 / 47 (0%)00 / 3 (0%)0
Intervertebral disc protrusion ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)01 / 27 (3.7%)10 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Spinal pain ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)01 / 60 (1.67%)10 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Nervous system disorders
Brain compression ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)01 / 47 (2.13%)10 / 3 (0%)0
Brain oedema ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)01 / 46 (2.17%)10 / 47 (0%)00 / 3 (0%)0
Cerebrovascular accident ∗ A 0 / 3 (0%)01 / 3 (33.33%)10 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Cognitive disorder ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)01 / 60 (1.67%)10 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Haemorrhage intracranial ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)01 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)01 / 46 (2.17%)10 / 47 (0%)00 / 3 (0%)0
Headache ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 4 (25%)30 / 30 (0%)00 / 27 (0%)01 / 60 (1.67%)11 / 65 (1.54%)10 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Hydrocephalus ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)01 / 65 (1.54%)10 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Ischaemic stroke ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)01 / 47 (2.13%)10 / 3 (0%)0
Lacunar stroke ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)01 / 65 (1.54%)10 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Partial seizures ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)01 / 47 (2.13%)10 / 3 (0%)0
Peripheral sensory neuropathy ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)01 / 46 (2.17%)10 / 47 (0%)00 / 3 (0%)0
Presyncope ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 3 (33.33%)10 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)01 / 47 (2.13%)10 / 3 (0%)0
Seizure ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)01 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 4 (25%)10 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Syncope ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)01 / 60 (1.67%)10 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Vagus nerve disorder ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)01 / 65 (1.54%)10 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Psychiatric disorders
Confusional state ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)01 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)01 / 30 (3.33%)10 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Delirium ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)01 / 17 (5.88%)20 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Hallucination ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)01 / 3 (33.33%)20 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Mental status changes ∗ A 1 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 12 (0%)01 / 17 (5.88%)11 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)01 / 65 (1.54%)11 / 46 (2.17%)11 / 47 (2.13%)10 / 3 (0%)0
Respiratory, thoracic and mediastinal disorders
Acute pulmonary oedema ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)01 / 60 (1.67%)10 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Acute respiratory failure ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)01 / 60 (1.67%)11 / 65 (1.54%)10 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Asthma ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)01 / 30 (3.33%)10 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Chronic obstructive pulmonary disease ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)01 / 60 (1.67%)10 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Dyspnoea ∗ A 1 / 3 (33.33%)30 / 3 (0%)00 / 3 (0%)00 / 12 (0%)01 / 17 (5.88%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 4 (25%)11 / 30 (3.33%)10 / 27 (0%)01 / 60 (1.67%)13 / 65 (4.62%)31 / 46 (2.17%)20 / 47 (0%)00 / 3 (0%)0
Dyspnoea exertional ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)01 / 60 (1.67%)10 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Epistaxis ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)01 / 30 (3.33%)10 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Haemoptysis ∗ A 0 / 3 (0%)00 / 3 (0%)01 / 3 (33.33%)10 / 12 (0%)01 / 17 (5.88%)10 / 3 (0%)01 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Hypoxia ∗ A 1 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)01 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)01 / 65 (1.54%)10 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Interstitial lung disease ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)01 / 46 (2.17%)10 / 47 (0%)00 / 3 (0%)0
Lung disorder ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)01 / 65 (1.54%)10 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Pleural effusion ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)01 / 17 (5.88%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)01 / 60 (1.67%)21 / 65 (1.54%)10 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Pleuritic pain ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)01 / 46 (2.17%)10 / 47 (0%)00 / 3 (0%)0
Pneumonitis ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)02 / 65 (3.08%)20 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Pulmonary congestion ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)01 / 60 (1.67%)10 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Pulmonary embolism ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)02 / 65 (3.08%)21 / 46 (2.17%)10 / 47 (0%)00 / 3 (0%)0
Pulmonary hypertension ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)01 / 27 (3.7%)10 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Respiratory distress ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)01 / 27 (3.7%)10 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Respiratory failure ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)01 / 60 (1.67%)11 / 65 (1.54%)10 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Skin and subcutaneous tissue disorders
Dermatomyositis ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)01 / 3 (33.33%)20 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Vascular disorders
Aortic dissection ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)01 / 47 (2.13%)10 / 3 (0%)0
Deep vein thrombosis ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)01 / 65 (1.54%)10 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Embolism ∗ A 0 / 3 (0%)01 / 3 (33.33%)10 / 3 (0%)00 / 12 (0%)00 / 17 (0%)01 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)01 / 65 (1.54%)11 / 46 (2.17%)10 / 47 (0%)00 / 3 (0%)0
Embolism venous ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)01 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Hypertensive crisis ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)01 / 65 (1.54%)10 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Peripheral artery occlusion ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)01 / 65 (1.54%)20 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Superior vena cava syndrome ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)02 / 65 (3.08%)20 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Thrombosis ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)02 / 46 (4.35%)20 / 47 (0%)00 / 3 (0%)0
∗Indicates events were collected by non-systematic methods.
ATerm from vocabulary, MedDRA 20.0
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%)3 / 3 (100%)3 / 3 (100%)12 / 12 (100%)17 / 17 (100%)3 / 3 (100%)3 / 3 (100%)3 / 3 (100%)3 / 3 (100%)4 / 4 (100%)30 / 30 (100%)27 / 27 (100%)59 / 60 (98.33%)65 / 65 (100%)45 / 46 (97.83%)47 / 47 (100%)3 / 3 (100%)
Blood and lymphatic system disorders
Anaemia ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)02 / 12 (16.67%)36 / 17 (35.29%)143 / 3 (100%)51 / 3 (33.33%)11 / 3 (33.33%)12 / 3 (66.67%)42 / 4 (50%)25 / 30 (16.67%)91 / 27 (3.7%)13 / 60 (5%)312 / 65 (18.46%)187 / 46 (15.22%)83 / 47 (6.38%)80 / 3 (0%)0
Febrile neutropenia ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 4 (25%)10 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Haemorrhagic diathesis ∗ A 1 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Iron deficiency anaemia ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)01 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Leukocytosis ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)02 / 12 (16.67%)20 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Neutropenia ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)01 / 17 (5.88%)20 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Thrombocytopenia ∗ A 1 / 3 (33.33%)11 / 3 (33.33%)10 / 3 (0%)01 / 12 (8.33%)12 / 17 (11.76%)20 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)01 / 27 (3.7%)11 / 60 (1.67%)11 / 65 (1.54%)10 / 46 (0%)03 / 47 (6.38%)80 / 3 (0%)0
Thrombocytosis ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)01 / 17 (5.88%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Cardiac disorders
Atrial fibrillation ∗ A 0 / 3 (0%)01 / 3 (33.33%)10 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)01 / 3 (33.33%)10 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Pericardial effusion ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)02 / 30 (6.67%)20 / 27 (0%)00 / 60 (0%)00 / 65 (0%)03 / 46 (6.52%)40 / 47 (0%)00 / 3 (0%)0
Tachycardia ∗ A 0 / 3 (0%)00 / 3 (0%)01 / 3 (33.33%)10 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)01 / 27 (3.7%)10 / 60 (0%)05 / 65 (7.69%)62 / 46 (4.35%)23 / 47 (6.38%)30 / 3 (0%)0
Ventricular dysfunction ∗ A 1 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Ear and labyrinth disorders
Ear discomfort ∗ A 0 / 3 (0%)01 / 3 (33.33%)10 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Hypoacusis ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 12 (8.33%)21 / 17 (5.88%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Tinnitus ∗ A 0 / 3 (0%)00 / 3 (0%)01 / 3 (33.33%)33 / 12 (25%)43 / 17 (17.65%)31 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 4 (25%)12 / 30 (6.67%)22 / 27 (7.41%)83 / 60 (5%)37 / 65 (10.77%)104 / 46 (8.7%)41 / 47 (2.13%)10 / 3 (0%)0
Vertigo ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 12 (8.33%)10 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Vertigo positional ∗ A 0 / 3 (0%)01 / 3 (33.33%)10 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Endocrine disorders
Cushingoid ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)01 / 17 (5.88%)20 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Hyperparathyroidism ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)01 / 3 (33.33%)10 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Hypothyroidism ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 12 (8.33%)10 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Eye disorders
Asthenopia ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 3 (33.33%)10 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Astigmatism ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)01 / 17 (5.88%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Conjunctival oedema ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)01 / 17 (5.88%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Diplopia ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 12 (8.33%)10 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Dry eye ∗ A 1 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Eye irritation ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)02 / 30 (6.67%)20 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Photophobia ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)01 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Photopsia ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)01 / 17 (5.88%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)01 / 3 (33.33%)1
Presbyopia ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)01 / 17 (5.88%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Retinal vein occlusion ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)01 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Vision blurred ∗ A 1 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 12 (0%)02 / 17 (11.76%)20 / 3 (0%)01 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 4 (0%)03 / 30 (10%)32 / 27 (7.41%)20 / 60 (0%)03 / 65 (4.62%)33 / 46 (6.52%)32 / 47 (4.26%)20 / 3 (0%)0
Visual acuity reduced ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 12 (8.33%)11 / 17 (5.88%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 3 (33.33%)10 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Visual impairment ∗ A 0 / 3 (0%)01 / 3 (33.33%)10 / 3 (0%)01 / 12 (8.33%)10 / 17 (0%)01 / 3 (33.33%)31 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)01 / 27 (3.7%)11 / 60 (1.67%)13 / 65 (4.62%)33 / 46 (6.52%)32 / 47 (4.26%)40 / 3 (0%)0
Gastrointestinal disorders
Abdominal discomfort ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)01 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)01 / 3 (33.33%)10 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Abdominal distension ∗ A 1 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 12 (0%)01 / 17 (5.88%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)02 / 30 (6.67%)21 / 27 (3.7%)10 / 60 (0%)04 / 65 (6.15%)43 / 46 (6.52%)65 / 47 (10.64%)50 / 3 (0%)0
Abdominal pain ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)02 / 12 (16.67%)21 / 17 (5.88%)10 / 3 (0%)01 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)01 / 4 (25%)30 / 30 (0%)01 / 27 (3.7%)12 / 60 (3.33%)24 / 65 (6.15%)43 / 46 (6.52%)41 / 47 (2.13%)10 / 3 (0%)0
Abdominal pain upper ∗ A 1 / 3 (33.33%)10 / 3 (0%)01 / 3 (33.33%)10 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)01 / 3 (33.33%)11 / 3 (33.33%)12 / 4 (50%)20 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Ascites ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 3 (33.33%)10 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Constipation ∗ A 0 / 3 (0%)01 / 3 (33.33%)10 / 3 (0%)03 / 12 (25%)33 / 17 (17.65%)40 / 3 (0%)02 / 3 (66.67%)21 / 3 (33.33%)11 / 3 (33.33%)10 / 4 (0%)08 / 30 (26.67%)95 / 27 (18.52%)68 / 60 (13.33%)108 / 65 (12.31%)85 / 46 (10.87%)55 / 47 (10.64%)50 / 3 (0%)0
Crohn's disease ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 4 (25%)10 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Diarrhoea ∗ A 0 / 3 (0%)00 / 3 (0%)01 / 3 (33.33%)13 / 12 (25%)63 / 17 (17.65%)41 / 3 (33.33%)12 / 3 (66.67%)40 / 3 (0%)00 / 3 (0%)03 / 4 (75%)57 / 30 (23.33%)134 / 27 (14.81%)67 / 60 (11.67%)1416 / 65 (24.62%)228 / 46 (17.39%)97 / 47 (14.89%)70 / 3 (0%)0
Dry mouth ∗ A 1 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 12 (0%)01 / 17 (5.88%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Dyspepsia ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 12 (8.33%)10 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)01 / 30 (3.33%)11 / 27 (3.7%)12 / 60 (3.33%)25 / 65 (7.69%)50 / 46 (0%)01 / 47 (2.13%)10 / 3 (0%)0
Dysphagia ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 12 (8.33%)10 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)01 / 27 (3.7%)13 / 60 (5%)34 / 65 (6.15%)42 / 46 (4.35%)20 / 47 (0%)00 / 3 (0%)0
Faeces discoloured ∗ A 0 / 3 (0%)00 / 3 (0%)01 / 3 (33.33%)10 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Gastrointestinal disorder ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 12 (8.33%)10 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Gastrooesophageal reflux disease ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 12 (8.33%)12 / 17 (11.76%)20 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)01 / 30 (3.33%)10 / 27 (0%)04 / 60 (6.67%)41 / 65 (1.54%)12 / 46 (4.35%)43 / 47 (6.38%)30 / 3 (0%)0
Intestinal obstruction ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)01 / 17 (5.88%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Nausea ∗ A 1 / 3 (33.33%)11 / 3 (33.33%)10 / 3 (0%)02 / 12 (16.67%)22 / 17 (11.76%)30 / 3 (0%)01 / 3 (33.33%)10 / 3 (0%)01 / 3 (33.33%)12 / 4 (50%)44 / 30 (13.33%)43 / 27 (11.11%)44 / 60 (6.67%)415 / 65 (23.08%)167 / 46 (15.22%)96 / 47 (12.77%)81 / 3 (33.33%)1
Odynophagia ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)02 / 27 (7.41%)21 / 60 (1.67%)10 / 65 (0%)01 / 46 (2.17%)10 / 47 (0%)00 / 3 (0%)0
Stomatitis ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)01 / 30 (3.33%)12 / 27 (7.41%)32 / 60 (3.33%)22 / 65 (3.08%)21 / 46 (2.17%)12 / 47 (4.26%)20 / 3 (0%)0
Swollen tongue ∗ A 1 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Toothache ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)02 / 30 (6.67%)20 / 27 (0%)01 / 60 (1.67%)10 / 65 (0%)01 / 46 (2.17%)11 / 47 (2.13%)10 / 3 (0%)0
Vomiting ∗ A 0 / 3 (0%)02 / 3 (66.67%)21 / 3 (33.33%)11 / 12 (8.33%)13 / 17 (17.65%)40 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)02 / 4 (50%)64 / 30 (13.33%)70 / 27 (0%)05 / 60 (8.33%)57 / 65 (10.77%)103 / 46 (6.52%)35 / 47 (10.64%)50 / 3 (0%)0
General disorders
Asthenia ∗ A 1 / 3 (33.33%)10 / 3 (0%)02 / 3 (66.67%)23 / 12 (25%)73 / 17 (17.65%)30 / 3 (0%)01 / 3 (33.33%)20 / 3 (0%)00 / 3 (0%)00 / 4 (0%)03 / 30 (10%)32 / 27 (7.41%)38 / 60 (13.33%)106 / 65 (9.23%)125 / 46 (10.87%)72 / 47 (4.26%)20 / 3 (0%)0
Axillary pain ∗ A 0 / 3 (0%)00 / 3 (0%)01 / 3 (33.33%)10 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Catheter site extravasation ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)01 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Chest discomfort ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 3 (33.33%)10 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Chest pain ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)01 / 17 (5.88%)20 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)01 / 27 (3.7%)22 / 60 (3.33%)26 / 65 (9.23%)65 / 46 (10.87%)62 / 47 (4.26%)20 / 3 (0%)0
Chills ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 12 (8.33%)10 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Disease progression ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 12 (8.33%)10 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Face oedema ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 12 (8.33%)10 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)02 / 30 (6.67%)20 / 27 (0%)02 / 60 (3.33%)21 / 65 (1.54%)11 / 46 (2.17%)11 / 47 (2.13%)10 / 3 (0%)0
Fatigue ∗ A 1 / 3 (33.33%)11 / 3 (33.33%)10 / 3 (0%)04 / 12 (33.33%)44 / 17 (23.53%)52 / 3 (66.67%)41 / 3 (33.33%)20 / 3 (0%)01 / 3 (33.33%)13 / 4 (75%)58 / 30 (26.67%)114 / 27 (14.81%)73 / 60 (5%)411 / 65 (16.92%)224 / 46 (8.7%)47 / 47 (14.89%)90 / 3 (0%)0
Gait disturbance ∗ A 1 / 3 (33.33%)11 / 3 (33.33%)21 / 3 (33.33%)21 / 12 (8.33%)11 / 17 (5.88%)10 / 3 (0%)01 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)05 / 65 (7.69%)53 / 46 (6.52%)50 / 47 (0%)00 / 3 (0%)0
Generalised oedema ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)01 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Mucosal inflammation ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 3 (33.33%)20 / 4 (0%)03 / 30 (10%)30 / 27 (0%)01 / 60 (1.67%)12 / 65 (3.08%)21 / 46 (2.17%)10 / 47 (0%)00 / 3 (0%)0
Non-cardiac chest pain ∗ A 0 / 3 (0%)00 / 3 (0%)01 / 3 (33.33%)10 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Oedema ∗ A 0 / 3 (0%)01 / 3 (33.33%)11 / 3 (33.33%)12 / 12 (16.67%)30 / 17 (0%)00 / 3 (0%)02 / 3 (66.67%)20 / 3 (0%)00 / 3 (0%)01 / 4 (25%)14 / 30 (13.33%)61 / 27 (3.7%)64 / 60 (6.67%)46 / 65 (9.23%)74 / 46 (8.7%)43 / 47 (6.38%)30 / 3 (0%)0
Oedema peripheral ∗ A 3 / 3 (100%)31 / 3 (33.33%)11 / 3 (33.33%)13 / 12 (25%)49 / 17 (52.94%)163 / 3 (100%)71 / 3 (33.33%)10 / 3 (0%)02 / 3 (66.67%)33 / 4 (75%)712 / 30 (40%)1712 / 27 (44.44%)1829 / 60 (48.33%)4321 / 65 (32.31%)3715 / 46 (32.61%)2424 / 47 (51.06%)301 / 3 (33.33%)1
Pain ∗ A 1 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)02 / 30 (6.67%)20 / 27 (0%)01 / 60 (1.67%)14 / 65 (6.15%)82 / 46 (4.35%)22 / 47 (4.26%)20 / 3 (0%)0
Performance status decreased ∗ A 1 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Peripheral swelling ∗ A 1 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)02 / 12 (16.67%)40 / 17 (0%)00 / 3 (0%)01 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)02 / 27 (7.41%)21 / 60 (1.67%)17 / 65 (10.77%)124 / 46 (8.7%)53 / 47 (6.38%)30 / 3 (0%)0
Pyrexia ∗ A 0 / 3 (0%)00 / 3 (0%)01 / 3 (33.33%)10 / 12 (0%)03 / 17 (17.65%)31 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)02 / 30 (6.67%)41 / 27 (3.7%)25 / 60 (8.33%)67 / 65 (10.77%)71 / 46 (2.17%)15 / 47 (10.64%)50 / 3 (0%)0
Swelling ∗ A 1 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Hepatobiliary disorders
Hepatocellular injury ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 4 (25%)10 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Immune system disorders
Hypersensitivity ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)01 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Infections and infestations
Bacterial infection ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)01 / 17 (5.88%)20 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Bronchitis ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)02 / 17 (11.76%)31 / 3 (33.33%)11 / 3 (33.33%)10 / 3 (0%)01 / 3 (33.33%)31 / 4 (25%)11 / 30 (3.33%)12 / 27 (7.41%)21 / 60 (1.67%)13 / 65 (4.62%)40 / 46 (0%)01 / 47 (2.13%)20 / 3 (0%)0
Candida infection ∗ A 1 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Cellulitis ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 12 (8.33%)10 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Chronic sinusitis ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 4 (25%)10 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Clostridium difficile colitis ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)01 / 17 (5.88%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Conjunctivitis ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)01 / 3 (33.33%)1
Enteritis infectious ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 12 (8.33%)10 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Enterococcal bacteraemia ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)01 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Gastroenteritis ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)01 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Helicobacter infection ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)01 / 17 (5.88%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Herpes virus infection ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)01 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Herpes zoster ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)01 / 3 (33.33%)1
Influenza ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)01 / 17 (5.88%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)02 / 30 (6.67%)21 / 27 (3.7%)11 / 60 (1.67%)13 / 65 (4.62%)30 / 46 (0%)01 / 47 (2.13%)10 / 3 (0%)0
Laryngitis ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)01 / 17 (5.88%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Lower respiratory tract infection ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 12 (8.33%)10 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 4 (25%)10 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Lung infection ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)01 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)02 / 27 (7.41%)23 / 60 (5%)32 / 65 (3.08%)20 / 46 (0%)01 / 47 (2.13%)10 / 3 (0%)0
Nasopharyngitis ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 4 (25%)10 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Oral candidiasis ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)01 / 17 (5.88%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Periodontitis ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)01 / 17 (5.88%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Pharyngitis ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)01 / 17 (5.88%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)01 / 3 (33.33%)2
Pneumonia ∗ A 0 / 3 (0%)00 / 3 (0%)01 / 3 (33.33%)10 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 4 (25%)10 / 30 (0%)01 / 27 (3.7%)10 / 60 (0%)08 / 65 (12.31%)81 / 46 (2.17%)10 / 47 (0%)00 / 3 (0%)0
Respiratory tract infection ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 12 (8.33%)12 / 17 (11.76%)30 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Rhinitis ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 12 (8.33%)20 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)01 / 27 (3.7%)15 / 60 (8.33%)72 / 65 (3.08%)30 / 46 (0%)03 / 47 (6.38%)30 / 3 (0%)0
Sinusitis ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 12 (8.33%)20 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)02 / 60 (3.33%)30 / 65 (0%)01 / 46 (2.17%)13 / 47 (6.38%)30 / 3 (0%)0
Soft tissue infection ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)01 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Tooth abscess ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 4 (25%)10 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Upper respiratory tract infection ∗ A 0 / 3 (0%)00 / 3 (0%)01 / 3 (33.33%)22 / 12 (16.67%)64 / 17 (23.53%)61 / 3 (33.33%)12 / 3 (66.67%)20 / 3 (0%)00 / 3 (0%)00 / 4 (0%)05 / 30 (16.67%)62 / 27 (7.41%)22 / 60 (3.33%)36 / 65 (9.23%)71 / 46 (2.17%)13 / 47 (6.38%)30 / 3 (0%)0
Urinary tract infection ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 12 (8.33%)12 / 17 (11.76%)30 / 3 (0%)02 / 3 (66.67%)30 / 3 (0%)00 / 3 (0%)01 / 4 (25%)10 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Viral rhinitis ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 4 (25%)10 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Viral upper respiratory tract infection ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)01 / 17 (5.88%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)01 / 30 (3.33%)13 / 27 (11.11%)42 / 60 (3.33%)42 / 65 (3.08%)22 / 46 (4.35%)33 / 47 (6.38%)30 / 3 (0%)0
Injury, poisoning and procedural complications
Contusion ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)01 / 17 (5.88%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Fall ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)01 / 17 (5.88%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)05 / 65 (7.69%)112 / 46 (4.35%)52 / 47 (4.26%)30 / 3 (0%)0
Incision site pain ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)01 / 3 (33.33%)10 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Joint dislocation ∗ A 0 / 3 (0%)01 / 3 (33.33%)10 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Laceration ∗ A 0 / 3 (0%)01 / 3 (33.33%)10 / 3 (0%)00 / 12 (0%)01 / 17 (5.88%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Ligament sprain ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)01 / 17 (5.88%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Limb injury ∗ A 0 / 3 (0%)01 / 3 (33.33%)10 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Procedural pain ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)01 / 65 (1.54%)10 / 46 (0%)03 / 47 (6.38%)40 / 3 (0%)0
Toxicity to various agents ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)01 / 17 (5.88%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Investigations
Alanine aminotransferase increased ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)02 / 12 (16.67%)42 / 17 (11.76%)30 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 4 (25%)55 / 30 (16.67%)61 / 27 (3.7%)16 / 60 (10%)125 / 65 (7.69%)135 / 46 (10.87%)77 / 47 (14.89%)72 / 3 (66.67%)2
Amylase increased ∗ A 2 / 3 (66.67%)30 / 3 (0%)00 / 3 (0%)01 / 12 (8.33%)34 / 17 (23.53%)110 / 3 (0%)01 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 4 (0%)01 / 30 (3.33%)20 / 27 (0%)04 / 60 (6.67%)57 / 65 (10.77%)172 / 46 (4.35%)37 / 47 (14.89%)110 / 3 (0%)0
Aspartate aminotransferase increased ∗ A 0 / 3 (0%)01 / 3 (33.33%)11 / 3 (33.33%)12 / 12 (16.67%)52 / 17 (11.76%)30 / 3 (0%)02 / 3 (66.67%)20 / 3 (0%)00 / 3 (0%)01 / 4 (25%)77 / 30 (23.33%)91 / 27 (3.7%)17 / 60 (11.67%)117 / 65 (10.77%)96 / 46 (13.04%)84 / 47 (8.51%)41 / 3 (33.33%)1
Blood alkaline phosphatase increased ∗ A 1 / 3 (33.33%)11 / 3 (33.33%)10 / 3 (0%)01 / 12 (8.33%)11 / 17 (5.88%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Blood cholesterol increased ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)06 / 12 (50%)93 / 17 (17.65%)81 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 4 (25%)313 / 30 (43.33%)4113 / 27 (48.15%)5518 / 60 (30%)6717 / 65 (26.15%)4416 / 46 (34.78%)4218 / 47 (38.3%)493 / 3 (100%)10
Blood creatine phosphokinase increased ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)01 / 17 (5.88%)40 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 3 (33.33%)10 / 4 (0%)01 / 30 (3.33%)31 / 27 (3.7%)15 / 60 (8.33%)100 / 65 (0%)00 / 46 (0%)02 / 47 (4.26%)22 / 3 (66.67%)16
Blood creatinine increased ∗ A 1 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)01 / 12 (8.33%)30 / 17 (0%)02 / 3 (66.67%)20 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Blood phosphorus decreased ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)01 / 3 (33.33%)10 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Blood triglycerides increased ∗ A 0 / 3 (0%)01 / 3 (33.33%)20 / 3 (0%)02 / 12 (16.67%)33 / 17 (17.65%)81 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 4 (25%)62 / 30 (6.67%)22 / 27 (7.41%)44 / 60 (6.67%)83 / 65 (4.62%)33 / 46 (6.52%)43 / 47 (6.38%)80 / 3 (0%)0
Candida test positive ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)01 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Ejection fraction decreased ∗ A 1 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)02 / 3 (66.67%)20 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 4 (25%)20 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Electrocardiogram PR prolongation ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)01 / 3 (33.33%)1
Electrocardiogram QT prolonged ∗ A 2 / 3 (66.67%)20 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)01 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 4 (25%)10 / 30 (0%)01 / 27 (3.7%)23 / 60 (5%)74 / 65 (6.15%)49 / 46 (19.57%)102 / 47 (4.26%)20 / 3 (0%)0
Gamma-glutamyltransferase increased ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 12 (8.33%)30 / 17 (0%)00 / 3 (0%)00 / 3 (0%)01 / 3 (33.33%)10 / 3 (0%)02 / 4 (50%)120 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Glucose urine present ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)01 / 17 (5.88%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
International normalised ratio increased ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)01 / 17 (5.88%)20 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Lipase increased ∗ A 2 / 3 (66.67%)20 / 3 (0%)00 / 3 (0%)02 / 12 (16.67%)55 / 17 (29.41%)200 / 3 (0%)01 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)01 / 4 (25%)23 / 30 (10%)54 / 27 (14.81%)61 / 60 (1.67%)17 / 65 (10.77%)145 / 46 (10.87%)66 / 47 (12.77%)121 / 3 (33.33%)4
Lipids increased ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)01 / 17 (5.88%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 4 (25%)10 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Liver function test increased ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)01 / 17 (5.88%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Transaminases increased ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)01 / 17 (5.88%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Weight decreased ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)01 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Weight increased ∗ A 0 / 3 (0%)01 / 3 (33.33%)11 / 3 (33.33%)13 / 12 (25%)73 / 17 (17.65%)51 / 3 (33.33%)11 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)02 / 4 (50%)34 / 30 (13.33%)114 / 27 (14.81%)611 / 60 (18.33%)1818 / 65 (27.69%)2310 / 46 (21.74%)1210 / 47 (21.28%)171 / 3 (33.33%)2
Metabolism and nutrition disorders
Decreased appetite ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)02 / 4 (50%)34 / 30 (13.33%)41 / 27 (3.7%)10 / 60 (0%)05 / 65 (7.69%)52 / 46 (4.35%)22 / 47 (4.26%)20 / 3 (0%)0
Dehydration ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 12 (8.33%)11 / 17 (5.88%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Fluid retention ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)02 / 12 (16.67%)20 / 17 (0%)00 / 3 (0%)00 / 3 (0%)01 / 3 (33.33%)10 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Hypercalcaemia ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)01 / 3 (33.33%)10 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Hypercholesterolaemia ∗ A 1 / 3 (33.33%)12 / 3 (66.67%)61 / 3 (33.33%)27 / 12 (58.33%)2512 / 17 (70.59%)382 / 3 (66.67%)43 / 3 (100%)181 / 3 (33.33%)11 / 3 (33.33%)51 / 4 (25%)514 / 30 (46.67%)6111 / 27 (40.74%)3933 / 60 (55%)12637 / 65 (56.92%)10225 / 46 (54.35%)6225 / 47 (53.19%)600 / 3 (0%)0
Hyperglycaemia ∗ A 0 / 3 (0%)01 / 3 (33.33%)50 / 3 (0%)00 / 12 (0%)01 / 17 (5.88%)60 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)03 / 30 (10%)71 / 27 (3.7%)12 / 60 (3.33%)73 / 65 (4.62%)96 / 46 (13.04%)235 / 47 (10.64%)83 / 3 (100%)11
Hyperlipidaemia ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)02 / 17 (11.76%)40 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)02 / 30 (6.67%)20 / 27 (0%)00 / 60 (0%)00 / 65 (0%)02 / 46 (4.35%)20 / 47 (0%)00 / 3 (0%)0
Hypertriglyceridaemia ∗ A 0 / 3 (0%)01 / 3 (33.33%)91 / 3 (33.33%)44 / 12 (33.33%)96 / 17 (35.29%)271 / 3 (33.33%)12 / 3 (66.67%)100 / 3 (0%)01 / 3 (33.33%)21 / 4 (25%)320 / 30 (66.67%)10612 / 27 (44.44%)3427 / 60 (45%)9944 / 65 (67.69%)13529 / 46 (63.04%)10023 / 47 (48.94%)780 / 3 (0%)0
Hyperuricaemia ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)01 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 4 (25%)12 / 30 (6.67%)21 / 27 (3.7%)12 / 60 (3.33%)21 / 65 (1.54%)13 / 46 (6.52%)33 / 47 (6.38%)30 / 3 (0%)0
Hypoalbuminaemia ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)03 / 30 (10%)50 / 27 (0%)03 / 60 (5%)64 / 65 (6.15%)54 / 46 (8.7%)62 / 47 (4.26%)20 / 3 (0%)0
Hypocalcaemia ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)01 / 3 (33.33%)40 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Hypocholesterolaemia ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)01 / 17 (5.88%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Hypokalaemia ∗ A 0 / 3 (0%)00 / 3 (0%)01 / 3 (33.33%)10 / 12 (0%)01 / 17 (5.88%)12 / 3 (66.67%)71 / 3 (33.33%)111 / 3 (33.33%)10 / 3 (0%)00 / 4 (0%)02 / 30 (6.67%)40 / 27 (0%)04 / 60 (6.67%)44 / 65 (6.15%)62 / 46 (4.35%)23 / 47 (6.38%)30 / 3 (0%)0
Hypomagnesaemia ∗ A 0 / 3 (0%)01 / 3 (33.33%)21 / 3 (33.33%)10 / 12 (0%)00 / 17 (0%)03 / 3 (100%)50 / 3 (0%)01 / 3 (33.33%)10 / 3 (0%)00 / 4 (0%)02 / 30 (6.67%)30 / 27 (0%)02 / 60 (3.33%)21 / 65 (1.54%)13 / 46 (6.52%)33 / 47 (6.38%)40 / 3 (0%)0
Hypophosphataemia ∗ A 1 / 3 (33.33%)12 / 3 (66.67%)50 / 3 (0%)00 / 12 (0%)00 / 17 (0%)01 / 3 (33.33%)41 / 3 (33.33%)20 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)02 / 27 (7.41%)22 / 60 (3.33%)21 / 65 (1.54%)13 / 46 (6.52%)43 / 47 (6.38%)50 / 3 (0%)0
Increased appetite ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)01 / 3 (33.33%)1
Musculoskeletal and connective tissue disorders
Arthralgia ∗ A 1 / 3 (33.33%)21 / 3 (33.33%)10 / 3 (0%)02 / 12 (16.67%)34 / 17 (23.53%)50 / 3 (0%)01 / 3 (33.33%)10 / 3 (0%)01 / 3 (33.33%)11 / 4 (25%)15 / 30 (16.67%)94 / 27 (14.81%)49 / 60 (15%)1211 / 65 (16.92%)1811 / 46 (23.91%)1314 / 47 (29.79%)170 / 3 (0%)0
Arthritis ∗ A 0 / 3 (0%)01 / 3 (33.33%)10 / 3 (0%)01 / 12 (8.33%)10 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Back pain ∗ A 0 / 3 (0%)01 / 3 (33.33%)10 / 3 (0%)02 / 12 (16.67%)26 / 17 (35.29%)70 / 3 (0%)02 / 3 (66.67%)40 / 3 (0%)01 / 3 (33.33%)12 / 4 (50%)22 / 30 (6.67%)25 / 27 (18.52%)62 / 60 (3.33%)210 / 65 (15.38%)105 / 46 (10.87%)53 / 47 (6.38%)31 / 3 (33.33%)1
Bone lesion ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)01 / 17 (5.88%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Bone pain ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 12 (8.33%)11 / 17 (5.88%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)01 / 30 (3.33%)10 / 27 (0%)01 / 60 (1.67%)10 / 65 (0%)03 / 46 (6.52%)30 / 47 (0%)00 / 3 (0%)0
Flank pain ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)02 / 17 (11.76%)20 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Joint swelling ∗ A 1 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 12 (0%)01 / 17 (5.88%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)01 / 27 (3.7%)30 / 60 (0%)02 / 65 (3.08%)30 / 46 (0%)03 / 47 (6.38%)30 / 3 (0%)0
Limb discomfort ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 12 (8.33%)10 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Muscle spasms ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 3 (33.33%)11 / 4 (25%)10 / 30 (0%)00 / 27 (0%)03 / 60 (5%)31 / 65 (1.54%)23 / 46 (6.52%)35 / 47 (10.64%)50 / 3 (0%)0
Muscular weakness ∗ A 1 / 3 (33.33%)11 / 3 (33.33%)10 / 3 (0%)01 / 12 (8.33%)10 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)02 / 30 (6.67%)20 / 27 (0%)06 / 60 (10%)63 / 65 (4.62%)51 / 46 (2.17%)13 / 47 (6.38%)30 / 3 (0%)0
Musculoskeletal chest pain ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)01 / 17 (5.88%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)03 / 60 (5%)30 / 65 (0%)01 / 46 (2.17%)14 / 47 (8.51%)40 / 3 (0%)0
Musculoskeletal discomfort ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)01 / 17 (5.88%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Musculoskeletal pain ∗ A 1 / 3 (33.33%)10 / 3 (0%)01 / 3 (33.33%)10 / 12 (0%)02 / 17 (11.76%)20 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)04 / 30 (13.33%)52 / 27 (7.41%)33 / 60 (5%)43 / 65 (4.62%)32 / 46 (4.35%)22 / 47 (4.26%)21 / 3 (33.33%)1
Musculoskeletal stiffness ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)01 / 30 (3.33%)10 / 27 (0%)00 / 60 (0%)03 / 65 (4.62%)31 / 46 (2.17%)14 / 47 (8.51%)40 / 3 (0%)0
Myalgia ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 12 (8.33%)12 / 17 (11.76%)20 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 4 (25%)13 / 30 (10%)32 / 27 (7.41%)25 / 60 (8.33%)56 / 65 (9.23%)75 / 46 (10.87%)56 / 47 (12.77%)72 / 3 (66.67%)2
Neck pain ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 12 (8.33%)12 / 17 (11.76%)20 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Osteoarthritis ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 12 (8.33%)10 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Osteoporosis ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 4 (25%)10 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Pain in extremity ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 12 (8.33%)11 / 17 (5.88%)11 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)01 / 3 (33.33%)20 / 4 (0%)02 / 30 (6.67%)48 / 27 (29.63%)104 / 60 (6.67%)86 / 65 (9.23%)64 / 46 (8.7%)48 / 47 (17.02%)90 / 3 (0%)0
Pain in jaw ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)02 / 17 (11.76%)20 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Plantar fasciitis ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)01 / 17 (5.88%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Torticollis ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 3 (33.33%)10 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Melanocytic naevus ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)01 / 17 (5.88%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Tumour pain ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)01 / 3 (33.33%)1
Nervous system disorders
Amnesia ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)01 / 3 (33.33%)10 / 3 (0%)01 / 3 (33.33%)10 / 4 (0%)00 / 30 (0%)00 / 27 (0%)06 / 60 (10%)66 / 65 (9.23%)102 / 46 (4.35%)42 / 47 (4.26%)20 / 3 (0%)0
Aphasia ∗ A 2 / 3 (66.67%)20 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)01 / 3 (33.33%)10 / 3 (0%)01 / 3 (33.33%)10 / 4 (0%)00 / 30 (0%)02 / 27 (7.41%)20 / 60 (0%)02 / 65 (3.08%)22 / 46 (4.35%)21 / 47 (2.13%)10 / 3 (0%)0
Ataxia ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 3 (33.33%)10 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Balance disorder ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 4 (25%)10 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Carpal tunnel syndrome ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 12 (8.33%)10 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 3 (33.33%)10 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Cognitive disorder ∗ A 1 / 3 (33.33%)11 / 3 (33.33%)10 / 3 (0%)02 / 12 (16.67%)20 / 17 (0%)02 / 3 (66.67%)21 / 3 (33.33%)30 / 3 (0%)00 / 3 (0%)01 / 4 (25%)11 / 30 (3.33%)11 / 27 (3.7%)35 / 60 (8.33%)56 / 65 (9.23%)72 / 46 (4.35%)23 / 47 (6.38%)60 / 3 (0%)0
Disturbance in attention ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)02 / 12 (16.67%)20 / 17 (0%)00 / 3 (0%)01 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)01 / 60 (1.67%)12 / 65 (3.08%)131 / 46 (2.17%)13 / 47 (6.38%)30 / 3 (0%)0
Dizziness ∗ A 1 / 3 (33.33%)11 / 3 (33.33%)20 / 3 (0%)01 / 12 (8.33%)12 / 17 (11.76%)20 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 4 (25%)16 / 30 (20%)124 / 27 (14.81%)125 / 60 (8.33%)59 / 65 (13.85%)127 / 46 (15.22%)811 / 47 (23.4%)200 / 3 (0%)0
Dysaesthesia ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)01 / 17 (5.88%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Dysarthria ∗ A 0 / 3 (0%)01 / 3 (33.33%)40 / 3 (0%)01 / 12 (8.33%)10 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 3 (33.33%)10 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)01 / 3 (33.33%)1
Dysgeusia ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)02 / 12 (16.67%)20 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 4 (25%)12 / 30 (6.67%)20 / 27 (0%)01 / 60 (1.67%)16 / 65 (9.23%)62 / 46 (4.35%)21 / 47 (2.13%)10 / 3 (0%)0
Formication ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)01 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Headache ∗ A 1 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)03 / 12 (25%)31 / 17 (5.88%)21 / 3 (33.33%)11 / 3 (33.33%)11 / 3 (33.33%)11 / 3 (33.33%)12 / 4 (50%)35 / 30 (16.67%)86 / 27 (22.22%)78 / 60 (13.33%)1011 / 65 (16.92%)1510 / 46 (21.74%)112 / 47 (4.26%)21 / 3 (33.33%)1
Hemiparesis ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)01 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Hypoaesthesia ∗ A 0 / 3 (0%)01 / 3 (33.33%)10 / 3 (0%)03 / 12 (25%)31 / 17 (5.88%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 3 (33.33%)10 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Memory impairment ∗ A 0 / 3 (0%)01 / 3 (33.33%)10 / 3 (0%)01 / 12 (8.33%)12 / 17 (11.76%)20 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 4 (25%)22 / 30 (6.67%)23 / 27 (11.11%)34 / 60 (6.67%)56 / 65 (9.23%)122 / 46 (4.35%)27 / 47 (14.89%)160 / 3 (0%)0
Mental impairment ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)01 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Migraine ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 12 (8.33%)10 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Nervous system disorder ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)01 / 17 (5.88%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Neuralgia ∗ A 0 / 3 (0%)01 / 3 (33.33%)10 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Neuropathy peripheral ∗ A 2 / 3 (66.67%)20 / 3 (0%)01 / 3 (33.33%)15 / 12 (41.67%)72 / 17 (11.76%)21 / 3 (33.33%)32 / 3 (66.67%)40 / 3 (0%)01 / 3 (33.33%)10 / 4 (0%)05 / 30 (16.67%)63 / 27 (11.11%)46 / 60 (10%)77 / 65 (10.77%)75 / 46 (10.87%)55 / 47 (10.64%)80 / 3 (0%)0
Neurotoxicity ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)01 / 17 (5.88%)50 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Paraesthesia ∗ A 0 / 3 (0%)02 / 3 (66.67%)20 / 3 (0%)01 / 12 (8.33%)42 / 17 (11.76%)20 / 3 (0%)01 / 3 (33.33%)11 / 3 (33.33%)11 / 3 (33.33%)12 / 4 (50%)43 / 30 (10%)54 / 27 (14.81%)711 / 60 (18.33%)139 / 65 (13.85%)95 / 46 (10.87%)65 / 47 (10.64%)60 / 3 (0%)0
Partial seizures ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)01 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Peripheral sensory neuropathy ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 12 (8.33%)11 / 17 (5.88%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)03 / 30 (10%)33 / 27 (11.11%)47 / 60 (11.67%)143 / 65 (4.62%)34 / 46 (8.7%)42 / 47 (4.26%)22 / 3 (66.67%)2
Peroneal nerve palsy ∗ A 1 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Presyncope ∗ A 1 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 4 (25%)10 / 30 (0%)00 / 27 (0%)01 / 60 (1.67%)10 / 65 (0%)00 / 46 (0%)03 / 47 (6.38%)30 / 3 (0%)0
Psychomotor hyperactivity ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)01 / 17 (5.88%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Seizure ∗ A 0 / 3 (0%)01 / 3 (33.33%)10 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Sensory disturbance ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)01 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Slow speech ∗ A 0 / 3 (0%)00 / 3 (0%)01 / 3 (33.33%)21 / 12 (8.33%)13 / 17 (17.65%)40 / 3 (0%)01 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)05 / 60 (8.33%)92 / 65 (3.08%)20 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Speech disorder ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)02 / 12 (16.67%)21 / 17 (5.88%)10 / 3 (0%)01 / 3 (33.33%)10 / 3 (0%)01 / 3 (33.33%)10 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Tremor ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 12 (8.33%)10 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Psychiatric disorders
Abnormal dreams ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)01 / 3 (33.33%)11 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Affect lability ∗ A 1 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)03 / 12 (25%)50 / 17 (0%)00 / 3 (0%)01 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)02 / 60 (3.33%)42 / 65 (3.08%)30 / 46 (0%)03 / 47 (6.38%)30 / 3 (0%)0
Agitation ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)01 / 3 (33.33%)20 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Anxiety ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)02 / 12 (16.67%)20 / 17 (0%)00 / 3 (0%)00 / 3 (0%)01 / 3 (33.33%)20 / 3 (0%)01 / 4 (25%)10 / 30 (0%)02 / 27 (7.41%)21 / 60 (1.67%)17 / 65 (10.77%)71 / 46 (2.17%)14 / 47 (8.51%)60 / 3 (0%)0
Attention deficit/hyperactivity disorder ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)01 / 17 (5.88%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Bradyphrenia ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 12 (8.33%)10 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Confusional state ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)02 / 17 (11.76%)21 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)01 / 3 (33.33%)10 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Depressed mood ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 12 (8.33%)10 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 3 (33.33%)10 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Depression ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)01 / 30 (3.33%)12 / 27 (7.41%)56 / 60 (10%)71 / 65 (1.54%)11 / 46 (2.17%)11 / 47 (2.13%)10 / 3 (0%)0
Hallucination ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)01 / 3 (33.33%)20 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Hallucination, auditory ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)01 / 3 (33.33%)1
Insomnia ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 12 (8.33%)10 / 17 (0%)01 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)04 / 30 (13.33%)53 / 27 (11.11%)35 / 60 (8.33%)63 / 65 (4.62%)33 / 46 (6.52%)34 / 47 (8.51%)40 / 3 (0%)0
Irritability ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)02 / 17 (11.76%)20 / 3 (0%)01 / 3 (33.33%)20 / 3 (0%)00 / 3 (0%)00 / 4 (0%)03 / 30 (10%)31 / 27 (3.7%)13 / 60 (5%)42 / 65 (3.08%)26 / 46 (13.04%)61 / 47 (2.13%)10 / 3 (0%)0
Mental status changes ∗ A 1 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Mood swings ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)02 / 30 (6.67%)21 / 27 (3.7%)10 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Nightmare ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)01 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Reading disorder ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)01 / 17 (5.88%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Sleep disorder ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 3 (33.33%)10 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Renal and urinary disorders
Chronic kidney disease ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)01 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Haematuria ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)02 / 17 (11.76%)20 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)02 / 30 (6.67%)20 / 27 (0%)01 / 60 (1.67%)11 / 65 (1.54%)10 / 46 (0%)02 / 47 (4.26%)30 / 3 (0%)0
Hydronephrosis ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)01 / 17 (5.88%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Micturition urgency ∗ A 1 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 12 (0%)01 / 17 (5.88%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Pollakiuria ∗ A 1 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 12 (0%)01 / 17 (5.88%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Proteinuria ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)01 / 17 (5.88%)11 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)01 / 3 (33.33%)1
Urinary incontinence ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)01 / 17 (5.88%)11 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 4 (25%)10 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Reproductive system and breast disorders
Menstruation irregular ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)01 / 17 (5.88%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Vaginal haemorrhage ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 12 (8.33%)10 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)01 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Bronchitis chronic ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)01 / 17 (5.88%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Cough ∗ A 1 / 3 (33.33%)12 / 3 (66.67%)21 / 3 (33.33%)11 / 12 (8.33%)11 / 17 (5.88%)10 / 3 (0%)01 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)02 / 4 (50%)29 / 30 (30%)133 / 27 (11.11%)57 / 60 (11.67%)1011 / 65 (16.92%)148 / 46 (17.39%)129 / 47 (19.15%)120 / 3 (0%)0
Dysphonia ∗ A 1 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 4 (25%)11 / 30 (3.33%)10 / 27 (0%)04 / 60 (6.67%)42 / 65 (3.08%)22 / 46 (4.35%)20 / 47 (0%)00 / 3 (0%)0
Dyspnoea ∗ A 1 / 3 (33.33%)11 / 3 (33.33%)11 / 3 (33.33%)10 / 12 (0%)03 / 17 (17.65%)30 / 3 (0%)00 / 3 (0%)02 / 3 (66.67%)31 / 3 (33.33%)32 / 4 (50%)57 / 30 (23.33%)83 / 27 (11.11%)314 / 60 (23.33%)1613 / 65 (20%)149 / 46 (19.57%)1114 / 47 (29.79%)201 / 3 (33.33%)1
Dyspnoea exertional ∗ A 0 / 3 (0%)01 / 3 (33.33%)10 / 3 (0%)00 / 12 (0%)01 / 17 (5.88%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)01 / 30 (3.33%)11 / 27 (3.7%)13 / 60 (5%)66 / 65 (9.23%)83 / 46 (6.52%)51 / 47 (2.13%)20 / 3 (0%)0
Epistaxis ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)01 / 17 (5.88%)11 / 3 (33.33%)10 / 3 (0%)01 / 3 (33.33%)10 / 3 (0%)00 / 4 (0%)00 / 30 (0%)02 / 27 (7.41%)23 / 60 (5%)33 / 65 (4.62%)40 / 46 (0%)01 / 47 (2.13%)10 / 3 (0%)0
Haemoptysis ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)02 / 3 (66.67%)20 / 3 (0%)00 / 3 (0%)00 / 4 (0%)02 / 30 (6.67%)30 / 27 (0%)02 / 60 (3.33%)25 / 65 (7.69%)61 / 46 (2.17%)10 / 47 (0%)00 / 3 (0%)0
Hypoxia ∗ A 1 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)01 / 65 (1.54%)15 / 46 (10.87%)101 / 47 (2.13%)20 / 3 (0%)0
Laryngeal inflammation ∗ A 0 / 3 (0%)00 / 3 (0%)01 / 3 (33.33%)10 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Nasal congestion ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 12 (8.33%)10 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Oropharyngeal pain ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)01 / 17 (5.88%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 4 (25%)10 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Pleural effusion ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)01 / 3 (33.33%)10 / 3 (0%)00 / 4 (0%)01 / 30 (3.33%)10 / 27 (0%)00 / 60 (0%)05 / 65 (7.69%)51 / 46 (2.17%)14 / 47 (8.51%)40 / 3 (0%)0
Pleuritic pain ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)01 / 17 (5.88%)20 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 3 (33.33%)10 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Productive cough ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)01 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Pulmonary embolism ∗ A 1 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Pulmonary hypertension ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 4 (25%)20 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Pulmonary oedema ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)01 / 3 (33.33%)10 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Rales ∗ A 0 / 3 (0%)00 / 3 (0%)01 / 3 (33.33%)10 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Respiratory tract congestion ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)01 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Rhinorrhoea ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 4 (25%)10 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Sinus congestion ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)01 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Wheezing ∗ A 0 / 3 (0%)00 / 3 (0%)01 / 3 (33.33%)10 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)01 / 3 (33.33%)10 / 3 (0%)00 / 4 (0%)01 / 30 (3.33%)10 / 27 (0%)01 / 60 (1.67%)12 / 65 (3.08%)23 / 46 (6.52%)32 / 47 (4.26%)20 / 3 (0%)0
Skin and subcutaneous tissue disorders
Alopecia ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 12 (8.33%)10 / 17 (0%)00 / 3 (0%)01 / 3 (33.33%)20 / 3 (0%)00 / 3 (0%)01 / 4 (25%)12 / 30 (6.67%)22 / 27 (7.41%)22 / 60 (3.33%)22 / 65 (3.08%)23 / 46 (6.52%)32 / 47 (4.26%)21 / 3 (33.33%)1
Dermatitis acneiform ∗ A 0 / 3 (0%)01 / 3 (33.33%)10 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Dermatitis contact ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)01 / 17 (5.88%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Dermatomyositis ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)01 / 3 (33.33%)20 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Dry skin ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)01 / 17 (5.88%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 3 (33.33%)11 / 4 (25%)13 / 30 (10%)31 / 27 (3.7%)12 / 60 (3.33%)20 / 65 (0%)00 / 46 (0%)01 / 47 (2.13%)11 / 3 (33.33%)1
Erythema ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)02 / 27 (7.41%)21 / 60 (1.67%)11 / 65 (1.54%)10 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Hyperhidrosis ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)02 / 12 (16.67%)20 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)01 / 27 (3.7%)12 / 60 (3.33%)25 / 65 (7.69%)51 / 46 (2.17%)14 / 47 (8.51%)40 / 3 (0%)0
Night sweats ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 12 (8.33%)10 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Photosensitivity reaction ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)01 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Pruritus ∗ A 1 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)01 / 65 (1.54%)14 / 46 (8.7%)41 / 47 (2.13%)10 / 3 (0%)0
Rash ∗ A 1 / 3 (33.33%)11 / 3 (33.33%)10 / 3 (0%)03 / 12 (25%)41 / 17 (5.88%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)05 / 30 (16.67%)93 / 27 (11.11%)42 / 60 (3.33%)27 / 65 (10.77%)72 / 46 (4.35%)24 / 47 (8.51%)40 / 3 (0%)0
Rash erythematous ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)01 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Rash maculo-papular ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)01 / 17 (5.88%)20 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)01 / 3 (33.33%)1
Rash pruritic ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 12 (8.33%)10 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Rosacea ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 4 (25%)10 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Seborrhoeic dermatitis ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 12 (8.33%)10 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Skin lesion ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)01 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Swelling face ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 4 (25%)10 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Vascular disorders
Deep vein thrombosis ∗ A 1 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 4 (25%)10 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Haematoma ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 4 (25%)10 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Haemorrhage ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 12 (8.33%)10 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Hot flush ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)00 / 3 (0%)01 / 3 (33.33%)11 / 4 (25%)10 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Hypertension ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)02 / 12 (16.67%)31 / 17 (5.88%)11 / 3 (33.33%)10 / 3 (0%)01 / 3 (33.33%)10 / 3 (0%)00 / 4 (0%)02 / 30 (6.67%)21 / 27 (3.7%)12 / 60 (3.33%)68 / 65 (12.31%)174 / 46 (8.7%)113 / 47 (6.38%)60 / 3 (0%)0
Hypotension ∗ A 1 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)01 / 3 (33.33%)10 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
Shock ∗ A 0 / 3 (0%)00 / 3 (0%)00 / 3 (0%)00 / 12 (0%)00 / 17 (0%)00 / 3 (0%)00 / 3 (0%)01 / 3 (33.33%)10 / 3 (0%)00 / 4 (0%)00 / 30 (0%)00 / 27 (0%)00 / 60 (0%)00 / 65 (0%)00 / 46 (0%)00 / 47 (0%)00 / 3 (0%)0
∗Indicates events were collected by non-systematic methods.
ATerm from vocabulary, MedDRA 20.0
Open or close this module Limitations and Caveats
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.
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Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between the Principal Investigator 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.
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Organization:
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Phone:
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Email:
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