The classic website will no longer be available as of June 25, 2024. Please use the modernized ClinicalTrials.gov.
Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

Study of Pembrolizumab (MK-3475) in Participants With Progressive Locally Advanced or Metastatic Carcinoma, Melanoma, or Non-small Cell Lung Carcinoma (P07990/MK-3475-001/KEYNOTE-001) (KEYNOTE-001)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01295827
Recruitment Status : Completed
First Posted : February 15, 2011
Results First Posted : December 13, 2019
Last Update Posted : December 13, 2019
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme LLC

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Cancer, Solid Tumor
Intervention Biological: Pembrolizumab
Enrollment 1260
Recruitment Details Participants with a histologically- or cytologically-confirmed diagnosis of any type of carcinoma (solid tumors), melanoma (MEL), or non-small cell lung cancer (NSCLC), with progressive locally advanced or metastatic disease, were recruited.
Pre-assignment Details Of 1260 participants enrolled or randomized to the study, 1235 received at least one dose of treatment (All Treated Population) and were evaluable for all safety and efficacy analyses. Part E did not enroll any participants.
Arm/Group Title Solid Tumors: Pembrolizumab 1 mg/kg Q2W (Part A) Solid Tumors: Pembrolizumab 3 mg/kg Q2W (Part A) Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) Solid Tumors: Pembrolizumab Titration Cohort 1 Q3W (Part A2) Solid Tumors: Pembrolizumab Titration Cohort 2 Q3W (Part A2) Solid Tumors: Pembrolizumab Titration Cohort 3 Q3W (Part A2) MEL: Pembrolizumab 2 mg/kg Q3W (Parts B+D) MEL: Pembrolizumab 10 mg/kg Q3W (Parts B+D) MEL: Pembrolizumab 10 mg/kg Q2W (Part B) NSCLC: Pembrolizumab 2 mg/kg Q3W (Part F) NSCLC: Pembrolizumab 10 mg/kg Q3W (Parts C+F) NSCLC: Pembrolizumab 10 mg/kg Q2W (Part F) NSCLC: Pembrolizumab 2 mg/kg Q3W (Part E-Not Enrolled) NSCLC: Pembrolizumab 5 mg/kg Q3W (Part E-Not Enrolled) NSCLC: Pembrolizumab 10 mg/kg Q3W (Part E-Not Enrolled)
Hide Arm/Group Description During Cycle 1 participants received a dose of 1 mg/kg pembrolizumab intravenous (IV) infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 1 mg/kg every 2 weeks (Q2W) starting with Cycle 2. During Cycle 1 participants received a dose of 3 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 3 mg/kg Q2W starting with Cycle 2. During Cycle 1 participants received a dose of 10 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W starting with Cycle 2. During Cycle 1 participants received pembrolizumab dose titration from 0.005 mg/kg to 0.3 mg/kg to 2.0 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 2 mg/kg every 3 weeks (Q3W) starting with Cycle 2. During Cycle 1 participants received pembrolizumab dose titration from 0.02 mg/kg to 0.3 mg/kg to 2.0 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 2 mg/kg Q3W starting with Cycle 2. During Cycle 1 participants received pembrolizumab dose titration from 0.06 mg/kg to 1.0 mg/kg to 10 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 10 mg/kg Q3W starting with Cycle 2. Participants received pembrolizumab IV at a dose of 2 mg/kg Q2W. After Amendment 3, participants received dosing Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data. Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 7, participants received dosing Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data. Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data. Participants received pembrolizumab IV at a dose of 2 mg/kg Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data. Participants received pembrolizumab IV at a dose of 10 mg/kg Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data. Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data. Participants were to receive pembrolizumab IV at a dose of 2 mg/kg Q3W. No participants were enrolled in this arm. Participants were to receive pembrolizumab IV at a dose of 5 mg/kg Q3W. No participants were enrolled in this arm. Participants were to receive pembrolizumab IV at a dose of 10 mg/kg Q3W. No participants were enrolled in this arm.
Period Title: Overall Study
Started 4 3 12 4 3 6 164 321 183 61 296 203 0 0 0
Treated (All Treated Population) 4 3 10 4 3 6 162 313 180 61 287 202 0 0 0
Completed 0 0 0 0 1 0 18 24 14 6 20 17 0 0 0
Not Completed 4 3 12 4 2 6 146 297 169 55 276 186 0 0 0
Reason Not Completed
Adverse Event             1             2             2             1             1             4             15             49             22             7             50             21             0             0             0
Lost to Follow-up             0             0             3             0             1             0             4             8             7             4             7             3             0             0             0
Not Reported             0             0             0             1             0             0             24             58             41             2             23             13             0             0             0
Progressive Disease             2             1             5             2             0             1             87             144             85             40             175             136             0             0             0
Screen Failure             0             0             0             0             0             0             2             2             2             0             1             0             0             0             0
Withdrawal by Subject             1             0             2             0             0             1             13             35             11             2             18             13             0             0             0
Other             0             0             0             0             0             0             1             1             1             0             2             0             0             0             0
Arm/Group Title Solid Tumors: Pembrolizumab 1 mg/kg Q2W (Part A) Solid Tumors: Pembrolizumab 3 mg/kg Q2W (Part A) Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) Solid Tumors: Pembrolizumab Titration Cohort 1 Q3W (Part A2) Solid Tumors: Pembrolizumab Titration Cohort 2 Q3W (Part A2) Solid Tumors: Pembrolizumab Titration Cohort 3 Q3W (Part A2) MEL: Pembrolizumab 2 mg/kg Q3W (Parts B+D) MEL: Pembrolizumab 10 mg/kg Q3W (Parts B+D) MEL: Pembrolizumab 10 mg/kg Q2W (Part B) NSCLC: Pembrolizumab 2 mg/kg Q3W (Part F) NSCLC: Pembrolizumab 10 mg/kg Q3W (Parts C+F) NSCLC: Pembrolizumab 10 mg/kg Q2W (Part F) Total
Hide Arm/Group Description During Cycle 1 participants received a dose of 1 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 1 mg/kg Q2W starting with Cycle 2. During Cycle 1 participants received a dose of 3 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 3 mg/kg Q2W starting with Cycle 2. During Cycle 1 participants received a dose of 10 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W starting with Cycle 2. During Cycle 1 participants received pembrolizumab dose titration from 0.005 mg/kg to 0.3 mg/kg to 2.0 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 2 mg/kg every 3 weeks (Q3W) starting with Cycle 2. During Cycle 1 participants received pembrolizumab dose titration from 0.02 mg/kg to 0.3 mg/kg to 2.0 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 2 mg/kg Q3W starting with Cycle 2. During Cycle 1 participants received pembrolizumab dose titration from 0.06 mg/kg to 1.0 mg/kg to 10 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 10 mg/kg Q3W starting with Cycle 2. Participants received pembrolizumab IV at a dose of 2 mg/kg Q2W. After Amendment 3, participants received dosing Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data. Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 7, participants received dosing Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data. Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data. Participants received pembrolizumab IV at a dose of 2 mg/kg Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data. Participants received pembrolizumab IV at a dose of 10 mg/kg Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data. Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data. Total of all reporting groups
Overall Number of Baseline Participants 4 3 12 4 3 6 164 321 183 61 296 203 1260
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 4 participants 3 participants 12 participants 4 participants 3 participants 6 participants 164 participants 321 participants 183 participants 61 participants 296 participants 203 participants 1260 participants
71.0  (6.4) 76.0  (8.7) 62.7  (16.1) 53.8  (11.7) 53.3  (23.5) 69.0  (7.6) 57.9  (13.5) 60.5  (13.5) 60.1  (14.4) 61.9  (11.0) 61.8  (11.2) 63.0  (10.2) 61.0  (12.6)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 4 participants 3 participants 12 participants 4 participants 3 participants 6 participants 164 participants 321 participants 183 participants 61 participants 296 participants 203 participants 1260 participants
Female
3
  75.0%
2
  66.7%
3
  25.0%
0
   0.0%
0
   0.0%
0
   0.0%
69
  42.1%
125
  38.9%
122
  66.7%
29
  47.5%
145
  49.0%
91
  44.8%
589
  46.7%
Male
1
  25.0%
1
  33.3%
9
  75.0%
4
 100.0%
3
 100.0%
6
 100.0%
95
  57.9%
196
  61.1%
61
  33.3%
32
  52.5%
151
  51.0%
112
  55.2%
671
  53.3%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 4 participants 3 participants 12 participants 4 participants 3 participants 6 participants 164 participants 321 participants 183 participants 61 participants 296 participants 203 participants 1260 participants
Hispanic or Latino
2
  50.0%
1
  33.3%
3
  25.0%
0
   0.0%
0
   0.0%
0
   0.0%
12
   7.3%
13
   4.0%
3
   1.6%
1
   1.6%
20
   6.8%
8
   3.9%
63
   5.0%
Not Hispanic or Latino
2
  50.0%
2
  66.7%
9
  75.0%
4
 100.0%
3
 100.0%
6
 100.0%
152
  92.7%
308
  96.0%
180
  98.4%
60
  98.4%
274
  92.6%
195
  96.1%
1195
  94.8%
Unknown or Not Reported
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%
2
   0.7%
0
   0.0%
2
   0.2%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 4 participants 3 participants 12 participants 4 participants 3 participants 6 participants 164 participants 321 participants 183 participants 61 participants 296 participants 203 participants 1260 participants
American Indian or Alaska Native
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
   0.5%
0
   0.0%
0
   0.0%
1
   0.5%
2
   0.2%
Asian
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
2
   1.2%
6
   1.9%
2
   1.1%
6
   9.8%
46
  15.5%
19
   9.4%
81
   6.4%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
1
   0.3%
0
   0.0%
1
   1.6%
0
   0.0%
0
   0.0%
2
   0.2%
Black or African American
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
1
  33.3%
0
   0.0%
1
   0.6%
2
   0.6%
2
   1.1%
0
   0.0%
12
   4.1%
8
   3.9%
26
   2.1%
White
4
 100.0%
3
 100.0%
12
 100.0%
4
 100.0%
2
  66.7%
6
 100.0%
161
  98.2%
310
  96.6%
178
  97.3%
53
  86.9%
237
  80.1%
174
  85.7%
1144
  90.8%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
2
   0.6%
0
   0.0%
1
   1.6%
1
   0.3%
0
   0.0%
4
   0.3%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
1
   0.5%
1
   0.1%
1.Primary Outcome
Title Number of Participants Experiencing Dose-Limiting Toxicities (DLTs) According to National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v.4.0) in Participants With Solid Tumors (Parts A and A1)
Hide Description DLTs were assessed according to NCI-CTCAE v.4.0 during the first cycle (28 days) and were defined as occurrence of any of the following toxicities if judged by the investigator to be possibly, probably or definitely related to study drug administration: Grade (Gr) 4 nonhematologic toxicity; Gr 4 hematologic toxicity lasting ≥14 days; Gr 3 nonhematologic toxicity lasting >3 days despite optimal supportive care; any Grade 3 non-hematologic laboratory value if medical intervention was required to treat the participant, the abnormality led to hospitalization, or the abnormality persisted for >1 week; Gr 3 or 4 febrile neutropenia; thrombocytopenia <25,000 cells/mm^3 (if associated with a bleeding event requiring an elective platelet transfusion, or a life-threatening bleeding event which resulted in urgent intervention and admission to an Intensive Care Unit); or Gr 5 toxicity. The number of participants in Part A and Part A1 with a DLT were reported by pembrolizumab dose received.
Time Frame Up to 28 days in Cycle 1
Hide Outcome Measure Data
Hide Analysis Population Description
All participants in Parts A and A1 who received ≥1 dose of study treatment and either 1) had a DLT in Cycle 1 or 2) received ≥90% of the prescribed dose of pembrolizumab in Cycle 1 and completed all safety evaluations ≥28 days after the first administration of pembrolizumab without experiencing DLT. Per protocol, Parts A2 and B-F were not analyzed.
Arm/Group Title Solid Tumors: Pembrolizumab 1 mg/kg Q2W (Part A) Solid Tumors: Pembrolizumab 3 mg/kg Q2W (Part A) Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) Solid Tumors: Pembrolizumab Titration Cohort 1 Q3W (Part A2) Solid Tumors: Pembrolizumab Titration Cohort 2 Q3W (Part A2) Solid Tumors: Pembrolizumab Titration Cohort 3 Q3W (Part A2) MEL: Pembrolizumab 2 mg/kg Q3W (Parts B+D) MEL: Pembrolizumab 10 mg/kg Q3W (Parts B+D) MEL: Pembrolizumab 10 mg/kg Q2W (Part B) NSCLC: Pembrolizumab 2 mg/kg Q3W (Part F) NSCLC: Pembrolizumab 10 mg/kg Q3W (Parts C+F) NSCLC: Pembrolizumab 10 mg/kg Q2W (Part F)
Hide Arm/Group Description:
During Cycle 1 participants received a dose of 1 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 1 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received a dose of 3 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 3 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received a dose of 10 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.005 mg/kg to 0.3 mg/kg to 2.0 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 2 mg/kg every 3 weeks (Q3W) starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.02 mg/kg to 0.3 mg/kg to 2.0 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 2 mg/kg Q3W starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.06 mg/kg to 1.0 mg/kg to 10 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 10 mg/kg Q3W starting with Cycle 2.
Participants received pembrolizumab IV at a dose of 2 mg/kg Q2W. After Amendment 3, participants received dosing Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 7, participants received dosing Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 2 mg/kg Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Overall Number of Participants Analyzed 4 3 10 0 0 0 0 0 0 0 0 0
Measure Type: Number
Unit of Measure: Participants
0 0 0
2.Primary Outcome
Title Number of Participants Who Experienced an Adverse Event (AE)
Hide Description An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the Sponsor's product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition which was temporally associated with the use of the Sponsor's product was also an AE. The number of participants who experienced an AE was reported for each arm.
Time Frame Up to approximately 91 months (through Final Database cut-off date of 05-Nov-2018)
Hide Outcome Measure Data
Hide Analysis Population Description
All participants who received at least 1 dose of study treatment.
Arm/Group Title Solid Tumors: Pembrolizumab 1 mg/kg Q2W (Part A) Solid Tumors: Pembrolizumab 3 mg/kg Q2W (Part A) Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) Solid Tumors: Pembrolizumab Titration Cohort 1 Q3W (Part A2) Solid Tumors: Pembrolizumab Titration Cohort 2 Q3W (Part A2) Solid Tumors: Pembrolizumab Titration Cohort 3 Q3W (Part A2) MEL: Pembrolizumab 2 mg/kg Q3W (Parts B+D) MEL: Pembrolizumab 10 mg/kg Q3W (Parts B+D) MEL: Pembrolizumab 10 mg/kg Q2W (Part B) NSCLC: Pembrolizumab 2 mg/kg Q3W (Part F) NSCLC: Pembrolizumab 10 mg/kg Q3W (Parts C+F) NSCLC: Pembrolizumab 10 mg/kg Q2W (Part F)
Hide Arm/Group Description:
During Cycle 1 participants received a dose of 1 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 1 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received a dose of 3 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 3 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received a dose of 10 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.005 mg/kg to 0.3 mg/kg to 2.0 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 2 mg/kg every 3 weeks (Q3W) starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.02 mg/kg to 0.3 mg/kg to 2.0 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 2 mg/kg Q3W starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.06 mg/kg to 1.0 mg/kg to 10 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 10 mg/kg Q3W starting with Cycle 2.
Participants received pembrolizumab IV at a dose of 2 mg/kg Q2W. After Amendment 3, participants received dosing Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 7, participants received dosing Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 2 mg/kg Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Overall Number of Participants Analyzed 4 3 10 4 3 6 162 313 180 61 287 202
Measure Type: Number
Unit of Measure: Participants
4 3 9 4 3 6 161 308 178 60 277 198
3.Primary Outcome
Title Overall Response Rate (ORR) According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Integrated Radiology and Oncology (IRO): Melanoma Participants (Parts B Plus D)
Hide Description ORR was defined as the percentage of participants in the analysis population who had a confirmed Complete Response (CR: disappearance of all lesions) or Partial Response (PR: at least a 30% decrease in the sum of diameters [SOD] of target lesions, taking as reference the baseline SOD) according to RECIST 1.1, which was modified for this study to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. The percentage of participants who experienced a confirmed CR or PR according to RECIST 1.1 as assessed by IRO was reported as the ORR for each melanoma dose arm (Parts B plus D).
Time Frame Up to approximately 53 months (through Interim Database cut-off date of 18-Sep-2015)
Hide Outcome Measure Data
Hide Analysis Population Description
All melanoma (Parts B plus D) participants that received ≥1 dose of study treatment. Per protocol, Part A (dose-escalation) was not analyzed for efficacy. NSCLC (Parts C plus F) participants were analyzed and presented separately and are not included in this analysis.
Arm/Group Title Solid Tumors: Pembrolizumab 1 mg/kg Q2W (Part A) Solid Tumors: Pembrolizumab 3 mg/kg Q2W (Part A) Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) Solid Tumors: Pembrolizumab Titration Cohort 1 Q3W (Part A2) Solid Tumors: Pembrolizumab Titration Cohort 2 Q3W (Part A2) Solid Tumors: Pembrolizumab Titration Cohort 3 Q3W (Part A2) MEL: Pembrolizumab 2 mg/kg Q3W (Parts B+D) MEL: Pembrolizumab 10 mg/kg Q3W (Parts B+D) MEL: Pembrolizumab 10 mg/kg Q2W (Part B) NSCLC: Pembrolizumab 2 mg/kg Q3W (Part F) NSCLC: Pembrolizumab 10 mg/kg Q3W (Parts C+F) NSCLC: Pembrolizumab 10 mg/kg Q2W (Part F)
Hide Arm/Group Description:
During Cycle 1 participants received a dose of 1 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 1 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received a dose of 3 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 3 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received a dose of 10 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.005 mg/kg to 0.3 mg/kg to 2.0 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 2 mg/kg every 3 weeks (Q3W) starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.02 mg/kg to 0.3 mg/kg to 2.0 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 2 mg/kg Q3W starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.06 mg/kg to 1.0 mg/kg to 10 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 10 mg/kg Q3W starting with Cycle 2.
Participants received pembrolizumab IV at a dose of 2 mg/kg Q2W. After Amendment 3, participants received dosing Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 7, participants received dosing Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 2 mg/kg Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Overall Number of Participants Analyzed 0 0 0 0 0 0 162 313 180 0 0 0
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of Participants
30.2
(23.3 to 37.9)
29.4
(24.4 to 34.8)
36.7
(29.6 to 44.2)
4.Primary Outcome
Title ORR According to RECIST 1.1 as Assessed by Independent Review Committee (IRC): Non-Small Cell Lung Cancer (NSCLC) Participants (Parts C Plus F)
Hide Description ORR was defined as the percentage of participants in the analysis population who had a confirmed CR (disappearance of all lesions) or PR (at least a 30% decrease in the sum of diameters [SOD] of target lesions, taking as reference the baseline SOD) according to RECIST 1.1, which was modified for this study to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. The percentage of participants who experienced a confirmed CR or PR according to RECIST 1.1 as assessed by IRC was reported as the ORR for each NSCLC dose arm (Parts C plus F).
Time Frame Up to approximately 53 months (through Interim Database cut-off date of 18-Sep-2015)
Hide Outcome Measure Data
Hide Analysis Population Description
All NSCLC (Parts C plus F) participants that received ≥1 dose of study treatment. Per protocol, Part A (dose-escalation) was not analyzed for efficacy. Melanoma (Parts B plus D) participants were analyzed and presented separately and are not included in this analysis.
Arm/Group Title Solid Tumors: Pembrolizumab 1 mg/kg Q2W (Part A) Solid Tumors: Pembrolizumab 3 mg/kg Q2W (Part A) Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) Solid Tumors: Pembrolizumab Titration Cohort 1 Q3W (Part A2) Solid Tumors: Pembrolizumab Titration Cohort 2 Q3W (Part A2) Solid Tumors: Pembrolizumab Titration Cohort 3 Q3W (Part A2) MEL: Pembrolizumab 2 mg/kg Q3W (Parts B+D) MEL: Pembrolizumab 10 mg/kg Q3W (Parts B+D) MEL: Pembrolizumab 10 mg/kg Q2W (Part B) NSCLC: Pembrolizumab 2 mg/kg Q3W (Part F) NSCLC: Pembrolizumab 10 mg/kg Q3W (Parts C+F) NSCLC: Pembrolizumab 10 mg/kg Q2W (Part F)
Hide Arm/Group Description:
During Cycle 1 participants received a dose of 1 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 1 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received a dose of 3 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 3 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received a dose of 10 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.005 mg/kg to 0.3 mg/kg to 2.0 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 2 mg/kg every 3 weeks (Q3W) starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.02 mg/kg to 0.3 mg/kg to 2.0 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 2 mg/kg Q3W starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.06 mg/kg to 1.0 mg/kg to 10 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 10 mg/kg Q3W starting with Cycle 2.
Participants received pembrolizumab IV at a dose of 2 mg/kg Q2W. After Amendment 3, participants received dosing Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 7, participants received dosing Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 2 mg/kg Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Overall Number of Participants Analyzed 0 0 0 0 0 0 0 0 0 61 287 202
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of Participants
19.7
(10.6 to 31.8)
21.6
(17.0 to 26.8)
19.3
(14.1 to 25.4)
5.Secondary Outcome
Title ORR According to Immune-related Response Criteria (irRC) as Assessed by Investigator in Melanoma Participants (Parts B Plus D)
Hide Description ORR was defined as the percentage of participants in the analysis population who had a confirmed immune-related Complete Response (irCR: complete disappearance of all tumor lesions whether measurable or not, and no new lesions) or immune-related Partial Response (irPR: decrease in sum of the products of the two largest perpendicular diameters (SPD) of ≥50% by a consecutive assessment ≥4 weeks after first documentation) according to irRC. The percentage of participants who experienced a confirmed irCR or irPR according to irRC as assessed by the investigator was reported as the ORR for each melanoma dose arm (Parts B plus D).
Time Frame Up to approximately 53 months (through Interim Database cut-off date of 18-Sep-2015)
Hide Outcome Measure Data
Hide Analysis Population Description
All melanoma (Parts B plus D) participants that received ≥1 dose of study treatment. Per protocol, Part A (dose-escalation) was not analyzed for efficacy. NSCLC (Parts C plus F) participants were analyzed and presented separately and are not included in this analysis.
Arm/Group Title Solid Tumors: Pembrolizumab 1 mg/kg Q2W (Part A) Solid Tumors: Pembrolizumab 3 mg/kg Q2W (Part A) Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) Solid Tumors: Pembrolizumab Titration Cohort 1 Q3W (Part A2) Solid Tumors: Pembrolizumab Titration Cohort 2 Q3W (Part A2) Solid Tumors: Pembrolizumab Titration Cohort 3 Q3W (Part A2) MEL: Pembrolizumab 2 mg/kg Q3W (Parts B+D) MEL: Pembrolizumab 10 mg/kg Q3W (Parts B+D) MEL: Pembrolizumab 10 mg/kg Q2W (Part B) NSCLC: Pembrolizumab 2 mg/kg Q3W (Part F) NSCLC: Pembrolizumab 10 mg/kg Q3W (Parts C+F) NSCLC: Pembrolizumab 10 mg/kg Q2W (Part F)
Hide Arm/Group Description:
During Cycle 1 participants received a dose of 1 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 1 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received a dose of 3 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 3 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received a dose of 10 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.005 mg/kg to 0.3 mg/kg to 2.0 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 2 mg/kg every 3 weeks (Q3W) starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.02 mg/kg to 0.3 mg/kg to 2.0 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 2 mg/kg Q3W starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.06 mg/kg to 1.0 mg/kg to 10 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 10 mg/kg Q3W starting with Cycle 2.
Participants received pembrolizumab IV at a dose of 2 mg/kg Q2W. After Amendment 3, participants received dosing Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 7, participants received dosing Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 2 mg/kg Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Overall Number of Participants Analyzed 0 0 0 0 0 0 162 313 180 0 0 0
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of Participants
35.2
(27.9 to 43.1)
39.9
(34.5 to 45.6)
45.6
(38.1 to 53.1)
6.Secondary Outcome
Title ORR According to irRC as Assessed by Investigator in NSCLC Participants (Parts C Plus F)
Hide Description ORR was defined as the percentage of participants in the analysis population who had a confirmed irCR (complete disappearance of all tumor lesions whether measurable or not, and no new lesions) or irPR (decrease in sum of the products of the two largest perpendicular diameters (SPD) of ≥50% by a consecutive assessment ≥4 weeks after first documentation) according to irRC. The percentage of participants who experienced a confirmed irCR or irPR according to irRC as assessed by the investigator was reported as the ORR for each NSCLC dose arm (Parts C plus F).
Time Frame Up to approximately 53 months (through Interim Database cut-off date of 18-Sep-2015)
Hide Outcome Measure Data
Hide Analysis Population Description
All NSCLC (Parts C plus F) participants that received ≥1 dose of study treatment. Per protocol, Part A (dose-escalation) was not analyzed for efficacy. Melanoma (Parts B plus D) participants were analyzed and presented separately and are not included in this analysis.
Arm/Group Title Solid Tumors: Pembrolizumab 1 mg/kg Q2W (Part A) Solid Tumors: Pembrolizumab 3 mg/kg Q2W (Part A) Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) Solid Tumors: Pembrolizumab Titration Cohort 1 Q3W (Part A2) Solid Tumors: Pembrolizumab Titration Cohort 2 Q3W (Part A2) Solid Tumors: Pembrolizumab Titration Cohort 3 Q3W (Part A2) MEL: Pembrolizumab 2 mg/kg Q3W (Parts B+D) MEL: Pembrolizumab 10 mg/kg Q3W (Parts B+D) MEL: Pembrolizumab 10 mg/kg Q2W (Part B) NSCLC: Pembrolizumab 2 mg/kg Q3W (Part F) NSCLC: Pembrolizumab 10 mg/kg Q3W (Parts C+F) NSCLC: Pembrolizumab 10 mg/kg Q2W (Part F)
Hide Arm/Group Description:
During Cycle 1 participants received a dose of 1 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 1 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received a dose of 3 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 3 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received a dose of 10 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.005 mg/kg to 0.3 mg/kg to 2.0 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 2 mg/kg every 3 weeks (Q3W) starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.02 mg/kg to 0.3 mg/kg to 2.0 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 2 mg/kg Q3W starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.06 mg/kg to 1.0 mg/kg to 10 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 10 mg/kg Q3W starting with Cycle 2.
Participants received pembrolizumab IV at a dose of 2 mg/kg Q2W. After Amendment 3, participants received dosing Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 7, participants received dosing Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 2 mg/kg Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Overall Number of Participants Analyzed 0 0 0 0 0 0 0 0 0 61 287 202
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of Participants
23.0
(13.2 to 35.5)
28.9
(23.7 to 34.5)
22.3
(16.7 to 28.6)
7.Secondary Outcome
Title Area Under the Concentration-Time Curve of Pembrolizumab From Time 0 to Day 28 (AUC 0-28) in Solid Tumor Participants (Parts A and A1)
Hide Description Blood samples were collected at specified intervals for the determination of AUC0-28. AUC0-28 was defined as the area under the concentration-time curve of pembrolizumab from time zero to Day 28. AUC0-28 was based on noncompartmental analysis and reported for participants in Parts A and A1.
Time Frame Cycle 1: Pre-dose, post-dose at 0.5, 6, 24, and 48 hours and Days 8, 15, and 22 (Cycle 1 = 28 days)
Hide Outcome Measure Data
Hide Analysis Population Description
All participants in Parts A and A1 receiving a single dose of drug during Cycle 1 (28 days) and having available AUC0-28 data. Two participants were excluded from analysis due to discontinuation. Per protocol, participants in Parts A2, B, C, D, C, and F were not included in the single dose pharmacokinetic (PK) analysis.
Arm/Group Title Solid Tumors: Pembrolizumab 1 mg/kg Q2W (Part A) Solid Tumors: Pembrolizumab 3 mg/kg Q2W (Part A) Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) Solid Tumors: Pembrolizumab Titration Cohort 1 Q3W (Part A2) Solid Tumors: Pembrolizumab Titration Cohort 2 Q3W (Part A2) Solid Tumors: Pembrolizumab Titration Cohort 3 Q3W (Part A2) MEL: Pembrolizumab 2 mg/kg Q3W (Parts B+D) MEL: Pembrolizumab 10 mg/kg Q3W (Parts B+D) MEL: Pembrolizumab 10 mg/kg Q2W (Part B) NSCLC: Pembrolizumab 2 mg/kg Q3W (Part F) NSCLC: Pembrolizumab 10 mg/kg Q3W (Parts C+F) NSCLC: Pembrolizumab 10 mg/kg Q2W (Part F)
Hide Arm/Group Description:
During Cycle 1 participants received a dose of 1 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 1 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received a dose of 3 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 3 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received a dose of 10 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.005 mg/kg to 0.3 mg/kg to 2.0 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 2 mg/kg every 3 weeks (Q3W) starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.02 mg/kg to 0.3 mg/kg to 2.0 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 2 mg/kg Q3W starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.06 mg/kg to 1.0 mg/kg to 10 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 10 mg/kg Q3W starting with Cycle 2.
Participants received pembrolizumab IV at a dose of 2 mg/kg Q2W. After Amendment 3, participants received dosing Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 7, participants received dosing Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 2 mg/kg Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Overall Number of Participants Analyzed 3 3 9 0 0 0 0 0 0 0 0 0
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: μg•day/mL
157
(16%)
955
(23%)
2160
(31%)
8.Secondary Outcome
Title Area Under the Concentration-Time Curve of Pembrolizumab From Time 0 to Infinity (AUC 0-inf) in Solid Tumor Participants (Parts A and A1)
Hide Description Blood samples were collected at specified intervals for the determination of AUC0-inf. AUC0-inf was defined as the area under the concentration-time curve of pembrolizumab from time zero to infinity. AUC0-inf was based on noncompartmental analysis and reported for participants in Parts A and A1.
Time Frame Cycle 1: Pre-dose, post-dose at 0.5, 6, 24, and 48 hours and Days 8, 15, and 22 (Cycle 1 = 28 days)
Hide Outcome Measure Data
Hide Analysis Population Description
All participants in Parts A and A1 receiving a single dose of drug during Cycle 1 (28 days) and having available AUC0-inf data. Two participants were excluded from analysis due to discontinuation. Per protocol, participants in Parts A2, B, C, D, C, and F were not included in the single dose PK analysis.
Arm/Group Title Solid Tumors: Pembrolizumab 1 mg/kg Q2W (Part A) Solid Tumors: Pembrolizumab 3 mg/kg Q2W (Part A) Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) Solid Tumors: Pembrolizumab Titration Cohort 1 Q3W (Part A2) Solid Tumors: Pembrolizumab Titration Cohort 2 Q3W (Part A2) Solid Tumors: Pembrolizumab Titration Cohort 3 Q3W (Part A2) MEL: Pembrolizumab 2 mg/kg Q3W (Parts B+D) MEL: Pembrolizumab 10 mg/kg Q3W (Parts B+D) MEL: Pembrolizumab 10 mg/kg Q2W (Part B) NSCLC: Pembrolizumab 2 mg/kg Q3W (Part F) NSCLC: Pembrolizumab 10 mg/kg Q3W (Parts C+F) NSCLC: Pembrolizumab 10 mg/kg Q2W (Part F)
Hide Arm/Group Description:
During Cycle 1 participants received a dose of 1 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 1 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received a dose of 3 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 3 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received a dose of 10 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.005 mg/kg to 0.3 mg/kg to 2.0 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 2 mg/kg every 3 weeks (Q3W) starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.02 mg/kg to 0.3 mg/kg to 2.0 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 2 mg/kg Q3W starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.06 mg/kg to 1.0 mg/kg to 10 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 10 mg/kg Q3W starting with Cycle 2.
Participants received pembrolizumab IV at a dose of 2 mg/kg Q2W. After Amendment 3, participants received dosing Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 7, participants received dosing Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 2 mg/kg Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Overall Number of Participants Analyzed 3 3 9 0 0 0 0 0 0 0 0 0
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: μg•day/mL
212
(36%)
1530
(28%)
3230
(44%)
9.Secondary Outcome
Title Maximum Concentration (Cmax) of Pembrolizumab in Solid Tumor Participants (Parts A and A1)
Hide Description Blood samples were collected at specified intervals for the determination of Cmax. Cmax was defined as the maximum concentration of pembrolizumab reached. Cmax was based on noncompartmental analysis and reported for participants in Parts A and A1.
Time Frame Cycle 1: Pre-dose, post-dose at 0.5, 6, 24, and 48 hours and Days 8, 15, and 22 (Cycle 1 = 28 days)
Hide Outcome Measure Data
Hide Analysis Population Description
All participants in Parts A and A1 receiving a single dose of drug during Cycle 1 (28 days) and having available Cmax data. Per protocol, participants in Parts A2, B, C, D, C, and F were not included in the single dose PK analysis.
Arm/Group Title Solid Tumors: Pembrolizumab 1 mg/kg Q2W (Part A) Solid Tumors: Pembrolizumab 3 mg/kg Q2W (Part A) Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) Solid Tumors: Pembrolizumab Titration Cohort 1 Q3W (Part A2) Solid Tumors: Pembrolizumab Titration Cohort 2 Q3W (Part A2) Solid Tumors: Pembrolizumab Titration Cohort 3 Q3W (Part A2) MEL: Pembrolizumab 2 mg/kg Q3W (Parts B+D) MEL: Pembrolizumab 10 mg/kg Q3W (Parts B+D) MEL: Pembrolizumab 10 mg/kg Q2W (Part B) NSCLC: Pembrolizumab 2 mg/kg Q3W (Part F) NSCLC: Pembrolizumab 10 mg/kg Q3W (Parts C+F) NSCLC: Pembrolizumab 10 mg/kg Q2W (Part F)
Hide Arm/Group Description:
During Cycle 1 participants received a dose of 1 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 1 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received a dose of 3 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 3 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received a dose of 10 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.005 mg/kg to 0.3 mg/kg to 2.0 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 2 mg/kg every 3 weeks (Q3W) starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.02 mg/kg to 0.3 mg/kg to 2.0 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 2 mg/kg Q3W starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.06 mg/kg to 1.0 mg/kg to 10 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 10 mg/kg Q3W starting with Cycle 2.
Participants received pembrolizumab IV at a dose of 2 mg/kg Q2W. After Amendment 3, participants received dosing Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 7, participants received dosing Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 2 mg/kg Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Overall Number of Participants Analyzed 4 3 10 0 0 0 0 0 0 0 0 0
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: μg/mL
16.4
(22%)
107
(26%)
256
(37%)
10.Secondary Outcome
Title Time to Maximum Concentration (Tmax) of Pembrolizumab in Solid Tumor Participants (Parts A and A1)
Hide Description Blood samples were collected at specified intervals for the determination of Tmax. Tmax was defined as time to the maximum concentration of pembrolizumab reached. Tmax was based on noncompartmental analysis and reported for participants in Parts A and A1.
Time Frame Cycle 1: Pre-dose, post-dose at 0.5, 6, 24, and 48 hours and Days 8, 15, and 22 (Cycle 1 = 28 days)
Hide Outcome Measure Data
Hide Analysis Population Description
All participants in Parts A and A1 receiving a single dose of drug during Cycle 1 (28 days) and having available Tmax data. Per protocol, participants in Parts A2, B, C, D, C, and F were not included in the single dose PK analysis.
Arm/Group Title Solid Tumors: Pembrolizumab 1 mg/kg Q2W (Part A) Solid Tumors: Pembrolizumab 3 mg/kg Q2W (Part A) Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) Solid Tumors: Pembrolizumab Titration Cohort 1 Q3W (Part A2) Solid Tumors: Pembrolizumab Titration Cohort 2 Q3W (Part A2) Solid Tumors: Pembrolizumab Titration Cohort 3 Q3W (Part A2) MEL: Pembrolizumab 2 mg/kg Q3W (Parts B+D) MEL: Pembrolizumab 10 mg/kg Q3W (Parts B+D) MEL: Pembrolizumab 10 mg/kg Q2W (Part B) NSCLC: Pembrolizumab 2 mg/kg Q3W (Part F) NSCLC: Pembrolizumab 10 mg/kg Q3W (Parts C+F) NSCLC: Pembrolizumab 10 mg/kg Q2W (Part F)
Hide Arm/Group Description:
During Cycle 1 participants received a dose of 1 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 1 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received a dose of 3 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 3 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received a dose of 10 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.005 mg/kg to 0.3 mg/kg to 2.0 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 2 mg/kg every 3 weeks (Q3W) starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.02 mg/kg to 0.3 mg/kg to 2.0 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 2 mg/kg Q3W starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.06 mg/kg to 1.0 mg/kg to 10 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 10 mg/kg Q3W starting with Cycle 2.
Participants received pembrolizumab IV at a dose of 2 mg/kg Q2W. After Amendment 3, participants received dosing Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 7, participants received dosing Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 2 mg/kg Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Overall Number of Participants Analyzed 4 3 10 0 0 0 0 0 0 0 0 0
Median (Full Range)
Unit of Measure: days
0.05
(0.02 to 0.17)
0.17
(0.17 to 0.17)
0.17
(0.03 to 0.99)
11.Secondary Outcome
Title Terminal Half-Life (t ½) of Pembrolizumab in Solid Tumor Participants (Parts A and A1)
Hide Description Blood samples were collected at specified intervals for the determination of t½. t½ was defined as the time required to divide the pembrolizumab plasma concentration by two after reaching pseudo-equilibrium, following a single dose of pembrolizumab. t½ was based on noncompartmental analysis and reported for participants in Parts A and A1.
Time Frame Cycle 1: Pre-dose, post-dose at 0.5, 6, 24, and 48 hours and Days 8, 15, and 22 (Cycle 1 = 28 days)
Hide Outcome Measure Data
Hide Analysis Population Description
All participants in Parts A and A1 receiving a single dose of drug during Cycle 1 (28 days) and having available t½ data. Two participants were excluded from analysis due to discontinuation. Per protocol, participants in Parts A2, B, C, D, C, and F were not included in the single dose PK analysis.
Arm/Group Title Solid Tumors: Pembrolizumab 1 mg/kg Q2W (Part A) Solid Tumors: Pembrolizumab 3 mg/kg Q2W (Part A) Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) Solid Tumors: Pembrolizumab Titration Cohort 1 Q3W (Part A2) Solid Tumors: Pembrolizumab Titration Cohort 2 Q3W (Part A2) Solid Tumors: Pembrolizumab Titration Cohort 3 Q3W (Part A2) MEL: Pembrolizumab 2 mg/kg Q3W (Parts B+D) MEL: Pembrolizumab 10 mg/kg Q3W (Parts B+D) MEL: Pembrolizumab 10 mg/kg Q2W (Part B) NSCLC: Pembrolizumab 2 mg/kg Q3W (Part F) NSCLC: Pembrolizumab 10 mg/kg Q3W (Parts C+F) NSCLC: Pembrolizumab 10 mg/kg Q2W (Part F)
Hide Arm/Group Description:
During Cycle 1 participants received a dose of 1 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 1 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received a dose of 3 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 3 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received a dose of 10 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.005 mg/kg to 0.3 mg/kg to 2.0 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 2 mg/kg every 3 weeks (Q3W) starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.02 mg/kg to 0.3 mg/kg to 2.0 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 2 mg/kg Q3W starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.06 mg/kg to 1.0 mg/kg to 10 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 10 mg/kg Q3W starting with Cycle 2.
Participants received pembrolizumab IV at a dose of 2 mg/kg Q2W. After Amendment 3, participants received dosing Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 7, participants received dosing Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 2 mg/kg Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Overall Number of Participants Analyzed 3 3 9 0 0 0 0 0 0 0 0 0
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: days
14.1
(51%)
21.6
(10%)
17.5
(54%)
12.Secondary Outcome
Title Area Under the Concentration-Time Curve of Pembrolizumab From Time 0 to Day 21 (AUC 0-21) in Solid Tumor Participants (Part A2)
Hide Description Blood samples were collected at specified intervals for the determination of AUC0-21. AUC0-21 was defined as the area under the concentration-time curve of pembrolizumab from time zero to Study Day 21. AUC0-21 was based on noncompartmental analysis and reported for participants in Part A2.
Time Frame Cycle 1: Day 1: Pre-dose, post-dose at 0.5, 6, 24, and 48 hours; Day 5, Day 8: pre- and post-dose; Day 15 (Cycle = 21 days)
Hide Outcome Measure Data
Hide Analysis Population Description
All participants in Part A2 receiving escalating doses of drug during Cycle 1 (21 days) and having available AUC0-21 data. One participant was excluded from analysis due to discontinuation. Per protocol, participants in Parts A, A1, B, C, D, C, and F were not included in the escalating dose PK analysis.
Arm/Group Title Solid Tumors: Pembrolizumab 1 mg/kg Q2W (Part A) Solid Tumors: Pembrolizumab 3 mg/kg Q2W (Part A) Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) Solid Tumors: Pembrolizumab Titration Cohort 1 Q3W (Part A2) Solid Tumors: Pembrolizumab Titration Cohort 2 Q3W (Part A2) Solid Tumors: Pembrolizumab Titration Cohort 3 Q3W (Part A2) MEL: Pembrolizumab 2 mg/kg Q3W (Parts B+D) MEL: Pembrolizumab 10 mg/kg Q3W (Parts B+D) MEL: Pembrolizumab 10 mg/kg Q2W (Part B) NSCLC: Pembrolizumab 2 mg/kg Q3W (Part F) NSCLC: Pembrolizumab 10 mg/kg Q3W (Parts C+F) NSCLC: Pembrolizumab 10 mg/kg Q2W (Part F)
Hide Arm/Group Description:
During Cycle 1 participants received a dose of 1 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 1 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received a dose of 3 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 3 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received a dose of 10 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.005 mg/kg to 0.3 mg/kg to 2.0 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 2 mg/kg every 3 weeks (Q3W) starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.02 mg/kg to 0.3 mg/kg to 2.0 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 2 mg/kg Q3W starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.06 mg/kg to 1.0 mg/kg to 10 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 10 mg/kg Q3W starting with Cycle 2.
Participants received pembrolizumab IV at a dose of 2 mg/kg Q2W. After Amendment 3, participants received dosing Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 7, participants received dosing Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 2 mg/kg Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Overall Number of Participants Analyzed 0 0 0 4 3 5 0 0 0 0 0 0
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: μg•day/mL
57.1
(21%)
50.4
(28%)
186
(28%)
13.Secondary Outcome
Title Area Under the Concentration-Time Curve of Pembrolizumab From Day 21 to Day 42 (AUC21-42) in Solid Tumor Participants (Part A2)
Hide Description Blood samples were collected at specified intervals for the determination of AUC21-42. AUC21-42 was defined as the area under the concentration-time curve of pembrolizumab from Study Day 21 (end of Cycle 1) through Study Day 42 (end of Cycle 2). AUC21-42 was based on noncompartmental analysis and reported for participants in Part A2.
Time Frame Cycle 1: Day 21; Cycle 2: Day 1: Pre-dose, post-dose at 0.5 and 24 hours, Day 3, Day 8, Day 15 (Cycle = 21 days)
Hide Outcome Measure Data
Hide Analysis Population Description
All participants in Part A2 receiving escalating doses of drug during Cycle 1 and having available AUC21-42 data during Cycle 2. Two participants were excluded from analysis due to discontinuation. Per protocol, participants in Parts A, A1, B, C, D, C, and F were not included in the escalating dose PK analysis.
Arm/Group Title Solid Tumors: Pembrolizumab 1 mg/kg Q2W (Part A) Solid Tumors: Pembrolizumab 3 mg/kg Q2W (Part A) Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) Solid Tumors: Pembrolizumab Titration Cohort 1 Q3W (Part A2) Solid Tumors: Pembrolizumab Titration Cohort 2 Q3W (Part A2) Solid Tumors: Pembrolizumab Titration Cohort 3 Q3W (Part A2) MEL: Pembrolizumab 2 mg/kg Q3W (Parts B+D) MEL: Pembrolizumab 10 mg/kg Q3W (Parts B+D) MEL: Pembrolizumab 10 mg/kg Q2W (Part B) NSCLC: Pembrolizumab 2 mg/kg Q3W (Part F) NSCLC: Pembrolizumab 10 mg/kg Q3W (Parts C+F) NSCLC: Pembrolizumab 10 mg/kg Q2W (Part F)
Hide Arm/Group Description:
During Cycle 1 participants received a dose of 1 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 1 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received a dose of 3 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 3 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received a dose of 10 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.005 mg/kg to 0.3 mg/kg to 2.0 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 2 mg/kg every 3 weeks (Q3W) starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.02 mg/kg to 0.3 mg/kg to 2.0 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 2 mg/kg Q3W starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.06 mg/kg to 1.0 mg/kg to 10 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 10 mg/kg Q3W starting with Cycle 2.
Participants received pembrolizumab IV at a dose of 2 mg/kg Q2W. After Amendment 3, participants received dosing Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 7, participants received dosing Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 2 mg/kg Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Overall Number of Participants Analyzed 0 0 0 4 2 5 0 0 0 0 0 0
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: μg•day/mL
486
(16%)
348
(18%)
2280
(24%)
14.Secondary Outcome
Title Lowest Plasma Concentration (Ctrough) of Pembrolizumab in Solid Tumor Participants (Parts A, A1, and A2)
Hide Description Pre-dose samples were collected 24 hours before infusion of pembrolizumab at specified intervals for the determination of Ctrough. Ctrough was defined as the lowest concentration of pembrolizumab reached before the next dose was administered. Ctrough was reported for each Part A arm according to cycle and nominal time after first dose (Day). Results for each cycle reported for arms with N>1 at that timepoint. Ctrough data for melanoma (Parts B and D) and NSCLC (Parts C and F) participants are presented separately and are not included here.
Time Frame Parts A and A1: pre-dose at Cycles 2, 4, 6, 8, 10, 12, 14 (cycle=14 days); A2 Cohorts: pre-dose at Cycles 2, 3, 5, 7, 9, 11 (cycle=21 days)
Hide Outcome Measure Data
Hide Analysis Population Description
All Part A participants receiving ≥1 dose of drug and having available Ctrough samples collected pre-dose before each cycle. Due to differing dosing schedules or N<1, some time points were not applicable for certain arms if data were not collected or analyzed (indicated by zero participants analyzed entered in the table).
Arm/Group Title Solid Tumors: Pembrolizumab 1 mg/kg Q2W (Part A) Solid Tumors: Pembrolizumab 3 mg/kg Q2W (Part A) Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) Solid Tumors: Pembrolizumab Titration Cohort 1 Q3W (Part A2) Solid Tumors: Pembrolizumab Titration Cohort 2 Q3W (Part A2) Solid Tumors: Pembrolizumab Titration Cohort 3 Q3W (Part A2)
Hide Arm/Group Description:
During Cycle 1 participants received a dose of 1 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 1 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received a dose of 3 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 3 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received a dose of 10 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.005 mg/kg to 0.3 mg/kg to 2.0 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 2 mg/kg every 3 weeks (Q3W) starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.02 mg/kg to 0.3 mg/kg to 2.0 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 2 mg/kg Q3W starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.06 mg/kg to 1.0 mg/kg to 10 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 10 mg/kg Q3W starting with Cycle 2.
Overall Number of Participants Analyzed 3 3 8 4 3 5
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: μg/mL
Cycle 2 (Day 21) Number Analyzed 0 participants 0 participants 0 participants 4 participants 3 participants 5 participants
2.3
(46.2%)
1.9
(19.9%)
7.77
(46.1%)
Cycle 2 (Day 28) Number Analyzed 3 participants 3 participants 8 participants 0 participants 0 participants 0 participants
2.19
(62.4%)
18.8
(42.1%)
41.7
(44.6%)
Cycle 3 (Day 42) Number Analyzed 0 participants 0 participants 0 participants 4 participants 2 participants 3 participants
10.6
(15.9%)
11.1
(28.9%)
70.1
(15.6%)
Cycle 4 (Day 56) Number Analyzed 2 participants 2 participants 4 participants 0 participants 0 participants 0 participants
6.45
(13%)
50.0
(36.9%)
122
(37.2%)
Cycle 5 (Day 84) Number Analyzed 0 participants 0 participants 0 participants 3 participants 2 participants 3 participants
14.8
(33.4%)
18.3
(34.1%)
126
(53.9%)
Cycle 6 (Day 84) Number Analyzed 2 participants 2 participants 3 participants 0 participants 0 participants 0 participants
9.93
(5.6%)
55.2
(33.8%)
168
(49.5%)
Cycle 8 (Day 112) Number Analyzed 0 participants 2 participants 2 participants 0 participants 0 participants 0 participants
66.8
(11.1%)
260
(1.4%)
Cycle 7 (Day 126) Number Analyzed 0 participants 0 participants 0 participants 2 participants 2 participants 3 participants
29.9
(7.3%)
22.1
(49.2%)
151
(48%)
Cycle 10 (Day 140) Number Analyzed 0 participants 2 participants 2 participants 0 participants 0 participants 0 participants
63.0
(29.8%)
200
(4.9%)
Cycle 9 (Day 168) Number Analyzed 0 participants 0 participants 0 participants 2 participants 0 participants 3 participants
29.8
(1%)
150
(29.4%)
Cycle 12 (Day 168) Number Analyzed 0 participants 2 participants 0 participants 0 participants 0 participants 0 participants
62.8
(1.7%)
Cycle 14 (Day 196) Number Analyzed 0 participants 2 participants 0 participants 0 participants 0 participants 0 participants
54.1
(4.3%)
Cycle 11 (Day 210) Number Analyzed 0 participants 0 participants 0 participants 2 participants 0 participants 2 participants
40.7
(38.6%)
179
(37.8%)
15.Secondary Outcome
Title Ctrough of Pembrolizumab in Melanoma Participants (Parts B and D)
Hide Description Pre-dose samples were collected 24 hours before infusion of pembrolizumab at specified intervals for the determination of Ctrough. Ctrough was defined as the lowest concentration of pembrolizumab reached before the next dose was administered. For the purposes of the Ctrough analysis, samples were collected and analyzed separately for each Part B and D enrolment cohort, and Ctrough was reported for each cohort according to cycle and nominal time after first dose (Day). Results for each cycle reported for arms with N>1 at that timepoint. Ctrough data for solid tumor (Part A) and NSCLC (Parts C and F) participants are presented separately and are not included here.
Time Frame Part B arms treated every 3 weeks: pre-dose at Cycles 2,5,9,13,17,25,33 (cycle=21 days); Part B treated every 2 weeks: pre-dose at Cycles 2,3,7,13,19,25,31,37 (cycle=14 days); Part D: pre-dose at Cycles 2,3,6,8,12,16,24,32 (cycle=21 days)
Hide Outcome Measure Data
Hide Analysis Population Description
All melanoma participants receiving ≥1 dose of drug and having available samples collected pre-dose before each cycle. Per protocol, Ctrough analyzed separately by Part, dose, and dosing schedule. Due to differing dosing schedules, some time points were not applicable for certain arms (indicated by zero participants analyzed entered in the table).
Arm/Group Title MEL: Pembrolizumab 2 mg/kg Q3W (Part B) MEL: Pembrolizumab 10 mg/kg Q3W (Part B) MEL: Pembrolizumab 10 mg/kg Q2W (Part B) MEL: Pembrolizumab 2 mg/kg Q3W (Part D) MEL: Pembrolizumab 10 mg/kg Q3W (Part D)
Hide Arm/Group Description:
Participants received pembrolizumab IV at a dose of 2 mg/kg Q3W.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q3W.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W.
Participants received pembrolizumab IV at a dose of 2 mg/kg Q3W.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q3W.
Overall Number of Participants Analyzed 91 208 150 52 48
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: µg/mL
Cycle 2 (Day 14) Number Analyzed 0 participants 0 participants 5 participants 0 participants 0 participants
63.7
(13.6%)
Cycle 2 (Day 21) Number Analyzed 91 participants 208 participants 0 participants 52 participants 48 participants
8.69
(48.9%)
48.5
(37.9%)
10.1
(56.3%)
62.6
(37.2%)
Cycle 3 (Day 28) Number Analyzed 0 participants 0 participants 150 participants 0 participants 0 participants
94.0
(47.2%)
Cycle 3 (Day 42) Number Analyzed 0 participants 2 participants 0 participants 46 participants 46 participants
80.3
(1.2%)
16.8
(57.2%)
94.3
(37.1%)
Cycle 5 (Day 84) Number Analyzed 60 participants 154 participants 0 participants 0 participants 0 participants
19.5
(58.3%)
119
(50.7%)
Cycle 7 (Day 84) Number Analyzed 0 participants 0 participants 110 participants 0 participants 0 participants
173
(49.7%)
Cycle 6 (Day 105) Number Analyzed 0 participants 0 participants 0 participants 35 participants 33 participants
25.3
(52.4%)
132
(45.6%)
Cycle 7 (Day 126) Number Analyzed 0 participants 2 participants 0 participants 0 participants 0 participants
89.2
(34.4%)
Cycle 8 (Day 147) Number Analyzed 0 participants 2 participants 0 participants 31 participants 29 participants
166
(5.1%)
23.5
(50.1%)
152
(40.7%)
Cycle 9 (Day 168 ) Number Analyzed 44 participants 112 participants 0 participants 0 participants 0 participants
25.5
(59.6%)
161
(38.4%)
Cycle 13 (Day 168) Number Analyzed 0 participants 0 participants 85 participants 0 participants 0 participants
232
(44.1%)
Cycle 12 (Day 231) Number Analyzed 0 participants 3 participants 0 participants 23 participants 26 participants
193
(21.1%)
29.3
(34.7%)
173
(38.9%)
Cycle 18 (Day 238) Number Analyzed 0 participants 0 participants 3 participants 0 participants 0 participants
171
(27.7%)
Cycle 13 (Day 252) Number Analyzed 45 participants 104 participants 0 participants 0 participants 0 participants
27.2
(50.4%)
153
(39.6%)
Cycle 19 (Day 252) Number Analyzed 0 participants 0 participants 65 participants 0 participants 0 participants
253
(37.5%)
Cycle 16 (Day 315) Number Analyzed 0 participants 0 participants 0 participants 17 participants 17 participants
30.5
(50.6%)
183
(37.8%)
Cycle 24 (Day 322) Number Analyzed 0 participants 0 participants 2 participants 0 participants 0 participants
246
(18.2%)
Cycle 17 (Day 336) Number Analyzed 37 participants 84 participants 0 participants 0 participants 3 participants
31.4
(48.9%)
168
(48.5%)
157
(47%)
Cycle 25 (Day 336) Number Analyzed 0 participants 0 participants 45 participants 0 participants 0 participants
242
(39.9%)
Cycle 31 (Day 420) Number Analyzed 0 participants 0 participants 4 participants 0 participants 0 participants
184
(29.2%)
Cycle 33 (Day 448) Number Analyzed 0 participants 0 participants 2 participants 0 participants 0 participants
80.0
(57.9%)
Cycle 24 (Day 483) Number Analyzed 0 participants 2 participants 0 participants 8 participants 14 participants
152
(7.5%)
30.3
(40.1%)
147
(47.0%)
Cycle 25 (Day 504) Number Analyzed 23 participants 57 participants 0 participants 0 participants 0 participants
29.3
(42.4%)
165
(41.4%)
Cycle 37 (Day 504) Number Analyzed 0 participants 0 participants 37 participants 0 participants 0 participants
232
(63.8%)
Cycle 32 (Day 651) Number Analyzed 0 participants 0 participants 0 participants 6 participants 12 participants
23.0
(44.6%)
155
(38.5%)
Cycle 48 (Day 658) Number Analyzed 0 participants 0 participants 2 participants 0 participants 0 participants
169
(25.3%)
Cycle 33 (Day 672) Number Analyzed 18 participants 51 participants 0 participants 0 participants 0 participants
31.4
(34.0%)
166
(37.7%)
Cycle 49 (Day 672) Number Analyzed 0 participants 0 participants 27 participants 0 participants 0 participants
255
(42.6%)
16.Secondary Outcome
Title Ctrough of Pembrolizumab in NSCLC Participants (Parts C and F)
Hide Description Pre-dose samples were collected 24 hours before infusion of pembrolizumab at specified intervals for the determination of Ctrough. Ctrough was defined as the lowest concentration reached by pembrolizumab before the next dose was administered. For the purposes of the Ctrough analysis, samples were collected and analyzed separately for each Part C and F enrolment cohort, and Ctrough was reported for each cohort according to cycle and nominal time after first dose (Day). Results for each cycle reported for arms with N>1 at that timepoint. Ctrough data for solid tumor (Part A) and melanoma (Parts B and D) participants are presented separately and are not included here.
Time Frame Part C: pre-dose at Cycles 2,5,9,13,17,21 (cycle=21 days); Part F treated every 3 weeks: pre-dose at Cycles 2,3,6,8,12,14,16,24,32 (cycle=21 days); Part F treated every 2 weeks: pre-dose at Cycles 2,3,6,7,8,9,12,16,18,24,32,36,40,48 (cycle=14 days)
Hide Outcome Measure Data
Hide Analysis Population Description
All NSCLC participants receiving ≥1 dose of drug and having available samples collected pre-dose before each cycle. Per protocol, Ctrough analyzed separately by Part, dose, and dosing schedule. Due to differing dosing schedules, some time points were not applicable for certain arms (indicated by zero participants analyzed entered in the table).
Arm/Group Title NSCLC: Pembrolizumab 10 mg/kg Q3W (Part C) NSCLC: Pembrolizumab 2 mg/kg Q3W (Part F) NSCLC: Pembrolizumab 10 mg/kg Q2W (Part F) NSCLC: Pembrolizumab 10 mg/kg Q3W (Part F)
Hide Arm/Group Description:
Participants received pembrolizumab IV at a dose of 10 mg/kg Q3W.
Participants received pembrolizumab IV at a dose of 2 mg/kg Q3W.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q3W.
Overall Number of Participants Analyzed 33 44 186 230
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: µg/mL
Cycle 2 (Day 14) Number Analyzed 0 participants 0 participants 186 participants 0 participants
55.0
(33.8%)
Cycle 2 (Day 21) Number Analyzed 33 participants 44 participants 0 participants 230 participants
52.0
(31.7%)
8.23
(41.1%)
43.6
(42.6%)
Cycle 3 (Day 28) Number Analyzed 0 participants 0 participants 173 participants 0 participants
89.3
(39.4%)
Cycle 3 (Day 42) Number Analyzed 0 participants 39 participants 0 participants 208 participants
11.8
(62.1%)
67.9
(45.5%)
Cycle 4 (Day 42) Number Analyzed 0 participants 0 participants 2 participants 0 participants
173
(36.3%)
Cycle 6 (Day 70) Number Analyzed 0 participants 0 participants 114 participants 0 participants
149
(40.6%)
Cycle 5 (Day 84) Number Analyzed 17 participants 0 participants 0 participants 0 participants
136
(29.6%)
Cycle 7 (Day 84) Number Analyzed 0 participants 0 participants 5 participants 0 participants
159
(19.5%)
Cycle 8 (Day 98) Number Analyzed 0 participants 0 participants 91 participants 0 participants
180
(42.1%)
Cycle 6 (Day 105) Number Analyzed 0 participants 28 participants 0 participants 127 participants
18.3
(40.8%)
99.7
(53.9%)
Cycle 9 (Day 112) Number Analyzed 0 participants 0 participants 10 participants 0 participants
145
(44.7%)
Cycle 8 (Day 147) Number Analyzed 0 participants 21 participants 0 participants 106 participants
20.6
(46.2%)
118
(51.3%)
Cycle 12 (Day 154) Number Analyzed 0 participants 0 participants 75 participants 0 participants
206
(42.6%)
Cycle 9 (Day 168) Number Analyzed 8 participants 0 participants 0 participants 2 participants
168
(26.3%)
96.8
(47.2%)
Cycle 16 (Day 210) Number Analyzed 0 participants 0 participants 33 participants 0 participants
205
(46%)
Cycle 12 (Day 231) Number Analyzed 0 participants 14 participants 0 participants 68 participants
20.0
(60.1%)
125
(41.3%)
Cycle 18 (Day 238) Number Analyzed 0 participants 0 participants 28 participants 0 participants
214
(34.7%)
Cycle 13 (Day 252) Number Analyzed 9 participants 0 participants 0 participants 0 participants
197
(47.1%)
Cycle 20 (Day 266) Number Analyzed 0 participants 0 participants 2 participants 0 participants
215
(0.98%)
Cycle 14 (Day 273) Number Analyzed 0 participants 0 participants 0 participants 4 participants
121
(56.6%)
Cycle 22 (Day 294) Number Analyzed 0 participants 0 participants 3 participants 0 participants
209
(17.9%)
Cycle 16 (Day 315) Number Analyzed 0 participants 9 participants 0 participants 56 participants
23.3
(29.1%)
124
(48.6%)
Cycle 24 (Day 322) Number Analyzed 0 participants 0 participants 39 participants 0 participants
234
(33.5%)
Cycle 17 (Day 336) Number Analyzed 6 participants 0 participants 0 participants 0 participants
184
(34.8%)
Cycle 26 (Day 350) Number Analyzed 0 participants 0 participants 3 participants 0 participants
202
(13.2%)
Cycle 18 (Day 357) Number Analyzed 0 participants 0 participants 0 participants 3 participants
105
(48.6%)
Cycle 28 (Day 378) Number Analyzed 0 participants 0 participants 2 participants 0 participants
140
(33.5%)
Cycle 20 (Day 399) Number Analyzed 0 participants 0 participants 0 participants 2 participants
81.9
(74.5%)
Cycle 30 (Day 406) Number Analyzed 0 participants 0 participants 2 participants 0 participants
149
(16.2%)
Cycle 21 (Day 420) Number Analyzed 6 participants 0 participants 0 participants 0 participants
167
(40.2%)
Cycle 32 (Day 434) Number Analyzed 0 participants 0 participants 7 participants 0 participants
244
(47.7%)
Cycle 24 (Day 483) Number Analyzed 0 participants 6 participants 0 participants 35 participants
24.3
(26%)
137
(43.4%)
Cycle 36 (Day 490) Number Analyzed 0 participants 0 participants 25 participants 0 participants
221
(39.9%)
Cycle 25 (Day 504) Number Analyzed 2 participants 0 participants 0 participants 0 participants
207
(67.9%)
Cycle 40 (Day 546) Number Analyzed 0 participants 0 participants 4 participants 0 participants
219
(52.2%)
Cycle 29 (Day 588) Number Analyzed 3 participants 3 participants 0 participants 0 participants
173
(39.0%)
32.9
(13.2%)
Cycle 32 (Day 651) Number Analyzed 0 participants 3 participants 0 participants 25 participants
30.5
(11.6%)
141
(49.8%)
Cycle 48 (Day 658) Number Analyzed 0 participants 0 participants 21 participants 0 participants
206
(111.2%)
Cycle 33 (Day 672) Number Analyzed 0 participants 3 participants 0 participants 0 participants
40.6
(32.5%)
17.Secondary Outcome
Title Maximum Change From Baseline (CFB) in Tumor Size Assessed by IRC Per RECIST 1.1 According to Programmed Death-Ligand 1 (PD-L1) Immunohistochemical (IHC) Expression Status in Ipilimumab (Ipi)-Exposed and Ipi-Naive Melanoma Participants (Parts B Plus D)
Hide Description The percent change from baseline in tumor size based on IRC per RECIST 1.1 was reported according to PD-L1 status in Ipi-Exposed and Ipi-Naïve melanoma participants. Tumor PD-L1 status was measured by the tumor proportion score (TPS), which was the percentage of tumor cells identified using IHC analysis that expressed PD-L1. Tumors with ≥1% positive staining for PD-L1 were considered positive. Maximum tumor change was defined as the percent change of the participant's smallest post-baseline tumor size from the baseline. The number of participants in a percent change from baseline range was reported categorically according to PD-L1 status (PD-L1-Positive, PD-L1 Negative, PD-L1 Status Unknown). Negative percent change from baseline values indicate tumor size reduction, with the greatest reduction possible indicated as "≤ -30%". As specified by the protocol, this analysis of melanoma participants was performed according to ipilimumab exposure (Ipi-Exposed and Ipi-Naïve).
Time Frame Baseline, last available tumor assessment (up to approximately 53 months through Interim Database cut-off date of 18-Sep-2015)
Hide Outcome Measure Data
Hide Analysis Population Description
Melanoma participants that received ≥1 dose of study treatment, had a valid PD-L1 expression measurement, and had both baseline and post-baseline tumor assessments. Per protocol, Part A was not analyzed for biomarker analysis. NSCLC (Parts C plus F) participants were analyzed and presented separately and are not included in this analysis.
Arm/Group Title MEL (Parts B+D): Ipi-Exposed PD-L1 Positive MEL (Parts B+D): Ipi-Exposed PD-L1 Negative MEL (Parts B+D): Ipi-Exposed PD-L1 Unknown MEL (Parts B+D): All Ipi-Exposed Participants MEL (Parts B+D): Ipi-Naive PD-L1 Positive MEL (Parts B+D): Ipi- Naive PD-L1 Negative MEL (Parts B+D): Ipi- Naive PD-L1 Unknown MEL (Parts B+D): All Ipi- Naive Participants
Hide Arm/Group Description:
Ipi-Exposed melanoma participants that received IV pembrolizumab on study and whose tumors were positive for PD-L1 (TPS ≥1%)
Ipi-Exposed melanoma participants that received IV pembrolizumab on study and whose tumors were negative for PD-L1 (TPS <1%)
Ipi-Exposed melanoma participants that received IV pembrolizumab on study and whose tumors had an unknown PD-L1 status.
All Ipi-Exposed melanoma participants that received IV pembrolizumab on study.
Ipi-Naive melanoma participants that received IV pembrolizumab on study and whose tumors were positive for PD-L1 (TPS ≥1%).
Ipi-Naive melanoma participants that received IV pembrolizumab on study and whose tumors were negative for PD-L1 (TPS <1%).
Ipi-Naive melanoma participants that received IV pembrolizumab on study and whose tumors had an unknown PD-L1 status.
All Ipi-Naive melanoma participants that received IV pembrolizumab on study.
Overall Number of Participants Analyzed 176 37 47 260 140 50 61 251
Measure Type: Count of Participants
Unit of Measure: Participants
Number of Participants with ≤ -30% CFB
93
  52.8%
8
  21.6%
25
  53.2%
126
  48.5%
94
  67.1%
22
  44.0%
35
  57.4%
151
  60.2%
Number of Participants with > -30% to <20% CFB
57
  32.4%
17
  45.9%
14
  29.8%
88
  33.8%
32
  22.9%
10
  20.0%
11
  18.0%
53
  21.1%
Number of Participants with ≥ 20% CFB
26
  14.8%
12
  32.4%
8
  17.0%
46
  17.7%
14
  10.0%
18
  36.0%
15
  24.6%
47
  18.7%
18.Secondary Outcome
Title Maximum Change From Baseline (CFB) in Tumor Size Assessed by IRC Per RECIST 1.1 According to PD-L1 IHC Expression Status in Prior Treatment (TRT)-Naïve and Previously-Treated NSCLC Participants (Parts C Plus F)
Hide Description Percent CFB in tumor size based on IRC per RECIST 1.1 was reported according to PD-L1 status in prior treatment-naïve and previously-treated NSCLC participants. Tumor PD-L1 status was measured by TPS, which was the percentage of tumor cells identified using IHC analysis that expressed PD-L1, as follows: TPS ≥50% =tumor strongly positive, TPS of 1%-49% =tumor weakly positive, TPS <1% =tumor considered negative, or TPS unknown. Maximum tumor change for a participant was defined as the percent change of the participant's smallest post-baseline tumor size from baseline. The number of participants in a percent CFB range was reported categorically according to PD-L1 status (TPS ≥50%, TPS = 1-49%, TPS <1%, TPS Unknown). Negative percent CFB values indicate tumor size reduction, with the greatest reduction possible indicated as "≤ -30%". As specified by the protocol, analysis of NSCLC participants was performed according to prior treatment exposure (Treatment Naive and Previously Treated).
Time Frame Baseline, last available tumor assessment (up to approximately 53 months through Interim Database cut-off date of 18-Sep-2015)
Hide Outcome Measure Data
Hide Analysis Population Description
NSCLC participants that received ≥1 dose of study treatment, had a valid PD-L1 expression measurement, and had both baseline and post-baseline tumor assessments. Per protocol, Part A was not analyzed for biomarker analysis. Melanoma (Parts B plus D) participants were analyzed and presented separately and are not included in this analysis.
Arm/Group Title NSCLC (Parts C+F): TRT-Naïve TPS ≥50% NSCLC (Parts C+F): TRT-Naïve TPS = 1-49% NSCLC (Parts C+F): TRT-Naïve TPS <1% NSCLC (Parts C+F): TRT-Naïve TPS Unknown NSCLC (Parts C+F): All TRT-Naïve Participants NSCLC (Parts C+F): Previously Treated TPS ≥50% NSCLC (Parts C+F): Previously Treated TPS = 1-49% NSCLC (Parts C+F): Previously Treated TPS <1% NSCLC (Parts C+F): Previously Treated TPS Unknown NSCLC (Parts C+F): All Previously Treated Participants
Hide Arm/Group Description:
Prior treatment (TRT)-naïve NSCLC participants that received IV pembrolizumab on study and whose tumors were strongly positive for PD-L1 (TPS ≥50%).
Prior TRT-naïve NSCLC participants that received IV pembrolizumab on study and whose tumors were weakly positive for PD-L1 (TPS 1-49%).
Prior TRT-naïve NSCLC participants that received IV pembrolizumab on study and whose tumors were negative for PD-L1 (TPS <1%).
Prior TRT-naïve NSCLC participants that received IV pembrolizumab on study and whose tumors had an unknown PD-L1 status.
All prior TRT-naïve NSCLC participants that received IV pembrolizumab on study.
Previously-treated NSCLC participants that received IV pembrolizumab on study and whose tumors were strongly positive for PD-L1 (TPS ≥50%).
Previously-treated NSCLC participants that received IV pembrolizumab on study and whose tumors were weakly positive for PD-L1 (TPS 1-49%).
Previously-treated NSCLC participants that received IV pembrolizumab on study and whose tumors were negative for PD-L1 (TPS <1%).
Previously-treated NSCLC participants that received IV pembrolizumab on study and whose tumors had an unknown PD-L1 status.
All Previously-treated NSCLC participants that received IV pembrolizumab on study.
Overall Number of Participants Analyzed 23 39 10 9 81 110 137 66 38 351
Measure Type: Count of Participants
Unit of Measure: Participants
Number of Participants with ≤ -30% CFB
16
  69.6%
15
  38.5%
2
  20.0%
4
  44.4%
37
  45.7%
58
  52.7%
42
  30.7%
15
  22.7%
14
  36.8%
129
  36.8%
Number of Participants with > -30% to <20% CFB
7
  30.4%
20
  51.3%
6
  60.0%
4
  44.4%
37
  45.7%
32
  29.1%
65
  47.4%
38
  57.6%
14
  36.8%
149
  42.5%
Number of Participants with ≥ 20% CFB
0
   0.0%
4
  10.3%
2
  20.0%
1
  11.1%
7
   8.6%
20
  18.2%
30
  21.9%
13
  19.7%
10
  26.3%
73
  20.8%
19.Secondary Outcome
Title Disease Control Rate (DCR) According to RECIST 1.1 as Assessed by IRO in Melanoma Participants (Parts B and D)
Hide Description DCR was defined as the percentage of participants who had a CR (disappearance of all target lesions), PR (at least a 30% decrease in the sum of diameters of target lesions), or Stable Disease (SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease [PD: at least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered PD]). The percentage of participants who experienced a confirmed CR, PR, or SD according to RECIST 1.1 as assessed by IRO was reported as the DCR for each melanoma dose arm (Parts B plus D).
Time Frame Up to approximately 53 months (through Interim Database cut-off date of 18-Sep-2015)
Hide Outcome Measure Data
Hide Analysis Population Description
All melanoma (Parts B plus D) participants that received ≥1 dose of study treatment. Per protocol, Part A (dose-escalation) was not analyzed for efficacy. NSCLC (Parts C plus F) participants were analyzed and presented separately and are not included in this analysis.
Arm/Group Title Solid Tumors: Pembrolizumab 1 mg/kg Q2W (Part A) Solid Tumors: Pembrolizumab 3 mg/kg Q2W (Part A) Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) Solid Tumors: Pembrolizumab Titration Cohort 1 Q3W (Part A2) Solid Tumors: Pembrolizumab Titration Cohort 2 Q3W (Part A2) Solid Tumors: Pembrolizumab Titration Cohort 3 Q3W (Part A2) MEL: Pembrolizumab 2 mg/kg Q3W (Parts B+D) MEL: Pembrolizumab 10 mg/kg Q3W (Parts B+D) MEL: Pembrolizumab 10 mg/kg Q2W (Part B) NSCLC: Pembrolizumab 2 mg/kg Q3W (Part F) NSCLC: Pembrolizumab 10 mg/kg Q3W (Parts C+F) NSCLC: Pembrolizumab 10 mg/kg Q2W (Part F)
Hide Arm/Group Description:
During Cycle 1 participants received a dose of 1 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 1 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received a dose of 3 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 3 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received a dose of 10 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.005 mg/kg to 0.3 mg/kg to 2.0 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 2 mg/kg every 3 weeks (Q3W) starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.02 mg/kg to 0.3 mg/kg to 2.0 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 2 mg/kg Q3W starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.06 mg/kg to 1.0 mg/kg to 10 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 10 mg/kg Q3W starting with Cycle 2.
Participants received pembrolizumab IV at a dose of 2 mg/kg Q2W. After Amendment 3, participants received dosing Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 7, participants received dosing Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 2 mg/kg Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Overall Number of Participants Analyzed 0 0 0 0 0 0 162 313 180 0 0 0
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of Participants
48.1
(40.2 to 56.1)
47.6
(42.0 to 53.3)
56.1
(48.5 to 63.5)
20.Secondary Outcome
Title Duration of Response (DOR) According to RECIST 1.1 as Assessed by IRO in Melanoma Participants (Parts B and D)
Hide Description For participants who demonstrated a confirmed CR (disappearance of all target lesions) or PR (At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1, DOR was defined as the time from first documented evidence of a CR or PR until progressive disease (PD) or death. DOR for participants who had not progressed or died at the time of analysis was censored at the date of their last tumor assessment. Per RECIST 1.1, PD was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered PD. DOR assessments were based on IRO with confirmation. The DOR according to RECIST 1.1 for all participants who experienced a confirmed CR or PR was reported for each melanoma dose arm (Parts B plus D).
Time Frame From time of first documented evidence of CR or PR through Interim Database cut-off date of 18-Sep-2015 (Up to approximately 53 months)
Hide Outcome Measure Data
Hide Analysis Population Description
All melanoma (Parts B plus D) participants that received ≥1 dose of study treatment and who demonstrated a confirmed response (CR or PR). Per protocol, Part A (dose-escalation) was not analyzed for efficacy. NSCLC (Parts C plus F) participants were analyzed and presented separately and are not included in this analysis.
Arm/Group Title Solid Tumors: Pembrolizumab 1 mg/kg Q2W (Part A) Solid Tumors: Pembrolizumab 3 mg/kg Q2W (Part A) Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) Solid Tumors: Pembrolizumab Titration Cohort 1 Q3W (Part A2) Solid Tumors: Pembrolizumab Titration Cohort 2 Q3W (Part A2) Solid Tumors: Pembrolizumab Titration Cohort 3 Q3W (Part A2) MEL: Pembrolizumab 2 mg/kg Q3W (Parts B+D) MEL: Pembrolizumab 10 mg/kg Q3W (Parts B+D) MEL: Pembrolizumab 10 mg/kg Q2W (Part B) NSCLC: Pembrolizumab 2 mg/kg Q3W (Part F) NSCLC: Pembrolizumab 10 mg/kg Q3W (Parts C+F) NSCLC: Pembrolizumab 10 mg/kg Q2W (Part F)
Hide Arm/Group Description:
During Cycle 1 participants received a dose of 1 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 1 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received a dose of 3 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 3 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received a dose of 10 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.005 mg/kg to 0.3 mg/kg to 2.0 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 2 mg/kg every 3 weeks (Q3W) starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.02 mg/kg to 0.3 mg/kg to 2.0 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 2 mg/kg Q3W starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.06 mg/kg to 1.0 mg/kg to 10 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 10 mg/kg Q3W starting with Cycle 2.
Participants received pembrolizumab IV at a dose of 2 mg/kg Q2W. After Amendment 3, participants received dosing Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 7, participants received dosing Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 2 mg/kg Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Overall Number of Participants Analyzed 0 0 0 0 0 0 49 92 66 0 0 0
Median (Full Range)
Unit of Measure: Weeks
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
NA [2] 
(16.1 to NA)
[1]
NA=Median DOR and DOR range lower and upper limit not reached (no progressive disease by time of last disease assessment)
[2]
NA=Median DOR and DOR range upper limit not reached (no progressive disease by time of last disease assessment)
21.Secondary Outcome
Title Progression Free Survival (PFS) According to RECIST 1.1 as Assessed by IRO in Melanoma Participants (Parts B Plus D)
Hide Description PFS was defined as the time from randomization to the first documented PD or death due to any cause, whichever occurred first. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. PFS according to RECIST 1.1 as assessed by IRO was reported for each melanoma dose arm (Parts B plus D).
Time Frame Up to approximately 53 months (through Interim Database cut-off date of 18-Sep-2015)
Hide Outcome Measure Data
Hide Analysis Population Description
All melanoma (Parts B plus D) participants that received ≥1 dose of study treatment. Per protocol, Part A (dose-escalation) was not analyzed for efficacy. NSCLC (Parts C plus F) participants were analyzed and presented separately and are not included in this analysis.
Arm/Group Title Solid Tumors: Pembrolizumab 1 mg/kg Q2W (Part A) Solid Tumors: Pembrolizumab 3 mg/kg Q2W (Part A) Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) Solid Tumors: Pembrolizumab Titration Cohort 1 Q3W (Part A2) Solid Tumors: Pembrolizumab Titration Cohort 2 Q3W (Part A2) Solid Tumors: Pembrolizumab Titration Cohort 3 Q3W (Part A2) MEL: Pembrolizumab 2 mg/kg Q3W (Parts B+D) MEL: Pembrolizumab 10 mg/kg Q3W (Parts B+D) MEL: Pembrolizumab 10 mg/kg Q2W (Part B) NSCLC: Pembrolizumab 2 mg/kg Q3W (Part F) NSCLC: Pembrolizumab 10 mg/kg Q3W (Parts C+F) NSCLC: Pembrolizumab 10 mg/kg Q2W (Part F)
Hide Arm/Group Description:
During Cycle 1 participants received a dose of 1 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 1 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received a dose of 3 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 3 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received a dose of 10 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.005 mg/kg to 0.3 mg/kg to 2.0 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 2 mg/kg every 3 weeks (Q3W) starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.02 mg/kg to 0.3 mg/kg to 2.0 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 2 mg/kg Q3W starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.06 mg/kg to 1.0 mg/kg to 10 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 10 mg/kg Q3W starting with Cycle 2.
Participants received pembrolizumab IV at a dose of 2 mg/kg Q2W. After Amendment 3, participants received dosing Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 7, participants received dosing Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 2 mg/kg Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Overall Number of Participants Analyzed 0 0 0 0 0 0 162 313 180 0 0 0
Median (Full Range)
Unit of Measure: Months
4.9
(2.8 to 8.3)
3.7
(2.8 to 5.5)
5.6
(3.3 to 10.0)
22.Secondary Outcome
Title Overall Survival (OS) in Melanoma Participants (Parts B Plus D)
Hide Description OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the final analysis were to be censored at the date of the last follow-up. OS was reported for each melanoma dose arm (Parts B plus D).
Time Frame Up to approximately 91 months (through Final Database cut-off date of 05-Nov-2018)
Hide Outcome Measure Data
Hide Analysis Population Description
All melanoma (Parts B plus D) participants that received ≥1 dose of study treatment. Per protocol, Part A (dose-escalation) was not analyzed for efficacy. NSCLC (Parts C plus F) participants were analyzed and presented separately and are not included in this analysis.
Arm/Group Title Solid Tumors: Pembrolizumab 1 mg/kg Q2W (Part A) Solid Tumors: Pembrolizumab 3 mg/kg Q2W (Part A) Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) Solid Tumors: Pembrolizumab Titration Cohort 1 Q3W (Part A2) Solid Tumors: Pembrolizumab Titration Cohort 2 Q3W (Part A2) Solid Tumors: Pembrolizumab Titration Cohort 3 Q3W (Part A2) MEL: Pembrolizumab 2 mg/kg Q3W (Parts B+D) MEL: Pembrolizumab 10 mg/kg Q3W (Parts B+D) MEL: Pembrolizumab 10 mg/kg Q2W (Part B) NSCLC: Pembrolizumab 2 mg/kg Q3W (Part F) NSCLC: Pembrolizumab 10 mg/kg Q3W (Parts C+F) NSCLC: Pembrolizumab 10 mg/kg Q2W (Part F)
Hide Arm/Group Description:
During Cycle 1 participants received a dose of 1 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 1 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received a dose of 3 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 3 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received a dose of 10 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.005 mg/kg to 0.3 mg/kg to 2.0 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 2 mg/kg every 3 weeks (Q3W) starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.02 mg/kg to 0.3 mg/kg to 2.0 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 2 mg/kg Q3W starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.06 mg/kg to 1.0 mg/kg to 10 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 10 mg/kg Q3W starting with Cycle 2.
Participants received pembrolizumab IV at a dose of 2 mg/kg Q2W. After Amendment 3, participants received dosing Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 7, participants received dosing Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 2 mg/kg Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Overall Number of Participants Analyzed 0 0 0 0 0 0 162 313 180 0 0 0
Median (95% Confidence Interval)
Unit of Measure: Months
23.1
(17.8 to 33.1)
22.5
(18.5 to 32.0)
26.8
(19.6 to 41.8)
23.Secondary Outcome
Title DCR According to irRC as Assessed by Investigator in Melanoma Participants (Parts B Plus D)
Hide Description DCR according to irRC was defined as the percentage of participants who had a irCR (complete disappearance of all tumor lesions whether measurable or not, and no new lesions), irPR (decrease in SPD of ≥50% by a consecutive assessment ≥4 weeks after first documentation), or SD (neither sufficient shrinkage to qualify for irPR nor sufficient increase to qualify for PD [at least a 25% increase in SPD relative to nadir (minimum recorded tumor burden) with confirmation by a repeat, consecutive assessment no less than 4 weeks from the data first documented]). The percentage of participants who experienced a confirmed CR, PR, or SD according to irRC as assessed by the investigator was reported as the DCR for each melanoma dose arm (Parts B plus D).
Time Frame Up to approximately 53 months (through Interim Database cut-off date of 18-Sep-2015)
Hide Outcome Measure Data
Hide Analysis Population Description
All melanoma (Parts B plus D) participants that received ≥1 dose of study treatment. Per protocol, Part A (dose-escalation) was not analyzed for efficacy. NSCLC (Parts C plus F) participants were analyzed and presented separately and are not included in this analysis.
Arm/Group Title Solid Tumors: Pembrolizumab 1 mg/kg Q2W (Part A) Solid Tumors: Pembrolizumab 3 mg/kg Q2W (Part A) Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) Solid Tumors: Pembrolizumab Titration Cohort 1 Q3W (Part A2) Solid Tumors: Pembrolizumab Titration Cohort 2 Q3W (Part A2) Solid Tumors: Pembrolizumab Titration Cohort 3 Q3W (Part A2) MEL: Pembrolizumab 2 mg/kg Q3W (Parts B+D) MEL: Pembrolizumab 10 mg/kg Q3W (Parts B+D) MEL: Pembrolizumab 10 mg/kg Q2W (Part B) NSCLC: Pembrolizumab 2 mg/kg Q3W (Part F) NSCLC: Pembrolizumab 10 mg/kg Q3W (Parts C+F) NSCLC: Pembrolizumab 10 mg/kg Q2W (Part F)
Hide Arm/Group Description:
During Cycle 1 participants received a dose of 1 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 1 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received a dose of 3 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 3 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received a dose of 10 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.005 mg/kg to 0.3 mg/kg to 2.0 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 2 mg/kg every 3 weeks (Q3W) starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.02 mg/kg to 0.3 mg/kg to 2.0 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 2 mg/kg Q3W starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.06 mg/kg to 1.0 mg/kg to 10 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 10 mg/kg Q3W starting with Cycle 2.
Participants received pembrolizumab IV at a dose of 2 mg/kg Q2W. After Amendment 3, participants received dosing Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 7, participants received dosing Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 2 mg/kg Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Overall Number of Participants Analyzed 0 0 0 0 0 0 162 313 180 0 0 0
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of Participants
62.3
(54.4 to 69.8)
62.6
(57.0 to 68.0)
69.4
(62.2 to 76.1)
24.Secondary Outcome
Title DOR According to irRC as Assessed by Investigator in Melanoma Participants (Parts B Plus D)
Hide Description For participants who demonstrated a confirmed irCR (complete disappearance of all tumor lesions whether measurable or not, and no new lesions) or irPR (decrease in SPD of ≥50% by a consecutive assessment ≥4 weeks after first documentation) according to irRC, DOR was defined as the time from first documented evidence of an irCR or irPR until PD or death. DOR for participants who had not progressed or died at the time of analysis was censored at the date of their last tumor assessment. According to irRC, PD was defined as at least a 25% increase in SPD relative to nadir (minimum recorded tumor burden) with confirmation by a repeat, consecutive assessment no less than 4 weeks from the data first documented. The DOR according to irRC as assessed by the investigator for all participants who experienced a confirmed irCR or irPR was reported for each melanoma dose arm (Parts B plus D).
Time Frame From time of first documented evidence of iCR or iPR through Interim Database cut-off date of 18-Sep-2015 (Up to approximately 53 months)
Hide Outcome Measure Data
Hide Analysis Population Description
All melanoma (Parts B plus D) participants that received ≥1 dose of study treatment and who demonstrated a confirmed irRC response (irCR or irPR). Per protocol, Part A (dose-escalation) was not analyzed for efficacy. NSCLC (Parts C plus F) participants were analyzed and presented separately and are not included in this analysis.
Arm/Group Title Solid Tumors: Pembrolizumab 1 mg/kg Q2W (Part A) Solid Tumors: Pembrolizumab 3 mg/kg Q2W (Part A) Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) Solid Tumors: Pembrolizumab Titration Cohort 1 Q3W (Part A2) Solid Tumors: Pembrolizumab Titration Cohort 2 Q3W (Part A2) Solid Tumors: Pembrolizumab Titration Cohort 3 Q3W (Part A2) MEL: Pembrolizumab 2 mg/kg Q3W (Parts B+D) MEL: Pembrolizumab 10 mg/kg Q3W (Parts B+D) MEL: Pembrolizumab 10 mg/kg Q2W (Part B) NSCLC: Pembrolizumab 2 mg/kg Q3W (Part F) NSCLC: Pembrolizumab 10 mg/kg Q3W (Parts C+F) NSCLC: Pembrolizumab 10 mg/kg Q2W (Part F)
Hide Arm/Group Description:
During Cycle 1 participants received a dose of 1 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 1 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received a dose of 3 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 3 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received a dose of 10 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.005 mg/kg to 0.3 mg/kg to 2.0 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 2 mg/kg every 3 weeks (Q3W) starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.02 mg/kg to 0.3 mg/kg to 2.0 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 2 mg/kg Q3W starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.06 mg/kg to 1.0 mg/kg to 10 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 10 mg/kg Q3W starting with Cycle 2.
Participants received pembrolizumab IV at a dose of 2 mg/kg Q2W. After Amendment 3, participants received dosing Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 7, participants received dosing Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 2 mg/kg Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Overall Number of Participants Analyzed 0 0 0 0 0 0 57 125 82 0 0 0
Median (Full Range)
Unit of Measure: Months
NA [1] 
(2.1 to NA)
NA [2] 
(NA to NA)
NA [1] 
(2.7 to NA)
[1]
NA=Median DOR and DOR range upper limit not reached (no progressive disease by time of last disease assessment)
[2]
NA=Median DOR and DOR range lower and upper limit not reached (no progressive disease by time of last disease assessment)
25.Secondary Outcome
Title PFS According to irRC as Assessed by Investigator in Melanoma Participants (Parts B Plus D)
Hide Description PFS was defined as the time from randomization to the first documented PD or death due to any cause, whichever occurred first. According to irRC, PD was defined as at least a 25% increase in SPD relative to nadir (minimum recorded tumor burden) with confirmation by a repeat, consecutive assessment no less than 4 weeks from the data first documented. PFS according to irRC as assessed by the investigator was reported for each melanoma dose arm (Parts B plus D).
Time Frame Up to approximately 53 months (through Interim Database cut-off date of 18-Sep-2015)
Hide Outcome Measure Data
Hide Analysis Population Description
All melanoma (Parts B plus D) participants that received ≥1 dose of study treatment. Per protocol, Part A (dose-escalation) was not analyzed for efficacy. NSCLC (Parts C plus F) participants were analyzed and presented separately and are not included in this analysis.
Arm/Group Title Solid Tumors: Pembrolizumab 1 mg/kg Q2W (Part A) Solid Tumors: Pembrolizumab 3 mg/kg Q2W (Part A) Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) Solid Tumors: Pembrolizumab Titration Cohort 1 Q3W (Part A2) Solid Tumors: Pembrolizumab Titration Cohort 2 Q3W (Part A2) Solid Tumors: Pembrolizumab Titration Cohort 3 Q3W (Part A2) MEL: Pembrolizumab 2 mg/kg Q3W (Parts B+D) MEL: Pembrolizumab 10 mg/kg Q3W (Parts B+D) MEL: Pembrolizumab 10 mg/kg Q2W (Part B) NSCLC: Pembrolizumab 2 mg/kg Q3W (Part F) NSCLC: Pembrolizumab 10 mg/kg Q3W (Parts C+F) NSCLC: Pembrolizumab 10 mg/kg Q2W (Part F)
Hide Arm/Group Description:
During Cycle 1 participants received a dose of 1 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 1 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received a dose of 3 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 3 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received a dose of 10 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.005 mg/kg to 0.3 mg/kg to 2.0 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 2 mg/kg every 3 weeks (Q3W) starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.02 mg/kg to 0.3 mg/kg to 2.0 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 2 mg/kg Q3W starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.06 mg/kg to 1.0 mg/kg to 10 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 10 mg/kg Q3W starting with Cycle 2.
Participants received pembrolizumab IV at a dose of 2 mg/kg Q2W. After Amendment 3, participants received dosing Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 7, participants received dosing Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 2 mg/kg Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Overall Number of Participants Analyzed 0 0 0 0 0 0 162 313 180 0 0 0
Median (95% Confidence Interval)
Unit of Measure: Months
8.2
(5.6 to 13.6)
6.6
(5.5 to 10.5)
9.6
(5.6 to 19.3)
26.Secondary Outcome
Title DCR According to RECIST 1.1 as Assessed by IRC in NSCLC Participants (Parts C Plus F)
Hide Description DCR was defined as the percentage of participants who had a CR (disappearance of all target lesions), PR (at least a 30% decrease in the sum of diameters of target lesions), or SD (neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease [PD: at least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered PD]). The percentage of participants who experienced a confirmed CR, PR, or SD according to RECIST 1.1 as assessed by IRC was reported as the DCR for each NSCLC dose arm (Parts C plus F).
Time Frame Up to approximately 53 months (through Interim Database cut-off date of 18-Sep-2015)
Hide Outcome Measure Data
Hide Analysis Population Description
All NSCLC (Parts C plus F) participants that received ≥1 dose of study treatment. Per protocol, Part A (dose-escalation) was not analyzed for efficacy. Melanoma (Parts B plus D) participants were analyzed and presented separately and are not included in this analysis.
Arm/Group Title Solid Tumors: Pembrolizumab 1 mg/kg Q2W (Part A) Solid Tumors: Pembrolizumab 3 mg/kg Q2W (Part A) Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) Solid Tumors: Pembrolizumab Titration Cohort 1 Q3W (Part A2) Solid Tumors: Pembrolizumab Titration Cohort 2 Q3W (Part A2) Solid Tumors: Pembrolizumab Titration Cohort 3 Q3W (Part A2) MEL: Pembrolizumab 2 mg/kg Q3W (Parts B+D) MEL: Pembrolizumab 10 mg/kg Q3W (Parts B+D) MEL: Pembrolizumab 10 mg/kg Q2W (Part B) NSCLC: Pembrolizumab 2 mg/kg Q3W (Part F) NSCLC: Pembrolizumab 10 mg/kg Q3W (Parts C+F) NSCLC: Pembrolizumab 10 mg/kg Q2W (Part F)
Hide Arm/Group Description:
During Cycle 1 participants received a dose of 1 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 1 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received a dose of 3 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 3 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received a dose of 10 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.005 mg/kg to 0.3 mg/kg to 2.0 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 2 mg/kg every 3 weeks (Q3W) starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.02 mg/kg to 0.3 mg/kg to 2.0 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 2 mg/kg Q3W starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.06 mg/kg to 1.0 mg/kg to 10 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 10 mg/kg Q3W starting with Cycle 2.
Participants received pembrolizumab IV at a dose of 2 mg/kg Q2W. After Amendment 3, participants received dosing Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 7, participants received dosing Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 2 mg/kg Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Overall Number of Participants Analyzed 0 0 0 0 0 0 0 0 0 61 287 202
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of Participants
50.8
(37.7 to 63.9)
51.6
(45.6 to 57.5)
49.0
(41.9 to 56.1)
27.Secondary Outcome
Title DOR According to RECIST 1.1 as Assessed by IRC in NSCLC Participants (Parts C Plus F)
Hide Description For participants who demonstrated a confirmed CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1, DOR was defined as the time from first documented evidence of a CR or PR until PD or death. DOR for participants who had not progressed or died at the time of analysis was censored at the date of their last tumor assessment. Per RECIST 1.1, PD was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered PD. DOR assessments were based on IRC with confirmation. The DOR according to RECIST 1.1 for all participants who experienced a confirmed CR or PR was reported for each NSCLC dose arm (Parts C plus F).
Time Frame From time of first documented evidence of CR or PR through Interim Database cut-off date of 18-Sep-2015 (Up to approximately 53 months)
Hide Outcome Measure Data
Hide Analysis Population Description
All NSCLC (Parts C plus F) participants that received ≥1 dose of study treatment and who demonstrated a confirmed response (CR or PR). Per protocol, Part A (dose-escalation) was not analyzed for efficacy. Melanoma (Parts B and D) participants were analyzed and presented separately and are not included in this analysis.
Arm/Group Title Solid Tumors: Pembrolizumab 1 mg/kg Q2W (Part A) Solid Tumors: Pembrolizumab 3 mg/kg Q2W (Part A) Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) Solid Tumors: Pembrolizumab Titration Cohort 1 Q3W (Part A2) Solid Tumors: Pembrolizumab Titration Cohort 2 Q3W (Part A2) Solid Tumors: Pembrolizumab Titration Cohort 3 Q3W (Part A2) MEL: Pembrolizumab 2 mg/kg Q3W (Parts B+D) MEL: Pembrolizumab 10 mg/kg Q3W (Parts B+D) MEL: Pembrolizumab 10 mg/kg Q2W (Part B) NSCLC: Pembrolizumab 2 mg/kg Q3W (Part F) NSCLC: Pembrolizumab 10 mg/kg Q3W (Parts C+F) NSCLC: Pembrolizumab 10 mg/kg Q2W (Part F)
Hide Arm/Group Description:
During Cycle 1 participants received a dose of 1 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 1 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received a dose of 3 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 3 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received a dose of 10 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.005 mg/kg to 0.3 mg/kg to 2.0 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 2 mg/kg every 3 weeks (Q3W) starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.02 mg/kg to 0.3 mg/kg to 2.0 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 2 mg/kg Q3W starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.06 mg/kg to 1.0 mg/kg to 10 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 10 mg/kg Q3W starting with Cycle 2.
Participants received pembrolizumab IV at a dose of 2 mg/kg Q2W. After Amendment 3, participants received dosing Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 7, participants received dosing Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 2 mg/kg Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Overall Number of Participants Analyzed 0 0 0 0 0 0 0 0 0 12 62 39
Median (Full Range)
Unit of Measure: Months
NA [1] 
(NA to 19.0)
NA [2] 
(NA to NA)
20.7 [3] 
(2.8 to NA)
[1]
NA=Median DOR and DOR range lower limit not reached (no progressive disease by time of last disease assessment)
[2]
NA=Median DOR and DOR range lower and upper limit not reached (no progressive disease by time of last disease assessment)
[3]
NA=DOR range upper limit not reached (no progressive disease by time of last disease assessment)
28.Secondary Outcome
Title PFS According to RECIST 1.1 as Assessed by IRC in NSCLC Participants (Parts C Plus F)
Hide Description PFS was defined as the time from randomization to the first documented PD or death due to any cause, whichever occurred first. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. PFS according to RECIST 1.1 as assessed by IRC was reported for each NSCLC dose arm (Parts C plus F).
Time Frame Up to approximately 53 months (through Interim Database cut-off date of 18-Sep-2015)
Hide Outcome Measure Data
Hide Analysis Population Description
All NSCLC (Parts C plus F) participants that received ≥1 dose of study treatment. Per protocol, Part A (dose-escalation) was not analyzed for efficacy. Melanoma (Parts B plus D) participants were analyzed and presented separately and are not included in this analysis.
Arm/Group Title Solid Tumors: Pembrolizumab 1 mg/kg Q2W (Part A) Solid Tumors: Pembrolizumab 3 mg/kg Q2W (Part A) Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) Solid Tumors: Pembrolizumab Titration Cohort 1 Q3W (Part A2) Solid Tumors: Pembrolizumab Titration Cohort 2 Q3W (Part A2) Solid Tumors: Pembrolizumab Titration Cohort 3 Q3W (Part A2) MEL: Pembrolizumab 2 mg/kg Q3W (Parts B+D) MEL: Pembrolizumab 10 mg/kg Q3W (Parts B+D) MEL: Pembrolizumab 10 mg/kg Q2W (Part B) NSCLC: Pembrolizumab 2 mg/kg Q3W (Part F) NSCLC: Pembrolizumab 10 mg/kg Q3W (Parts C+F) NSCLC: Pembrolizumab 10 mg/kg Q2W (Part F)
Hide Arm/Group Description:
During Cycle 1 participants received a dose of 1 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 1 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received a dose of 3 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 3 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received a dose of 10 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.005 mg/kg to 0.3 mg/kg to 2.0 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 2 mg/kg every 3 weeks (Q3W) starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.02 mg/kg to 0.3 mg/kg to 2.0 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 2 mg/kg Q3W starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.06 mg/kg to 1.0 mg/kg to 10 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 10 mg/kg Q3W starting with Cycle 2.
Participants received pembrolizumab IV at a dose of 2 mg/kg Q2W. After Amendment 3, participants received dosing Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 7, participants received dosing Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 2 mg/kg Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Overall Number of Participants Analyzed 0 0 0 0 0 0 0 0 0 61 287 202
Median (95% Confidence Interval)
Unit of Measure: Months
3.3
(2.0 to 4.4)
3.7
(2.4 to 4.2)
3.4
(2.3 to 4.2)
29.Secondary Outcome
Title OS in NSCLC Participants (Parts C Plus F)
Hide Description OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the final analysis were to be censored at the date of the last follow-up. OS was reported for each NSCLC dose arm (Parts C plus F).
Time Frame Up to approximately 91 months (through Final Database cut-off date of 05-Nov-2018)
Hide Outcome Measure Data
Hide Analysis Population Description
All NSCLC (Parts C plus F) participants that received ≥1 dose of study treatment. Per protocol, Part A (dose-escalation) was not analyzed for efficacy. Melanoma (Parts B plus D) participants were analyzed and presented separately and are not included in this analysis.
Arm/Group Title Solid Tumors: Pembrolizumab 1 mg/kg Q2W (Part A) Solid Tumors: Pembrolizumab 3 mg/kg Q2W (Part A) Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) Solid Tumors: Pembrolizumab Titration Cohort 1 Q3W (Part A2) Solid Tumors: Pembrolizumab Titration Cohort 2 Q3W (Part A2) Solid Tumors: Pembrolizumab Titration Cohort 3 Q3W (Part A2) MEL: Pembrolizumab 2 mg/kg Q3W (Parts B+D) MEL: Pembrolizumab 10 mg/kg Q3W (Parts B+D) MEL: Pembrolizumab 10 mg/kg Q2W (Part B) NSCLC: Pembrolizumab 2 mg/kg Q3W (Part F) NSCLC: Pembrolizumab 10 mg/kg Q3W (Parts C+F) NSCLC: Pembrolizumab 10 mg/kg Q2W (Part F)
Hide Arm/Group Description:
During Cycle 1 participants received a dose of 1 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 1 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received a dose of 3 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 3 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received a dose of 10 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.005 mg/kg to 0.3 mg/kg to 2.0 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 2 mg/kg every 3 weeks (Q3W) starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.02 mg/kg to 0.3 mg/kg to 2.0 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 2 mg/kg Q3W starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.06 mg/kg to 1.0 mg/kg to 10 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 10 mg/kg Q3W starting with Cycle 2.
Participants received pembrolizumab IV at a dose of 2 mg/kg Q2W. After Amendment 3, participants received dosing Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 7, participants received dosing Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 2 mg/kg Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Overall Number of Participants Analyzed 0 0 0 0 0 0 0 0 0 61 287 202
Median (95% Confidence Interval)
Unit of Measure: Months
8.9
(5.8 to 15.4)
13.1
(10.3 to 17.3)
13.4
(9.4 to 15.7)
30.Secondary Outcome
Title DCR According to irRC as Assessed by Investigator in NSCLC Participants (Parts C Plus F)
Hide Description DCR according to irRC was defined as the percentage of participants who had a irCR (complete disappearance of all tumor lesions whether measurable or not, and no new lesions), irPR (decrease in SPD of ≥50% by a consecutive assessment ≥4 weeks after first documentation), or SD (neither sufficient shrinkage to qualify for irPR nor sufficient increase to qualify for PD [at least a 25% increase in SPD relative to nadir (minimum recorded tumor burden) with confirmation by a repeat, consecutive assessment no less than 4 weeks from the data first documented]). The percentage of participants who experienced a confirmed CR, PR, or SD according to irRC as assessed by the investigator was reported as the DCR for each NSCLC dose arm (Parts C plus F).
Time Frame Up to approximately 53 months (through Interim Database cut-off date of 18-Sep-2015)
Hide Outcome Measure Data
Hide Analysis Population Description
All NSCLC (Parts C plus F) participants that received ≥1 dose of study treatment. Per protocol, Part A (dose-escalation) was not analyzed for efficacy. Melanoma (Parts B plus D) participants were analyzed and presented separately and are not included in this analysis.
Arm/Group Title Solid Tumors: Pembrolizumab 1 mg/kg Q2W (Part A) Solid Tumors: Pembrolizumab 3 mg/kg Q2W (Part A) Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) Solid Tumors: Pembrolizumab Titration Cohort 1 Q3W (Part A2) Solid Tumors: Pembrolizumab Titration Cohort 2 Q3W (Part A2) Solid Tumors: Pembrolizumab Titration Cohort 3 Q3W (Part A2) MEL: Pembrolizumab 2 mg/kg Q3W (Parts B+D) MEL: Pembrolizumab 10 mg/kg Q3W (Parts B+D) MEL: Pembrolizumab 10 mg/kg Q2W (Part B) NSCLC: Pembrolizumab 2 mg/kg Q3W (Part F) NSCLC: Pembrolizumab 10 mg/kg Q3W (Parts C+F) NSCLC: Pembrolizumab 10 mg/kg Q2W (Part F)
Hide Arm/Group Description:
During Cycle 1 participants received a dose of 1 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 1 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received a dose of 3 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 3 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received a dose of 10 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.005 mg/kg to 0.3 mg/kg to 2.0 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 2 mg/kg every 3 weeks (Q3W) starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.02 mg/kg to 0.3 mg/kg to 2.0 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 2 mg/kg Q3W starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.06 mg/kg to 1.0 mg/kg to 10 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 10 mg/kg Q3W starting with Cycle 2.
Participants received pembrolizumab IV at a dose of 2 mg/kg Q2W. After Amendment 3, participants received dosing Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 7, participants received dosing Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 2 mg/kg Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Overall Number of Participants Analyzed 0 0 0 0 0 0 0 0 0 61 287 202
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of Participants
57.4
(44.1 to 70.1)
62.7
(56.8 to 68.3)
65.3
(58.3 to 71.9)
31.Secondary Outcome
Title DOR According to irRC as Assessed by Investigator in NSCLC Participants (Parts C Plus F)
Hide Description For participants who demonstrated a confirmed irCR (complete disappearance of all tumor lesions whether measurable or not, and no new lesions) or irPR (decrease in SPD of ≥50% by a consecutive assessment ≥4 weeks after first documentation) according to irRC, DOR was defined as the time from first documented evidence of an irCR or irPR until PD or death. DOR for participants who had not progressed or died at the time of analysis was censored at the date of their last tumor assessment. According to irRC, PD was defined as at least a 25% increase in SPD relative to nadir (minimum recorded tumor burden) with confirmation by a repeat, consecutive assessment no less than 4 weeks from the data first documented. The DOR according to irRC as assessed by the investigator for all participants who experienced a confirmed irCR or irPR was reported for each NSCLC dose arm (Parts C plus F).
Time Frame From time of first documented evidence of iCR or iPR through Interim Database cut-off date of 18-Sep-2015 (Up to approximately 53 months)
Hide Outcome Measure Data
Hide Analysis Population Description
All NSCLC (Parts C plus F) participants that received ≥1 dose of study treatment and who demonstrated a confirmed response (CR or PR). Per protocol, Part A (dose-escalation) was not analyzed for efficacy. Melanoma (Parts B and D) participants were analyzed and presented separately and are not included in this analysis.
Arm/Group Title Solid Tumors: Pembrolizumab 1 mg/kg Q2W (Part A) Solid Tumors: Pembrolizumab 3 mg/kg Q2W (Part A) Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) Solid Tumors: Pembrolizumab Titration Cohort 1 Q3W (Part A2) Solid Tumors: Pembrolizumab Titration Cohort 2 Q3W (Part A2) Solid Tumors: Pembrolizumab Titration Cohort 3 Q3W (Part A2) MEL: Pembrolizumab 2 mg/kg Q3W (Parts B+D) MEL: Pembrolizumab 10 mg/kg Q3W (Parts B+D) MEL: Pembrolizumab 10 mg/kg Q2W (Part B) NSCLC: Pembrolizumab 2 mg/kg Q3W (Part F) NSCLC: Pembrolizumab 10 mg/kg Q3W (Parts C+F) NSCLC: Pembrolizumab 10 mg/kg Q2W (Part F)
Hide Arm/Group Description:
During Cycle 1 participants received a dose of 1 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 1 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received a dose of 3 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 3 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received a dose of 10 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.005 mg/kg to 0.3 mg/kg to 2.0 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 2 mg/kg every 3 weeks (Q3W) starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.02 mg/kg to 0.3 mg/kg to 2.0 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 2 mg/kg Q3W starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.06 mg/kg to 1.0 mg/kg to 10 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 10 mg/kg Q3W starting with Cycle 2.
Participants received pembrolizumab IV at a dose of 2 mg/kg Q2W. After Amendment 3, participants received dosing Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 7, participants received dosing Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 2 mg/kg Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Overall Number of Participants Analyzed 0 0 0 0 0 0 0 0 0 14 83 45
Median (Full Range)
Unit of Measure: Months
NA [1] 
(NA to 21.9)
NA [2] 
(NA to NA)
NA [3] 
(3.0 to NA)
[1]
NA= Median DOR and DOR range lower limit not reached (no progressive disease by time of last disease assessment)
[2]
NA= Median DOR and DOR range lower and upper limit not reached (no progressive disease by time of last disease assessment)
[3]
NA=Median DOR and DOR range upper limit not reached (no progressive disease by time of last disease assessment)
32.Secondary Outcome
Title PFS According to irRC as Assessed by Investigator in NSCLC Participants (Parts C Plus F)
Hide Description PFS was defined as the time from randomization to the first documented PD or death due to any cause, whichever occurred first. According to irRC, PD was defined as at least a 25% increase in SPD relative to nadir (minimum recorded tumor burden) with confirmation by a repeat, consecutive assessment no less than 4 weeks from the data first documented. PFS according to irRC as assessed by the investigator was reported for each NSCLC dose arm (Parts C plus F).
Time Frame Up to approximately 53 months (through Interim Database cut-off date of 18-Sep-2015)
Hide Outcome Measure Data
Hide Analysis Population Description
All NSCLC (Parts C plus F) participants that received ≥1 dose of study treatment. Per protocol, Part A (dose-escalation) was not analyzed for efficacy. Melanoma (Parts B plus D) participants were analyzed and presented separately and are not included in this analysis.
Arm/Group Title Solid Tumors: Pembrolizumab 1 mg/kg Q2W (Part A) Solid Tumors: Pembrolizumab 3 mg/kg Q2W (Part A) Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) Solid Tumors: Pembrolizumab Titration Cohort 1 Q3W (Part A2) Solid Tumors: Pembrolizumab Titration Cohort 2 Q3W (Part A2) Solid Tumors: Pembrolizumab Titration Cohort 3 Q3W (Part A2) MEL: Pembrolizumab 2 mg/kg Q3W (Parts B+D) MEL: Pembrolizumab 10 mg/kg Q3W (Parts B+D) MEL: Pembrolizumab 10 mg/kg Q2W (Part B) NSCLC: Pembrolizumab 2 mg/kg Q3W (Part F) NSCLC: Pembrolizumab 10 mg/kg Q3W (Parts C+F) NSCLC: Pembrolizumab 10 mg/kg Q2W (Part F)
Hide Arm/Group Description:
During Cycle 1 participants received a dose of 1 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 1 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received a dose of 3 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 3 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received a dose of 10 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.005 mg/kg to 0.3 mg/kg to 2.0 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 2 mg/kg every 3 weeks (Q3W) starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.02 mg/kg to 0.3 mg/kg to 2.0 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 2 mg/kg Q3W starting with Cycle 2.
During Cycle 1 participants received pembrolizumab dose titration from 0.06 mg/kg to 1.0 mg/kg to 10 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 10 mg/kg Q3W starting with Cycle 2.
Participants received pembrolizumab IV at a dose of 2 mg/kg Q2W. After Amendment 3, participants received dosing Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 7, participants received dosing Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 2 mg/kg Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
Overall Number of Participants Analyzed 0 0 0 0 0 0 0 0 0 61 287 202
Median (95% Confidence Interval)
Unit of Measure: Months
4.3
(2.3 to 6.1)
4.4
(4.0 to 6.2)
5.6
(4.1 to 6.5)
Time Frame Up to approximately 91 months (through Final Database cut-off date of 05-Nov-2018)
Adverse Event Reporting Description All-Cause Mortality reported for all randomized/enrolled participants. AEs reported for All Treated Population.Per protocol, disease progression on study not considered an AE unless related to drug. Thus, MedDRA preferred terms "Neoplasm progression", "Malignant neoplasm progression" and "Disease progression" unrelated to drug excluded as AEs. 5 participants were not assessed by cutoff and were followed to study completion; end of study assessments are missing for these 5 and status is unknown
 
Arm/Group Title Solid Tumors: Pembrolizumab 1 mg/kg Q2W (Part A) Solid Tumors: Pembrolizumab 3 mg/kg Q2W (Part A) Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) Solid Tumors: Pembrolizumab Titration Cohort 1 Q3W (Part A2) Solid Tumors: Pembrolizumab Titration Cohort 2 Q3W (Part A2) Solid Tumors: Pembrolizumab Titration Cohort 3 Q3W (Part A2) MEL: Pembrolizumab 2 mg/kg Q3W (Parts B+D) MEL: Pembrolizumab 10 mg/kg Q3W (Parts B+D) MEL: Pembrolizumab 10 mg/kg Q2W (Part B) NSCLC: Pembrolizumab 2 mg/kg Q3W (Part F) NSCLC: Pembrolizumab 10 mg/kg Q3W (Parts C+F) NSCLC: Pembrolizumab 10 mg/kg Q2W (Part F)
Hide Arm/Group Description During Cycle 1 participants received a dose of 1 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 1 mg/kg Q2W starting with Cycle 2. During Cycle 1 participants received a dose of 3 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 3 mg/kg Q2W starting with Cycle 2. During Cycle 1 participants received a dose of 10 mg/kg pembrolizumab IV infusion over 30 minutes on Day 1 of a 28-day cycle for evaluation of dose-limiting toxicities and pharmacokinetics. Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W starting with Cycle 2. During Cycle 1 participants received pembrolizumab dose titration from 0.005 mg/kg to 0.3 mg/kg to 2.0 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 2 mg/kg Q3W starting with Cycle 2. During Cycle 1 participants received pembrolizumab dose titration from 0.02 mg/kg to 0.3 mg/kg to 2.0 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 2 mg/kg Q3W starting with Cycle 2. During Cycle 1 participants received pembrolizumab dose titration from 0.06 mg/kg to 1.0 mg/kg to 10 mg/kg on Days 1, 8, and 22, administered as an IV infusion over 30 minutes. Participants received 10 mg/kg Q3W starting with Cycle 2. Participants received pembrolizumab IV at a dose of 2 mg/kg Q2W. After Amendment 3, participants received dosing Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data. Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 7, participants received dosing Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data. Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data. Participants received pembrolizumab IV at a dose of 2 mg/kg Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data. Participants received pembrolizumab IV at a dose of 10 mg/kg Q3W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data. Participants received pembrolizumab IV at a dose of 10 mg/kg Q2W. After Amendment 10, all remaining and ongoing participants were treated with a 200 mg fixed dose of pembrolizumab IV Q3W based on analysis of safety and efficacy data.
All-Cause Mortality
Solid Tumors: Pembrolizumab 1 mg/kg Q2W (Part A) Solid Tumors: Pembrolizumab 3 mg/kg Q2W (Part A) Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) Solid Tumors: Pembrolizumab Titration Cohort 1 Q3W (Part A2) Solid Tumors: Pembrolizumab Titration Cohort 2 Q3W (Part A2) Solid Tumors: Pembrolizumab Titration Cohort 3 Q3W (Part A2) MEL: Pembrolizumab 2 mg/kg Q3W (Parts B+D) MEL: Pembrolizumab 10 mg/kg Q3W (Parts B+D) MEL: Pembrolizumab 10 mg/kg Q2W (Part B) NSCLC: Pembrolizumab 2 mg/kg Q3W (Part F) NSCLC: Pembrolizumab 10 mg/kg Q3W (Parts C+F) NSCLC: Pembrolizumab 10 mg/kg Q2W (Part F)
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   2/4 (50.00%)      1/3 (33.33%)      6/12 (50.00%)      2/4 (50.00%)      1/3 (33.33%)      5/6 (83.33%)      111/164 (67.68%)      213/321 (66.36%)      110/183 (60.11%)      52/61 (85.25%)      240/296 (81.08%)      166/203 (81.77%)    
Hide Serious Adverse Events
Solid Tumors: Pembrolizumab 1 mg/kg Q2W (Part A) Solid Tumors: Pembrolizumab 3 mg/kg Q2W (Part A) Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) Solid Tumors: Pembrolizumab Titration Cohort 1 Q3W (Part A2) Solid Tumors: Pembrolizumab Titration Cohort 2 Q3W (Part A2) Solid Tumors: Pembrolizumab Titration Cohort 3 Q3W (Part A2) MEL: Pembrolizumab 2 mg/kg Q3W (Parts B+D) MEL: Pembrolizumab 10 mg/kg Q3W (Parts B+D) MEL: Pembrolizumab 10 mg/kg Q2W (Part B) NSCLC: Pembrolizumab 2 mg/kg Q3W (Part F) NSCLC: Pembrolizumab 10 mg/kg Q3W (Parts C+F) NSCLC: Pembrolizumab 10 mg/kg Q2W (Part F)
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   1/4 (25.00%)      1/3 (33.33%)      3/10 (30.00%)      0/4 (0.00%)      2/3 (66.67%)      2/6 (33.33%)      69/162 (42.59%)      129/313 (41.21%)      79/180 (43.89%)      34/61 (55.74%)      119/287 (41.46%)      86/202 (42.57%)    
Blood and lymphatic system disorders                         
Anaemia † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 3/162 (1.85%)  6 4/313 (1.28%)  5 4/180 (2.22%)  4 0/61 (0.00%)  0 0/287 (0.00%)  0 1/202 (0.50%)  1
Autoimmune haemolytic anaemia † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 1/202 (0.50%)  1
Disseminated intravascular coagulation † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 1/180 (0.56%)  1 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Haemolytic anaemia † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 1/180 (0.56%)  1 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Immune thrombocytopenic purpura † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 1/180 (0.56%)  1 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Iron deficiency anaemia † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 1/180 (0.56%)  1 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Leukocytosis † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Lymphadenopathy † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 1/202 (0.50%)  1
Neutropenia † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 1/202 (0.50%)  1
Pancytopenia † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 1/180 (0.56%)  1 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Splenic infarction † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 1/180 (0.56%)  1 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Thrombocytopenia † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/162 (0.62%)  1 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 1/202 (0.50%)  2
Cardiac disorders                         
Acute coronary syndrome † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 1/287 (0.35%)  1 0/202 (0.00%)  0
Acute myocardial infarction † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 2/313 (0.64%)  2 2/180 (1.11%)  2 0/61 (0.00%)  0 2/287 (0.70%)  2 1/202 (0.50%)  1
Angina pectoris † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/162 (0.62%)  1 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Angina unstable † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 1/287 (0.35%)  1 0/202 (0.00%)  0
Atrial fibrillation † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 2/162 (1.23%)  2 6/313 (1.92%)  6 1/180 (0.56%)  1 0/61 (0.00%)  0 1/287 (0.35%)  1 1/202 (0.50%)  1
Atrial flutter † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/162 (0.62%)  1 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 2/202 (0.99%)  2
Atrial thrombosis † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Cardiac arrest † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Cardiac failure † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 1/180 (0.56%)  1 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Cardiac failure congestive † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 2/162 (1.23%)  2 2/313 (0.64%)  3 0/180 (0.00%)  0 0/61 (0.00%)  0 2/287 (0.70%)  3 0/202 (0.00%)  0
Cardiac tamponade † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 2/61 (3.28%)  2 2/287 (0.70%)  2 1/202 (0.50%)  1
Cardio-respiratory arrest † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 1/61 (1.64%)  1 0/287 (0.00%)  0 1/202 (0.50%)  1
Coronary artery disease † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/162 (0.62%)  1 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Left ventricular failure † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 1/180 (0.56%)  1 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Myocardial infarction † 1  0/4 (0.00%)  0 1/3 (33.33%)  1 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 1/202 (0.50%)  1
Pericardial effusion † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 2/162 (1.23%)  2 1/313 (0.32%)  1 0/180 (0.00%)  0 1/61 (1.64%)  1 3/287 (1.05%)  4 1/202 (0.50%)  1
Pericarditis † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/162 (0.62%)  1 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Right ventricular failure † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 1/202 (0.50%)  1
Supraventricular tachycardia † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 1/180 (0.56%)  1 0/61 (0.00%)  0 1/287 (0.35%)  1 1/202 (0.50%)  1
Tachycardia † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Ventricular fibrillation † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 1/180 (0.56%)  1 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Ventricular tachycardia † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 2/313 (0.64%)  4 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Mitral valve prolapse † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 1/61 (1.64%)  1 0/287 (0.00%)  0 0/202 (0.00%)  0
Endocrine disorders                         
Adrenal haemorrhage † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 1/202 (0.50%)  1
Adrenal insufficiency † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/162 (0.62%)  1 3/313 (0.96%)  4 1/180 (0.56%)  1 0/61 (0.00%)  0 2/287 (0.70%)  2 1/202 (0.50%)  1
Hyperthyroidism † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/162 (0.62%)  1 1/313 (0.32%)  1 1/180 (0.56%)  1 0/61 (0.00%)  0 1/287 (0.35%)  1 0/202 (0.00%)  0
Hypophysitis † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 2/162 (1.23%)  3 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 1/287 (0.35%)  1 0/202 (0.00%)  0
Hypothyroidism † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 2/287 (0.70%)  2 0/202 (0.00%)  0
Eye disorders                         
Uveitis † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 1/180 (0.56%)  2 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Visual acuity reduced † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Gastrointestinal disorders                         
Abdominal mass † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/162 (0.62%)  1 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Abdominal pain † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/162 (0.62%)  1 5/313 (1.60%)  5 3/180 (1.67%)  3 1/61 (1.64%)  1 2/287 (0.70%)  2 1/202 (0.50%)  1
Ascites † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/162 (0.62%)  1 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 1/287 (0.35%)  1 1/202 (0.50%)  1
Colitis † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 4/162 (2.47%)  5 6/313 (1.92%)  6 2/180 (1.11%)  2 2/61 (3.28%)  2 2/287 (0.70%)  3 0/202 (0.00%)  0
Colitis microscopic † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 1/180 (0.56%)  1 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Constipation † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/162 (0.62%)  1 3/313 (0.96%)  4 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Diarrhoea † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/162 (0.62%)  1 3/313 (0.96%)  3 5/180 (2.78%)  5 0/61 (0.00%)  0 2/287 (0.70%)  2 0/202 (0.00%)  0
Dysphagia † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Enterocolitis † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 1/180 (0.56%)  1 0/61 (0.00%)  0 1/287 (0.35%)  1 0/202 (0.00%)  0
Erosive duodenitis † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 1/202 (0.50%)  1
Faecalith † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 1/202 (0.50%)  1
Gastric perforation † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 1/287 (0.35%)  1 0/202 (0.00%)  0
Gastric ulcer haemorrhage † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Gastritis † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/162 (0.62%)  1 0/313 (0.00%)  0 1/180 (0.56%)  1 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Gastritis erosive † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 1/202 (0.50%)  1
Gastrointestinal haemorrhage † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 5/180 (2.78%)  5 0/61 (0.00%)  0 1/287 (0.35%)  1 0/202 (0.00%)  0
Gastrointestinal pain † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 1/202 (0.50%)  1
Gastrointestinal perforation † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 1/202 (0.50%)  1
Gastrointestinal ulcer † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 1/180 (0.56%)  1 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Haematochezia † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  2 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Ileus † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Inguinal hernia † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 1/287 (0.35%)  1 0/202 (0.00%)  0
Intestinal mass † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 1/180 (0.56%)  1 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Intestinal obstruction † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 2/162 (1.23%)  2 2/313 (0.64%)  2 1/180 (0.56%)  1 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Intestinal perforation † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 1/180 (0.56%)  1 0/61 (0.00%)  0 1/287 (0.35%)  1 0/202 (0.00%)  0
Intra-abdominal haematoma † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 1/180 (0.56%)  1 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Intussusception † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 2/313 (0.64%)  2 2/180 (1.11%)  2 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Nausea † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 2/162 (1.23%)  3 4/313 (1.28%)  4 3/180 (1.67%)  3 0/61 (0.00%)  0 6/287 (2.09%)  7 1/202 (0.50%)  2
Oesophagitis † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/162 (0.62%)  1 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Pancreatic cyst † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 1/3 (33.33%)  1 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Pancreatitis † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Proctalgia † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Rectal haemorrhage † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 1/202 (0.50%)  1
Retroperitoneal haemorrhage † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 2/313 (0.64%)  2 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Small intestinal obstruction † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/162 (0.62%)  3 2/313 (0.64%)  2 1/180 (0.56%)  2 0/61 (0.00%)  0 1/287 (0.35%)  1 0/202 (0.00%)  0
Vomiting † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 2/162 (1.23%)  3 3/313 (0.96%)  3 3/180 (1.67%)  3 0/61 (0.00%)  0 2/287 (0.70%)  2 1/202 (0.50%)  1
Obstruction gastric † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 1/180 (0.56%)  1 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
General disorders                         
Asthenia † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/162 (0.62%)  1 3/313 (0.96%)  3 1/180 (0.56%)  1 1/61 (1.64%)  1 0/287 (0.00%)  0 2/202 (0.99%)  3
Chest pain † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 1/180 (0.56%)  1 0/61 (0.00%)  0 2/287 (0.70%)  2 1/202 (0.50%)  1
Chills † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/162 (0.62%)  1 0/313 (0.00%)  0 0/180 (0.00%)  0 1/61 (1.64%)  1 1/287 (0.35%)  1 0/202 (0.00%)  0
Death † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 2/180 (1.11%)  2 0/61 (0.00%)  0 0/287 (0.00%)  0 2/202 (0.99%)  2
Drug withdrawal syndrome † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 1/202 (0.50%)  1
Fatigue † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 2/313 (0.64%)  2 2/180 (1.11%)  2 0/61 (0.00%)  0 3/287 (1.05%)  3 2/202 (0.99%)  2
Gait disturbance † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 1/180 (0.56%)  1 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
General physical health deterioration † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 2/313 (0.64%)  3 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 1/202 (0.50%)  1
Generalised oedema † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/162 (0.62%)  1 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 1/287 (0.35%)  1 0/202 (0.00%)  0
Impaired healing † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Inflammation † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 1/180 (0.56%)  1 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Influenza like illness † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 1/180 (0.56%)  1 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Malaise † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/162 (0.62%)  1 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Non-cardiac chest pain † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/162 (0.62%)  1 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 1/287 (0.35%)  1 0/202 (0.00%)  0
Oedema † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 2/202 (0.99%)  2
Pain † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/162 (0.62%)  1 3/313 (0.96%)  3 0/180 (0.00%)  0 1/61 (1.64%)  1 2/287 (0.70%)  2 1/202 (0.50%)  1
Pyrexia † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 2/162 (1.23%)  3 4/313 (1.28%)  4 3/180 (1.67%)  3 3/61 (4.92%)  3 6/287 (2.09%)  6 2/202 (0.99%)  3
Oedema peripheral † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Hepatobiliary disorders                         
Autoimmune hepatitis † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 2/162 (1.23%)  2 0/313 (0.00%)  0 1/180 (0.56%)  1 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Bile duct stone † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 1/180 (0.56%)  1 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Cholecystitis † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 1/180 (0.56%)  1 0/61 (0.00%)  0 0/287 (0.00%)  0 2/202 (0.99%)  2
Hepatic failure † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 1/61 (1.64%)  1 0/287 (0.00%)  0 0/202 (0.00%)  0
Bile duct obstruction † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/162 (0.62%)  1 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Hepatitis † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Infections and infestations                         
Arthritis bacterial † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 1/287 (0.35%)  2 0/202 (0.00%)  0
Bacillus bacteraemia † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 1/287 (0.35%)  1 0/202 (0.00%)  0
Bacterial sepsis † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 1/202 (0.50%)  1
Bronchitis † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 2/313 (0.64%)  2 0/180 (0.00%)  0 1/61 (1.64%)  1 2/287 (0.70%)  2 0/202 (0.00%)  0
Catheter site infection † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/162 (0.62%)  1 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Cellulitis † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/162 (0.62%)  2 8/313 (2.56%)  10 3/180 (1.67%)  3 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Chorioretinitis † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 1/180 (0.56%)  2 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Clostridium difficile colitis † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 1/180 (0.56%)  1 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Clostridium difficile infection † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 1/180 (0.56%)  1 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Diverticulitis † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 1/180 (0.56%)  1 0/61 (0.00%)  0 0/287 (0.00%)  0 1/202 (0.50%)  1
Diverticulitis intestinal haemorrhagic † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Enterocolitis infectious † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Erysipelas † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/162 (0.62%)  1 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Extradural abscess † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 1/180 (0.56%)  1 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Gastroenteritis † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/162 (0.62%)  1 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Gastroenteritis viral † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/162 (0.62%)  1 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Herpes zoster † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 1/287 (0.35%)  1 1/202 (0.50%)  1
Infectious pleural effusion † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 1/287 (0.35%)  1 0/202 (0.00%)  0
Infective exacerbation of chronic obstructive airways disease † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 1/61 (1.64%)  1 1/287 (0.35%)  1 0/202 (0.00%)  0
Influenza † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 1/180 (0.56%)  1 0/61 (0.00%)  0 0/287 (0.00%)  0 1/202 (0.50%)  1
Intervertebral discitis † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 1/180 (0.56%)  1 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Localised infection † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 1/180 (0.56%)  1 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Lower respiratory tract infection † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 2/61 (3.28%)  2 1/287 (0.35%)  1 3/202 (1.49%)  3
Lung infection † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/162 (0.62%)  1 1/313 (0.32%)  1 0/180 (0.00%)  0 1/61 (1.64%)  1 4/287 (1.39%)  4 0/202 (0.00%)  0
Lyme disease † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Lymphangitis † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 1/202 (0.50%)  1
Meningitis † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 1/202 (0.50%)  1
Meningitis aseptic † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 1/61 (1.64%)  1 0/287 (0.00%)  0 0/202 (0.00%)  0
Oesophageal candidiasis † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 1/287 (0.35%)  1 0/202 (0.00%)  0
Osteomyelitis † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 1/180 (0.56%)  1 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Pelvic infection † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 1/61 (1.64%)  1 0/287 (0.00%)  0 0/202 (0.00%)  0
Pleural infection † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 1/202 (0.50%)  1
Pneumonia † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 1/10 (10.00%)  1 0/4 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  1 5/162 (3.09%)  7 9/313 (2.88%)  12 8/180 (4.44%)  8 6/61 (9.84%)  8 7/287 (2.44%)  8 13/202 (6.44%)  15
Pneumonia bacterial † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 1/180 (0.56%)  1 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Pneumonia cryptococcal † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 1/202 (0.50%)  1
Pneumonia viral † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 2/287 (0.70%)  2 0/202 (0.00%)  0
Post procedural infection † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Respiratory tract infection † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 2/287 (0.70%)  3 1/202 (0.50%)  1
Sepsis † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 4/162 (2.47%)  5 2/313 (0.64%)  3 4/180 (2.22%)  4 1/61 (1.64%)  1 2/287 (0.70%)  2 1/202 (0.50%)  1
Septic shock † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/162 (0.62%)  1 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 1/287 (0.35%)  1 1/202 (0.50%)  1
Sinusitis † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 1/287 (0.35%)  1 0/202 (0.00%)  0
Skin infection † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 0/180 (0.00%)  0 1/61 (1.64%)  1 0/287 (0.00%)  0 0/202 (0.00%)  0
Staphylococcal bacteraemia † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 1/61 (1.64%)  1 0/287 (0.00%)  0 0/202 (0.00%)  0
Thrombophlebitis septic † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 1/61 (1.64%)  1 0/287 (0.00%)  0 0/202 (0.00%)  0
Tuberculosis † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Upper respiratory tract infection † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/162 (0.62%)  1 0/313 (0.00%)  0 1/180 (0.56%)  1 0/61 (0.00%)  0 1/287 (0.35%)  1 0/202 (0.00%)  0
Ureteritis † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 1/202 (0.50%)  1
Urinary tract infection † 1  1/4 (25.00%)  1 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 2/162 (1.23%)  2 5/313 (1.60%)  5 3/180 (1.67%)  3 0/61 (0.00%)  0 1/287 (0.35%)  1 1/202 (0.50%)  1
Urosepsis † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 1/202 (0.50%)  1
Viral infection † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/162 (0.62%)  1 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 1/287 (0.35%)  1 0/202 (0.00%)  0
Wound infection † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/162 (0.62%)  1 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Abdominal abscess † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/162 (0.62%)  1 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Disseminated cryptococcosis † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 1/10 (10.00%)  1 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Herpes simplex encephalitis † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 1/180 (0.56%)  2 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Listeriosis † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 1/287 (0.35%)  1 0/202 (0.00%)  0
Lymph gland infection † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 1/61 (1.64%)  1 0/287 (0.00%)  0 0/202 (0.00%)  0
Meningitis listeria † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 1/287 (0.35%)  1 0/202 (0.00%)  0
Injury, poisoning and procedural complications                         
Back injury † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Clavicle fracture † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Fall † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 1/180 (0.56%)  1 0/61 (0.00%)  0 1/287 (0.35%)  1 1/202 (0.50%)  1
Femoral neck fracture † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 1/202 (0.50%)  1
Hip fracture † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 2/313 (0.64%)  2 0/180 (0.00%)  0 0/61 (0.00%)  0 1/287 (0.35%)  1 0/202 (0.00%)  0
Humerus fracture † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  2 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Radius fracture † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 1/180 (0.56%)  1 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Rib fracture † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Subdural haematoma † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 1/10 (10.00%)  1 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/162 (0.62%)  1 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Thoracic vertebral fracture † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 1/202 (0.50%)  1
Wound decomposition † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Wound haemorrhage † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Investigations                         
Aspartate aminotransferase increased † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 1/287 (0.35%)  1 0/202 (0.00%)  0
Blood bilirubin increased † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 2/287 (0.70%)  2 0/202 (0.00%)  0
Blood creatine phosphokinase increased † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 1/202 (0.50%)  1
Electrocardiogram change † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Medical observation † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 1/287 (0.35%)  1 0/202 (0.00%)  0
Ejection fraction decreased † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Metabolism and nutrition disorders                         
Cachexia † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 1/202 (0.50%)  1
Decreased appetite † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 1/287 (0.35%)  1 1/202 (0.50%)  1
Dehydration † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 1/10 (10.00%)  1 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 3/162 (1.85%)  3 2/313 (0.64%)  2 3/180 (1.67%)  3 2/61 (3.28%)  2 3/287 (1.05%)  3 0/202 (0.00%)  0
Diabetes mellitus † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/162 (0.62%)  1 1/313 (0.32%)  1 1/180 (0.56%)  1 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Electrolyte imbalance † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Failure to thrive † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/162 (0.62%)  1 2/313 (0.64%)  2 2/180 (1.11%)  2 0/61 (0.00%)  0 1/287 (0.35%)  1 0/202 (0.00%)  0
Fluid overload † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 1/287 (0.35%)  1 0/202 (0.00%)  0
Hypercalcaemia † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 3/287 (1.05%)  3 1/202 (0.50%)  1
Hyperglycaemia † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/162 (0.62%)  1 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Hyperkalaemia † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 1/180 (0.56%)  1 1/61 (1.64%)  1 0/287 (0.00%)  0 0/202 (0.00%)  0
Hyperuricaemia † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/162 (0.62%)  1 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Hypoalbuminaemia † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 1/180 (0.56%)  1 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Hypoglycaemia † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 2/313 (0.64%)  2 0/180 (0.00%)  0 1/61 (1.64%)  1 0/287 (0.00%)  0 0/202 (0.00%)  0
Hypokalaemia † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Hypomagnesaemia † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 1/287 (0.35%)  1 0/202 (0.00%)  0
Hyponatraemia † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 2/162 (1.23%)  2 4/313 (1.28%)  4 4/180 (2.22%)  8 0/61 (0.00%)  0 2/287 (0.70%)  2 1/202 (0.50%)  1
Hypovolaemia † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 1/202 (0.50%)  1
Insulin resistant diabetes † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/162 (0.62%)  1 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Malnutrition † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 2/313 (0.64%)  2 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Metabolic acidosis † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 1/180 (0.56%)  1 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Type 1 diabetes mellitus † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Musculoskeletal and connective tissue disorders                         
Arthralgia † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 2/313 (0.64%)  2 0/180 (0.00%)  0 2/61 (3.28%)  2 2/287 (0.70%)  2 0/202 (0.00%)  0
Back pain † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/162 (0.62%)  1 1/313 (0.32%)  1 2/180 (1.11%)  2 0/61 (0.00%)  0 3/287 (1.05%)  4 1/202 (0.50%)  1
Bone pain † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 1/287 (0.35%)  1 0/202 (0.00%)  0
Costochondritis † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 1/180 (0.56%)  1 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Intervertebral disc protrusion † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 1/287 (0.35%)  1 0/202 (0.00%)  0
Muscular weakness † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 1/180 (0.56%)  1 0/61 (0.00%)  0 3/287 (1.05%)  4 0/202 (0.00%)  0
Musculoskeletal chest pain † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 2/287 (0.70%)  2 0/202 (0.00%)  0
Musculoskeletal pain † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/162 (0.62%)  1 0/313 (0.00%)  0 1/180 (0.56%)  1 0/61 (0.00%)  0 2/287 (0.70%)  2 0/202 (0.00%)  0
Myopathy † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 1/180 (0.56%)  1 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Myositis † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 2/313 (0.64%)  2 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Neck pain † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 1/202 (0.50%)  1
Osteoarthritis † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/162 (0.62%)  1 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Pain in extremity † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 2/162 (1.23%)  2 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Pathological fracture † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 1/202 (0.50%)  1
Polyarthritis † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/162 (0.62%)  2 0/313 (0.00%)  0 1/180 (0.56%)  3 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Psoriatic arthropathy † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/162 (0.62%)  1 0/313 (0.00%)  0 0/180 (0.00%)  0 1/61 (1.64%)  1 0/287 (0.00%)  0 0/202 (0.00%)  0
Rhabdomyolysis † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Spinal column stenosis † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/162 (0.62%)  1 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Spinal pain † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/162 (0.62%)  1 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Synovial cyst † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Eosinophilic fasciitis † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 1/180 (0.56%)  1 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Flank pain † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 1/180 (0.56%)  1 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Myalgia † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)                         
Basal cell carcinoma † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 6/162 (3.70%)  11 8/313 (2.56%)  14 4/180 (2.22%)  4 0/61 (0.00%)  0 2/287 (0.70%)  3 0/202 (0.00%)  0
Bowen's disease † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 2/313 (0.64%)  2 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Breast cancer † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 1/287 (0.35%)  1 0/202 (0.00%)  0
Cancer pain † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/162 (0.62%)  1 0/313 (0.00%)  0 1/180 (0.56%)  1 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Leiomyosarcoma † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 1/287 (0.35%)  1 0/202 (0.00%)  0
Lung adenocarcinoma † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Lymphangiosis carcinomatosa † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 1/61 (1.64%)  1 0/287 (0.00%)  0 0/202 (0.00%)  0
Malignant melanoma † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 2/162 (1.23%)  2 0/313 (0.00%)  0 1/180 (0.56%)  1 0/61 (0.00%)  0 0/287 (0.00%)  0 1/202 (0.50%)  1
Malignant pleural effusion † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 1/287 (0.35%)  1 2/202 (0.99%)  2
Metastases to central nervous system † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/162 (0.62%)  1 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Metastases to meninges † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Pericardial effusion malignant † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 2/287 (0.70%)  2 0/202 (0.00%)  0
Prostate cancer † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 1/180 (0.56%)  1 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Prostate cancer recurrent † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Squamous cell carcinoma † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 5/162 (3.09%)  5 10/313 (3.19%)  13 7/180 (3.89%)  8 0/61 (0.00%)  0 1/287 (0.35%)  1 0/202 (0.00%)  0
Squamous cell carcinoma of skin † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/162 (0.62%)  1 2/313 (0.64%)  6 1/180 (0.56%)  1 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Transitional cell carcinoma † 1  1/4 (25.00%)  1 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Tumour haemorrhage † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/162 (0.62%)  1 2/313 (0.64%)  4 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Tumour pain † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 2/162 (1.23%)  2 1/313 (0.32%)  1 0/180 (0.00%)  0 1/61 (1.64%)  1 2/287 (0.70%)  2 0/202 (0.00%)  0
Adenocarcinoma gastric † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/162 (0.62%)  1 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Myelodysplastic syndrome † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Nervous system disorders                         
Ataxia † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 1/287 (0.35%)  1 0/202 (0.00%)  0
Brain oedema † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 1/202 (0.50%)  1
Brain stem infarction † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 1/202 (0.50%)  1
Carotid artery stenosis † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Cerebrovascular accident † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/162 (0.62%)  1 2/313 (0.64%)  2 0/180 (0.00%)  0 0/61 (0.00%)  0 3/287 (1.05%)  3 1/202 (0.50%)  1
Depressed level of consciousness † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 1/202 (0.50%)  1
Dizziness † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/162 (0.62%)  1 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 1/287 (0.35%)  1 0/202 (0.00%)  0
Dysarthria † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Embolic stroke † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 1/287 (0.35%)  1 0/202 (0.00%)  0
Encephalopathy † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/162 (0.62%)  1 0/313 (0.00%)  0 1/180 (0.56%)  1 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Epilepsy † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Haemorrhage intracranial † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 2/162 (1.23%)  2 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Headache † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 1/287 (0.35%)  1 1/202 (0.50%)  1
Ischaemic stroke † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Lethargy † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 1/61 (1.64%)  1 0/287 (0.00%)  0 0/202 (0.00%)  0
Migraine † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Myasthenia gravis † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Neuralgia † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 1/202 (0.50%)  1
Neuropathy peripheral † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/162 (0.62%)  1 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Partial seizures † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/162 (0.62%)  1 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Peripheral paralysis † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  1 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Peripheral sensory neuropathy † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 1/180 (0.56%)  1 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Presyncope † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 1/180 (0.56%)  1 0/61 (0.00%)  0 1/287 (0.35%)  1 0/202 (0.00%)  0
Sciatica † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Seizure † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 3/313 (0.96%)  3 2/180 (1.11%)  2 0/61 (0.00%)  0 0/287 (0.00%)  0 2/202 (0.99%)  2
Spinal cord compression † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  1 1/162 (0.62%)  1 2/313 (0.64%)  2 3/180 (1.67%)  3 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Syncope † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 2/313 (0.64%)  2 2/180 (1.11%)  2 1/61 (1.64%)  1 1/287 (0.35%)  1 1/202 (0.50%)  1
Transient ischaemic attack † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 1/180 (0.56%)  1 1/61 (1.64%)  1 0/287 (0.00%)  0 0/202 (0.00%)  0
Vasogenic cerebral oedema † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 1/202 (0.50%)  1
Dyskinesia † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 1/287 (0.35%)  1 0/202 (0.00%)  0
Hydrocephalus † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Psychiatric disorders                         
Anxiety † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 1/180 (0.56%)  1 0/61 (0.00%)  0 1/287 (0.35%)  1 0/202 (0.00%)  0
Completed suicide † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 1/180 (0.56%)  1 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Confusional state † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/162 (0.62%)  2 2/313 (0.64%)  2 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Mental status changes † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/162 (0.62%)  1 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Renal and urinary disorders                         
Acute kidney injury † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 1/3 (33.33%)  2 0/6 (0.00%)  0 0/162 (0.00%)  0 4/313 (1.28%)  4 2/180 (1.11%)  2 1/61 (1.64%)  1 1/287 (0.35%)  1 2/202 (0.99%)  2
Calculus urinary † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 1/287 (0.35%)  1 0/202 (0.00%)  0
Dysuria † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 1/287 (0.35%)  1 1/202 (0.50%)  1
Hydronephrosis † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Nephritis † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 1/180 (0.56%)  1 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Nephrolithiasis † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 2/180 (1.11%)  2 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Renal failure † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 4/313 (1.28%)  6 3/180 (1.67%)  3 0/61 (0.00%)  0 1/287 (0.35%)  1 1/202 (0.50%)  1
Renal infarct † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 1/180 (0.56%)  1 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Tubulointerstitial nephritis † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 1/180 (0.56%)  1 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Urethral haemorrhage † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 1/180 (0.56%)  1 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Urethral stenosis † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 1/202 (0.50%)  1
Urge incontinence † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 1/287 (0.35%)  1 0/202 (0.00%)  0
Urinary incontinence † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 1/180 (0.56%)  1 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Urinary retention † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Urinary tract obstruction † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 1/287 (0.35%)  1 0/202 (0.00%)  0
Reproductive system and breast disorders                         
Metrorrhagia † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Prostatitis † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Respiratory, thoracic and mediastinal disorders                         
Acute respiratory failure † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 1/180 (0.56%)  1 0/61 (0.00%)  0 2/287 (0.70%)  2 3/202 (1.49%)  3
Atelectasis † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/162 (0.62%)  1 0/313 (0.00%)  0 0/180 (0.00%)  0 1/61 (1.64%)  1 0/287 (0.00%)  0 0/202 (0.00%)  0
Bronchial obstruction † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/162 (0.62%)  1 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Bronchopleural fistula † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Bronchospasm † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 1/202 (0.50%)  1
Chronic obstructive pulmonary disease † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  1 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 1/287 (0.35%)  1 6/202 (2.97%)  6
Cough † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 1/180 (0.56%)  1 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Diffuse alveolar damage † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 1/202 (0.50%)  1
Dyspnoea † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  1 5/162 (3.09%)  7 7/313 (2.24%)  7 2/180 (1.11%)  2 2/61 (3.28%)  2 9/287 (3.14%)  9 5/202 (2.48%)  6
Haemoptysis † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 1/287 (0.35%)  1 5/202 (2.48%)  5
Hiccups † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 1/180 (0.56%)  1 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Hypoxia † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/162 (0.62%)  1 1/313 (0.32%)  1 0/180 (0.00%)  0 1/61 (1.64%)  1 1/287 (0.35%)  1 4/202 (1.98%)  4
Interstitial lung disease † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 1/287 (0.35%)  1 1/202 (0.50%)  1
Lung consolidation † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/162 (0.62%)  1 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Lung infiltration † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Obstructive airways disorder † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 1/287 (0.35%)  1 0/202 (0.00%)  0
Oropharyngeal pain † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Pleural effusion † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 1/3 (33.33%)  1 0/6 (0.00%)  0 4/162 (2.47%)  5 5/313 (1.60%)  5 2/180 (1.11%)  2 3/61 (4.92%)  3 14/287 (4.88%)  19 8/202 (3.96%)  9
Pleuritic pain † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 1/180 (0.56%)  1 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Pneumonitis † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 2/162 (1.23%)  3 4/313 (1.28%)  4 2/180 (1.11%)  3 2/61 (3.28%)  3 7/287 (2.44%)  8 4/202 (1.98%)  4
Pneumothorax † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 2/180 (1.11%)  2 0/61 (0.00%)  0 5/287 (1.74%)  7 2/202 (0.99%)  2
Pulmonary embolism † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 5/313 (1.60%)  6 4/180 (2.22%)  4 2/61 (3.28%)  2 8/287 (2.79%)  9 4/202 (1.98%)  4
Pulmonary haemorrhage † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  2 0/180 (0.00%)  0 1/61 (1.64%)  1 1/287 (0.35%)  1 0/202 (0.00%)  0
Pulmonary hypertension † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 1/287 (0.35%)  1 0/202 (0.00%)  0
Pulmonary oedema † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 2/287 (0.70%)  2 0/202 (0.00%)  0
Pulmonary vasculitis † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 1/61 (1.64%)  1 0/287 (0.00%)  0 0/202 (0.00%)  0
Respiratory failure † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 1/180 (0.56%)  1 0/61 (0.00%)  0 6/287 (2.09%)  7 6/202 (2.97%)  6
Wheezing † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 1/287 (0.35%)  1 0/202 (0.00%)  0
Laryngeal oedema † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/162 (0.62%)  1 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Lung disorder † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Pneumonia aspiration † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  2 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Skin and subcutaneous tissue disorders                         
Dermatitis † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 1/202 (0.50%)  1
Erythema multiforme † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 1/202 (0.50%)  1
Haemorrhage subcutaneous † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/162 (0.62%)  1 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Pemphigoid † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/162 (0.62%)  1 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Rash † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 1/287 (0.35%)  1 1/202 (0.50%)  1
Rash generalised † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Vascular disorders                         
Deep vein thrombosis † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 2/313 (0.64%)  2 2/180 (1.11%)  2 0/61 (0.00%)  0 2/287 (0.70%)  2 1/202 (0.50%)  1
Embolism † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 3/313 (0.96%)  3 0/180 (0.00%)  0 0/61 (0.00%)  0 2/287 (0.70%)  2 3/202 (1.49%)  3
Haemorrhage † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Hypotension † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 3/180 (1.67%)  3 0/61 (0.00%)  0 2/287 (0.70%)  2 0/202 (0.00%)  0
Peripheral ischaemia † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/162 (0.62%)  1 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 1/202 (0.50%)  1
Shock haemorrhagic † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 1/202 (0.50%)  1
Superior vena cava occlusion † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 1/61 (1.64%)  1 0/287 (0.00%)  0 0/202 (0.00%)  0
Superior vena cava syndrome † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 1/61 (1.64%)  1 0/287 (0.00%)  0 0/202 (0.00%)  0
Vasculitis † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 1/180 (0.56%)  1 0/61 (0.00%)  0 1/287 (0.35%)  1 0/202 (0.00%)  0
Vena cava thrombosis † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  2 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Orthostatic hypotension † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
1
Term from vocabulary, MedDRA 21.1
†
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Solid Tumors: Pembrolizumab 1 mg/kg Q2W (Part A) Solid Tumors: Pembrolizumab 3 mg/kg Q2W (Part A) Solid Tumors: Pembrolizumab 10 mg/kg Q2W (Parts A+A1) Solid Tumors: Pembrolizumab Titration Cohort 1 Q3W (Part A2) Solid Tumors: Pembrolizumab Titration Cohort 2 Q3W (Part A2) Solid Tumors: Pembrolizumab Titration Cohort 3 Q3W (Part A2) MEL: Pembrolizumab 2 mg/kg Q3W (Parts B+D) MEL: Pembrolizumab 10 mg/kg Q3W (Parts B+D) MEL: Pembrolizumab 10 mg/kg Q2W (Part B) NSCLC: Pembrolizumab 2 mg/kg Q3W (Part F) NSCLC: Pembrolizumab 10 mg/kg Q3W (Parts C+F) NSCLC: Pembrolizumab 10 mg/kg Q2W (Part F)
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   4/4 (100.00%)      3/3 (100.00%)      8/10 (80.00%)      4/4 (100.00%)      3/3 (100.00%)      5/6 (83.33%)      158/162 (97.53%)      303/313 (96.81%)      175/180 (97.22%)      55/61 (90.16%)      271/287 (94.43%)      191/202 (94.55%)    
Blood and lymphatic system disorders                         
Anaemia † 1  1/4 (25.00%)  1 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 27/162 (16.67%)  58 61/313 (19.49%)  113 30/180 (16.67%)  57 5/61 (8.20%)  5 37/287 (12.89%)  52 38/202 (18.81%)  72
Cardiac disorders                         
Atrial fibrillation † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 1/10 (10.00%)  1 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 2/162 (1.23%)  2 7/313 (2.24%)  8 3/180 (1.67%)  3 0/61 (0.00%)  0 4/287 (1.39%)  5 5/202 (2.48%)  5
Bradycardia † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 1/4 (25.00%)  1 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 4/313 (1.28%)  5 0/180 (0.00%)  0 0/61 (0.00%)  0 1/287 (0.35%)  1 1/202 (0.50%)  1
Endocrine disorders                         
Hypothyroidism † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 1/4 (25.00%)  1 1/3 (33.33%)  1 1/6 (16.67%)  1 16/162 (9.88%)  17 23/313 (7.35%)  25 28/180 (15.56%)  37 6/61 (9.84%)  7 20/287 (6.97%)  26 22/202 (10.89%)  22
Eye disorders                         
Dry eye † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 7/162 (4.32%)  7 9/313 (2.88%)  10 10/180 (5.56%)  12 0/61 (0.00%)  0 2/287 (0.70%)  2 2/202 (0.99%)  2
Vision blurred † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 1/3 (33.33%)  2 0/6 (0.00%)  0 6/162 (3.70%)  6 21/313 (6.71%)  22 10/180 (5.56%)  11 2/61 (3.28%)  2 7/287 (2.44%)  8 3/202 (1.49%)  3
Visual impairment † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 9/162 (5.56%)  10 13/313 (4.15%)  13 7/180 (3.89%)  11 0/61 (0.00%)  0 4/287 (1.39%)  5 3/202 (1.49%)  3
Gastrointestinal disorders                         
Abdominal distension † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 6/162 (3.70%)  6 10/313 (3.19%)  11 10/180 (5.56%)  10 0/61 (0.00%)  0 10/287 (3.48%)  10 7/202 (3.47%)  7
Abdominal pain † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 26/162 (16.05%)  40 38/313 (12.14%)  49 31/180 (17.22%)  55 5/61 (8.20%)  5 29/287 (10.10%)  37 20/202 (9.90%)  24
Abdominal pain upper † 1  1/4 (25.00%)  1 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 10/162 (6.17%)  12 22/313 (7.03%)  22 13/180 (7.22%)  18 1/61 (1.64%)  1 10/287 (3.48%)  12 6/202 (2.97%)  7
Constipation † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 2/10 (20.00%)  3 0/4 (0.00%)  0 1/3 (33.33%)  1 0/6 (0.00%)  0 45/162 (27.78%)  60 68/313 (21.73%)  85 41/180 (22.78%)  65 10/61 (16.39%)  12 47/287 (16.38%)  51 46/202 (22.77%)  56
Diarrhoea † 1  0/4 (0.00%)  0 1/3 (33.33%)  1 1/10 (10.00%)  1 1/4 (25.00%)  1 2/3 (66.67%)  2 0/6 (0.00%)  0 54/162 (33.33%)  112 111/313 (35.46%)  195 70/180 (38.89%)  145 12/61 (19.67%)  16 67/287 (23.34%)  127 39/202 (19.31%)  62
Dry mouth † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 7/162 (4.32%)  10 23/313 (7.35%)  23 18/180 (10.00%)  22 3/61 (4.92%)  4 12/287 (4.18%)  16 10/202 (4.95%)  11
Dyspepsia † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 6/162 (3.70%)  10 11/313 (3.51%)  13 11/180 (6.11%)  14 0/61 (0.00%)  0 7/287 (2.44%)  7 5/202 (2.48%)  5
Gastritis † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 1/10 (10.00%)  1 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 3/313 (0.96%)  3 5/180 (2.78%)  8 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Gastrooesophageal reflux disease † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 15/162 (9.26%)  22 10/313 (3.19%)  12 13/180 (7.22%)  19 1/61 (1.64%)  2 17/287 (5.92%)  17 5/202 (2.48%)  5
Inguinal hernia † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 1/3 (33.33%)  1 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 2/287 (0.70%)  2 1/202 (0.50%)  1
Intussusception † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 1/4 (25.00%)  1 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 1/180 (0.56%)  1 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Nausea † 1  0/4 (0.00%)  0 2/3 (66.67%)  2 2/10 (20.00%)  2 1/4 (25.00%)  1 1/3 (33.33%)  2 2/6 (33.33%)  3 56/162 (34.57%)  91 108/313 (34.50%)  144 69/180 (38.33%)  109 9/61 (14.75%)  11 60/287 (20.91%)  79 47/202 (23.27%)  60
Oral pain † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 1/10 (10.00%)  1 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 2/162 (1.23%)  2 4/313 (1.28%)  5 2/180 (1.11%)  2 0/61 (0.00%)  0 5/287 (1.74%)  6 1/202 (0.50%)  1
Stomatitis † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 2/162 (1.23%)  2 6/313 (1.92%)  6 5/180 (2.78%)  6 4/61 (6.56%)  6 3/287 (1.05%)  3 7/202 (3.47%)  10
Vomiting † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 1/4 (25.00%)  1 0/3 (0.00%)  0 1/6 (16.67%)  1 33/162 (20.37%)  50 62/313 (19.81%)  84 43/180 (23.89%)  56 9/61 (14.75%)  13 44/287 (15.33%)  59 28/202 (13.86%)  53
General disorders                         
Asthenia † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  2 20/162 (12.35%)  41 50/313 (15.97%)  82 28/180 (15.56%)  72 7/61 (11.48%)  11 24/287 (8.36%)  44 23/202 (11.39%)  46
Chest pain † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 9/162 (5.56%)  10 19/313 (6.07%)  23 12/180 (6.67%)  18 2/61 (3.28%)  4 22/287 (7.67%)  23 20/202 (9.90%)  24
Chills † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 17/162 (10.49%)  18 43/313 (13.74%)  60 24/180 (13.33%)  28 0/61 (0.00%)  0 12/287 (4.18%)  12 12/202 (5.94%)  12
Early satiety † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 1/10 (10.00%)  1 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 1/287 (0.35%)  1 3/202 (1.49%)  3
Face oedema † 1  1/4 (25.00%)  1 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 4/162 (2.47%)  4 1/313 (0.32%)  1 2/180 (1.11%)  2 0/61 (0.00%)  0 2/287 (0.70%)  2 3/202 (1.49%)  4
Fatigue † 1  1/4 (25.00%)  1 1/3 (33.33%)  1 5/10 (50.00%)  5 1/4 (25.00%)  2 2/3 (66.67%)  2 3/6 (50.00%)  4 77/162 (47.53%)  157 163/313 (52.08%)  249 106/180 (58.89%)  220 17/61 (27.87%)  23 122/287 (42.51%)  172 78/202 (38.61%)  110
Gait disturbance † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 1/3 (33.33%)  1 0/6 (0.00%)  0 3/162 (1.85%)  3 10/313 (3.19%)  10 3/180 (1.67%)  4 0/61 (0.00%)  0 2/287 (0.70%)  2 3/202 (1.49%)  3
Impaired healing † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 1/3 (33.33%)  2 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Influenza like illness † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 10/162 (6.17%)  10 25/313 (7.99%)  27 11/180 (6.11%)  21 1/61 (1.64%)  2 5/287 (1.74%)  5 4/202 (1.98%)  6
Oedema peripheral † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 28/162 (17.28%)  35 53/313 (16.93%)  68 37/180 (20.56%)  48 4/61 (6.56%)  4 38/287 (13.24%)  47 23/202 (11.39%)  27
Pain † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 1/4 (25.00%)  1 0/3 (0.00%)  0 0/6 (0.00%)  0 9/162 (5.56%)  11 14/313 (4.47%)  17 11/180 (6.11%)  17 5/61 (8.20%)  9 24/287 (8.36%)  27 20/202 (9.90%)  26
Pyrexia † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 1/10 (10.00%)  1 0/4 (0.00%)  0 1/3 (33.33%)  1 0/6 (0.00%)  0 16/162 (9.88%)  24 50/313 (15.97%)  72 38/180 (21.11%)  53 5/61 (8.20%)  9 36/287 (12.54%)  63 24/202 (11.88%)  29
Secretion discharge † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 1/4 (25.00%)  1 0/3 (0.00%)  0 0/6 (0.00%)  0 1/162 (0.62%)  1 3/313 (0.96%)  3 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Swelling † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 1/4 (25.00%)  1 0/3 (0.00%)  0 0/6 (0.00%)  0 2/162 (1.23%)  2 4/313 (1.28%)  4 1/180 (0.56%)  1 0/61 (0.00%)  0 1/287 (0.35%)  1 2/202 (0.99%)  3
Infections and infestations                         
Bronchitis † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  2 3/162 (1.85%)  3 8/313 (2.56%)  9 7/180 (3.89%)  8 4/61 (6.56%)  4 7/287 (2.44%)  9 3/202 (1.49%)  3
Lower respiratory tract infection † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 1/10 (10.00%)  1 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/162 (0.62%)  1 2/313 (0.64%)  2 0/180 (0.00%)  0 1/61 (1.64%)  1 10/287 (3.48%)  12 7/202 (3.47%)  23
Lung infection † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  1 4/162 (2.47%)  4 3/313 (0.96%)  3 2/180 (1.11%)  2 1/61 (1.64%)  1 4/287 (1.39%)  4 5/202 (2.48%)  5
Nasopharyngitis † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 26/162 (16.05%)  43 31/313 (9.90%)  45 26/180 (14.44%)  47 4/61 (6.56%)  6 8/287 (2.79%)  11 3/202 (1.49%)  4
Oral candidiasis † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 1/10 (10.00%)  1 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/162 (0.62%)  1 8/313 (2.56%)  8 0/180 (0.00%)  0 0/61 (0.00%)  0 4/287 (1.39%)  4 8/202 (3.96%)  9
Oral herpes † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  1 3/162 (1.85%)  3 3/313 (0.96%)  3 4/180 (2.22%)  4 0/61 (0.00%)  0 2/287 (0.70%)  3 1/202 (0.50%)  1
Otitis externa † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 1/3 (33.33%)  1 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 1/180 (0.56%)  1 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Pneumonia † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 1/10 (10.00%)  1 0/4 (0.00%)  0 1/3 (33.33%)  1 0/6 (0.00%)  0 4/162 (2.47%)  4 8/313 (2.56%)  9 7/180 (3.89%)  7 4/61 (6.56%)  4 18/287 (6.27%)  22 11/202 (5.45%)  11
Rhinitis † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 1/10 (10.00%)  1 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 4/162 (2.47%)  5 9/313 (2.88%)  14 4/180 (2.22%)  6 1/61 (1.64%)  1 7/287 (2.44%)  7 5/202 (2.48%)  5
Sinusitis † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 1/10 (10.00%)  1 0/4 (0.00%)  0 1/3 (33.33%)  1 0/6 (0.00%)  0 7/162 (4.32%)  8 13/313 (4.15%)  16 19/180 (10.56%)  26 0/61 (0.00%)  0 7/287 (2.44%)  11 7/202 (3.47%)  7
Upper respiratory tract infection † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  1 23/162 (14.20%)  49 28/313 (8.95%)  47 28/180 (15.56%)  48 1/61 (1.64%)  1 34/287 (11.85%)  66 25/202 (12.38%)  32
Urinary tract infection † 1  1/4 (25.00%)  1 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 1/3 (33.33%)  1 0/6 (0.00%)  0 16/162 (9.88%)  18 25/313 (7.99%)  43 20/180 (11.11%)  37 2/61 (3.28%)  2 16/287 (5.57%)  21 11/202 (5.45%)  26
Injury, poisoning and procedural complications                         
Back injury † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 1/3 (33.33%)  1 0/6 (0.00%)  0 0/162 (0.00%)  0 2/313 (0.64%)  2 1/180 (0.56%)  1 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Contusion † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 6/162 (3.70%)  8 12/313 (3.83%)  14 11/180 (6.11%)  11 2/61 (3.28%)  2 2/287 (0.70%)  2 5/202 (2.48%)  7
Fall † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 9/162 (5.56%)  12 10/313 (3.19%)  20 9/180 (5.00%)  12 2/61 (3.28%)  2 10/287 (3.48%)  12 10/202 (4.95%)  12
Stoma site haemorrhage † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 1/3 (33.33%)  1 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Urostomy complication † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 1/3 (33.33%)  1 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Investigations                         
Alanine aminotransferase increased † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 12/162 (7.41%)  17 30/313 (9.58%)  38 21/180 (11.67%)  30 2/61 (3.28%)  3 16/287 (5.57%)  23 11/202 (5.45%)  19
Aspartate aminotransferase increased † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 9/162 (5.56%)  10 33/313 (10.54%)  53 23/180 (12.78%)  36 1/61 (1.64%)  2 21/287 (7.32%)  25 13/202 (6.44%)  20
Blood alkaline phosphatase increased † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 4/162 (2.47%)  4 16/313 (5.11%)  21 13/180 (7.22%)  21 5/61 (8.20%)  7 14/287 (4.88%)  17 9/202 (4.46%)  14
Blood cholesterol increased † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/162 (0.62%)  5 16/313 (5.11%)  33 5/180 (2.78%)  5 1/61 (1.64%)  1 9/287 (3.14%)  19 8/202 (3.96%)  10
Blood creatinine increased † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 1/3 (33.33%)  1 0/6 (0.00%)  0 7/162 (4.32%)  10 14/313 (4.47%)  16 13/180 (7.22%)  19 3/61 (4.92%)  4 12/287 (4.18%)  17 6/202 (2.97%)  9
Weight decreased † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 1/10 (10.00%)  2 0/4 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  1 16/162 (9.88%)  21 36/313 (11.50%)  53 13/180 (7.22%)  15 4/61 (6.56%)  6 26/287 (9.06%)  32 23/202 (11.39%)  25
Weight increased † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 11/162 (6.79%)  20 17/313 (5.43%)  44 8/180 (4.44%)  22 0/61 (0.00%)  0 8/287 (2.79%)  11 10/202 (4.95%)  11
Metabolism and nutrition disorders                         
Decreased appetite † 1  1/4 (25.00%)  1 0/3 (0.00%)  0 3/10 (30.00%)  3 0/4 (0.00%)  0 0/3 (0.00%)  0 4/6 (66.67%)  4 36/162 (22.22%)  47 70/313 (22.36%)  92 47/180 (26.11%)  59 10/61 (16.39%)  14 88/287 (30.66%)  125 55/202 (27.23%)  62
Dehydration † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 10/162 (6.17%)  17 13/313 (4.15%)  19 10/180 (5.56%)  12 1/61 (1.64%)  1 14/287 (4.88%)  16 6/202 (2.97%)  8
Hyperglycaemia † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 4/162 (2.47%)  6 19/313 (6.07%)  60 11/180 (6.11%)  42 2/61 (3.28%)  3 23/287 (8.01%)  41 16/202 (7.92%)  50
Hypertriglyceridaemia † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 3/162 (1.85%)  5 17/313 (5.43%)  48 12/180 (6.67%)  25 0/61 (0.00%)  0 8/287 (2.79%)  15 4/202 (1.98%)  5
Hypoalbuminaemia † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 3/162 (1.85%)  3 17/313 (5.43%)  37 13/180 (7.22%)  26 4/61 (6.56%)  5 13/287 (4.53%)  13 7/202 (3.47%)  10
Hypokalaemia † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 1/4 (25.00%)  1 1/3 (33.33%)  1 0/6 (0.00%)  0 5/162 (3.09%)  5 15/313 (4.79%)  24 16/180 (8.89%)  24 3/61 (4.92%)  3 17/287 (5.92%)  22 12/202 (5.94%)  13
Hypomagnesaemia † 1  1/4 (25.00%)  1 0/3 (0.00%)  0 1/10 (10.00%)  2 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 3/162 (1.85%)  3 20/313 (6.39%)  38 10/180 (5.56%)  17 2/61 (3.28%)  2 16/287 (5.57%)  17 13/202 (6.44%)  18
Hyponatraemia † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 8/162 (4.94%)  9 18/313 (5.75%)  30 22/180 (12.22%)  36 3/61 (4.92%)  6 16/287 (5.57%)  28 16/202 (7.92%)  26
Hypophosphataemia † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 9/162 (5.56%)  16 15/313 (4.79%)  29 8/180 (4.44%)  15 0/61 (0.00%)  0 10/287 (3.48%)  14 5/202 (2.48%)  8
Iron deficiency † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 1/10 (10.00%)  1 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 3/162 (1.85%)  3 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 1/287 (0.35%)  1 1/202 (0.50%)  1
Hyperkalaemia † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 6/162 (3.70%)  9 16/313 (5.11%)  19 9/180 (5.00%)  16 1/61 (1.64%)  1 6/287 (2.09%)  12 6/202 (2.97%)  23
Musculoskeletal and connective tissue disorders                         
Arthralgia † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 1/3 (33.33%)  1 0/6 (0.00%)  0 50/162 (30.86%)  103 93/313 (29.71%)  175 60/180 (33.33%)  128 9/61 (14.75%)  18 54/287 (18.82%)  89 47/202 (23.27%)  82
Back pain † 1  0/4 (0.00%)  0 2/3 (66.67%)  2 0/10 (0.00%)  0 0/4 (0.00%)  0 1/3 (33.33%)  1 1/6 (16.67%)  1 35/162 (21.60%)  47 53/313 (16.93%)  74 32/180 (17.78%)  43 5/61 (8.20%)  6 36/287 (12.54%)  47 28/202 (13.86%)  38
Flank pain † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 1/3 (33.33%)  2 0/6 (0.00%)  0 7/162 (4.32%)  10 18/313 (5.75%)  19 5/180 (2.78%)  5 0/61 (0.00%)  0 5/287 (1.74%)  6 5/202 (2.48%)  5
Muscle spasms † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 11/162 (6.79%)  15 13/313 (4.15%)  16 14/180 (7.78%)  17 3/61 (4.92%)  4 10/287 (3.48%)  11 7/202 (3.47%)  20
Muscular weakness † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 1/3 (33.33%)  1 0/6 (0.00%)  0 16/162 (9.88%)  22 19/313 (6.07%)  20 15/180 (8.33%)  21 1/61 (1.64%)  1 11/287 (3.83%)  12 4/202 (1.98%)  4
Musculoskeletal chest pain † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 9/162 (5.56%)  9 17/313 (5.43%)  20 11/180 (6.11%)  12 0/61 (0.00%)  0 21/287 (7.32%)  30 13/202 (6.44%)  14
Musculoskeletal pain † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 18/162 (11.11%)  20 29/313 (9.27%)  33 17/180 (9.44%)  21 7/61 (11.48%)  9 24/287 (8.36%)  29 17/202 (8.42%)  23
Musculoskeletal stiffness † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 1/3 (33.33%)  1 0/6 (0.00%)  0 7/162 (4.32%)  8 9/313 (2.88%)  9 7/180 (3.89%)  11 0/61 (0.00%)  0 3/287 (1.05%)  3 3/202 (1.49%)  3
Myalgia † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 23/162 (14.20%)  38 48/313 (15.34%)  68 45/180 (25.00%)  85 2/61 (3.28%)  2 23/287 (8.01%)  35 24/202 (11.88%)  28
Neck pain † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 8/162 (4.94%)  9 16/313 (5.11%)  18 5/180 (2.78%)  5 3/61 (4.92%)  3 6/287 (2.09%)  8 11/202 (5.45%)  14
Osteonecrosis of jaw † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  1 1/162 (0.62%)  1 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 1/287 (0.35%)  1 1/202 (0.50%)  1
Pain in extremity † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 1/3 (33.33%)  1 1/6 (16.67%)  1 30/162 (18.52%)  45 40/313 (12.78%)  58 32/180 (17.78%)  47 2/61 (3.28%)  2 21/287 (7.32%)  29 12/202 (5.94%)  15
Neoplasms benign, malignant and unspecified (incl cysts and polyps)                         
Tumour pain † 1  1/4 (25.00%)  1 0/3 (0.00%)  0 1/10 (10.00%)  1 1/4 (25.00%)  2 0/3 (0.00%)  0 1/6 (16.67%)  2 2/162 (1.23%)  2 7/313 (2.24%)  10 6/180 (3.33%)  9 1/61 (1.64%)  2 6/287 (2.09%)  7 4/202 (1.98%)  10
Nervous system disorders                         
Dizziness † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 1/3 (33.33%)  1 0/6 (0.00%)  0 21/162 (12.96%)  34 34/313 (10.86%)  46 26/180 (14.44%)  34 5/61 (8.20%)  7 40/287 (13.94%)  52 20/202 (9.90%)  24
Dysgeusia † 1  1/4 (25.00%)  1 0/3 (0.00%)  0 1/10 (10.00%)  1 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 5/162 (3.09%)  5 11/313 (3.51%)  15 6/180 (3.33%)  6 0/61 (0.00%)  0 11/287 (3.83%)  11 3/202 (1.49%)  3
Headache † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  1 36/162 (22.22%)  58 79/313 (25.24%)  127 52/180 (28.89%)  91 5/61 (8.20%)  7 41/287 (14.29%)  46 19/202 (9.41%)  23
Hypoaesthesia † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 1/3 (33.33%)  1 0/6 (0.00%)  0 9/162 (5.56%)  12 9/313 (2.88%)  10 9/180 (5.00%)  11 1/61 (1.64%)  1 4/287 (1.39%)  4 2/202 (0.99%)  2
Memory impairment † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 1/3 (33.33%)  1 0/6 (0.00%)  0 6/162 (3.70%)  6 5/313 (1.60%)  5 5/180 (2.78%)  6 0/61 (0.00%)  0 3/287 (1.05%)  3 1/202 (0.50%)  1
Neuropathy peripheral † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 10/162 (6.17%)  16 14/313 (4.47%)  19 13/180 (7.22%)  22 1/61 (1.64%)  1 14/287 (4.88%)  16 4/202 (1.98%)  6
Paraesthesia † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 10/162 (6.17%)  11 19/313 (6.07%)  22 13/180 (7.22%)  15 3/61 (4.92%)  3 7/287 (2.44%)  9 9/202 (4.46%)  13
Sciatica † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 1/10 (10.00%)  1 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 2/162 (1.23%)  2 8/313 (2.56%)  10 2/180 (1.11%)  2 1/61 (1.64%)  1 3/287 (1.05%)  4 4/202 (1.98%)  5
Cognitive disorder † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  1 2/162 (1.23%)  2 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 1/287 (0.35%)  1 2/202 (0.99%)  3
Psychiatric disorders                         
Anxiety † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 9/162 (5.56%)  10 24/313 (7.67%)  27 15/180 (8.33%)  17 4/61 (6.56%)  7 17/287 (5.92%)  17 12/202 (5.94%)  12
Depressed mood † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 1/3 (33.33%)  1 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 1/287 (0.35%)  1 3/202 (1.49%)  3
Depression † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 2/6 (33.33%)  2 6/162 (3.70%)  6 9/313 (2.88%)  9 12/180 (6.67%)  13 1/61 (1.64%)  1 7/287 (2.44%)  8 14/202 (6.93%)  14
Insomnia † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 1/3 (33.33%)  2 1/6 (16.67%)  1 29/162 (17.90%)  39 36/313 (11.50%)  41 19/180 (10.56%)  24 3/61 (4.92%)  5 32/287 (11.15%)  34 16/202 (7.92%)  16
Renal and urinary disorders                         
Urinary tract obstruction † 1  1/4 (25.00%)  1 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 0/180 (0.00%)  0 0/61 (0.00%)  0 1/287 (0.35%)  1 1/202 (0.50%)  1
Reproductive system and breast disorders                         
Breast pain † 1  0/4 (0.00%)  0 1/3 (33.33%)  1 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 2/162 (1.23%)  2 5/313 (1.60%)  7 0/180 (0.00%)  0 0/61 (0.00%)  0 1/287 (0.35%)  1 0/202 (0.00%)  0
Nipple pain † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 1/3 (33.33%)  1 0/6 (0.00%)  0 0/162 (0.00%)  0 1/313 (0.32%)  1 2/180 (1.11%)  2 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Respiratory, thoracic and mediastinal disorders                         
Cough † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 2/10 (20.00%)  2 0/4 (0.00%)  0 1/3 (33.33%)  1 1/6 (16.67%)  1 51/162 (31.48%)  81 92/313 (29.39%)  151 58/180 (32.22%)  92 10/61 (16.39%)  13 86/287 (29.97%)  127 51/202 (25.25%)  72
Dyspnoea † 1  1/4 (25.00%)  1 0/3 (0.00%)  0 1/10 (10.00%)  1 0/4 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  4 30/162 (18.52%)  44 65/313 (20.77%)  85 42/180 (23.33%)  60 10/61 (16.39%)  14 80/287 (27.87%)  97 52/202 (25.74%)  66
Dyspnoea exertional † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 1/3 (33.33%)  1 0/6 (0.00%)  0 10/162 (6.17%)  12 10/313 (3.19%)  13 9/180 (5.00%)  9 2/61 (3.28%)  2 19/287 (6.62%)  20 10/202 (4.95%)  17
Haemoptysis † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  1 3/162 (1.85%)  4 4/313 (1.28%)  7 1/180 (0.56%)  1 2/61 (3.28%)  4 21/287 (7.32%)  24 15/202 (7.43%)  17
Nasal congestion † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 12/162 (7.41%)  19 27/313 (8.63%)  42 18/180 (10.00%)  24 0/61 (0.00%)  0 11/287 (3.83%)  14 9/202 (4.46%)  11
Oropharyngeal pain † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 9/162 (5.56%)  12 23/313 (7.35%)  33 14/180 (7.78%)  26 0/61 (0.00%)  0 12/287 (4.18%)  13 5/202 (2.48%)  5
Pleural effusion † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 3/162 (1.85%)  6 4/313 (1.28%)  4 3/180 (1.67%)  4 6/61 (9.84%)  9 15/287 (5.23%)  16 15/202 (7.43%)  17
Pleuritic pain † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  1 4/162 (2.47%)  4 3/313 (0.96%)  3 2/180 (1.11%)  2 0/61 (0.00%)  0 2/287 (0.70%)  2 3/202 (1.49%)  3
Pneumonia aspiration † 1  0/4 (0.00%)  0 1/3 (33.33%)  1 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 1/180 (0.56%)  1 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Pneumonitis † 1  0/4 (0.00%)  0 1/3 (33.33%)  1 0/10 (0.00%)  0 1/4 (25.00%)  1 0/3 (0.00%)  0 0/6 (0.00%)  0 3/162 (1.85%)  4 12/313 (3.83%)  17 10/180 (5.56%)  14 2/61 (3.28%)  3 12/287 (4.18%)  16 5/202 (2.48%)  6
Productive cough † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 18/162 (11.11%)  21 20/313 (6.39%)  30 12/180 (6.67%)  15 3/61 (4.92%)  3 20/287 (6.97%)  24 22/202 (10.89%)  27
Pulmonary pain † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  1 1/162 (0.62%)  1 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 1/287 (0.35%)  1 0/202 (0.00%)  0
Dysphonia † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 1/10 (10.00%)  1 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 2/162 (1.23%)  2 13/313 (4.15%)  16 5/180 (2.78%)  5 1/61 (1.64%)  1 8/287 (2.79%)  9 8/202 (3.96%)  9
Skin and subcutaneous tissue disorders                         
Dermatitis acneiform † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 1/3 (33.33%)  1 0/6 (0.00%)  0 4/162 (2.47%)  4 3/313 (0.96%)  3 1/180 (0.56%)  1 2/61 (3.28%)  2 9/287 (3.14%)  10 2/202 (0.99%)  2
Dry skin † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 11/162 (6.79%)  11 27/313 (8.63%)  32 12/180 (6.67%)  15 3/61 (4.92%)  3 19/287 (6.62%)  24 21/202 (10.40%)  25
Erythema † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 1/3 (33.33%)  1 0/6 (0.00%)  0 10/162 (6.17%)  13 18/313 (5.75%)  22 10/180 (5.56%)  12 0/61 (0.00%)  0 10/287 (3.48%)  12 3/202 (1.49%)  4
Hyperhidrosis † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 3/162 (1.85%)  3 8/313 (2.56%)  8 10/180 (5.56%)  10 0/61 (0.00%)  0 5/287 (1.74%)  5 3/202 (1.49%)  3
Night sweats † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 1/10 (10.00%)  1 1/4 (25.00%)  1 0/3 (0.00%)  0 0/6 (0.00%)  0 15/162 (9.26%)  20 18/313 (5.75%)  23 15/180 (8.33%)  16 0/61 (0.00%)  0 2/287 (0.70%)  2 6/202 (2.97%)  7
Pruritus † 1  3/4 (75.00%)  3 1/3 (33.33%)  1 1/10 (10.00%)  1 0/4 (0.00%)  0 2/3 (66.67%)  2 0/6 (0.00%)  0 49/162 (30.25%)  92 99/313 (31.63%)  165 66/180 (36.67%)  121 4/61 (6.56%)  7 52/287 (18.12%)  73 27/202 (13.37%)  36
Pruritus generalised † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 1/3 (33.33%)  1 0/6 (0.00%)  0 3/162 (1.85%)  6 9/313 (2.88%)  9 7/180 (3.89%)  9 1/61 (1.64%)  1 1/287 (0.35%)  1 1/202 (0.50%)  1
Rash † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 1/10 (10.00%)  1 1/4 (25.00%)  1 1/3 (33.33%)  1 0/6 (0.00%)  0 47/162 (29.01%)  84 87/313 (27.80%)  189 45/180 (25.00%)  103 7/61 (11.48%)  10 43/287 (14.98%)  71 27/202 (13.37%)  42
Rash maculo-papular † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 1/10 (10.00%)  1 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 8/162 (4.94%)  10 22/313 (7.03%)  37 6/180 (3.33%)  8 0/61 (0.00%)  0 9/287 (3.14%)  11 8/202 (3.96%)  12
Skin hypopigmentation † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 1/10 (10.00%)  1 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 10/313 (3.19%)  12 3/180 (1.67%)  3 0/61 (0.00%)  0 0/287 (0.00%)  0 1/202 (0.50%)  1
Skin induration † 1  1/4 (25.00%)  1 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/162 (0.00%)  0 0/313 (0.00%)  0 0/180 (0.00%)  0 0/61 (0.00%)  0 0/287 (0.00%)  0 0/202 (0.00%)  0
Vitiligo † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 21/162 (12.96%)  33 44/313 (14.06%)  57 28/180 (15.56%)  37 1/61 (1.64%)  1 0/287 (0.00%)  0 0/202 (0.00%)  0
Vascular disorders                         
Hot flush † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 9/162 (5.56%)  11 6/313 (1.92%)  7 5/180 (2.78%)  5 0/61 (0.00%)  0 6/287 (2.09%)  7 3/202 (1.49%)  3
Hypertension † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 0/10 (0.00%)  0 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 4/162 (2.47%)  8 31/313 (9.90%)  87 11/180 (6.11%)  21 2/61 (3.28%)  2 11/287 (3.83%)  19 8/202 (3.96%)  11
Hypotension † 1  0/4 (0.00%)  0 0/3 (0.00%)  0 1/10 (10.00%)  1 0/4 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 3/162 (1.85%)  3 16/313 (5.11%)  21 5/180 (2.78%)  5 0/61 (0.00%)  0 5/287 (1.74%)  6 5/202 (2.48%)  5
1
Term from vocabulary, MedDRA 21.1
†
Indicates events were collected by systematic assessment
[Not Specified]
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The Sponsor must have the opportunity to review all proposed abstracts, manuscripts, or presentations regarding this study 60 days prior to submission for publication/presentation. Any information identified by the Sponsor as confidential must be deleted prior to submission. Sponsor review can be expedited to meet publication timelines.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Senior Vice President, Global Clinical Development
Organization: Merck Sharp & Dohme Corp.
Phone: 1-800-672-6372
EMail: ClinicalTrialsDisclosure@merck.com
Publications of Results:
Robert C, Ribas A, Wolchok JD, Hodi FS, Hamid O, Kefford R, Weber JS, Joshua AM, Hwu WJ, Gangadhar TC, Patnaik A, Dronca R, Zarour H, Joseph RW, Boasberg P, Chmielowski B, Mateus C, Postow MA, Gergich K, Elassaiss-Schaap J, Li XN, Iannone R, Ebbinghaus SW, Kang SP, Daud A. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet. 2014 Sep 20;384(9948):1109-17. doi: 10.1016/S0140-6736(14)60958-2. Epub 2014 Jul 15.
Patnaik A, Kang SP, Rasco D, Papadopoulos KP, Elassaiss-Schaap J, Beeram M, Drengler R, Chen C, Smith L, Espino G, Gergich K, Delgado L, Daud A, Lindia JA, Li XN, Pierce RH, Yearley JH, Wu D, Laterza O, Lehnert M, Iannone R, Tolcher AW. Phase I Study of Pembrolizumab (MK-3475; Anti-PD-1 Monoclonal Antibody) in Patients with Advanced Solid Tumors. Clin Cancer Res. 2015 Oct 1;21(19):4286-93. doi: 10.1158/1078-0432.CCR-14-2607. Epub 2015 May 14.
Chatterjee M, Turner DC, Felip E, Lena H, Cappuzzo F, Horn L, Garon EB, Hui R, Arkenau HT, Gubens MA, Hellmann MD, Dong D, Li C, Mayawala K, Freshwater T, Ahamadi M, Stone J, Lubiniecki GM, Zhang J, Im E, De Alwis DP, Kondic AG, Flotten O. Systematic evaluation of pembrolizumab dosing in patients with advanced non-small-cell lung cancer. Ann Oncol. 2016 Jul;27(7):1291-8. doi: 10.1093/annonc/mdw174. Epub 2016 Apr 26.
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Layout table for additonal information
Responsible Party: Merck Sharp & Dohme LLC
ClinicalTrials.gov Identifier: NCT01295827    
Other Study ID Numbers: P07990
MK-3475-001 ( Other Identifier: Merck Protocol Number )
2011-002371-42 ( EudraCT Number )
P07990 ( Other Identifier: Merck )
KEYNOTE-001 ( Other Identifier: Merck )
First Submitted: February 10, 2011
First Posted: February 15, 2011
Results First Submitted: October 21, 2019
Results First Posted: December 13, 2019
Last Update Posted: December 13, 2019