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A Study of the Safety and Efficacy of Pembrolizumab (MK-3475) in Combination With Trametinib and Dabrafenib in Participants With Advanced Melanoma (MK-3475-022/KEYNOTE-022)

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: NCT02130466
Recruitment Status : Completed
First Posted : May 5, 2014
Results First Posted : August 1, 2022
Last Update Posted : August 1, 2022
Sponsor:
Collaborator:
Novartis Pharmaceuticals
Information provided by (Responsible Party):
Merck Sharp & Dohme LLC

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Conditions Melanoma
Solid Tumors
Interventions Biological: Pembrolizumab
Drug: Dabrafenib
Drug: Trametinib
Drug: Placebo
Enrollment 184
Recruitment Details  
Pre-assignment Details For Parts 1 and 2 of the study the optional pembrolizumab+trametinib arm was added to the study but the optional pembrolizumab+dabrafenib arm was not implemented.
Arm/Group Title Part 1:Pembrolizumab 2 mg/kg+Dabrafenib 150 mg+Trametinib 2 mg Part 1:Pembrolizumab 2 mg/kg+Trametinib 2 mg Part 1:Pembrolizumab 2 mg/kg+Trametinib 1.5 mg Part 2:Pembrolizumab 2 mg/kg+Dabrafenib 150 mg+Trametinib 2 mg Part 2:Pembrolizumab 2 mg/kg+Trametinib 1.5 mg Part 3:Pembrolizumab 2 mg/kg+Dabrafenib 150 mg+Trametinib 2 mg Part 3:Placebo+Dabrafenib 150 mg+Trametinib 2 mg Part 4:4 Weeks Trametinib (Tra) 2mg; Pembrolizumab+Tra 2mg Part 4:2 Weeks Tra 1.5mg; Pembrolizumab+Tra 1.5mg Part 4:4 Weeks Tra 1.5mg; Pembrolizumab+Tra 1.5mg Part 4:2 Weeks Tra 2mg; Pembrolizumab+Tra 2mg Intermittent Part 4:2 Weeks Tra 1.5mg; Pembrolizumab+Tra 1.5mg Intermittent Part 5:2 Weeks Tra 1.5mg; Pembrolizumab+Tra 1.5mg Part 5:2 Weeks Tra 2mg; Pembrolizumab+Tra 2mg Intermittent
Hide Arm/Group Description Participants with BRAF mutant melanoma received 2 mg/kg pembrolizumab administered by intravenous (IV) infusion on Days 1 and 22 of each 6-week cycle (Q6W); 150 mg/day total dabrafenib orally, in a divided dose, twice a day (BID) starting on Day 1 and continuing up until study treatment discontinuation; and 2 mg trametinib orally once a day (QD) starting on Day 1 and continuing up until study treatment discontinuation. Participants with BRAF wild-type melanoma received 2 mg/kg pembrolizumab administered by IV infusion on Days 1 and 22 Q6W and 2 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation. Participants with BRAF wild-type melanoma received 2 mg/kg pembrolizumab administered by IV infusion on Days 1 and 22 Q6W and 1.5 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation. Participants with BRAF mutant melanoma received 2 mg/kg pembrolizumab administered by IV infusion on Days 1 and 22 Q6W; 150 mg/day total dabrafenib orally, in a divided dose, BID starting on Day 1 and continuing up until study treatment discontinuation; and 2 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation. Participants with BRAF wild-type melanoma received 2 mg/kg pembrolizumab administered by IV infusion on Days 1 and 22 Q6W and 1.5 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation. Participants with BRAF mutant melanoma received 2 mg/kg pembrolizumab administered by IV infusion on Days 1 and 22 Q6W; 150 mg/day total dabrafenib orally, in a divided dose, BID starting on Day 1 and continuing up until study treatment discontinuation; and 2 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation. Participants with BRAF mutant melanoma received saline placebo administered by IV infusion on Days 1 and 22 Q6W; 150 mg/day total dabrafenib orally, in a divided dose, BID starting on Day 1 and continuing up until study treatment discontinuation; and 2 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation. Participants with BRAF wild-type melanoma or solid tumors (irrespective of BRAF status) received 2 mg trametinib orally QD for 4 weeks. Starting with Week 5, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 of each 3-week cycle (Q3W) and a concurrent dosing schedule of 2 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation. Participants with BRAF wild-type melanoma or solid tumors (irrespective of BRAF status) received 1.5 mg trametinib orally QD for 2 weeks. Starting with Week 3, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and a concurrent dosing schedule of 1.5 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation. Participants with BRAF wild-type melanoma or solid tumors (irrespective of BRAF status) received 1.5 mg trametinib orally QD for 4 weeks. Starting with Week 5, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and a concurrent dosing schedule of 1.5 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation. Participants with BRAF wild-type melanoma or solid tumors (irrespective of BRAF status) received 2 mg trametinib orally QD for 2 weeks. Starting with Week 3, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and an intermittent dose schedule of 2 mg trametinib orally QD with 1 week OFF trametinib and 2 weeks ON trametinib continuing up until study treatment discontinuation. Participants with BRAF wild-type melanoma or solid tumors (irrespective of BRAF status) received 1.5 mg trametinib orally QD for 2 weeks. Starting with Week 3, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and an intermittent dose schedule of 1.5 mg trametinib orally QD with 1 week OFF trametinib and 2 weeks ON trametinib continuing up until study treatment discontinuation. Participants with BRAF wild-type melanoma or solid tumors (irrespective of BRAF status) received 1.5 mg trametinib orally QD for 2 weeks. Starting with Week 3, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and a concurrent dosing schedule of 1.5 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation. Participants with BRAF wild-type melanoma or solid tumors (irrespective of BRAF status) received 2 mg trametinib orally QD for 2 weeks. Starting with Week 3, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and an intermittent dose schedule of 2 mg trametinib orally QD with 1 week OFF trametinib and 2 weeks ON trametinib continuing up until study treatment discontinuation.
Period Title: Overall Study
Started 7 3 2 8 2 60 60 3 4 5 6 3 12 9
Treated 7 3 2 8 2 60 60 3 4 5 6 3 12 9
Completed 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Not Completed 7 3 2 8 2 60 60 3 4 5 6 3 12 9
Reason Not Completed
Death             4             1             1             3             2             30             45             2             3             4             5             3             11             7
Lost to Follow-up             1             0             0             0             0             1             0             0             0             0             0             0             1             0
Physician Decision             0             0             0             0             0             1             1             0             0             0             0             0             0             0
Participation in Study Discontinued by Sponsor             1             2             1             5             0             27             14             1             0             1             1             0             0             2
Withdrawal by Subject             1             0             0             0             0             1             0             0             1             0             0             0             0             0
Arm/Group Title Part 1:Pembrolizumab 2 mg/kg+Dabrafenib 150 mg+Trametinib 2 mg Part 1:Pembrolizumab 2 mg/kg+Trametinib 2 mg Part 1:Pembrolizumab 2 mg/kg+Trametinib 1.5 mg Part 2:Pembrolizumab 2 mg/kg+Dabrafenib 150 mg+Trametinib 2 mg Part 2:Pembrolizumab 2 mg/kg+Trametinib 1.5 mg Part 3:Pembrolizumab 2 mg/kg+Dabrafenib 150 mg+Trametinib 2 mg Part 3:Placebo+Dabrafenib 150 mg+Trametinib 2 mg Part 4:4 Weeks Trametinib (Tra) 2mg; Pembrolizumab+Tra 2mg Part 4:2 Weeks Tra 1.5mg; Pembrolizumab+Tra 1.5mg Part 4:4 Weeks Tra 1.5mg; Pembrolizumab+Tra 1.5mg Part 4:2 Weeks Tra 2mg; Pembrolizumab+Tra 2mg Intermittent Part 4:2 Weeks Tra 1.5mg; Pembrolizumab+Tra 1.5mg Intermittent Part 5:2 Weeks Tra 1.5mg; Pembrolizumab+Tra 1.5mg Part 5:2 Weeks Tra 2mg; Pembrolizumab+Tra 2mg Intermittent Total
Hide Arm/Group Description Participants with BRAF mutant melanoma received 2 mg/kg pembrolizumab administered by intravenous (IV) infusion on Days 1 and 22 of each 6-week cycle (Q6W); 150 mg/day total dabrafenib orally, in a divided dose, twice a day (BID) starting on Day 1 and continuing up until study treatment discontinuation; and 2 mg trametinib orally once a day (QD) starting on Day 1 and continuing up until study treatment discontinuation. Participants with BRAF wild-type melanoma received 2 mg/kg pembrolizumab administered by IV infusion on Days 1 and 22 Q6W and 2 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation. Participants with BRAF wild-type melanoma received 2 mg/kg pembrolizumab administered by IV infusion on Days 1 and 22 Q6W and 1.5 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation. Participants with BRAF mutant melanoma received 2 mg/kg pembrolizumab administered by IV infusion on Days 1 and 22 Q6W; 150 mg/day total dabrafenib orally, in a divided dose, BID starting on Day 1 and continuing up until study treatment discontinuation; and 2 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation. Participants with BRAF wild-type melanoma received 2 mg/kg pembrolizumab administered by IV infusion on Days 1 and 22 Q6W and 1.5 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation. Participants with BRAF mutant melanoma received 2 mg/kg pembrolizumab administered by IV infusion on Days 1 and 22 Q6W; 150 mg/day total dabrafenib orally, in a divided dose, BID starting on Day 1 and continuing up until study treatment discontinuation; and 2 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation. Participants with BRAF mutant melanoma received saline placebo administered by IV infusion on Days 1 and 22 Q6W; 150 mg/day total dabrafenib orally, in a divided dose, BID starting on Day 1 and continuing up until study treatment discontinuation; and 2 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation. Participants with BRAF wild-type melanoma or solid tumors (irrespective of BRAF status) received 2 mg trametinib orally QD for 4 weeks. Starting with Week 5, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 of each 3-week cycle (Q3W) and a concurrent dosing schedule of 2 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation. Participants with BRAF wild-type melanoma or solid tumors (irrespective of BRAF status) received 1.5 mg trametinib orally QD for 2 weeks. Starting with Week 3, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and a concurrent dosing schedule of 1.5 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation. Participants with BRAF wild-type melanoma or solid tumors (irrespective of BRAF status) received 1.5 mg trametinib orally QD for 4 weeks. Starting with Week 5, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and a concurrent dosing schedule of 1.5 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation. Participants with BRAF wild-type melanoma or solid tumors (irrespective of BRAF status) received 2 mg trametinib orally QD for 2 weeks. Starting with Week 3, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and an intermittent dose schedule of 2 mg trametinib orally QD with 1 week OFF trametinib and 2 weeks ON trametinib continuing up until study treatment discontinuation. Participants with BRAF wild-type melanoma or solid tumors (irrespective of BRAF status) received 1.5 mg trametinib orally QD for 2 weeks. Starting with Week 3, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and an intermittent dose schedule of 1.5 mg trametinib orally QD with 1 week OFF trametinib and 2 weeks ON trametinib continuing up until study treatment discontinuation. Participants with BRAF wild-type melanoma or solid tumors (irrespective of BRAF status) received 1.5 mg trametinib orally QD for 2 weeks. Starting with Week 3, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and a concurrent dosing schedule of 1.5 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation. Participants with BRAF wild-type melanoma or solid tumors (irrespective of BRAF status) received 2 mg trametinib orally QD for 2 weeks. Starting with Week 3, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and an intermittent dose schedule of 2 mg trametinib orally QD with 1 week OFF trametinib and 2 weeks ON trametinib continuing up until study treatment discontinuation. Total of all reporting groups
Overall Number of Baseline Participants 7 3 2 8 2 60 60 3 4 5 6 3 12 9 184
Hide Baseline Analysis Population Description
All participants who received ≥1 dose of study treatment
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 7 participants 3 participants 2 participants 8 participants 2 participants 60 participants 60 participants 3 participants 4 participants 5 participants 6 participants 3 participants 12 participants 9 participants 184 participants
52.0  (14.0) 54.0  (15.7) 68.0  (2.8) 42.0  (14.2) 83.0  (5.7) 55.3  (12.0) 57.2  (14.6) 47.3  (19.9) 50.0  (18.0) 57.0  (18.0) 55.5  (17.9) 58.0  (12.2) 55.7  (14.1) 55.9  (13.3) 55.5  (14.2)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 7 participants 3 participants 2 participants 8 participants 2 participants 60 participants 60 participants 3 participants 4 participants 5 participants 6 participants 3 participants 12 participants 9 participants 184 participants
Female
3
  42.9%
0
   0.0%
1
  50.0%
5
  62.5%
0
   0.0%
27
  45.0%
24
  40.0%
0
   0.0%
2
  50.0%
3
  60.0%
5
  83.3%
2
  66.7%
8
  66.7%
6
  66.7%
86
  46.7%
Male
4
  57.1%
3
 100.0%
1
  50.0%
3
  37.5%
2
 100.0%
33
  55.0%
36
  60.0%
3
 100.0%
2
  50.0%
2
  40.0%
1
  16.7%
1
  33.3%
4
  33.3%
3
  33.3%
98
  53.3%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 7 participants 3 participants 2 participants 8 participants 2 participants 60 participants 60 participants 3 participants 4 participants 5 participants 6 participants 3 participants 12 participants 9 participants 184 participants
Hispanic or Latino
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
1
   1.7%
0
   0.0%
0
   0.0%
2
  40.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
3
   1.6%
Not Hispanic or Latino
7
 100.0%
3
 100.0%
2
 100.0%
7
  87.5%
2
 100.0%
57
  95.0%
57
  95.0%
3
 100.0%
2
  50.0%
2
  40.0%
4
  66.7%
2
  66.7%
12
 100.0%
9
 100.0%
169
  91.8%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
1
  12.5%
0
   0.0%
3
   5.0%
2
   3.3%
0
   0.0%
2
  50.0%
1
  20.0%
2
  33.3%
1
  33.3%
0
   0.0%
0
   0.0%
12
   6.5%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 7 participants 3 participants 2 participants 8 participants 2 participants 60 participants 60 participants 3 participants 4 participants 5 participants 6 participants 3 participants 12 participants 9 participants 184 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%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Asian
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
1
   1.7%
1
  33.3%
0
   0.0%
0
   0.0%
1
  16.7%
1
  33.3%
1
   8.3%
0
   0.0%
5
   2.7%
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%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
White
7
 100.0%
3
 100.0%
2
 100.0%
8
 100.0%
2
 100.0%
60
 100.0%
59
  98.3%
2
  66.7%
4
 100.0%
5
 100.0%
5
  83.3%
2
  66.7%
11
  91.7%
9
 100.0%
179
  97.3%
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%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
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%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
BRAF Mutation Status   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 7 participants 3 participants 2 participants 8 participants 2 participants 60 participants 60 participants 3 participants 4 participants 5 participants 6 participants 3 participants 12 participants 9 participants 184 participants
Mutant (BRAF Positive)
7
 100.0%
0
   0.0%
0
   0.0%
8
 100.0%
0
   0.0%
60
 100.0%
60
 100.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
135
  73.4%
Wild Type (BRAF Negative)
0
   0.0%
3
 100.0%
2
 100.0%
0
   0.0%
2
 100.0%
0
   0.0%
0
   0.0%
1
  33.3%
1
  25.0%
0
   0.0%
2
  33.3%
1
  33.3%
5
  41.7%
5
  55.6%
22
  12.0%
Undetermined
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
1
  25.0%
2
  40.0%
2
  33.3%
0
   0.0%
6
  50.0%
1
  11.1%
12
   6.5%
Data Missing
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
2
  66.7%
2
  50.0%
3
  60.0%
2
  33.3%
2
  66.7%
1
   8.3%
3
  33.3%
15
   8.2%
[1]
Measure Description: BRAF mutation testing was required for study inclusion and was done using methodology that detects both V600E and V600K mutations. Tumors that were BRAF mutation positive (V600 E or K) were eligible for treatment with pembrolizumab + trametinib + dabrafenib or trametinib + dabrafenib. Tumors that were BRAF mutation negative (wild type) were eligible for treatment with pembrolizumab + trametinib.
1.Primary Outcome
Title Parts 1, 2, 4, and 5: Number of Participants Who Experienced Dose-limiting Toxicities (DLTs)
Hide Description DLTs were graded using National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. Events were considered a DLT if occurred during the DLT evaluation period and met ≥1 of the following: significant hematologic toxicity; significant Grade ≥3 non-hematologic toxicity not previously identified or known to occur and cannot be controlled with routine supportive measures; drug-related toxicity that results in an interruption of any component of study therapy for >21 consecutive days and cannot be controlled ≤2 weeks from onset; any other Grade ≥2 non-hematological toxicity that is dose limiting with some exceptions; and liver chemistries meeting study stopping guidelines. The DLT evaluable population included all participants in Parts 1, 2, 4, and 5 who received ≥66% of planned treatments during the DLT observation period or discontinued treatment due to a DLT. Per protocol, DLT outcome analysis did not include Part 3.
Time Frame Up to approximately 6 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
The DLT evaluable population included all participants in Parts 1, 2, 4, and 5 who received at least 66% of all planned treatments during the 6-week DLT observation period or who discontinued treatment due to a DLT.
Arm/Group Title Part 1:Pembrolizumab 2 mg/kg+dabrafenib150 mg+Trametinib 2 mg Part 1:Pembrolizumab 2 mg/kg+Trametinib 2 mg Part 1:Pembrolizumab 2 mg/kg+Trametinib 1.5 mg Part 2:Pembrolizumab 2 mg/kg+Dabrafenib 150 mg+Trametinib 2 mg Part 2:Pembrolizumab 2 mg/kg+Trametinib 1.5 mg Part 4:4 Weeks Trametinib (Tra) 2mg; Pembrolizumab+Tra 2mg Part 4:2 Weeks Tra 1.5mg; Pembrolizumab+Tra 1.5mg Part 4:4 Weeks Tra 1.5mg; Pembrolizumab+Tra 1.5mg Part 4:2 Weeks Tra 2mg; Pembrolizumab+Tra 2mg Intermittent Part 4:2 Weeks Tra 1.5mg; Pembrolizumab+Tra 1.5mg Intermittent Part 5:2 Weeks Tra 1.5mg; Pembrolizumab+Tra 1.5mg Part 5:2 Weeks Tra 2mg; Pembrolizumab+Tra 2mg Intermittent
Hide Arm/Group Description:
Participants with BRAF mutant melanoma received 2 mg/kg pembrolizumab administered by IV infusion on Days 1 and 22 Q6W; 150 mg/day total dabrafenib orally, in a divided dose, BID starting on Day 1 and continuing up until study treatment discontinuation; and 2 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation.
Participants with BRAF wild-type melanoma received 2 mg/kg pembrolizumab administered by IV infusion on Days 1 and 22 Q6W and 2 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation.
Participants with BRAF wild-type melanoma received 2 mg/kg pembrolizumab administered by IV infusion on Days 1 and 22 Q6W and 1.5 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation.
Participants with BRAF mutant melanoma received 2 mg/kg pembrolizumab administered by IV infusion on Days 1 and 22 Q6W; 150 mg/day total dabrafenib orally, in a divided dose, BID starting on Day 1 and continuing up until study treatment discontinuation; and 2 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation.
Participants with BRAF wild-type melanoma received 2 mg/kg pembrolizumab administered by IV infusion on Days 1 and 22 Q6W and 1.5 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation.
Participants with BRAF wild-type melanoma or solid tumors (irrespective of BRAF status) received 2 mg trametinib orally QD for 4 weeks. Starting with Week 5, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 of each 3-week cycle (Q3W) and a concurrent dosing schedule of 2 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation.
Participants with BRAF wild-type melanoma or solid tumors (irrespective of BRAF status) received 1.5 mg trametinib orally QD for 2 weeks. Starting with Week 3, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and a concurrent dosing schedule of 1.5 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation.
Participants with BRAF wild-type melanoma or solid tumors (irrespective of BRAF status) received 1.5 mg trametinib orally QD for 4 weeks. Starting with Week 5, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and a concurrent dosing schedule of 1.5 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation.
Participants with BRAF wild-type melanoma or solid tumors (irrespective of BRAF status) received 2 mg trametinib orally QD for 2 weeks. Starting with Week 3, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and an intermittent dose schedule of 2 mg trametinib orally QD with 1 week OFF trametinib and 2 weeks ON trametinib continuing up until study treatment discontinuation.
Participants with BRAF wild-type melanoma or solid tumors (irrespective of BRAF status) received 1.5 mg trametinib orally QD for 2 weeks. Starting with Week 3, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and an intermittent dose schedule of 1.5 mg trametinib orally QD with 1 week OFF trametinib and 2 weeks ON trametinib continuing up until study treatment discontinuation.
Participants with BRAF wild-type melanoma or solid tumors (irrespective of BRAF status) received 1.5 mg trametinib orally QD for 2 weeks. Starting with Week 3, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and a concurrent dosing schedule of 1.5 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation.
Participants with BRAF wild-type melanoma or solid tumors (irrespective of BRAF status) received 2 mg trametinib orally QD for 2 weeks. Starting with Week 3, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and an intermittent dose schedule of 2 mg trametinib orally QD with 1 week OFF trametinib and 2 weeks ON trametinib continuing up until study treatment discontinuation.
Overall Number of Participants Analyzed 7 3 2 8 2 3 4 5 6 3 12 9
Measure Type: Count of Participants
Unit of Measure: Participants
1
  14.3%
1
  33.3%
1
  50.0%
2
  25.0%
1
  50.0%
2
  66.7%
0
   0.0%
0
   0.0%
2
  33.3%
0
   0.0%
4
  33.3%
2
  22.2%
2.Primary Outcome
Title Part 2: Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Investigator in Participants Without BRAF V600 E or K Mutations
Hide Description ORR was defined as the percentage of participants without BRAF V600 E or K mutation who had a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: divided into very good partial response [VGPR; >60% tumor reduction] and moderate partial response [MPR; >30-≤60% tumor reduction]) per RECIST 1.1 as assessed by investigator. The percentage of participants who experienced a CR or PR based on RECIST 1.1 as assessed by investigator were reported.
Time Frame Up to approximately 85 months
Hide Outcome Measure Data
Hide Analysis Population Description
All enrolled participants without BRAF V600 E or K mutations in Part 2
Arm/Group Title Part 2:Pembrolizumab 2 mg/kg+Trametinib 1.5 mg
Hide Arm/Group Description:
Participants with BRAF wild-type melanoma received 2 mg/kg pembrolizumab administered by IV infusion on Days 1 and 22 Q6W and 1.5 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation.
Overall Number of Participants Analyzed 2
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of Participants
50.0
(1.3 to 98.7)
3.Primary Outcome
Title Part 5: ORR Per RECIST 1.1 as Assessed by Investigator in Participants Without BRAF V600 E or K Mutations or With Solid Tumors Irrespective of BRAF Status
Hide Description ORR was defined as the percentage of participants without BRAF V600 E or K mutation who had a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: divided into very good partial response [VGPR; >60% tumor reduction] and moderate partial response [MPR; >30-≤60% tumor reduction]) per RECIST 1.1 as assessed by investigator. The percentage of participants who experienced a CR or PR based on RECIST 1.1 as assessed by investigator were reported.
Time Frame Up to approximately 85 months
Hide Outcome Measure Data
Hide Analysis Population Description
All enrolled participants without BRAF V600 E or K mutations in Part 5
Arm/Group Title Part 5:2 Weeks Tra 1.5mg; Pembrolizumab+Tra 1.5mg Part 5:2 Weeks Tra 2mg; Pembrolizumab+Tra 2mg Intermittent
Hide Arm/Group Description:
Participants with BRAF wild-type melanoma or solid tumors (irrespective of BRAF status) received 1.5 mg trametinib orally QD for 2 weeks. Starting with Week 3, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and a concurrent dosing schedule of 1.5 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation.
Participants with BRAF wild-type melanoma or solid tumors (irrespective of BRAF status) received 2 mg trametinib orally QD for 2 weeks. Starting with Week 3, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and an intermittent dose schedule of 2 mg trametinib orally QD with 1 week OFF trametinib and 2 weeks ON trametinib continuing up until study treatment discontinuation.
Overall Number of Participants Analyzed 12 9
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of Participants
0.0
(0.0 to 26.5)
33.3
(7.5 to 70.1)
4.Primary Outcome
Title Part 3: Progression-Free Survival (PFS) Per RECIST 1.1 as Assessed by Investigator in Participants With BRAF V600 E or K Mutations
Hide Description PFS was defined as the time from randomization to the first documented disease progression (PD) or death due to any cause, whichever occurred first, based on RECIST 1.1 by investigator review. Per RECIST 1.1, PD is defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. PFS was analyzed using the Kaplan-Meier method and was reported in months. Statistical analysis used a Cox regression model with treatment as a covariate and stratified by Eastern Cooperative Oncology Group performance status and Lactate Dehydrogenase.
Time Frame Up to approximately 85 months
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants with BRAF V600 E or K mutations in Part 3
Arm/Group Title Part 3:Pembrolizumab 2 mg/kg+Dabrafenib 150 mg+Trametinib 2 mg Part 3:Placebo+Dabrafenib 150 mg+Trametinib 2 mg
Hide Arm/Group Description:
Participants with BRAF mutant melanoma received 2 mg/kg pembrolizumab administered by IV infusion on Days 1 and 22 Q6W; 150 mg/day total dabrafenib orally, in a divided dose, BID starting on Day 1 and continuing up until study treatment discontinuation; and 2 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation.
Participants with BRAF mutant melanoma received saline placebo administered by IV infusion on Days 1 and 22 Q6W; 150 mg/day total dabrafenib orally, in a divided dose, BID starting on Day 1 and continuing up until study treatment discontinuation; and 2 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation.
Overall Number of Participants Analyzed 60 60
Median (95% Confidence Interval)
Unit of Measure: Months
17.0 [1] 
(11.3 to NA)
9.9
(6.7 to 15.6)
[1]
NA = Upper limit for PFS not reached at time of data cut-off due to insufficient number of participants with an event.
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Part 3:Pembrolizumab 2 mg/kg+Dabrafenib 150 mg+Trametinib 2 mg, Part 3:Placebo+Dabrafenib 150 mg+Trametinib 2 mg
Comments [Not Specified]
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.46
Confidence Interval (2-Sided) 95%
0.29 to 0.74
Estimation Comments Cox regression model
5.Primary Outcome
Title Parts 1, 2, 4, and 5: Number of Participants Who Experienced an Adverse Event (AE)
Hide Description An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have a causal relationship with this treatment. An AE was any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a pre-existing condition that was temporally associated with the use of the study drug, was also an AE. The number of participants who experienced an AE was reported. Per protocol, AE outcome analysis did not include Part 3.
Time Frame Up to approximately 32 months
Hide Outcome Measure Data
Hide Analysis Population Description
All participants who received at least one dose of study treatment in Parts 1, 2, 4, and 5.
Arm/Group Title Part 1:Pembrolizumab 2 mg/kg+dabrafenib150 mg+Trametinib 2 mg Part 1:Pembrolizumab 2 mg/kg+Trametinib 2 mg Part 1:Pembrolizumab 2 mg/kg+Trametinib 1.5 mg Part 2:Pembrolizumab 2 mg/kg+Dabrafenib 150 mg+Trametinib 2 mg Part 2:Pembrolizumab 2 mg/kg+Trametinib 1.5 mg Part 4:4 Weeks Trametinib (Tra) 2mg; Pembrolizumab+Tra 2mg Part 4:2 Weeks Tra 1.5mg; Pembrolizumab+Tra 1.5mg Part 4:4 Weeks Tra 1.5mg; Pembrolizumab+Tra 1.5mg Part 4:2 Weeks Tra 2mg; Pembrolizumab+Tra 2mg Intermittent Part 4:2 Weeks Tra 1.5mg; Pembrolizumab+Tra 1.5mg Intermittent Part 5:2 Weeks Tra 1.5mg; Pembrolizumab+Tra 1.5mg Part 5:2 Weeks Tra 2mg; Pembrolizumab+Tra 2mg Intermittent
Hide Arm/Group Description:
Participants with BRAF mutant melanoma received 2 mg/kg pembrolizumab administered by IV infusion on Days 1 and 22 Q6W; 150 mg/day total dabrafenib orally, in a divided dose, BID starting on Day 1 and continuing up until study treatment discontinuation; and 2 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation.
Participants with BRAF wild-type melanoma received 2 mg/kg pembrolizumab administered by IV infusion on Days 1 and 22 Q6W and 2 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation.
Participants with BRAF wild-type melanoma received 2 mg/kg pembrolizumab administered by IV infusion on Days 1 and 22 Q6W and 1.5 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation.
Participants with BRAF mutant melanoma received 2 mg/kg pembrolizumab administered by IV infusion on Days 1 and 22 Q6W; 150 mg/day total dabrafenib orally, in a divided dose, BID starting on Day 1 and continuing up until study treatment discontinuation; and 2 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation.
Participants with BRAF wild-type melanoma received 2 mg/kg pembrolizumab administered by IV infusion on Days 1 and 22 Q6W and 1.5 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation.
Participants with BRAF wild-type melanoma or solid tumors (irrespective of BRAF status) received 2 mg trametinib orally QD for 4 weeks. Starting with Week 5, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 of each 3-week cycle (Q3W) and a concurrent dosing schedule of 2 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation.
Participants with BRAF wild-type melanoma or solid tumors (irrespective of BRAF status) received 1.5 mg trametinib orally QD for 2 weeks. Starting with Week 3, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and a concurrent dosing schedule of 1.5 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation.
Participants with BRAF wild-type melanoma or solid tumors (irrespective of BRAF status) received 1.5 mg trametinib orally QD for 4 weeks. Starting with Week 5, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and a concurrent dosing schedule of 1.5 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation.
Participants with BRAF wild-type melanoma or solid tumors (irrespective of BRAF status) received 2 mg trametinib orally QD for 2 weeks. Starting with Week 3, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and an intermittent dose schedule of 2 mg trametinib orally QD with 1 week OFF trametinib and 2 weeks ON trametinib continuing up until study treatment discontinuation.
Participants with BRAF wild-type melanoma or solid tumors (irrespective of BRAF status) received 1.5 mg trametinib orally QD for 2 weeks. Starting with Week 3, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and an intermittent dose schedule of 1.5 mg trametinib orally QD with 1 week OFF trametinib and 2 weeks ON trametinib continuing up until study treatment discontinuation.
Participants with BRAF wild-type melanoma or solid tumors (irrespective of BRAF status) received 1.5 mg trametinib orally QD for 2 weeks. Starting with Week 3, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and a concurrent dosing schedule of 1.5 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation.
Participants with BRAF wild-type melanoma or solid tumors (irrespective of BRAF status) received 2 mg trametinib orally QD for 2 weeks. Starting with Week 3, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and an intermittent dose schedule of 2 mg trametinib orally QD with 1 week OFF trametinib and 2 weeks ON trametinib continuing up until study treatment discontinuation.
Overall Number of Participants Analyzed 7 3 2 8 2 3 4 5 6 3 12 9
Measure Type: Count of Participants
Unit of Measure: Participants
7
 100.0%
3
 100.0%
2
 100.0%
8
 100.0%
2
 100.0%
3
 100.0%
4
 100.0%
5
 100.0%
6
 100.0%
3
 100.0%
11
  91.7%
9
 100.0%
6.Primary Outcome
Title Parts 1, 2, 4, and 5: Number of Participants Who Discontinued Study Treatment Due to an AE
Hide Description An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily had to have a causal relationship with this treatment. An AE was any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a pre-existing condition that was temporally associated with the use of the study drug, was also an AE. The number of participants who discontinued study treatment due to an AE was reported. Per protocol, discontinuation outcome analysis did not include Part 3.
Time Frame Up to approximately 29 months
Hide Outcome Measure Data
Hide Analysis Population Description
All participants who received at least one dose of study treatment in Parts 1, 2, 4, and 5.
Arm/Group Title Part 1:Pembrolizumab 2 mg/kg+dabrafenib150 mg+Trametinib 2 mg Part 1:Pembrolizumab 2 mg/kg+Trametinib 2 mg Part 1:Pembrolizumab 2 mg/kg+Trametinib 1.5 mg Part 2:Pembrolizumab 2 mg/kg+Dabrafenib 150 mg+Trametinib 2 mg Part 2:Pembrolizumab 2 mg/kg+Trametinib 1.5 mg Part 4:4 Weeks Trametinib (Tra) 2mg; Pembrolizumab+Tra 2mg Part 4:2 Weeks Tra 1.5mg; Pembrolizumab+Tra 1.5mg Part 4:4 Weeks Tra 1.5mg; Pembrolizumab+Tra 1.5mg Part 4:2 Weeks Tra 2mg; Pembrolizumab+Tra 2mg Intermittent Part 4:2 Weeks Tra 1.5mg; Pembrolizumab+Tra 1.5mg Intermittent Part 5:2 Weeks Tra 1.5mg; Pembrolizumab+Tra 1.5mg Part 5:2 Weeks Tra 2mg; Pembrolizumab+Tra 2mg Intermittent
Hide Arm/Group Description:
Participants with BRAF mutant melanoma received 2 mg/kg pembrolizumab administered by IV infusion on Days 1 and 22 Q6W; 150 mg/day total dabrafenib orally, in a divided dose, BID starting on Day 1 and continuing up until study treatment discontinuation; and 2 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation.
Participants with BRAF wild-type melanoma received 2 mg/kg pembrolizumab administered by IV infusion on Days 1 and 22 Q6W and 2 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation.
Participants with BRAF wild-type melanoma received 2 mg/kg pembrolizumab administered by IV infusion on Days 1 and 22 Q6W and 1.5 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation.
Participants with BRAF mutant melanoma received 2 mg/kg pembrolizumab administered by IV infusion on Days 1 and 22 Q6W; 150 mg/day total dabrafenib orally, in a divided dose, BID starting on Day 1 and continuing up until study treatment discontinuation; and 2 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation.
Participants with BRAF wild-type melanoma received 2 mg/kg pembrolizumab administered by IV infusion on Days 1 and 22 Q6W and 1.5 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation.
Participants with BRAF wild-type melanoma or solid tumors (irrespective of BRAF status) received 2 mg trametinib orally QD for 4 weeks. Starting with Week 5, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 of each 3-week cycle (Q3W) and a concurrent dosing schedule of 2 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation.
Participants with BRAF wild-type melanoma or solid tumors (irrespective of BRAF status) received 1.5 mg trametinib orally QD for 2 weeks. Starting with Week 3, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and a concurrent dosing schedule of 1.5 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation.
Participants with BRAF wild-type melanoma or solid tumors (irrespective of BRAF status) received 1.5 mg trametinib orally QD for 4 weeks. Starting with Week 5, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and a concurrent dosing schedule of 1.5 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation.
Participants with BRAF wild-type melanoma or solid tumors (irrespective of BRAF status) received 2 mg trametinib orally QD for 2 weeks. Starting with Week 3, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and an intermittent dose schedule of 2 mg trametinib orally QD with 1 week OFF trametinib and 2 weeks ON trametinib continuing up until study treatment discontinuation.
Participants with BRAF wild-type melanoma or solid tumors (irrespective of BRAF status) received 1.5 mg trametinib orally QD for 2 weeks. Starting with Week 3, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and an intermittent dose schedule of 1.5 mg trametinib orally QD with 1 week OFF trametinib and 2 weeks ON trametinib continuing up until study treatment discontinuation.
Participants with BRAF wild-type melanoma or solid tumors (irrespective of BRAF status) received 1.5 mg trametinib orally QD for 2 weeks. Starting with Week 3, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and a concurrent dosing schedule of 1.5 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation.
Participants with BRAF wild-type melanoma or solid tumors (irrespective of BRAF status) received 2 mg trametinib orally QD for 2 weeks. Starting with Week 3, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and an intermittent dose schedule of 2 mg trametinib orally QD with 1 week OFF trametinib and 2 weeks ON trametinib continuing up until study treatment discontinuation.
Overall Number of Participants Analyzed 7 3 2 8 2 3 4 5 6 3 12 9
Measure Type: Count of Participants
Unit of Measure: Participants
2
  28.6%
2
  66.7%
1
  50.0%
5
  62.5%
2
 100.0%
1
  33.3%
0
   0.0%
4
  80.0%
2
  33.3%
1
  33.3%
2
  16.7%
2
  22.2%
7.Secondary Outcome
Title Part 1: ORR Per RECIST 1.1 as Assessed by Investigator in Participants With BRAF V600 E or K Mutations
Hide Description ORR was defined as the percentage of participants who had a CR (Disappearance of all target lesions) or a PR (divided into very good partial response [VGPR; >60% tumor reduction] and moderate partial response [MPR; >30-≤60% tumor reduction]) per RECIST 1.1 as assessed by investigator. The percentage of participants who experienced a CR or PR as assessed by the investigator was presented.
Time Frame Up to approximately 85 months
Hide Outcome Measure Data
Hide Analysis Population Description
All enrolled participants with BRAF V600 E or K mutations in Part 1
Arm/Group Title Part 1:Pembrolizumab 2 mg/kg+dabrafenib150 mg+Trametinib 2 mg
Hide Arm/Group Description:
Participants with BRAF mutant melanoma received 2 mg/kg pembrolizumab administered by IV infusion on Days 1 and 22 Q6W; 150 mg/day total dabrafenib orally, in a divided dose, BID starting on Day 1 and continuing up until study treatment discontinuation; and 2 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation.
Overall Number of Participants Analyzed 7
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of participants
57.1
(18.4 to 90.1)
8.Secondary Outcome
Title Part 2: ORR Per RECIST 1.1 as Assessed by Investigator in Participants With BRAF V600 E or K Mutations
Hide Description ORR was defined as the percentage of participants who had a CR (Disappearance of all target lesions) or a PR (divided into very good partial response [VGPR; >60% tumor reduction] and moderate partial response [MPR; >30-≤60% tumor reduction]) per RECIST 1.1 as assessed by investigator. The percentage of participants who experienced a CR or PR as assessed by the investigator was presented.
Time Frame Up to approximately 85 months
Hide Outcome Measure Data
Hide Analysis Population Description
All enrolled participants with BRAF V600 E or K mutations in Part 2
Arm/Group Title Part 2:Pembrolizumab 2 mg/kg+Dabrafenib 150 mg+Trametinib 2 mg
Hide Arm/Group Description:
Participants with BRAF mutant melanoma received 2 mg/kg pembrolizumab administered by IV infusion on Days 1 and 22 Q6W; 150 mg/day total dabrafenib orally, in a divided dose, BID starting on Day 1 and continuing up until study treatment discontinuation; and 2 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation.
Overall Number of Participants Analyzed 8
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of Participants
75.0
(34.9 to 96.8)
9.Secondary Outcome
Title Part 3: ORR Per RECIST 1.1 as Assessed by Investigator in Participants With BRAF V600 E or K Mutations
Hide Description ORR was defined as the percentage of participants who had a CR (Disappearance of all target lesions) or a PR (divided into very good partial response [VGPR; >60% tumor reduction] and moderate partial response [MPR; >30-≤60% tumor reduction]) per RECIST 1.1 as assessed by investigator. The percentage of participants who experienced a CR or PR as assessed by the investigator was presented.
Time Frame Up to approximately 85 months
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants with BRAF V600 E or K mutations in Part 3
Arm/Group Title Part 3:Pembrolizumab 2 mg/kg+Dabrafenib 150 mg+Trametinib 2 mg Part 3:Placebo+Dabrafenib 150 mg+Trametinib 2 mg
Hide Arm/Group Description:
Participants with BRAF mutant melanoma received 2 mg/kg pembrolizumab administered by IV infusion on Days 1 and 22 Q6W; 150 mg/day total dabrafenib orally, in a divided dose, BID starting on Day 1 and continuing up until study treatment discontinuation; and 2 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation.
Participants with BRAF mutant melanoma received saline placebo administered by IV infusion on Days 1 and 22 Q6W; 150 mg/day total dabrafenib orally, in a divided dose, BID starting on Day 1 and continuing up until study treatment discontinuation; and 2 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation.
Overall Number of Participants Analyzed 60 60
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of Participants
65.0
(51.6 to 76.9)
71.7
(58.6 to 82.5)
10.Secondary Outcome
Title Part 3: Duration of Response (DOR) Per RECIST 1.1 as Assessed by Investigator in Participants With BRAF V600 E or K Mutations
Hide Description For participants who demonstrated a confirmed CR (Disappearance of all target lesions) or a confirmed PR (divided by VGPR [>60% tumor reduction] and MPR [>30-≤60% tumor reduction]) per RECIST 1.1 as assessed by the investigator, DOR was defined as the time from first documented evidence of CR or PR until progressive disease (PD). 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. The DOR as assessed by the investigator was analyzed using Kaplan-Meier method and reported in months.
Time Frame Up to approximately 85 months
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants with BRAF V600 E or K mutations who had a confirmed CR or PR in Part 3
Arm/Group Title Part 3:Pembrolizumab 2 mg/kg+Dabrafenib 150 mg+Trametinib 2 mg Part 3:Placebo+Dabrafenib 150 mg+Trametinib 2 mg
Hide Arm/Group Description:
Participants with BRAF mutant melanoma received 2 mg/kg pembrolizumab administered by IV infusion on Days 1 and 22 Q6W; 150 mg/day total dabrafenib orally, in a divided dose, BID starting on Day 1 and continuing up until study treatment discontinuation; and 2 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation.
Participants with BRAF mutant melanoma received saline placebo administered by IV infusion on Days 1 and 22 Q6W; 150 mg/day total dabrafenib orally, in a divided dose, BID starting on Day 1 and continuing up until study treatment discontinuation; and 2 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation.
Overall Number of Participants Analyzed 39 43
Median (95% Confidence Interval)
Unit of Measure: Months
30.2 [1] 
(14.1 to NA)
12.1
(6.0 to 15.7)
[1]
NA = Upper limit for DOR was not reached at time of data cut-off due to insufficient number of responding participants with relapse
11.Secondary Outcome
Title Part 3: Overall Survival (OS) in Participants With BRAF V600 E or K Mutations
Hide Description OS was defined as the time from randomization to death due to any cause. OS was analyzed using the Kaplan-Meier method and was reported in months. Statistical analysis used a Cox regression model with treatment as a covariate and stratified by Eastern Cooperative Oncology Group performance status and Lactate Dehydrogenase.
Time Frame Up to approximately 85 months
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized participants with BRAF V600 E or K mutations in Part 3
Arm/Group Title Part 3:Pembrolizumab 2 mg/kg+Dabrafenib 150 mg+Trametinib 2 mg Part 3:Placebo+Dabrafenib 150 mg+Trametinib 2 mg
Hide Arm/Group Description:
Participants with BRAF mutant melanoma received 2 mg/kg pembrolizumab administered by IV infusion on Days 1 and 22 Q6W; 150 mg/day total dabrafenib orally, in a divided dose, BID starting on Day 1 and continuing up until study treatment discontinuation; and 2 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation.
Participants with BRAF mutant melanoma received saline placebo administered by IV infusion on Days 1 and 22 Q6W; 150 mg/day total dabrafenib orally, in a divided dose, BID starting on Day 1 and continuing up until study treatment discontinuation; and 2 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation.
Overall Number of Participants Analyzed 60 60
Median (95% Confidence Interval)
Unit of Measure: Months
46.3 [1] 
(23.9 to NA)
26.3
(18.2 to 38.6)
[1]
NA = Upper limit for OS was not reached at time of data cut-off due to insufficient number of participants with an event
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Part 3:Pembrolizumab 2 mg/kg+Dabrafenib 150 mg+Trametinib 2 mg
Comments [Not Specified]
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.60
Confidence Interval (2-Sided) 95%
0.38 to 0.95
Estimation Comments Cox regression model
12.Secondary Outcome
Title Maximum Concentration (Cmax) of Pembrolizumab Following Administration of 2 mg/kg Pembrolizumab in Combination With Dabrafenib and/or Trametinib in Participants Pooled From Parts 1 and 2
Hide Description Cmax was defined as the maximum concentration of pembrolizumab observed after administration of 2 mg/kg pembrolizumab in combination with dabrafenib and/or trametinib. Blood samples were collected at multiple time points to estimate the Cmax of pembrolizumab. All participants who received pembrolizumab from Parts 1 and 2 were handled as a single arm and analyzed as a single study population for this outcome measure since Part 2 was the dose confirmation phase of Part 1. The Cmax of pembrolizumab is presented.
Time Frame Cycle 1 Day 1: predose, postdose, 24 - 96 hours (hrs) postdose; Cycle 1 Day 22: predose, postdose; Cycle 2 Day 1: predose, postdose. Each cycle is a 21-day cycle.
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population consisted of all participants pooled from Parts 1 and 2 who received ≥1 dose of 2 mg/kg pembrolizumab and who had available data for the analysis of Cmax.
Arm/Group Title Pooled Parts 1+2:Pembrolizumab+Dabrafenib+1.5/2 mg Trametinib
Hide Arm/Group Description:
Participants pooled from Parts 1 and 2 received 2 mg/kg pembrolizumab in combination with dabrafenib and 2 mg trametinib OR 2 mg/kg pembrolizumab and 1.5 or 2 mg trametinib (without dabrafenib) Q6W continuing up until study treatment discontinuation.
Overall Number of Participants Analyzed 21
Mean (Standard Deviation)
Unit of Measure: µg/mL
52.3  (9.9)
13.Secondary Outcome
Title Maximum Concentration (Cmax) of Pembrolizumab Following Administration of 2 mg/kg Pembrolizumab in Combination With Dabrafenib and Trametinib in Participants From Part 3
Hide Description Cmax was defined as the maximum concentration of pembrolizumab observed after administration of 2 mg/kg pembrolizumab in combination with dabrafenib and trametinib. Blood samples were collected at multiple time points to estimate the Cmax of pembrolizumab. The Cmax of pembrolizumab is presented.
Time Frame Cycle 1 Day 1: predose, postdose, 24 - 96 hours (hrs) postdose; Cycle 1 Day 22: predose, postdose; Cycle 2 Day 1: predose, postdose. Each cycle is a 21-day cycle.
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population consisted of all participants from Part 3 who received ≥1 dose of 2 mg/kg pembrolizumab and who had available data for the analysis of Cmax.
Arm/Group Title Part 3: 2 mg/kg Pembrolizumab+Dabrafenib+Trametinib
Hide Arm/Group Description:
Participants received 2 mg/kg pembrolizumab in combination with 150 mg dabrafenib and 2 mg trametinib Q6W continuing up until study treatment discontinuation.
Overall Number of Participants Analyzed 58
Mean (Standard Deviation)
Unit of Measure: µg/mL
48.9  (11.4)
14.Secondary Outcome
Title Maximum Concentration (Cmax) of Pembrolizumab Following Administration of 200 mg Pembrolizumab in Combination With Trametinib in Participants From Part 4
Hide Description Cmax was defined as the maximum concentration of pembrolizumab observed after administration of 200 mg pembrolizumab in combination with trametinib. Blood samples were collected at multiple time points to estimate the Cmax of pembrolizumab. The Cmax of pembrolizumab is presented.
Time Frame Cycle 1 Day 15: predose, postdose, 24 - 96 hrs postdose; Cycle 1 Day 36: predose, postdose; Cycle 2 Day 1: predose, postdose. Each cycle is a 21-day cycle.
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population consisted of all participants from Part 4 who received ≥1 dose of 200 mg pembrolizumab and who had available data for the analysis of Cmax.
Arm/Group Title Part 4: 200 mg Pembrolizumab+Trametinib
Hide Arm/Group Description:
Participants received 2 mg or 1.5 mg trametinib orally QD for 2 or 4 weeks (depending on treatment regimen). Starting with Week 3 or 5 (depending on initial trametinib interval), participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and an intermittent or concurrent dose schedule of trametinib orally QD continuing up until study treatment discontinuation.
Overall Number of Participants Analyzed 14
Mean (Standard Deviation)
Unit of Measure: µg/mL
77.8  (16.1)
15.Secondary Outcome
Title Maximum Concentration (Cmax) of Pembrolizumab Following Administration of 200 mg Pembrolizumab in Combination With Trametinib in Participants From Part 5
Hide Description Cmax was defined as the maximum concentration of pembrolizumab observed after administration of 200 mg pembrolizumab in combination with trametinib. Blood samples were collected at multiple time points to estimate the Cmax of pembrolizumab. The Cmax of pembrolizumab is presented.
Time Frame Cycle 1 Day 15: predose, postdose, 24 - 96 hrs postdose; Cycle 1 Day 36: predose, postdose; Cycle 2 Day 1: predose, postdose. Each cycle is a 21-day cycle.
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population consisted of all participants from Part 5 who received ≥1 dose of 200 mg pembrolizumab and who had available data for the analysis of Cmax. There were no participants with data available for the analysis of Cmax in Part 5.
Arm/Group Title Part 5: 200 mg Pembrolizumab+Trametinib
Hide Arm/Group Description:
Participants received 2 mg or 1.5 mg trametinib orally QD for 2 weeks. Starting with Week 3, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and an intermittent or concurrent dose schedule of trametinib orally QD continuing up until study treatment discontinuation.
Overall Number of Participants Analyzed 0
No data displayed because Outcome Measure has zero total analyzed.
16.Secondary Outcome
Title Trough Concentration (Ctrough) of Pembrolizumab Following Administration of 2 mg/kg Pembrolizumab in Combination With Dabrafenib and/or Trametinib in Participants Pooled From Parts 1 and 2
Hide Description Ctrough was defined as the lowest concentration of pembrolizumab that occurred immediately prior to the next dose of 2 mg/kg pembrolizumab administered in combination with dabrafenib and/or trametinib. Blood samples were collected at multiple time points to estimate the Ctrough of pembrolizumab. All participants who received pembrolizumab from Parts 1 and 2 were handled as a single arm and analyzed as a single study population for this outcome measure since Part 2 was the dose confirmation phase of Part 1. The Ctrough of pembrolizumab is presented.
Time Frame Cycle 1 Day 1: predose, postdose, 24 - 96 hours (hrs) postdose; Cycle 1 Day 22: predose, postdose; Cycle 2 Day 1: predose, postdose. Each cycle is a 21-day cycle.
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population consisted of all participants pooled from Parts 1 and 2 who received ≥1 dose of 2 mg/kg pembrolizumab and who had available data for the analysis of Ctrough.
Arm/Group Title Pooled Parts 1+2:Pembrolizumab+Dabrafenib+1.5/2 mg Trametinib
Hide Arm/Group Description:
Participants pooled from Parts 1 and 2 received 2 mg/kg pembrolizumab in combination with dabrafenib and 2 mg trametinib OR 2 mg/kg pembrolizumab and 1.5 or 2 mg trametinib (without dabrafenib) Q6W continuing up until study treatment discontinuation.
Overall Number of Participants Analyzed 20
Mean (Standard Deviation)
Unit of Measure: µg/mL
11.2  (2.6)
17.Secondary Outcome
Title Trough Concentration (Ctrough) of Pembrolizumab Following Administration of 2 mg/kg Pembrolizumab in Combination With Dabrafenib and Trametinib in Participants From Part 3
Hide Description Ctrough was defined as the lowest concentration of pembrolizumab that occurred immediately prior to the next dose of 2 mg/kg pembrolizumab administered in combination with dabrafenib and trametinib. Blood samples were collected at multiple time points to estimate the Ctrough of pembrolizumab. The Ctrough of pembrolizumab is presented.
Time Frame Cycle 1 Day 1: predose, postdose, 24 - 96 hours (hrs) postdose; Cycle 1 Day 22: predose, postdose; Cycle 2 Day 1: predose, postdose. Each cycle is a 21-day cycle.
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population consisted of all participants from Part 3 who received ≥1 dose of 2 mg/kg pembrolizumab and who had available data for the analysis of Ctrough.
Arm/Group Title Part 3: 2 mg/kg Pembrolizumab+Dabrafenib+Trametinib
Hide Arm/Group Description:
Participants received 2 mg/kg pembrolizumab in combination with 150 mg dabrafenib and 2 mg trametinib Q6W continuing up until study treatment discontinuation.
Overall Number of Participants Analyzed 49
Mean (Standard Deviation)
Unit of Measure: µg/mL
10.6  (3.4)
18.Secondary Outcome
Title Trough Concentration (Ctrough) of Pembrolizumab Following Administration of 200 mg Pembrolizumab in Combination With Trametinib in Participants From Part 4
Hide Description Ctrough was defined as the lowest concentration of pembrolizumab that occurred immediately prior to the next dose of 200 mg pembrolizumab administered in combination with trametinib. Blood samples were collected at multiple time points to estimate the Ctrough of pembrolizumab. The Ctrough of pembrolizumab is presented.
Time Frame Cycle 1 Day 15: predose, postdose, 24 - 96 hrs postdose; Cycle 1 Day 36: predose, postdose; Cycle 2 Day 1: predose, postdose. Each cycle is a 21-day cycle.
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population consisted of all participants from Part 4 who received ≥1 dose of 200 mg pembrolizumab and who had available data for the analysis of Ctrough.
Arm/Group Title Part 4: 200 mg Pembrolizumab+Trametinib
Hide Arm/Group Description:
Participants received 2 mg or 1.5 mg trametinib orally QD for 2 or 4 weeks (depending on treatment regimen). Starting with Week 3 or 5 (depending on initial trametinib interval), participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and an intermittent or concurrent dose schedule of trametinib orally QD continuing up until study treatment discontinuation.
Overall Number of Participants Analyzed 15
Mean (Standard Deviation)
Unit of Measure: µg/mL
17.0  (7.1)
19.Secondary Outcome
Title Trough Concentration (Ctrough) of Pembrolizumab Following Administration of 200 mg Pembrolizumab in Combination With Trametinib in Participants From Part 5
Hide Description Ctrough was defined as the lowest concentration of pembrolizumab that occurred immediately prior to the next dose of 200 mg pembrolizumab administered in combination with trametinib. Blood samples were collected at multiple time points to estimate the Ctrough of pembrolizumab. The Ctrough of pembrolizumab is presented.
Time Frame Cycle 1 Day 15: predose, postdose, 24 - 96 hrs postdose; Cycle 1 Day 36: predose, postdose; Cycle 2 Day 1: predose, postdose. Each cycle is a 21-day cycle.
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population consisted of all participants from Part 5 who received ≥1 dose of 200 mg pembrolizumab and who had available data for the analysis of Ctrough. There were no participants with data available for the analysis of Ctrough in Part 5.
Arm/Group Title Part 5: 200 mg Pembrolizumab+Trametinib
Hide Arm/Group Description:
Participants received 2 mg or 1.5 mg trametinib orally QD for 2 weeks. Starting with Week 3, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and an intermittent or concurrent dose schedule of trametinib orally QD continuing up until study treatment discontinuation.
Overall Number of Participants Analyzed 0
No data displayed because Outcome Measure has zero total analyzed.
20.Secondary Outcome
Title Maximum Concentration (Cmax) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination With 2 mg/kg Pembrolizumab and 2 mg Trametinib in Participants Pooled From Parts 1 and 2
Hide Description Cmax was defined as the maximum concentration of dabrafenib observed after administration of 150 mg dabrafenib in combination with 2 mg/kg pembrolizumab and 2 mg trametinib. Blood samples were collected at multiple time points to estimate the Cmax of dabrafenib. All participants who received dabrafenib from Parts 1 and 2 were handled as a single arm and analyzed as a single study population for this outcome measure since Part 2 was the dose confirmation phase of Part 1. The Cmax of dabrafenib is presented.
Time Frame Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population consisted of all participants pooled from Parts 1 and 2 who received ≥1 dose of 150 mg dabrafenib and who had available data for the analysis of Cmax.
Arm/Group Title Pooled Parts 1+2:Pembrolizumab and/or Dabrafenib+2 mg Trametinib
Hide Arm/Group Description:
Participants pooled from Parts 1 and 2 received 2 mg/kg pembrolizumab and 150 mg dabrafenib and 2 mg trametinib Q6W continuing up until study treatment discontinuation.
Overall Number of Participants Analyzed 13
Mean (Standard Deviation)
Unit of Measure: ng/mL
683  (905)
21.Secondary Outcome
Title Maximum Concentration (Cmax) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination With 2 mg/kg Pembrolizumab and 2 mg Trametinib in Participants From Part 3
Hide Description Cmax was defined as the maximum concentration of dabrafenib observed after administration of 150 mg dabrafenib in combination with 2 mg/kg pembrolizumab and 2 mg trametinib. Blood samples were collected at multiple time points to estimate the Cmax of dabrafenib. The Cmax of dabrafenib is presented.
Time Frame Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population consisted of all participants from Part 3 who received ≥1 dose of 150 mg dabrafenib and pembrolizumab and who had available data for the analysis of Cmax.
Arm/Group Title Part 3: 2 mg/kg Pembrolizumab+Dabrafenib+Trametinib
Hide Arm/Group Description:
Participants received 2 mg/kg pembrolizumab in combination with 150 mg dabrafenib and 2 mg trametinib Q6W continuing up until study treatment discontinuation.
Overall Number of Participants Analyzed 53
Mean (Standard Deviation)
Unit of Measure: ng/mL
643  (643)
22.Secondary Outcome
Title Maximum Concentration (Cmax) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination With Placebo and 2 mg Trametinib in Participants From Part 3
Hide Description Cmax was defined as the maximum concentration of dabrafenib observed after administration of 150 mg dabrafenib in combination with saline placebo and 2 mg trametinib. Blood samples were collected at multiple time points to estimate the Cmax of dabrafenib. The Cmax of dabrafenib is presented.
Time Frame Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population consisted of all participants from Part 3 who received ≥1 dose of 150 mg dabrafenib and placebo and who had available data for the analysis of Cmax.
Arm/Group Title Part 3: Placebo+Dabrafenib+Trametinib
Hide Arm/Group Description:
Participants received saline placebo in combination with 150 mg dabrafenib and 2 mg trametinib Q6W continuing up until study treatment discontinuation.
Overall Number of Participants Analyzed 58
Mean (Standard Deviation)
Unit of Measure: ng/mL
642  (829)
23.Secondary Outcome
Title Trough Concentration (Ctrough) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination With 2 mg/kg Pembrolizumab and 2 mg Trametinib in Participants Pooled From Parts 1 and 2
Hide Description Ctrough was defined as the lowest concentration of dabrafenib that occurred immediately prior to the next dose of 150 mg dabrafenib administered in combination with 2 mg/kg pembrolizumab and 2 mg trametinib. Blood samples were collected at multiple time points to estimate the Ctrough of dabrafenib. All participants who received dabrafenib from Parts 1 and 2 were handled as a single arm and analyzed as a single study population for this outcome measure since Part 2 was the dose confirmation phase of Part 1. The Ctrough of dabrafenib is presented.
Time Frame Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population consisted of all participants pooled from Parts 1 and 2 who received ≥1 dose of 150 mg dabrafenib and who had available data for the analysis of Ctrough.
Arm/Group Title Pooled Parts 1+2:Pembrolizumab and/or Dabrafenib+2 mg Trametinib
Hide Arm/Group Description:
Participants pooled from Parts 1 and 2 received 2 mg/kg pembrolizumab in combination with 150 mg dabrafenib and 2 mg trametinib Q6W continuing up until study treatment discontinuation.
Overall Number of Participants Analyzed 14
Mean (Standard Deviation)
Unit of Measure: ng/mL
156  (367)
24.Secondary Outcome
Title Trough Concentration (Ctrough) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination With 2 mg/kg Pembrolizumab and 2 mg Trametinib in Participants From Part 3
Hide Description Ctrough was defined as the lowest concentration of dabrafenib that occurred immediately prior to the next dose of 150 mg dabrafenib administered in combination with 2 mg/kg pembrolizumab and 2 mg trametinib. Blood samples were collected at multiple time points to estimate the Ctrough of dabrafenib. The Ctrough of dabrafenib is presented.
Time Frame Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population consisted of all participants from Part 3 who received ≥1 dose of 150 mg dabrafenib and pembrolizumab and who had available data for the analysis of Ctrough.
Arm/Group Title Part 3: 2 mg/kg Pembrolizumab+Dabrafenib+Trametinib
Hide Arm/Group Description:
Participants received 2 mg/kg pembrolizumab in combination with 150 mg dabrafenib and 2 mg trametinib Q6W continuing up until study treatment discontinuation.
Overall Number of Participants Analyzed 55
Mean (Standard Deviation)
Unit of Measure: ng/mL
103  (204)
25.Secondary Outcome
Title Trough Concentration (Ctrough) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination With Placebo and 2 mg Trametinib in Participants From Part 3
Hide Description Ctrough was defined as the lowest concentration of dabrafenib that occurred immediately prior to the next dose of 150 mg dabrafenib administered in combination with saline placebo and 2 mg trametinib. Blood samples were collected at multiple time points to estimate the Ctrough of dabrafenib. The Ctrough of dabrafenib is presented.
Time Frame Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population consisted of all participants from Part 3 who received ≥1 dose of 150 mg dabrafenib and placebo and who had available data for the analysis of Ctrough.
Arm/Group Title Part 3: Placebo+Dabrafenib+Trametinib
Hide Arm/Group Description:
Participants received saline placebo in combination with 150 mg dabrafenib and 2 mg trametinib Q6W continuing up until study treatment discontinuation.
Overall Number of Participants Analyzed 58
Mean (Standard Deviation)
Unit of Measure: ng/mL
183  (384)
26.Secondary Outcome
Title Maximum Concentration (Cmax) of Trametinib Following Administration of 2 mg Trametinib in Combination With 2 mg/kg Pembrolizumab and 150 mg Dabrafenib in Participants Pooled From Parts 1 and 2
Hide Description Cmax was defined as the maximum concentration of trametinib observed after administration of 2 mg trametinib in combination with 2 mg/kg pembrolizumab and 150 mg dabrafenib. Blood samples were collected at multiple time points to estimate the Cmax of trametinib. All participants who received 2 mg trametinib from Parts 1 and 2 were treated as a single arm and analyzed as a single study population for this outcome measure since Part 2 was the dose confirmation phase of Part 1. The Cmax of trametinib is presented.
Time Frame Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population consisted of all participants pooled from Parts 1 and 2 who received ≥1 dose of 2 mg trametinib and who had available data for the analysis of Cmax.
Arm/Group Title Pooled Parts 1+2:Pembrolizumab+Dabrafenib+2 mg Trametinib
Hide Arm/Group Description:
Participants pooled from Parts 1 and 2 received 2 mg/kg pembrolizumab in combination with 150 mg dabrafenib and 2 mg trametinib Q6W continuing up until study treatment discontinuation.
Overall Number of Participants Analyzed 13
Mean (Standard Deviation)
Unit of Measure: ng/mL
19.3  (8.13)
27.Secondary Outcome
Title Maximum Concentration (Cmax) of Trametinib Following Administration of 1.5 mg Trametinib in Combination With 2 mg/kg Pembrolizumab in Participants Pooled From Parts 1 and 2
Hide Description Cmax was defined as the maximum concentration of trametinib observed after administration of 1.5 mg trametinib in combination with 2 mg/kg pembrolizumab. Blood samples were collected at multiple time points to estimate the Cmax of trametinib. All participants who received 1.5 mg trametinib from Parts 1 and 2 were treated as a single arm and analyzed as a single study population for this outcome measure since Part 2 was the dose confirmation phase of Part 1. The Cmax of trametinib is presented.
Time Frame Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population consisted of all participants pooled from Parts 1 and 2 who received ≥1 dose of 1.5 mg trametinib and who had available data for the analysis of Cmax.
Arm/Group Title Pooled Parts 1+2:Pembrolizumab+1.5 mg Trametinib
Hide Arm/Group Description:
Participants pooled from Parts 1 and 2 received 2 mg/kg pembrolizumab in combination with 1.5 mg trametinib Q6W continuing up until study treatment discontinuation.
Overall Number of Participants Analyzed 3
Mean (Standard Deviation)
Unit of Measure: ng/mL
30.3  (17.7)
28.Secondary Outcome
Title Maximum Concentration (Cmax) of Trametinib Following Administration of 2 mg Trametinib in Combination With 2 mg/kg Pembrolizumab and 150 mg Dabrafenib in Participants From Part 3
Hide Description Cmax was defined as the maximum concentration of trametinib observed after administration of 2 mg trametinib in combination with 2 mg/kg pembrolizumab and 150 mg dabrafenib. Blood samples were collected at multiple time points to estimate the Cmax of trametinib. The Cmax of trametinib is presented.
Time Frame Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population consisted of all participants from Part 3 who received ≥1 dose of 2 mg trametinib and pembrolizumab and who had available data for the analysis of Cmax.
Arm/Group Title Part 3: 2 mg/kg Pembrolizumab+Dabrafenib+Trametinib
Hide Arm/Group Description:
Participants received 2 mg/kg pembrolizumab in combination with 150 mg dabrafenib and 2 mg trametinib Q6W continuing up until study treatment discontinuation.
Overall Number of Participants Analyzed 47
Mean (Standard Deviation)
Unit of Measure: ng/mL
16.3  (6.80)
29.Secondary Outcome
Title Maximum Concentration (Cmax) of Trametinib Following Administration of 2 mg Trametinib in Combination With Placebo and 150 mg Dabrafenib in Participants From Part 3
Hide Description Cmax was defined as the maximum concentration of trametinib observed after administration of 2 mg trametinib in combination with saline placebo and 150 mg dabrafenib. Blood samples were collected at multiple time points to estimate the Cmax of trametinib. The Cmax of trametinib is presented.
Time Frame Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population consisted of all participants from Part 3 who received ≥1 dose of 2 mg trametinib and placebo and who had available data for the analysis of Cmax.
Arm/Group Title Part 3: Placebo+Dabrafenib+Trametinib
Hide Arm/Group Description:
Participants received saline placebo in combination with 150 mg dabrafenib and 2 mg trametinib Q6W continuing up until study treatment discontinuation.
Overall Number of Participants Analyzed 53
Mean (Standard Deviation)
Unit of Measure: ng/mL
16.2  (6.15)
30.Secondary Outcome
Title Maximum Concentration (Cmax) of Trametinib Following Administration of 2 mg Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 4
Hide Description Cmax was defined as the maximum concentration of trametinib observed after administration of 2 mg trametinib in combination with 200 mg pembrolizumab. Blood samples were collected at multiple time points to estimate the Cmax of trametinib. The Cmax of trametinib is presented.
Time Frame Cycle 1 Day 36: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population consisted of all participants from Part 4 who received ≥1 dose of 2 mg trametinib and who had available data for the analysis of Cmax.
Arm/Group Title Part 4: 200 mg Pembrolizumab+2 mg Trametinib
Hide Arm/Group Description:
Participants received 2 mg trametinib orally QD for 2 or 4 weeks (depending on treatment regimen). Starting with Week 3 or 5 (depending on initial trametinib interval), participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and an intermittent or concurrent dose schedule of 2 mg trametinib orally QD continuing up until study treatment discontinuation.
Overall Number of Participants Analyzed 4
Mean (Standard Deviation)
Unit of Measure: ng/mL
18.5  (12.9)
31.Secondary Outcome
Title Maximum Concentration (Cmax) of Trametinib Following Administration of 1.5 mg Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 4
Hide Description Cmax was defined as the maximum concentration of trametinib observed after administration of 1.5 mg trametinib in combination with 200 mg pembrolizumab. Blood samples were collected at multiple time points to estimate the Cmax of trametinib. The Cmax of trametinib is presented.
Time Frame Cycle 1 Day 36: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population consisted of all participants from Part 4 who received ≥1 dose of 1.5 mg trametinib and who had available data for the analysis of Cmax.
Arm/Group Title Part 4: 200 mg Pembrolizumab+1.5 mg Trametinib
Hide Arm/Group Description:
Participants received 1.5 mg trametinib orally QD for 2 or 4 weeks (depending on treatment regimen). Starting with Week 3 or 5 (depending on initial trametinib interval), participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and an intermittent or concurrent dose schedule of 1.5 mg trametinib orally QD continuing up until study treatment discontinuation.
Overall Number of Participants Analyzed 7
Mean (Standard Deviation)
Unit of Measure: ng/mL
16.7  (7.62)
32.Secondary Outcome
Title Maximum Concentration (Cmax) of Trametinib Following Administration of 2 mg of Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 5
Hide Description Cmax was defined as the maximum concentration of trametinib observed after administration of 2 mg trametinib in combination with 200 mg pembrolizumab. Blood samples were collected at multiple time points to estimate the Cmax of trametinib. The Cmax of trametinib is presented.
Time Frame Cycle 1 Day 36: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population consisted of all participants from Part 5 who received ≥1 dose of 2 mg trametinib and who had available data for the analysis of Cmax.
Arm/Group Title Part 5: 200 mg Pembrolizumab+2 mg Trametinib
Hide Arm/Group Description:
Participants received 2 mg trametinib orally QD for 2 weeks. Starting with Week 3, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and an intermittent or concurrent dose schedule of 2 mg trametinib orally QD continuing up until study treatment discontinuation.
Overall Number of Participants Analyzed 3
Mean (Standard Deviation)
Unit of Measure: ng/mL
7.54  (8.89)
33.Secondary Outcome
Title Maximum Concentration (Cmax) of Trametinib Following Administration of 1.5 mg of Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 5
Hide Description Cmax was defined as the maximum concentration of trametinib observed after administration of 1.5 mg trametinib in combination with 200 mg pembrolizumab. Blood samples were collected at multiple time points to estimate the Cmax of trametinib. The Cmax of trametinib is presented.
Time Frame Cycle 1 Day 36: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population consisted of all participants from Part 5 who received ≥1 dose of 1.5 mg trametinib and who had available data for the analysis of Cmax.
Arm/Group Title Part 5: 200 mg Pembrolizumab+1.5 mg Trametinib
Hide Arm/Group Description:
Participants received 1.5 mg trametinib orally QD for 2 weeks. Starting with Week 3, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and an intermittent or concurrent dose schedule of 1.5 mg trametinib orally QD continuing up until study treatment discontinuation.
Overall Number of Participants Analyzed 8
Mean (Standard Deviation)
Unit of Measure: ng/mL
14.3  (7.75)
34.Secondary Outcome
Title Trough Concentration (Ctrough) of Trametinib Following Administration of 2 mg Trametinib in Combination With 2 mg/kg Pembrolizumab and 150 mg Dabrafenib in Participants Pooled From Parts 1 and 2
Hide Description Ctrough was defined as the lowest concentration of trametinib that occurred immediately prior to the next dose of 2 mg trametinib administered in combination with 2 mg/kg pembrolizumab and 150 mg dabrafenib. Blood samples were collected at multiple time points to estimate the Ctrough of trametinib. All participants who received 2 mg trametinib from Parts 1 and 2 were treated as a single arm and analyzed as a single study population for this outcome measure since Part 2 was the dose confirmation phase of Part 1. The Ctrough of trametinib is presented.
Time Frame Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population consisted of all participants pooled from Parts 1 and 2 who received ≥1 dose of 2 mg trametinib and who had available data for the analysis of Ctrough.
Arm/Group Title Pooled Parts 1+2:Pembrolizumab+Dabrafenib+2 mg Trametinib
Hide Arm/Group Description:
Participants pooled from Parts 1 and 2 received 2 mg/kg pembrolizumab in combination with 150 mg dabrafenib and 2 mg trametinib Q6W continuing up until study treatment discontinuation.
Overall Number of Participants Analyzed 14
Mean (Standard Deviation)
Unit of Measure: ng/mL
13.7  (9.39)
35.Secondary Outcome
Title Trough Concentration (Ctrough) of Trametinib Following Administration of 1.5 mg Trametinib in Combination With 2 mg/kg Pembrolizumab in Participants Pooled From Parts 1 and 2
Hide Description Ctrough was defined as the lowest concentration of trametinib that occurred immediately prior to the next dose of 1.5 mg trametinib administered in combination with 2 mg/kg pembrolizumab. Blood samples were collected at multiple time points to estimate the Ctrough of trametinib. All participants who received 1.5 mg trametinib from Parts 1 and 2 were treated as a single arm and analyzed as a single study population for this outcome measure since Part 2 was the dose confirmation phase of Part 1. The Ctrough of trametinib is presented.
Time Frame Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population consisted of all participants pooled from Parts 1 and 2 who received ≥1 dose of 1.5 mg trametinib and who had available data for the analysis of Ctrough.
Arm/Group Title Pooled Parts 1+2:Pembrolizumab+1.5 mg Trametinib
Hide Arm/Group Description:
Participants pooled from Parts 1 and 2 received 2 mg/kg pembrolizumab in combination with 1.5 mg trametinib Q6W continuing up until study treatment discontinuation.
Overall Number of Participants Analyzed 3
Mean (Standard Deviation)
Unit of Measure: ng/mL
20.5  (9.23)
36.Secondary Outcome
Title Trough Concentration (Ctrough) of Trametinib Following Administration of 2 mg Trametinib in Combination With 2 mg/kg Pembrolizumab and 150 mg Dabrafenib in Participants From Part 3
Hide Description Ctrough was defined as the lowest concentration of trametinib that occurred immediately prior to the next dose of 2 mg trametinib administered in combination with 2 mg/kg pembrolizumab and 150 mg dabrafenib. Blood samples were collected at multiple time points to estimate the Ctrough of trametinib. The Ctrough of trametinib is presented.
Time Frame Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population consisted of all participants from Part 3 who received ≥1 dose of 2 mg trametinib and pembrolizumab and who had available data for the analysis of Ctrough.
Arm/Group Title Part 3: 2 mg/kg Pembrolizumab+Dabrafenib+Trametinib
Hide Arm/Group Description:
Participants received 2 mg/kg pembrolizumab in combination with 150 mg dabrafenib and 2 mg trametinib Q6W continuing up until study treatment discontinuation.
Overall Number of Participants Analyzed 54
Mean (Standard Deviation)
Unit of Measure: ng/mL
9.93  (5.48)
37.Secondary Outcome
Title Trough Concentration (Ctrough) of Trametinib Following Administration of 2 mg Trametinib in Combination With Placebo and 150 mg Dabrafenib in Participants From Part 3
Hide Description Ctrough was defined as the lowest concentration of trametinib that occurred immediately prior to the next dose of 2 mg trametinib administered in combination with saline placebo and 150 mg dabrafenib. Blood samples were collected at multiple time points to estimate the Ctrough of trametinib. The Ctrough of trametinib is presented.
Time Frame Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population consisted of all participants from Part 3 who received ≥1 dose of 2 mg trametinib and placebo and who had available data for the analysis of Ctrough.
Arm/Group Title Part 3: Placebo+Dabrafenib+Trametinib
Hide Arm/Group Description:
Participants received saline placebo in combination with 150 mg dabrafenib and 2 mg trametinib Q6W continuing up until study treatment discontinuation.
Overall Number of Participants Analyzed 58
Mean (Standard Deviation)
Unit of Measure: ng/mL
10.7  (5.14)
38.Secondary Outcome
Title Trough Concentration (Ctrough) of Trametinib Following Administration of 2 mg Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 4
Hide Description Ctrough was defined as the lowest concentration of trametinib that occurred immediately prior to the next dose of 2 mg trametinib administered in combination with 200 mg pembrolizumab. Blood samples were collected at multiple time points to estimate the Ctrough of trametinib. The Ctrough of trametinib is presented.
Time Frame Cycle 1 Day 36: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population consisted of all participants from Part 4 who received ≥1 dose of 2 mg trametinib and who had available data for the analysis of Ctrough.
Arm/Group Title Part 4: 200 mg Pembrolizumab+2 mg Trametinib
Hide Arm/Group Description:
Participants received 2 mg trametinib orally QD for 2 or 4 weeks (depending on treatment regimen). Starting with Week 3 or 5 (depending on initial trametinib interval), participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and an intermittent or concurrent dose schedule of 2 mg trametinib orally QD continuing up until study treatment discontinuation.
Overall Number of Participants Analyzed 6
Mean (Standard Deviation)
Unit of Measure: ng/mL
12.3  (9.45)
39.Secondary Outcome
Title Trough Concentration (Ctrough) of Trametinib Following Administration of 1.5 mg Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 4
Hide Description Ctrough was defined as the lowest concentration of trametinib that occurred immediately prior to the next dose of 1.5 mg trametinib administered in combination with 200 mg pembrolizumab. Blood samples were collected at multiple time points to estimate the Ctrough of trametinib. The Ctrough of trametinib is presented.
Time Frame Cycle 1 Day 36: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population consisted of all participants from Part 4 who received ≥1 dose of 1.5 mg trametinib and who had available data for the analysis of Ctrough.
Arm/Group Title Part 4: 200 mg Pembrolizumab+1.5 mg Trametinib
Hide Arm/Group Description:
Participants received 1.5 mg trametinib orally QD for 2 or 4 weeks (depending on treatment regimen). Starting with Week 3 or 5 (depending on initial trametinib interval), participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and an intermittent or concurrent dose schedule of 1.5 mg trametinib orally QD continuing up until study treatment discontinuation.
Overall Number of Participants Analyzed 7
Mean (Standard Deviation)
Unit of Measure: ng/mL
8.64  (5.65)
40.Secondary Outcome
Title Trough Concentration (Ctrough) of Trametinib Following Administration of 2 mg of Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 5
Hide Description Ctrough was defined as the lowest concentration of trametinib that occurred immediately prior to the next dose of 2 mg trametinib administered in combination with 200 mg pembrolizumab. Blood samples were collected at multiple time points to estimate the Ctrough of trametinib. The Ctrough of trametinib is presented.
Time Frame Cycle 1 Day 36: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population consisted of all participants from Part 5 who received ≥1 dose of 2 mg trametinib and who had available data for the analysis of Ctrough.
Arm/Group Title Part 5: 200 mg Pembrolizumab+2 mg Trametinib
Hide Arm/Group Description:
Participants received 2 mg trametinib orally QD for 2 weeks. Starting with Week 3, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and an intermittent or concurrent dose schedule of 2 mg trametinib orally QD continuing up until study treatment discontinuation.
Overall Number of Participants Analyzed 8
Mean (Standard Deviation)
Unit of Measure: ng/mL
6.69  (5.9)
41.Secondary Outcome
Title Trough Concentration (Ctrough) of Trametinib Following Administration of 1.5 mg of Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 5
Hide Description Ctrough was defined as the lowest concentration of trametinib that occurred immediately prior to the next dose of 1.5 mg trametinib administered in combination with 200 mg pembrolizumab. Blood samples were collected at multiple time points to estimate the Ctrough of trametinib. The Ctrough of trametinib is presented.
Time Frame Cycle 1 Day 36: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population consisted of all participants from Part 5 who received ≥1 dose of 1.5 mg trametinib and who had available data for the analysis of Ctrough.
Arm/Group Title Part 5: 200 mg Pembrolizumab+1.5 mg Trametinib
Hide Arm/Group Description:
Participants received 1.5 mg trametinib orally QD for 2 weeks. Starting with Week 3, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and an intermittent or concurrent dose schedule of 1.5 mg trametinib orally QD continuing up until study treatment discontinuation.
Overall Number of Participants Analyzed 9
Mean (Standard Deviation)
Unit of Measure: ng/mL
10.6  (6.79)
42.Secondary Outcome
Title Clearance (Cl) of Pembrolizumab Following Administration of 2 mg/kg Pembrolizumab in Combination With Dabrafenib and/or Trametinib in Participants Pooled From Parts 1 and 2
Hide Description Blood samples were to be collected at pre-specified time points for analysis of the Cl of pembrolizumab, defined as the volume of plasma from which pembrolizumab is eliminated per unit time following pembrolizumab administration. This analysis was not performed.
Time Frame Cycle 1 Day 1: predose, postdose, 24 - 96 hours (hrs) postdose; Cycle 1 Day 22: predose, postdose; Cycle 2 Day 1: predose, postdose. Each cycle is a 21-day cycle.
Hide Outcome Measure Data
Hide Analysis Population Description
As specified by the protocol, the Cl of pembrolizumab was only to be analyzed if required and no data were collected since, by the time of final analysis, pembrolizumab pharmacokinetics (PK) in melanoma participants had been well characterized and found to be consistent with the overall clinical pharmacology of pembrolizumab characterized across indications.
Arm/Group Title Pooled Parts 1+2:Pembrolizumab+Dabrafenib+1.5/2 mg Trametinib
Hide Arm/Group Description:
Participants pooled from Parts 1 and 2 received 2 mg/kg pembrolizumab in combination with dabrafenib and 2 mg trametinib OR 2 mg/kg pembrolizumab and 1.5 or 2 mg trametinib (without dabrafenib) Q6W continuing up until study treatment discontinuation.
Overall Number of Participants Analyzed 0
No data displayed because Outcome Measure has zero total analyzed.
43.Secondary Outcome
Title Clearance (Cl) of Pembrolizumab Following Administration of 2 mg/kg Pembrolizumab in Combination With Dabrafenib and Trametinib in Participants From Part 3
Hide Description Blood samples were to be collected at pre-specified time points for analysis of the Cl of pembrolizumab, defined as the volume of plasma from which pembrolizumab is eliminated per unit time following pembrolizumab administration. This analysis was not performed.
Time Frame Cycle 1 Day 1: predose, postdose, 24 - 96 hours (hrs) postdose; Cycle 1 Day 22: predose, postdose; Cycle 2 Day 1: predose, postdose. Each cycle is a 21-day cycle.
Hide Outcome Measure Data
Hide Analysis Population Description
As specified by the protocol, the Cl of pembrolizumab was only to be analyzed if required and no data were collected since, by the time of final analysis, pembrolizumab pharmacokinetics (PK) in melanoma participants had been well characterized and found to be consistent with the overall clinical pharmacology of pembrolizumab characterized across indications.
Arm/Group Title Part 3: 2 mg/kg Pembrolizumab+Dabrafenib+Trametinib
Hide Arm/Group Description:
Participants received 2 mg/kg pembrolizumab in combination with 150 mg dabrafenib and 2 mg trametinib Q6W continuing up until study treatment discontinuation.
Overall Number of Participants Analyzed 0
No data displayed because Outcome Measure has zero total analyzed.
44.Secondary Outcome
Title Clearance (Cl) of Pembrolizumab Following Administration of 200 mg Pembrolizumab in Combination With Trametinib in Participants From Part 4
Hide Description Blood samples were to be collected at pre-specified time points for analysis of the Cl of pembrolizumab, defined as the volume of plasma from which pembrolizumab is eliminated per unit time following pembrolizumab administration. This analysis was not performed.
Time Frame Cycle 1 Day 15: predose, postdose, 24 - 96 hrs postdose; Cycle 1 Day 36: predose, postdose; Cycle 2 Day 1: predose, postdose. Each cycle is a 21-day cycle.
Hide Outcome Measure Data
Hide Analysis Population Description
As specified by the protocol, the Cl of pembrolizumab was only to be analyzed if required and no data were collected since, by the time of final analysis, pembrolizumab pharmacokinetics (PK) in melanoma participants had been well characterized and found to be consistent with the overall clinical pharmacology of pembrolizumab characterized across indications.
Arm/Group Title Part 4: 200 mg Pembrolizumab+Trametinib
Hide Arm/Group Description:
Participants received 2 mg or 1.5 mg trametinib orally QD for 2 or 4 weeks (depending on treatment regimen). Starting with Week 3 or 5 (depending on initial trametinib interval), participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and an intermittent or concurrent dose schedule of trametinib orally QD continuing up until study treatment discontinuation.
Overall Number of Participants Analyzed 0
No data displayed because Outcome Measure has zero total analyzed.
45.Secondary Outcome
Title Clearance (Cl) of Pembrolizumab Following Administration of 200 mg Pembrolizumab in Combination With Trametinib in Participants From Part 5
Hide Description Blood samples were to be collected at pre-specified time points for analysis of the Cl of pembrolizumab, defined as the volume of plasma from which pembrolizumab is eliminated per unit time following pembrolizumab administration. This analysis was not performed.
Time Frame Cycle 1 Day 15: predose, postdose, 24 - 96 hrs postdose; Cycle 1 Day 36: predose, postdose; Cycle 2 Day 1: predose, postdose. Each cycle is a 21-day cycle.
Hide Outcome Measure Data
Hide Analysis Population Description
As specified by the protocol, the Cl of pembrolizumab was only to be analyzed if required and no data were collected since, by the time of final analysis, pembrolizumab pharmacokinetics (PK) in melanoma participants had been well characterized and found to be consistent with the overall clinical pharmacology of pembrolizumab characterized across indications.
Arm/Group Title Part 5: 200 mg Pembrolizumab+Trametinib
Hide Arm/Group Description:
Participants received 2 mg or 1.5 mg trametinib orally QD for 2 weeks. Starting with Week 3, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and an intermittent or concurrent dose schedule of trametinib orally QD continuing up until study treatment discontinuation.
Overall Number of Participants Analyzed 0
No data displayed because Outcome Measure has zero total analyzed.
46.Secondary Outcome
Title Clearance (Cl) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination With 2 mg/kg Pembrolizumab and 2 mg Trametinib in Participants Pooled From Parts 1 and 2
Hide Description Blood samples were to be collected at pre-specified time points for analysis of the Cl of dabrafenib, defined as the volume of plasma from which dabrafenib is eliminated per unit time following dabrafenib administration. This analysis was not performed.
Time Frame Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Hide Outcome Measure Data
Hide Analysis Population Description
As specified by the protocol, the Cl of dabrafenib was only to be analyzed if required and no data were collected since, by the time of final analysis, dabrafenib pharmacokinetics (PK) in melanoma participants had been well characterized and found to be consistent with the overall clinical pharmacology of dabrafenib characterized across indications.
Arm/Group Title Pooled Parts 1+2:Pembrolizumab+Dabrafenib+2 mg Trametinib
Hide Arm/Group Description:
Participants pooled from Parts 1 and 2 received 2 mg/kg pembrolizumab in combination with 150 mg dabrafenib and 2 mg trametinib Q6W continuing up until study treatment discontinuation.
Overall Number of Participants Analyzed 0
No data displayed because Outcome Measure has zero total analyzed.
47.Secondary Outcome
Title Clearance (Cl) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination With 2 mg/kg Pembrolizumab and 2 mg Trametinib in Participants From Part 3
Hide Description Blood samples were to be collected at pre-specified time points for analysis of the Cl of dabrafenib, defined as the volume of plasma from which dabrafenib is eliminated per unit time following dabrafenib administration. This analysis was not performed.
Time Frame Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Hide Outcome Measure Data
Hide Analysis Population Description
As specified by the protocol, the Cl of dabrafenib was only to be analyzed if required and no data were collected since, by the time of final analysis, dabrafenib pharmacokinetics (PK) in melanoma participants had been well characterized and found to be consistent with the overall clinical pharmacology of dabrafenib characterized across indications.
Arm/Group Title Part 3: 2 mg/kg Pembrolizumab+Dabrafenib+Trametinib
Hide Arm/Group Description:
Participants received 2 mg/kg pembrolizumab in combination with 150 mg dabrafenib and 2 mg trametinib Q6W continuing up until study treatment discontinuation.
Overall Number of Participants Analyzed 0
No data displayed because Outcome Measure has zero total analyzed.
48.Secondary Outcome
Title Clearance (Cl) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination With Placebo and 2 mg Trametinib in Participants From Part 3
Hide Description Blood samples were to be collected at pre-specified time points for analysis of the Cl of dabrafenib, defined as the volume of plasma from which dabrafenib is eliminated per unit time following dabrafenib administration. This analysis was not performed.
Time Frame Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Hide Outcome Measure Data
Hide Analysis Population Description
As specified by the protocol, the Cl of dabrafenib was only to be analyzed if required and no data were collected since, by the time of final analysis, dabrafenib pharmacokinetics (PK) in melanoma participants had been well characterized and found to be consistent with the overall clinical pharmacology of dabrafenib characterized across indications.
Arm/Group Title Part 3: Placebo+Dabrafenib+Trametinib
Hide Arm/Group Description:
Participants received saline placebo in combination with 150 mg dabrafenib and 2 mg trametinib Q6W continuing up until study treatment discontinuation.
Overall Number of Participants Analyzed 0
No data displayed because Outcome Measure has zero total analyzed.
49.Secondary Outcome
Title Clearance (Cl) of Trametinib Following Administration of 2 mg Trametinib in Combination With 2 mg/kg Pembrolizumab and 150 mg Dabrafenib in Participants Pooled From Parts 1 and 2
Hide Description Blood samples were to be collected at pre-specified time points for analysis of the Cl of trametinib, defined as the volume of plasma from which trametinib is eliminated per unit time following trametinib administration. This analysis was not performed.
Time Frame Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Hide Outcome Measure Data
Hide Analysis Population Description
As specified by the protocol, the Cl of trametinib was only to be analyzed if required and no data were collected since, by the time of final analysis, trametinib pharmacokinetics (PK) in melanoma participants had been well characterized and found to be consistent with the overall clinical pharmacology of trametinib characterized across indications.
Arm/Group Title Pooled Parts 1+2:Pembrolizumab+Dabrafenib+2 mg Trametinib
Hide Arm/Group Description:
Participants pooled from Parts 1 and 2 received 2 mg/kg pembrolizumab in combination with 150 mg dabrafenib and 2 mg trametinib Q6W continuing up until study treatment discontinuation.
Overall Number of Participants Analyzed 0
No data displayed because Outcome Measure has zero total analyzed.
50.Secondary Outcome
Title Clearance (Cl) of Trametinib Following Administration of 1.5 mg Trametinib in Combination With 2 mg/kg Pembrolizumab in Participants Pooled From Parts 1 and 2
Hide Description Blood samples were to be collected at pre-specified time points for analysis of the Cl of trametinib, defined as the volume of plasma from which trametinib is eliminated per unit time following trametinib administration. This analysis was not performed.
Time Frame Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Hide Outcome Measure Data
Hide Analysis Population Description
As specified by the protocol, the Cl of trametinib was only to be analyzed if required and no data were collected since, by the time of final analysis, trametinib pharmacokinetics (PK) in melanoma participants had been well characterized and found to be consistent with the overall clinical pharmacology of trametinib characterized across indications.
Arm/Group Title Pooled Parts 1+2:Pembrolizumab+1.5 mg Trametinib
Hide Arm/Group Description:
Participants pooled from Parts 1 and 2 received 2 mg/kg pembrolizumab in combination with 1.5 mg trametinib Q6W continuing up until study treatment discontinuation.
Overall Number of Participants Analyzed 0
No data displayed because Outcome Measure has zero total analyzed.
51.Secondary Outcome
Title Clearance (Cl) of Trametinib Following Administration of 2 mg Trametinib in Combination With 2 mg/kg Pembrolizumab and 150 mg Dabrafenib in Participants From Part 3
Hide Description Blood samples were to be collected at pre-specified time points for analysis of the Cl of trametinib, defined as the volume of plasma from which trametinib is eliminated per unit time following trametinib administration. This analysis was not performed.
Time Frame Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Hide Outcome Measure Data
Hide Analysis Population Description
As specified by the protocol, the Cl of trametinib was only to be analyzed if required and no data were collected since, by the time of final analysis, trametinib pharmacokinetics (PK) in melanoma participants had been well characterized and found to be consistent with the overall clinical pharmacology of trametinib characterized across indications.
Arm/Group Title Part 3: 2 mg/kg Pembrolizumab+Dabrafenib+Trametinib
Hide Arm/Group Description:
Participants received 2 mg/kg pembrolizumab in combination with 150 mg dabrafenib and 2 mg trametinib Q6W continuing up until study treatment discontinuation.
Overall Number of Participants Analyzed 0
No data displayed because Outcome Measure has zero total analyzed.
52.Secondary Outcome
Title Clearance (Cl) of Trametinib Following Administration of 2 mg Trametinib in Combination With Placebo and 150 mg Dabrafenib in Participants From Part 3
Hide Description Blood samples were to be collected at pre-specified time points for analysis of the Cl of trametinib, defined as the volume of plasma from which trametinib is eliminated per unit time following trametinib administration. This analysis was not performed.
Time Frame Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Hide Outcome Measure Data
Hide Analysis Population Description
As specified by the protocol, the Cl of trametinib was only to be analyzed if required and no data were collected since, by the time of final analysis, trametinib pharmacokinetics (PK) in melanoma participants had been well characterized and found to be consistent with the overall clinical pharmacology of trametinib characterized across indications.
Arm/Group Title Part 3: Placebo+Dabrafenib+Trametinib
Hide Arm/Group Description:
Participants received saline placebo in combination with 150 mg dabrafenib and 2 mg trametinib Q6W continuing up until study treatment discontinuation.
Overall Number of Participants Analyzed 0
No data displayed because Outcome Measure has zero total analyzed.
53.Secondary Outcome
Title Clearance (Cl) of Trametinib Following Administration of 2 mg Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 4
Hide Description Blood samples were to be collected at pre-specified time points for analysis of the Cl of trametinib, defined as the volume of plasma from which trametinib is eliminated per unit time following trametinib administration. This analysis was not performed.
Time Frame Cycle 1 Day 36: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Hide Outcome Measure Data
Hide Analysis Population Description
As specified by the protocol, the Cl of trametinib was only to be analyzed if required and no data were collected since, by the time of final analysis, trametinib pharmacokinetics (PK) in melanoma participants had been well characterized and found to be consistent with the overall clinical pharmacology of trametinib characterized across indications.
Arm/Group Title Part 4: 200 mg Pembrolizumab+2 mg Trametinib
Hide Arm/Group Description:
Participants received 2 mg trametinib orally QD for 2 or 4 weeks (depending on treatment regimen). Starting with Week 3 or 5 (depending on initial trametinib interval), participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and an intermittent or concurrent dose schedule of 2 mg trametinib orally QD continuing up until study treatment discontinuation.
Overall Number of Participants Analyzed 0
No data displayed because Outcome Measure has zero total analyzed.
54.Secondary Outcome
Title Clearance (Cl) of Trametinib Following Administration of 1.5 mg Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 4
Hide Description Blood samples were to be collected at pre-specified time points for analysis of the Cl of trametinib, defined as the volume of plasma from which trametinib is eliminated per unit time following trametinib administration. This analysis was not performed.
Time Frame Cycle 1 Day 36: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Hide Outcome Measure Data
Hide Analysis Population Description
As specified by the protocol, the Cl of trametinib was only to be analyzed if required and no data were collected since, by the time of final analysis, trametinib pharmacokinetics (PK) in melanoma participants had been well characterized and found to be consistent with the overall clinical pharmacology of trametinib characterized across indications.
Arm/Group Title Part 4: 200 mg Pembrolizumab+1.5 mg Trametinib
Hide Arm/Group Description:
Participants received 1.5 mg trametinib orally QD for 2 or 4 weeks (depending on treatment regimen). Starting with Week 3 or 5 (depending on initial trametinib interval), participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and an intermittent or concurrent dose schedule of 1.5 mg trametinib orally QD continuing up until study treatment discontinuation.
Overall Number of Participants Analyzed 0
No data displayed because Outcome Measure has zero total analyzed.
55.Secondary Outcome
Title Clearance (Cl) of Trametinib Following Administration of 2 mg of Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 5
Hide Description Blood samples were to be collected at pre-specified time points for analysis of the Cl of trametinib, defined as the volume of plasma from which trametinib is eliminated per unit time following trametinib administration. This analysis was not performed.
Time Frame Cycle 1 Day 36: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Hide Outcome Measure Data
Hide Analysis Population Description
As specified by the protocol, the Cl of trametinib was only to be analyzed if required and no data were collected since, by the time of final analysis, trametinib pharmacokinetics (PK) in melanoma participants had been well characterized and found to be consistent with the overall clinical pharmacology of trametinib characterized across indications.
Arm/Group Title Part 5: 200 mg Pembrolizumab+2 mg Trametinib
Hide Arm/Group Description:
Participants received 2 mg trametinib orally QD for 2 weeks. Starting with Week 3, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and an intermittent or concurrent dose schedule of 2 mg trametinib orally QD continuing up until study treatment discontinuation.
Overall Number of Participants Analyzed 0
No data displayed because Outcome Measure has zero total analyzed.
56.Secondary Outcome
Title Clearance (Cl) of Trametinib Following Administration of 1.5 mg of Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 5
Hide Description Blood samples were to be collected at pre-specified time points for analysis of the Cl of trametinib, defined as the volume of plasma from which trametinib is eliminated per unit time following trametinib administration. This analysis was not performed.
Time Frame Cycle 1 Day 36: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Hide Outcome Measure Data
Hide Analysis Population Description
As specified by the protocol, the Cl of trametinib was only to be analyzed if required and no data were collected since, by the time of final analysis, trametinib pharmacokinetics (PK) in melanoma participants had been well characterized and found to be consistent with the overall clinical pharmacology of trametinib characterized across indications.
Arm/Group Title Part 5: 200 mg Pembrolizumab+1.5 mg Trametinib
Hide Arm/Group Description:
Participants received 1.5 mg trametinib orally QD for 2 weeks. Starting with Week 3, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and an intermittent or concurrent dose schedule of 1.5 mg trametinib orally QD continuing up until study treatment discontinuation.
Overall Number of Participants Analyzed 0
No data displayed because Outcome Measure has zero total analyzed.
57.Secondary Outcome
Title Volume of Distribution (Vc) of Pembrolizumab Following Administration of 2 mg/kg Pembrolizumab in Combination With Dabrafenib and/or Trametinib in Participants Pooled From Parts 1 and 2
Hide Description Blood samples were to be collected at pre-specified time points for analysis of the Vc of pembrolizumab, defined as the theoretical volume that would be necessary to contain the total amount of administered pembrolizumab at the same concentration that it is observed in the blood plasma. This analysis was not performed.
Time Frame Cycle 1 Day 1: predose, postdose, 24 - 96 hours (hrs) postdose; Cycle 1 Day 22: predose, postdose; Cycle 2 Day 1: predose, postdose. Each cycle is a 21-day cycle.
Hide Outcome Measure Data
Hide Analysis Population Description
As specified by the protocol, the Vc of pembrolizumab was only to be analyzed if required and no data were collected since, by the time of final analysis, pembrolizumab pharmacokinetics (PK) in melanoma participants had been well characterized and found to be consistent with the overall clinical pharmacology of pembrolizumab characterized across indications.
Arm/Group Title Pooled Parts 1+2:Pembrolizumab+Dabrafenib+1.5/2 mg Trametinib
Hide Arm/Group Description:
Participants pooled from Parts 1 and 2 received 2 mg/kg pembrolizumab in combination with dabrafenib and 2 mg trametinib OR 2 mg/kg pembrolizumab and 1.5 or 2 mg trametinib (without dabrafenib) Q6W continuing up until study treatment discontinuation.
Overall Number of Participants Analyzed 0
No data displayed because Outcome Measure has zero total analyzed.
58.Secondary Outcome
Title Volume of Distribution (Vc) of Pembrolizumab Following Administration of 2 mg/kg Pembrolizumab in Combination With Dabrafenib and Trametinib in Participants From Part 3
Hide Description Blood samples were to be collected at pre-specified time points for analysis of the Vc of pembrolizumab, defined as the theoretical volume that would be necessary to contain the total amount of administered pembrolizumab at the same concentration that it is observed in the blood plasma. This analysis was not performed.
Time Frame Cycle 1 Day 1: predose, postdose, 24 - 96 hours (hrs) postdose; Cycle 1 Day 22: predose, postdose; Cycle 2 Day 1: predose, postdose. Each cycle is a 21-day cycle.
Hide Outcome Measure Data
Hide Analysis Population Description
As specified by the protocol, the Vc of pembrolizumab was only to be analyzed if required and no data were collected since, by the time of final analysis, pembrolizumab pharmacokinetics (PK) in melanoma participants had been well characterized and found to be consistent with the overall clinical pharmacology of pembrolizumab characterized across indications.
Arm/Group Title Part 3: 2 mg/kg Pembrolizumab+Dabrafenib+Trametinib
Hide Arm/Group Description:
Participants received 2 mg/kg pembrolizumab in combination with 150 mg dabrafenib and 2 mg trametinib Q6W continuing up until study treatment discontinuation.
Overall Number of Participants Analyzed 0
No data displayed because Outcome Measure has zero total analyzed.
59.Secondary Outcome
Title Volume of Distribution (Vc) of Pembrolizumab Following Administration of 200 mg Pembrolizumab in Combination With Trametinib in Participants From Part 4
Hide Description Blood samples were to be collected at pre-specified time points for analysis of the Vc of pembrolizumab, defined as the theoretical volume that would be necessary to contain the total amount of administered pembrolizumab at the same concentration that it is observed in the blood plasma. This analysis was not performed.
Time Frame Cycle 1 Day 15: predose, postdose, 24 - 96 hrs postdose; Cycle 1 Day 36: predose, postdose; Cycle 2 Day 1: predose, postdose. Each cycle is a 21-day cycle.
Hide Outcome Measure Data
Hide Analysis Population Description
As specified by the protocol, the Vc of pembrolizumab was only to be analyzed if required and no data were collected since, by the time of final analysis, pembrolizumab pharmacokinetics (PK) in melanoma participants had been well characterized and found to be consistent with the overall clinical pharmacology of pembrolizumab characterized across indications.
Arm/Group Title Part 4: 200 mg Pembrolizumab+Trametinib
Hide Arm/Group Description:
Participants received 2 mg or 1.5 mg trametinib orally QD for 2 or 4 weeks (depending on treatment regimen). Starting with Week 3 or 5 (depending on initial trametinib interval), participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and an intermittent or concurrent dose schedule of trametinib orally QD continuing up until study treatment discontinuation.
Overall Number of Participants Analyzed 0
No data displayed because Outcome Measure has zero total analyzed.
60.Secondary Outcome
Title Volume of Distribution (Vc) of Pembrolizumab Following Administration of 200 mg Pembrolizumab in Combination With Trametinib in Participants From Part 5
Hide Description Blood samples were to be collected at pre-specified time points for analysis of the Vc of pembrolizumab, defined as the theoretical volume that would be necessary to contain the total amount of administered pembrolizumab at the same concentration that it is observed in the blood plasma. This analysis was not performed.
Time Frame Cycle 1 Day 15: predose, postdose, 24 - 96 hrs postdose; Cycle 1 Day 36: predose, postdose; Cycle 2 Day 1: predose, postdose. Each cycle is a 21-day cycle.
Hide Outcome Measure Data
Hide Analysis Population Description
As specified by the protocol, the Vc of pembrolizumab was only to be analyzed if required and no data were collected since, by the time of final analysis, pembrolizumab pharmacokinetics (PK) in melanoma participants had been well characterized and found to be consistent with the overall clinical pharmacology of pembrolizumab characterized across indications.
Arm/Group Title Part 5: 200 mg Pembrolizumab+Trametinib
Hide Arm/Group Description:
Participants received 2 mg or 1.5 mg trametinib orally QD for 2 weeks. Starting with Week 3, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and an intermittent or concurrent dose schedule of trametinib orally QD continuing up until study treatment discontinuation.
Overall Number of Participants Analyzed 0
No data displayed because Outcome Measure has zero total analyzed.
61.Secondary Outcome
Title Volume of Distribution (Vc) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination With 2 mg/kg Pembrolizumab and 2 mg Trametinib in Participants Pooled From Parts 1 and 2
Hide Description Blood samples were to be collected at pre-specified time points for analysis of the Vc of dabrafenib, defined as the theoretical volume that would be necessary to contain the total amount of administered dabrafenib at the same concentration that it is observed in the blood plasma. This analysis was not performed.
Time Frame Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Hide Outcome Measure Data
Hide Analysis Population Description
As specified by the protocol, the Vc of dabrafenib was only to be analyzed if required and no data were collected since, by the time of final analysis, dabrafenib pharmacokinetics (PK) in melanoma participants had been well characterized and found to be consistent with the overall clinical pharmacology of dabrafenib characterized across indications.
Arm/Group Title Pooled Parts 1+2:Pembrolizumab+Dabrafenib+2 mg Trametinib
Hide Arm/Group Description:
Participants pooled from Parts 1 and 2 received 2 mg/kg pembrolizumab in combination with 150 mg dabrafenib and 2 mg trametinib Q6W continuing up until study treatment discontinuation.
Overall Number of Participants Analyzed 0
No data displayed because Outcome Measure has zero total analyzed.
62.Secondary Outcome
Title Volume of Distribution (Vc) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination With 2 mg/kg Pembrolizumab and 2 mg Trametinib in Participants From Part 3
Hide Description Blood samples were to be collected at pre-specified time points for analysis of the Vc of dabrafenib, defined as the theoretical volume that would be necessary to contain the total amount of administered dabrafenib at the same concentration that it is observed in the blood plasma. This analysis was not performed.
Time Frame Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Hide Outcome Measure Data
Hide Analysis Population Description
As specified by the protocol, the Vc of dabrafenib was only to be analyzed if required and no data were collected since, by the time of final analysis, dabrafenib pharmacokinetics (PK) in melanoma participants had been well characterized and found to be consistent with the overall clinical pharmacology of dabrafenib characterized across indications.
Arm/Group Title Part 3: 2 mg/kg Pembrolizumab+Dabrafenib+Trametinib
Hide Arm/Group Description:
Participants received 2 mg/kg pembrolizumab in combination with 150 mg dabrafenib and 2 mg trametinib Q6W continuing up until study treatment discontinuation.
Overall Number of Participants Analyzed 0
No data displayed because Outcome Measure has zero total analyzed.
63.Secondary Outcome
Title Volume of Distribution (Vc) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination With Placebo and 2 mg Trametinib in Participants From Part 3
Hide Description Blood samples were to be collected at pre-specified time points for analysis of the Vc of dabrafenib, defined as the theoretical volume that would be necessary to contain the total amount of administered dabrafenib at the same concentration that it is observed in the blood plasma. This analysis was not performed.
Time Frame Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Hide Outcome Measure Data
Hide Analysis Population Description
As specified by the protocol, the Vc of dabrafenib was only to be analyzed if required and no data were collected since, by the time of final analysis, dabrafenib pharmacokinetics (PK) in melanoma participants had been well characterized and found to be consistent with the overall clinical pharmacology of dabrafenib characterized across indications.
Arm/Group Title Part 3: Placebo+Dabrafenib+Trametinib
Hide Arm/Group Description:
Participants received saline placebo in combination with 150 mg dabrafenib and 2 mg trametinib Q6W continuing up until study treatment discontinuation.
Overall Number of Participants Analyzed 0
No data displayed because Outcome Measure has zero total analyzed.
64.Secondary Outcome
Title Volume of Distribution (Vc) of Trametinib Following Administration of 2 mg Trametinib in Combination With 2 mg/kg Pembrolizumab and 150 mg Dabrafenib in Participants Pooled From Parts 1 and 2
Hide Description Blood samples were to be collected at pre-specified time points for analysis of the Vc of trametinib, defined as the theoretical volume that would be necessary to contain the total amount of administered trametinib at the same concentration that it is observed in the blood plasma. This analysis was not performed.
Time Frame Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Hide Outcome Measure Data
Hide Analysis Population Description
As specified by the protocol, the Vc of trametinib was only to be analyzed if required and no data were collected since, by the time of final analysis, trametinib pharmacokinetics (PK) in melanoma participants had been well characterized and found to be consistent with the overall clinical pharmacology of trametinib characterized across indications.
Arm/Group Title Pooled Parts 1+2:Pembrolizumab+Dabrafenib+2 mg Trametinib
Hide Arm/Group Description:
Participants pooled from Parts 1 and 2 received 2 mg/kg pembrolizumab in combination with 150 mg dabrafenib and 2 mg trametinib Q6W continuing up until study treatment discontinuation.
Overall Number of Participants Analyzed 0
No data displayed because Outcome Measure has zero total analyzed.
65.Secondary Outcome
Title Volume of Distribution (Vc) of Trametinib Following Administration of 1.5 mg Trametinib in Combination With 2 mg/kg Pembrolizumab in Participants Pooled From Parts 1 and 2
Hide Description Blood samples were to be collected at pre-specified time points for analysis of the Vc of trametinib, defined as the theoretical volume that would be necessary to contain the total amount of administered trametinib at the same concentration that it is observed in the blood plasma. This analysis was not performed.
Time Frame Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Hide Outcome Measure Data
Hide Analysis Population Description
As specified by the protocol, the Vc of trametinib was only to be analyzed if required and no data were collected since, by the time of final analysis, trametinib pharmacokinetics (PK) in melanoma participants had been well characterized and found to be consistent with the overall clinical pharmacology of trametinib characterized across indications.
Arm/Group Title Pooled Parts 1+2:Pembrolizumab+1.5 mg Trametinib
Hide Arm/Group Description:
Participants pooled from Parts 1 and 2 received 2 mg/kg pembrolizumab in combination with 1.5 mg trametinib Q6W continuing up until study treatment discontinuation.
Overall Number of Participants Analyzed 0
No data displayed because Outcome Measure has zero total analyzed.
66.Secondary Outcome
Title Volume of Distribution (Vc) of Trametinib Following Administration of 2 mg Trametinib in Combination With 2 mg/kg Pembrolizumab and 150 mg Dabrafenib in Participants From Part 3
Hide Description Blood samples were to be collected at pre-specified time points for analysis of the Vc of trametinib, defined as the theoretical volume that would be necessary to contain the total amount of administered trametinib at the same concentration that it is observed in the blood plasma. This analysis was not performed.
Time Frame Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Hide Outcome Measure Data
Hide Analysis Population Description
As specified by the protocol, the Vc of trametinib was only to be analyzed if required and no data were collected since, by the time of final analysis, trametinib pharmacokinetics (PK) in melanoma participants had been well characterized and found to be consistent with the overall clinical pharmacology of trametinib characterized across indications.
Arm/Group Title Part 3: 2 mg/kg Pembrolizumab+Dabrafenib+Trametinib
Hide Arm/Group Description:
Participants received 2 mg/kg pembrolizumab in combination with 150 mg dabrafenib and 2 mg trametinib Q6W continuing up until study treatment discontinuation.
Overall Number of Participants Analyzed 0
No data displayed because Outcome Measure has zero total analyzed.
67.Secondary Outcome
Title Volume of Distribution (Vc) of Trametinib Following Administration of 2 mg Trametinib in Combination With Placebo and 150 mg Dabrafenib in Participants From Part 3
Hide Description Blood samples were to be collected at pre-specified time points for analysis of the Vc of trametinib, defined as the theoretical volume that would be necessary to contain the total amount of administered trametinib at the same concentration that it is observed in the blood plasma. This analysis was not performed.
Time Frame Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Hide Outcome Measure Data
Hide Analysis Population Description
As specified by the protocol, the Vc of trametinib was only to be analyzed if required and no data were collected since, by the time of final analysis, trametinib pharmacokinetics (PK) in melanoma participants had been well characterized and found to be consistent with the overall clinical pharmacology of trametinib characterized across indications.
Arm/Group Title Part 3: Placebo+Dabrafenib+Trametinib
Hide Arm/Group Description:
Participants received saline placebo in combination with 150 mg dabrafenib and 2 mg trametinib Q6W continuing up until study treatment discontinuation.
Overall Number of Participants Analyzed 0
No data displayed because Outcome Measure has zero total analyzed.
68.Secondary Outcome
Title Volume of Distribution (Vc) of Trametinib Following Administration of 2 mg Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 4
Hide Description Blood samples were to be collected at pre-specified time points for analysis of the Vc of trametinib, defined as the theoretical volume that would be necessary to contain the total amount of administered trametinib at the same concentration that it is observed in the blood plasma. This analysis was not performed.
Time Frame Cycle 1 Day 36: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Hide Outcome Measure Data
Hide Analysis Population Description
As specified by the protocol, the Vc of trametinib was only to be analyzed if required and no data were collected since, by the time of final analysis, trametinib pharmacokinetics (PK) in melanoma participants had been well characterized and found to be consistent with the overall clinical pharmacology of trametinib characterized across indications.
Arm/Group Title Part 4: 200 mg Pembrolizumab+2 mg Trametinib
Hide Arm/Group Description:
Participants received 2 mg trametinib orally QD for 2 or 4 weeks (depending on treatment regimen). Starting with Week 3 or 5 (depending on initial trametinib interval), participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and an intermittent or concurrent dose schedule of 2 mg trametinib orally QD continuing up until study treatment discontinuation.
Overall Number of Participants Analyzed 0
No data displayed because Outcome Measure has zero total analyzed.
69.Secondary Outcome
Title Volume of Distribution (Vc) of Trametinib Following Administration of 1.5 mg Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 4
Hide Description Blood samples were to be collected at pre-specified time points for analysis of the Vc of trametinib, defined as the theoretical volume that would be necessary to contain the total amount of administered trametinib at the same concentration that it is observed in the blood plasma. This analysis was not performed.
Time Frame Cycle 1 Day 36: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Hide Outcome Measure Data
Hide Analysis Population Description
As specified by the protocol, the Vc of trametinib was only to be analyzed if required and no data were collected since, by the time of final analysis, trametinib pharmacokinetics (PK) in melanoma participants had been well characterized and found to be consistent with the overall clinical pharmacology of trametinib characterized across indications.
Arm/Group Title Part 4: 200 mg Pembrolizumab+1.5 mg Trametinib
Hide Arm/Group Description:
Participants received 1.5 mg trametinib orally QD for 2 or 4 weeks (depending on treatment regimen). Starting with Week 3 or 5 (depending on initial trametinib interval), participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and an intermittent or concurrent dose schedule of 1.5 mg trametinib orally QD continuing up until study treatment discontinuation.
Overall Number of Participants Analyzed 0
No data displayed because Outcome Measure has zero total analyzed.
70.Secondary Outcome
Title Volume of Distribution (Vc) of Trametinib Following Administration of 2 mg of Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 5
Hide Description Blood samples were to be collected at pre-specified time points for analysis of the Vc of trametinib, defined as the theoretical volume that would be necessary to contain the total amount of administered trametinib at the same concentration that it is observed in the blood plasma. This analysis was not performed.
Time Frame Cycle 1 Day 36: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Hide Outcome Measure Data
Hide Analysis Population Description
As specified by the protocol, the Vc of trametinib was only to be analyzed if required and no data were collected since, by the time of final analysis, trametinib pharmacokinetics (PK) in melanoma participants had been well characterized and found to be consistent with the overall clinical pharmacology of trametinib characterized across indications.
Arm/Group Title Part 5: 200 mg Pembrolizumab+2 mg Trametinib
Hide Arm/Group Description:
Participants received 2 mg trametinib orally QD for 2 weeks. Starting with Week 3, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and an intermittent or concurrent dose schedule of 2 mg trametinib orally QD continuing up until study treatment discontinuation.
Overall Number of Participants Analyzed 0
No data displayed because Outcome Measure has zero total analyzed.
71.Secondary Outcome
Title Volume of Distribution (Vc) of Trametinib Following Administration of 1.5 mg of Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 5
Hide Description Blood samples were to be collected at pre-specified time points for analysis of the Vc of trametinib, defined as the theoretical volume that would be necessary to contain the total amount of administered trametinib at the same concentration that it is observed in the blood plasma. This analysis was not performed.
Time Frame Cycle 1 Day 36: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.
Hide Outcome Measure Data
Hide Analysis Population Description
As specified by the protocol, the Vc of trametinib was only to be analyzed if required and no data were collected since, by the time of final analysis, trametinib pharmacokinetics (PK) in melanoma participants had been well characterized and found to be consistent with the overall clinical pharmacology of trametinib characterized across indications.
Arm/Group Title Part 5: 200 mg Pembrolizumab+1.5 mg Trametinib
Hide Arm/Group Description:
Participants received 1.5 mg trametinib orally QD for 2 weeks. Starting with Week 3, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and an intermittent or concurrent dose schedule of 1.5 mg trametinib orally QD continuing up until study treatment discontinuation.
Overall Number of Participants Analyzed 0
No data displayed because Outcome Measure has zero total analyzed.
Time Frame Up to approximately 85 months
Adverse Event Reporting Description All-cause mortality=all randomized participants and adverse events (AE)=all participants who received ≥1 dose of treatment. Per protocol, disease progression was not considered an AE unless related to treatment. Medical Dictionary for Regulatory Activities (MedDRA) terms neoplasm progression, malignant neoplasm progression, and disease progression not related to treatment were excluded.
 
Arm/Group Title Part 1:Pembrolizumab 2 mg/kg+Dabrafenib 150 mg+Trametinib 2 mg Part 1:Pembrolizumab 2 mg/kg+Trametinib 2 mg Part 1:Pembrolizumab 2 mg/kg+Trametinib 1.5 mg Part 2:Pembrolizumab 2 mg/kg+Dabrafenib 150 mg+Trametinib 2 mg Part 2:Pembrolizumab 2 mg/kg+Trametinib 1.5 mg Part 3:Pembrolizumab 2 mg/kg+Dabrafenib 150 mg+Trametinib 2 mg Part 3:Placebo+Dabrafenib 150 mg+Trametinib 2 mg Part 4:4 Weeks Trametinib (Tra) 2mg; Pembrolizumab+Tra 2mg Part 4:2 Weeks Tra 1.5mg; Pembrolizumab+Tra 1.5mg Part 4:4 Weeks Tra 1.5mg; Pembrolizumab+Tra 1.5mg Part 4:2 Weeks Tra 2mg; Pembrolizumab+Tra 2mg Intermittent Part 4:2 Weeks Tra 1.5mg; Pembrolizumab+Tra 1.5mg Intermittent Part 5:2 Weeks Tra 1.5mg; Pembrolizumab+Tra 1.5mg Part 5:2 Weeks Tra 2mg; Pembrolizumab+Tra 2mg Intermittent
Hide Arm/Group Description Participants with BRAF mutant melanoma received 2 mg/kg pembrolizumab administered by intravenous (IV) infusion on Days 1 and 22 of each 6-week cycle (Q6W); 150 mg/day total dabrafenib orally, in a divided dose, twice a day (BID) starting on Day 1 and continuing up until study treatment discontinuation; and 2 mg trametinib orally once a day (QD) starting on Day 1 and continuing up until study treatment discontinuation. Participants with BRAF wild-type melanoma received 2 mg/kg pembrolizumab administered by IV infusion on Days 1 and 22 Q6W and 2 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation. Participants with BRAF wild-type melanoma received 2 mg/kg pembrolizumab administered by IV infusion on Days 1 and 22 Q6W and 1.5 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation. Participants with BRAF mutant melanoma received 2 mg/kg pembrolizumab administered by IV infusion on Days 1 and 22 Q6W; 150 mg/day total dabrafenib orally, in a divided dose, BID starting on Day 1 and continuing up until study treatment discontinuation; and 2 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation. Participants with BRAF wild-type melanoma received 2 mg/kg pembrolizumab administered by IV infusion on Days 1 and 22 Q6W and 1.5 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation. Participants with BRAF mutant melanoma received 2 mg/kg pembrolizumab administered by IV infusion on Days 1 and 22 Q6W; 150 mg/day total dabrafenib orally, in a divided dose, BID starting on Day 1 and continuing up until study treatment discontinuation; and 2 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation. Participants with BRAF mutant melanoma received saline placebo administered by IV infusion on Days 1 and 22 Q6W; 150 mg/day total dabrafenib orally, in a divided dose, BID starting on Day 1 and continuing up until study treatment discontinuation; and 2 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation. Participants with BRAF wild-type melanoma or solid tumors (irrespective of BRAF status) received 2 mg trametinib orally QD for 4 weeks. Starting with Week 5, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 of each 3-week cycle (Q3W) and a concurrent dosing schedule of 2 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation. Participants with BRAF wild-type melanoma or solid tumors (irrespective of BRAF status) received 1.5 mg trametinib orally QD for 2 weeks. Starting with Week 3, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and a concurrent dosing schedule of 1.5 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation. Participants with BRAF wild-type melanoma or solid tumors (irrespective of BRAF status) received 1.5 mg trametinib orally QD for 4 weeks. Starting with Week 5, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and a concurrent dosing schedule of 1.5 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation. Participants with BRAF wild-type melanoma or solid tumors (irrespective of BRAF status) received 2 mg trametinib orally QD for 2 weeks. Starting with Week 3, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and an intermittent dose schedule of 2 mg trametinib orally QD with 1 week OFF trametinib and 2 weeks ON trametinib continuing up until study treatment discontinuation. Participants with BRAF wild-type melanoma or solid tumors (irrespective of BRAF status) received 1.5 mg trametinib orally QD for 2 weeks. Starting with Week 3, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and an intermittent dose schedule of 1.5 mg trametinib orally QD with 1 week OFF trametinib and 2 weeks ON trametinib continuing up until study treatment discontinuation. Participants with BRAF wild-type melanoma or solid tumors (irrespective of BRAF status) received 1.5 mg trametinib orally QD for 2 weeks. Starting with Week 3, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and a concurrent dosing schedule of 1.5 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation. Participants with BRAF wild-type melanoma or solid tumors (irrespective of BRAF status) received 2 mg trametinib orally QD for 2 weeks. Starting with Week 3, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and an intermittent dose schedule of 2 mg trametinib orally QD with 1 week OFF trametinib and 2 weeks ON trametinib continuing up until study treatment discontinuation.
All-Cause Mortality
Part 1:Pembrolizumab 2 mg/kg+Dabrafenib 150 mg+Trametinib 2 mg Part 1:Pembrolizumab 2 mg/kg+Trametinib 2 mg Part 1:Pembrolizumab 2 mg/kg+Trametinib 1.5 mg Part 2:Pembrolizumab 2 mg/kg+Dabrafenib 150 mg+Trametinib 2 mg Part 2:Pembrolizumab 2 mg/kg+Trametinib 1.5 mg Part 3:Pembrolizumab 2 mg/kg+Dabrafenib 150 mg+Trametinib 2 mg Part 3:Placebo+Dabrafenib 150 mg+Trametinib 2 mg Part 4:4 Weeks Trametinib (Tra) 2mg; Pembrolizumab+Tra 2mg Part 4:2 Weeks Tra 1.5mg; Pembrolizumab+Tra 1.5mg Part 4:4 Weeks Tra 1.5mg; Pembrolizumab+Tra 1.5mg Part 4:2 Weeks Tra 2mg; Pembrolizumab+Tra 2mg Intermittent Part 4:2 Weeks Tra 1.5mg; Pembrolizumab+Tra 1.5mg Intermittent Part 5:2 Weeks Tra 1.5mg; Pembrolizumab+Tra 1.5mg Part 5:2 Weeks Tra 2mg; Pembrolizumab+Tra 2mg Intermittent
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   4/7 (57.14%)      1/3 (33.33%)      1/2 (50.00%)      3/8 (37.50%)      2/2 (100.00%)      31/60 (51.67%)      45/60 (75.00%)      2/3 (66.67%)      3/4 (75.00%)      4/5 (80.00%)      5/6 (83.33%)      3/3 (100.00%)      11/12 (91.67%)      7/9 (77.78%)    
Hide Serious Adverse Events
Part 1:Pembrolizumab 2 mg/kg+Dabrafenib 150 mg+Trametinib 2 mg Part 1:Pembrolizumab 2 mg/kg+Trametinib 2 mg Part 1:Pembrolizumab 2 mg/kg+Trametinib 1.5 mg Part 2:Pembrolizumab 2 mg/kg+Dabrafenib 150 mg+Trametinib 2 mg Part 2:Pembrolizumab 2 mg/kg+Trametinib 1.5 mg Part 3:Pembrolizumab 2 mg/kg+Dabrafenib 150 mg+Trametinib 2 mg Part 3:Placebo+Dabrafenib 150 mg+Trametinib 2 mg Part 4:4 Weeks Trametinib (Tra) 2mg; Pembrolizumab+Tra 2mg Part 4:2 Weeks Tra 1.5mg; Pembrolizumab+Tra 1.5mg Part 4:4 Weeks Tra 1.5mg; Pembrolizumab+Tra 1.5mg Part 4:2 Weeks Tra 2mg; Pembrolizumab+Tra 2mg Intermittent Part 4:2 Weeks Tra 1.5mg; Pembrolizumab+Tra 1.5mg Intermittent Part 5:2 Weeks Tra 1.5mg; Pembrolizumab+Tra 1.5mg Part 5:2 Weeks Tra 2mg; Pembrolizumab+Tra 2mg Intermittent
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   1/7 (14.29%)      0/3 (0.00%)      1/2 (50.00%)      3/8 (37.50%)      1/2 (50.00%)      36/60 (60.00%)      20/60 (33.33%)      1/3 (33.33%)      1/4 (25.00%)      4/5 (80.00%)      4/6 (66.67%)      1/3 (33.33%)      4/12 (33.33%)      2/9 (22.22%)    
Blood and lymphatic system disorders                             
Anaemia † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 1/3 (33.33%)  1 0/4 (0.00%)  0 0/5 (0.00%)  0 1/6 (16.67%)  1 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Febrile neutropenia † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 1/60 (1.67%)  1 0/60 (0.00%)  0 1/3 (33.33%)  1 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Neutropenia † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 1/60 (1.67%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Thrombocytopenia † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 1/3 (33.33%)  1 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Cardiac disorders                             
Atrial fibrillation † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 1/60 (1.67%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Mitral valve incompetence † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 1/60 (1.67%)  1 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Myocardial infarction † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 1/2 (50.00%)  1 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Tachycardia † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 1/60 (1.67%)  1 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Endocrine disorders                             
Hypophysitis † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 1/60 (1.67%)  1 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Eye disorders                             
Detachment of retinal pigment epithelium † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 1/60 (1.67%)  1 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Retinal detachment † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 1/60 (1.67%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Uveitis † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 1/60 (1.67%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Gastrointestinal disorders                             
Colitis † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 1/60 (1.67%)  1 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Diarrhoea † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 2/60 (3.33%)  2 1/60 (1.67%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Discoloured vomit † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 1/60 (1.67%)  1 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Dysphagia † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  1 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Faeces discoloured † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 1/60 (1.67%)  1 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Lip swelling † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 1/60 (1.67%)  1 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
General disorders                             
Chills † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 2/60 (3.33%)  2 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Death † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 1/60 (1.67%)  1 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Influenza like illness † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 1/60 (1.67%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Mucosal haemorrhage † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  2 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Oedema peripheral † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 1/60 (1.67%)  1 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Pyrexia † 1  1/7 (14.29%)  1 0/3 (0.00%)  0 0/2 (0.00%)  0 1/8 (12.50%)  1 0/2 (0.00%)  0 5/60 (8.33%)  9 8/60 (13.33%)  9 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/6 (16.67%)  1 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Hepatobiliary disorders                             
Cholecystitis † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 1/60 (1.67%)  1 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Drug-induced liver injury † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 1/60 (1.67%)  1 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Immune-mediated hepatitis † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 1/8 (12.50%)  1 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Infections and infestations                             
Abdominal infection † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 1/60 (1.67%)  1 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Bacterial sepsis † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  1 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Cellulitis † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  1 1/6 (16.67%)  1 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Gastroenteritis † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 1/60 (1.67%)  1 1/3 (33.33%)  1 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Gastroenteritis viral † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 1/60 (1.67%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Infection † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 1/60 (1.67%)  1 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Lymphangitis † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 1/60 (1.67%)  1 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Meningitis aseptic † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/6 (16.67%)  1 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Parotitis † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 1/60 (1.67%)  1 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Peritonitis bacterial † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/9 (11.11%)  1
Pneumonia † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 2/60 (3.33%)  2 0/60 (0.00%)  0 0/3 (0.00%)  0 1/4 (25.00%)  1 0/5 (0.00%)  0 0/6 (0.00%)  0 1/3 (33.33%)  1 1/12 (8.33%)  1 0/9 (0.00%)  0
Pneumonia chlamydial † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 0/9 (0.00%)  0
Respiratory tract infection † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/6 (16.67%)  1 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Sepsis † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 2/60 (3.33%)  2 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Septic shock † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 1/60 (1.67%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Streptococcal infection † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/9 (11.11%)  1
Tubo-ovarian abscess † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 1/60 (1.67%)  1 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Upper respiratory tract infection † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 1/60 (1.67%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Injury, poisoning and procedural complications                             
Tendon rupture † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 1/60 (1.67%)  1 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Investigations                             
Alanine aminotransferase increased † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 1/8 (12.50%)  1 0/2 (0.00%)  0 1/60 (1.67%)  1 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  1 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Amylase increased † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  1 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Aspartate aminotransferase increased † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 1/8 (12.50%)  1 0/2 (0.00%)  0 1/60 (1.67%)  1 1/60 (1.67%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  1 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Blood creatinine increased † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 1/60 (1.67%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Gamma-glutamyltransferase increased † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 1/8 (12.50%)  1 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Lipase increased † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  1 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Metabolism and nutrition disorders                             
Diabetes mellitus † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 1/60 (1.67%)  1 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Fluid retention † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 1/60 (1.67%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Hypocalcaemia † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 0/9 (0.00%)  0
Musculoskeletal and connective tissue disorders                             
Muscular weakness † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/6 (16.67%)  1 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Myalgia † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 1/60 (1.67%)  1 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Myositis † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 1/2 (50.00%)  1 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)                             
Angiosarcoma † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 1/60 (1.67%)  1 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Basal cell carcinoma † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 2/60 (3.33%)  2 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Bowen's disease † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 1/60 (1.67%)  2 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Breast cancer † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 1/60 (1.67%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Skin angiosarcoma † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 1/60 (1.67%)  1 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Squamous cell carcinoma † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 1/60 (1.67%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Squamous cell carcinoma of skin † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 1/60 (1.67%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Nervous system disorders                             
Acute motor axonal neuropathy † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 1/60 (1.67%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Brain oedema † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/6 (16.67%)  1 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Cerebral haemorrhage † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 1/60 (1.67%)  1 1/60 (1.67%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Haemorrhagic stroke † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 1/60 (1.67%)  1 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Headache † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 1/60 (1.67%)  1 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Peripheral motor neuropathy † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 1/60 (1.67%)  1 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Sciatica † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 1/8 (12.50%)  1 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Renal and urinary disorders                             
Acute kidney injury † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 0/9 (0.00%)  0
Nephrolithiasis † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 1/2 (50.00%)  1 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Renal impairment † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 1/60 (1.67%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Tubulointerstitial nephritis † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 2/60 (3.33%)  2 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Respiratory, thoracic and mediastinal disorders                             
Dyspnoea † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 1/60 (1.67%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Pneumomediastinum † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  1 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Pneumonitis † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 6/60 (10.00%)  7 1/60 (1.67%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  1 1/6 (16.67%)  1 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Pulmonary embolism † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 1/60 (1.67%)  1 0/60 (0.00%)  0 0/3 (0.00%)  0 1/4 (25.00%)  1 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Tonsillar hypertrophy † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 1/60 (1.67%)  1 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Skin and subcutaneous tissue disorders                             
Eczema † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 1/60 (1.67%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Rash erythematous † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/6 (16.67%)  1 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Vascular disorders                             
Arterial thrombosis † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 1/4 (25.00%)  1 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Deep vein thrombosis † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 2/60 (3.33%)  2 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Hypertension † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 1/60 (1.67%)  1 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Hypotension † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 1/60 (1.67%)  1 0/60 (0.00%)  0 0/3 (0.00%)  0 1/4 (25.00%)  1 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
1
Term from vocabulary, MedDRA 24.0
†
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Part 1:Pembrolizumab 2 mg/kg+Dabrafenib 150 mg+Trametinib 2 mg Part 1:Pembrolizumab 2 mg/kg+Trametinib 2 mg Part 1:Pembrolizumab 2 mg/kg+Trametinib 1.5 mg Part 2:Pembrolizumab 2 mg/kg+Dabrafenib 150 mg+Trametinib 2 mg Part 2:Pembrolizumab 2 mg/kg+Trametinib 1.5 mg Part 3:Pembrolizumab 2 mg/kg+Dabrafenib 150 mg+Trametinib 2 mg Part 3:Placebo+Dabrafenib 150 mg+Trametinib 2 mg Part 4:4 Weeks Trametinib (Tra) 2mg; Pembrolizumab+Tra 2mg Part 4:2 Weeks Tra 1.5mg; Pembrolizumab+Tra 1.5mg Part 4:4 Weeks Tra 1.5mg; Pembrolizumab+Tra 1.5mg Part 4:2 Weeks Tra 2mg; Pembrolizumab+Tra 2mg Intermittent Part 4:2 Weeks Tra 1.5mg; Pembrolizumab+Tra 1.5mg Intermittent Part 5:2 Weeks Tra 1.5mg; Pembrolizumab+Tra 1.5mg Part 5:2 Weeks Tra 2mg; Pembrolizumab+Tra 2mg Intermittent
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   7/7 (100.00%)      3/3 (100.00%)      2/2 (100.00%)      8/8 (100.00%)      2/2 (100.00%)      60/60 (100.00%)      58/60 (96.67%)      3/3 (100.00%)      4/4 (100.00%)      5/5 (100.00%)      6/6 (100.00%)      3/3 (100.00%)      11/12 (91.67%)      9/9 (100.00%)    
Blood and lymphatic system disorders                             
Anaemia † 1  2/7 (28.57%)  2 0/3 (0.00%)  0 0/2 (0.00%)  0 1/8 (12.50%)  1 0/2 (0.00%)  0 8/60 (13.33%)  13 3/60 (5.00%)  3 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 3/6 (50.00%)  3 1/3 (33.33%)  1 6/12 (50.00%)  6 1/9 (11.11%)  1
Leukocytosis † 1  0/7 (0.00%)  0 2/3 (66.67%)  2 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 1/60 (1.67%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Leukopenia † 1  1/7 (14.29%)  1 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 1/60 (1.67%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/9 (11.11%)  1
Lymphadenopathy † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 1/8 (12.50%)  1 0/2 (0.00%)  0 2/60 (3.33%)  3 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Neutropenia † 1  1/7 (14.29%)  2 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 1/60 (1.67%)  2 6/60 (10.00%)  9 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 1/9 (11.11%)  1
Thrombocytopenia † 1  1/7 (14.29%)  1 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 2/60 (3.33%)  3 0/60 (0.00%)  0 1/3 (33.33%)  1 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 2/12 (16.67%)  2 1/9 (11.11%)  1
Thrombocytosis † 1  0/7 (0.00%)  0 1/3 (33.33%)  1 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Cardiac disorders                             
Atrioventricular block † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  1 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Left ventricular dysfunction † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  1 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Myocardial ischaemia † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  1 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Palpitations † 1  0/7 (0.00%)  0 1/3 (33.33%)  1 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Sinus bradycardia † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 1/8 (12.50%)  1 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Sinus tachycardia † 1  1/7 (14.29%)  1 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 1/60 (1.67%)  1 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Tachycardia † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 1/8 (12.50%)  1 0/2 (0.00%)  0 2/60 (3.33%)  2 2/60 (3.33%)  2 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 0/9 (0.00%)  0
Ear and labyrinth disorders                             
Cerumen impaction † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 0/9 (0.00%)  0
Deafness unilateral † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  1 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Ear discomfort † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  1 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Ear pain † 1  1/7 (14.29%)  1 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 1/60 (1.67%)  1 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  1 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Middle ear effusion † 1  0/7 (0.00%)  0 1/3 (33.33%)  1 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Tympanic membrane disorder † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 1/8 (12.50%)  1 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Vertigo † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 4/60 (6.67%)  4 1/60 (1.67%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Endocrine disorders                             
Hyperthyroidism † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 3/8 (37.50%)  3 0/2 (0.00%)  0 3/60 (5.00%)  3 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/9 (11.11%)  1
Hypopituitarism † 1  1/7 (14.29%)  1 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Hypothyroidism † 1  1/7 (14.29%)  1 0/3 (0.00%)  0 0/2 (0.00%)  0 3/8 (37.50%)  3 0/2 (0.00%)  0 5/60 (8.33%)  6 1/60 (1.67%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 2/5 (40.00%)  2 1/6 (16.67%)  1 0/3 (0.00%)  0 0/12 (0.00%)  0 1/9 (11.11%)  1
Eye disorders                             
Cataract † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 1/8 (12.50%)  1 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 1/3 (33.33%)  1 0/12 (0.00%)  0 0/9 (0.00%)  0
Chorioretinal disorder † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 1/8 (12.50%)  1 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Chorioretinopathy † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  1 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Dry eye † 1  1/7 (14.29%)  1 0/3 (0.00%)  0 0/2 (0.00%)  0 1/8 (12.50%)  1 0/2 (0.00%)  0 3/60 (5.00%)  4 2/60 (3.33%)  2 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 0/9 (0.00%)  0
Eyelid rash † 1  1/7 (14.29%)  1 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Iridocyclitis † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 1/8 (12.50%)  1 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Keratitis † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 1/4 (25.00%)  1 0/5 (0.00%)  0 1/6 (16.67%)  1 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Ocular hyperaemia † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/9 (11.11%)  1
Papilloedema † 1  1/7 (14.29%)  1 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Periorbital oedema † 1  1/7 (14.29%)  1 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 1/60 (1.67%)  1 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/6 (16.67%)  1 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Periorbital swelling † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/9 (11.11%)  1
Photophobia † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 1/60 (1.67%)  1 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/6 (16.67%)  1 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Retinopathy † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 1/60 (1.67%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  1 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Uveitis † 1  1/7 (14.29%)  1 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 3/60 (5.00%)  3 1/60 (1.67%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Vision blurred † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 2/8 (25.00%)  3 0/2 (0.00%)  0 3/60 (5.00%)  3 1/60 (1.67%)  7 0/3 (0.00%)  0 1/4 (25.00%)  1 0/5 (0.00%)  0 1/6 (16.67%)  1 2/3 (66.67%)  2 0/12 (0.00%)  0 0/9 (0.00%)  0
Visual field defect † 1  0/7 (0.00%)  0 1/3 (33.33%)  1 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 1/60 (1.67%)  1 2/60 (3.33%)  2 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Visual impairment † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 2/60 (3.33%)  2 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 1/3 (33.33%)  1 0/12 (0.00%)  0 0/9 (0.00%)  0
Vitreous adhesions † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/9 (11.11%)  1
Vitreous detachment † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 1/60 (1.67%)  1 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/9 (11.11%)  1
Gastrointestinal disorders                             
Abdominal discomfort † 1  1/7 (14.29%)  1 2/3 (66.67%)  2 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 2/60 (3.33%)  2 1/60 (1.67%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Abdominal distension † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  1 1/6 (16.67%)  1 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Abdominal pain † 1  0/7 (0.00%)  0 1/3 (33.33%)  1 0/2 (0.00%)  0 2/8 (25.00%)  2 0/2 (0.00%)  0 3/60 (5.00%)  7 4/60 (6.67%)  4 0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  1 1/6 (16.67%)  4 0/3 (0.00%)  0 1/12 (8.33%)  1 3/9 (33.33%)  4
Abdominal pain lower † 1  1/7 (14.29%)  1 0/3 (0.00%)  0 0/2 (0.00%)  0 1/8 (12.50%)  1 0/2 (0.00%)  0 2/60 (3.33%)  2 1/60 (1.67%)  2 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/9 (11.11%)  1
Abdominal pain upper † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 9/60 (15.00%)  9 3/60 (5.00%)  3 1/3 (33.33%)  1 0/4 (0.00%)  0 1/5 (20.00%)  1 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/9 (11.11%)  1
Angular cheilitis † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 0/9 (0.00%)  0
Ascites † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 1/4 (25.00%)  1 1/5 (20.00%)  1 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 2/9 (22.22%)  2
Change of bowel habit † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/9 (11.11%)  1
Colitis † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 1/60 (1.67%)  2 1/60 (1.67%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/9 (11.11%)  3
Constipation † 1  1/7 (14.29%)  1 1/3 (33.33%)  3 2/2 (100.00%)  2 1/8 (12.50%)  1 0/2 (0.00%)  0 5/60 (8.33%)  7 7/60 (11.67%)  7 1/3 (33.33%)  1 0/4 (0.00%)  0 1/5 (20.00%)  2 3/6 (50.00%)  3 0/3 (0.00%)  0 2/12 (16.67%)  2 3/9 (33.33%)  3
Diarrhoea † 1  5/7 (71.43%)  9 2/3 (66.67%)  6 2/2 (100.00%)  5 6/8 (75.00%)  8 0/2 (0.00%)  0 28/60 (46.67%)  90 17/60 (28.33%)  29 3/3 (100.00%)  4 2/4 (50.00%)  3 2/5 (40.00%)  5 5/6 (83.33%)  15 1/3 (33.33%)  1 5/12 (41.67%)  12 5/9 (55.56%)  11
Dry mouth † 1  2/7 (28.57%)  2 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 8/60 (13.33%)  10 2/60 (3.33%)  2 0/3 (0.00%)  0 1/4 (25.00%)  1 0/5 (0.00%)  0 0/6 (0.00%)  0 1/3 (33.33%)  1 2/12 (16.67%)  2 1/9 (11.11%)  1
Dyspepsia † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 3/60 (5.00%)  5 2/60 (3.33%)  2 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  2 0/9 (0.00%)  0
Dysphagia † 1  0/7 (0.00%)  0 1/3 (33.33%)  1 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 1/60 (1.67%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Frequent bowel movements † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/6 (16.67%)  1 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Gastrooesophageal reflux disease † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 2/60 (3.33%)  2 4/60 (6.67%)  5 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Glossodynia † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  1 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Haematemesis † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 0/9 (0.00%)  0
Haematochezia † 1  1/7 (14.29%)  1 1/3 (33.33%)  1 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 1/60 (1.67%)  1 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/6 (16.67%)  1 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Haemorrhoids † 1  0/7 (0.00%)  0 1/3 (33.33%)  1 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 1/3 (33.33%)  1 0/4 (0.00%)  0 1/5 (20.00%)  1 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Intestinal obstruction † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/9 (11.11%)  1
Large intestine perforation † 1  0/7 (0.00%)  0 1/3 (33.33%)  1 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Lip blister † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/6 (16.67%)  1 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Lip disorder † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 1/2 (50.00%)  1 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Lip oedema † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 1/60 (1.67%)  1 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 0/9 (0.00%)  0
Lip pain † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 1/8 (12.50%)  1 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/6 (16.67%)  1 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Lip ulceration † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/6 (16.67%)  1 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Lower gastrointestinal haemorrhage † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/6 (16.67%)  1 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Mouth ulceration † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 1/8 (12.50%)  2 0/2 (0.00%)  0 3/60 (5.00%)  3 0/60 (0.00%)  0 2/3 (66.67%)  2 1/4 (25.00%)  1 1/5 (20.00%)  1 0/6 (0.00%)  0 1/3 (33.33%)  1 1/12 (8.33%)  1 0/9 (0.00%)  0
Nausea † 1  3/7 (42.86%)  3 3/3 (100.00%)  7 1/2 (50.00%)  2 5/8 (62.50%)  9 0/2 (0.00%)  0 23/60 (38.33%)  46 28/60 (46.67%)  47 0/3 (0.00%)  0 1/4 (25.00%)  1 3/5 (60.00%)  3 3/6 (50.00%)  5 2/3 (66.67%)  2 3/12 (25.00%)  4 2/9 (22.22%)  2
Oral disorder † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  1 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Oral pain † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  1 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Proctalgia † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 1/3 (33.33%)  1 1/12 (8.33%)  1 0/9 (0.00%)  0
Rectal haemorrhage † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 1/60 (1.67%)  1 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 1/3 (33.33%)  1 0/12 (0.00%)  0 0/9 (0.00%)  0
Rectal tenesmus † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 0/9 (0.00%)  0
Stomatitis † 1  0/7 (0.00%)  0 2/3 (66.67%)  3 0/2 (0.00%)  0 0/8 (0.00%)  0 1/2 (50.00%)  1 5/60 (8.33%)  5 3/60 (5.00%)  3 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 0/9 (0.00%)  0
Tongue disorder † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  1 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Tongue oedema † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 0/9 (0.00%)  0
Toothache † 1  1/7 (14.29%)  1 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 3/60 (5.00%)  3 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Vomiting † 1  2/7 (28.57%)  2 1/3 (33.33%)  1 2/2 (100.00%)  2 5/8 (62.50%)  7 0/2 (0.00%)  0 22/60 (36.67%)  55 17/60 (28.33%)  29 0/3 (0.00%)  0 1/4 (25.00%)  1 2/5 (40.00%)  3 3/6 (50.00%)  8 1/3 (33.33%)  1 2/12 (16.67%)  2 2/9 (22.22%)  3
General disorders                             
Asthenia † 1  3/7 (42.86%)  3 1/3 (33.33%)  1 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 19/60 (31.67%)  33 11/60 (18.33%)  14 1/3 (33.33%)  1 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 3/12 (25.00%)  4 1/9 (11.11%)  1
Axillary pain † 1  0/7 (0.00%)  0 1/3 (33.33%)  1 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 2/60 (3.33%)  3 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Catheter site pain † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 1/60 (1.67%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/9 (11.11%)  1
Chest pain † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 3/8 (37.50%)  3 0/2 (0.00%)  0 2/60 (3.33%)  2 2/60 (3.33%)  2 1/3 (33.33%)  1 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Chills † 1  6/7 (85.71%)  21 2/3 (66.67%)  2 0/2 (0.00%)  0 6/8 (75.00%)  12 0/2 (0.00%)  0 21/60 (35.00%)  59 23/60 (38.33%)  51 0/3 (0.00%)  0 2/4 (50.00%)  2 3/5 (60.00%)  5 1/6 (16.67%)  1 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Face oedema † 1  1/7 (14.29%)  1 1/3 (33.33%)  2 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 1/60 (1.67%)  2 0/60 (0.00%)  0 0/3 (0.00%)  0 1/4 (25.00%)  1 1/5 (20.00%)  1 1/6 (16.67%)  1 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Facial pain † 1  0/7 (0.00%)  0 1/3 (33.33%)  1 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Fatigue † 1  4/7 (57.14%)  5 1/3 (33.33%)  1 2/2 (100.00%)  2 6/8 (75.00%)  10 1/2 (50.00%)  2 22/60 (36.67%)  37 25/60 (41.67%)  41 1/3 (33.33%)  1 0/4 (0.00%)  0 1/5 (20.00%)  1 4/6 (66.67%)  4 1/3 (33.33%)  1 3/12 (25.00%)  3 3/9 (33.33%)  3
Feeling abnormal † 1  0/7 (0.00%)  0 1/3 (33.33%)  1 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Feeling cold † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 1/8 (12.50%)  2 0/2 (0.00%)  0 0/60 (0.00%)  0 1/60 (1.67%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Feeling hot † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 1/8 (12.50%)  1 0/2 (0.00%)  0 2/60 (3.33%)  2 1/60 (1.67%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Generalised oedema † 1  1/7 (14.29%)  1 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Impaired healing † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 1/2 (50.00%)  1 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Influenza like illness † 1  2/7 (28.57%)  2 2/3 (66.67%)  2 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 8/60 (13.33%)  15 8/60 (13.33%)  12 0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  1 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Localised oedema † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 1/3 (33.33%)  1 0/12 (0.00%)  0 0/9 (0.00%)  0
Malaise † 1  1/7 (14.29%)  1 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 1/60 (1.67%)  1 1/60 (1.67%)  2 0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  1 0/6 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 0/9 (0.00%)  0
Medical device site rash † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 1/4 (25.00%)  1 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Mucosal inflammation † 1  1/7 (14.29%)  1 1/3 (33.33%)  2 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 3/60 (5.00%)  4 1/60 (1.67%)  1 2/3 (66.67%)  2 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 1/9 (11.11%)  1
Non-cardiac chest pain † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 1/8 (12.50%)  1 0/2 (0.00%)  0 1/60 (1.67%)  1 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Oedema peripheral † 1  0/7 (0.00%)  0 3/3 (100.00%)  8 0/2 (0.00%)  0 2/8 (25.00%)  2 2/2 (100.00%)  2 10/60 (16.67%)  13 5/60 (8.33%)  5 1/3 (33.33%)  2 1/4 (25.00%)  1 2/5 (40.00%)  2 3/6 (50.00%)  3 1/3 (33.33%)  2 4/12 (33.33%)  5 4/9 (44.44%)  4
Pain † 1  1/7 (14.29%)  1 1/3 (33.33%)  1 0/2 (0.00%)  0 1/8 (12.50%)  1 0/2 (0.00%)  0 3/60 (5.00%)  3 1/60 (1.67%)  1 1/3 (33.33%)  1 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Peripheral swelling † 1  1/7 (14.29%)  1 0/3 (0.00%)  0 1/2 (50.00%)  1 1/8 (12.50%)  1 0/2 (0.00%)  0 1/60 (1.67%)  1 2/60 (3.33%)  2 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 1/3 (33.33%)  2 0/12 (0.00%)  0 2/9 (22.22%)  2
Pyrexia † 1  7/7 (100.00%)  23 2/3 (66.67%)  3 0/2 (0.00%)  0 8/8 (100.00%)  25 0/2 (0.00%)  0 50/60 (83.33%)  262 41/60 (68.33%)  118 1/3 (33.33%)  2 2/4 (50.00%)  2 1/5 (20.00%)  1 3/6 (50.00%)  4 1/3 (33.33%)  1 7/12 (58.33%)  14 3/9 (33.33%)  4
Swelling † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 1/60 (1.67%)  1 1/60 (1.67%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 0/9 (0.00%)  0
Temperature intolerance † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 1/2 (50.00%)  1 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 0/9 (0.00%)  0
Hepatobiliary disorders                             
Autoimmune hepatitis † 1  1/7 (14.29%)  1 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 1/60 (1.67%)  1 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Hepatitis † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 1/60 (1.67%)  1 1/60 (1.67%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/6 (16.67%)  1 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Hypertransaminasaemia † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 2/60 (3.33%)  2 1/60 (1.67%)  2 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 0/9 (0.00%)  0
Infections and infestations                             
Catheter site infection † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/9 (11.11%)  1
Cellulitis † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 1/8 (12.50%)  1 0/2 (0.00%)  0 2/60 (3.33%)  3 0/60 (0.00%)  0 1/3 (33.33%)  1 0/4 (0.00%)  0 1/5 (20.00%)  2 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Conjunctivitis † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 5/60 (8.33%)  5 1/60 (1.67%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  1 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Cystitis † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 4/60 (6.67%)  6 4/60 (6.67%)  7 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Ear infection † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 1/2 (50.00%)  1 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 1/60 (1.67%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  1 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Fungal infection † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 1/8 (12.50%)  1 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Fungal skin infection † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 3/60 (5.00%)  3 1/60 (1.67%)  1 1/3 (33.33%)  1 0/4 (0.00%)  0 1/5 (20.00%)  1 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Gastroenteritis † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 1/4 (25.00%)  1 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/9 (11.11%)  1
Genital herpes † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 1/3 (33.33%)  1 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Gingivitis † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/6 (16.67%)  1 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Herpes virus infection † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 1/60 (1.67%)  2 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 0/9 (0.00%)  0
Herpes zoster † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 1/3 (33.33%)  1 0/12 (0.00%)  0 0/9 (0.00%)  0
Influenza † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 1/60 (1.67%)  1 3/60 (5.00%)  4 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 0/9 (0.00%)  0
Nasopharyngitis † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 1/8 (12.50%)  1 0/2 (0.00%)  0 4/60 (6.67%)  5 6/60 (10.00%)  6 0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  2 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Oral candidiasis † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 2/60 (3.33%)  2 3/60 (5.00%)  3 0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  1 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Oral fungal infection † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 1/3 (33.33%)  1 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Oral herpes † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 2/8 (25.00%)  2 0/2 (0.00%)  0 3/60 (5.00%)  4 3/60 (5.00%)  4 0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  1 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Paronychia † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  1 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Pharyngitis † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 1/60 (1.67%)  1 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  1 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Pneumonia † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 4/60 (6.67%)  4 1/60 (1.67%)  2 0/3 (0.00%)  0 1/4 (25.00%)  1 2/5 (40.00%)  2 0/6 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 0/9 (0.00%)  0
Pneumonia klebsiella † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/6 (16.67%)  1 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Pustule † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 1/2 (50.00%)  1 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Rash pustular † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 1/8 (12.50%)  1 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  1 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Sinusitis † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 1/8 (12.50%)  1 0/2 (0.00%)  0 2/60 (3.33%)  2 3/60 (5.00%)  3 0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  1 0/6 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 0/9 (0.00%)  0
Staphylococcal bacteraemia † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 0/9 (0.00%)  0
Tonsillitis † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 0/9 (0.00%)  0
Upper respiratory tract infection † 1  0/7 (0.00%)  0 1/3 (33.33%)  1 0/2 (0.00%)  0 3/8 (37.50%)  3 0/2 (0.00%)  0 3/60 (5.00%)  4 2/60 (3.33%)  2 0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  1 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Urinary tract infection † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 1/2 (50.00%)  1 1/8 (12.50%)  2 0/2 (0.00%)  0 6/60 (10.00%)  9 5/60 (8.33%)  7 0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  2 1/6 (16.67%)  1 0/3 (0.00%)  0 1/12 (8.33%)  1 1/9 (11.11%)  1
Injury, poisoning and procedural complications                             
Accidental overdose † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 2/60 (3.33%)  4 8/60 (13.33%)  11 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/6 (16.67%)  1 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Back injury † 1  0/7 (0.00%)  0 1/3 (33.33%)  1 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Bone contusion † 1  1/7 (14.29%)  1 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Fall † 1  1/7 (14.29%)  2 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 1/60 (1.67%)  3 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Meniscus injury † 1  1/7 (14.29%)  1 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Mouth injury † 1  0/7 (0.00%)  0 1/3 (33.33%)  1 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Procedural pain † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 1/2 (50.00%)  1 0/8 (0.00%)  0 0/2 (0.00%)  0 1/60 (1.67%)  1 1/60 (1.67%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  1 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Rib fracture † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/9 (11.11%)  1
Skin abrasion † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 1/8 (12.50%)  1 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Skin laceration † 1  0/7 (0.00%)  0 1/3 (33.33%)  1 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Sunburn † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 1/8 (12.50%)  1 0/2 (0.00%)  0 0/60 (0.00%)  0 1/60 (1.67%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Wound haemorrhage † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 1/3 (33.33%)  1 0/12 (0.00%)  0 0/9 (0.00%)  0
Wound secretion † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 1/3 (33.33%)  2 0/12 (0.00%)  0 0/9 (0.00%)  0
Investigations                             
Activated partial thromboplastin time prolonged † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 0/9 (0.00%)  0
Alanine aminotransferase increased † 1  3/7 (42.86%)  5 2/3 (66.67%)  2 0/2 (0.00%)  0 2/8 (25.00%)  2 1/2 (50.00%)  1 11/60 (18.33%)  15 11/60 (18.33%)  12 0/3 (0.00%)  0 2/4 (50.00%)  2 2/5 (40.00%)  2 3/6 (50.00%)  3 0/3 (0.00%)  0 6/12 (50.00%)  8 3/9 (33.33%)  5
Amylase abnormal † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 0/9 (0.00%)  0
Amylase increased † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 4/60 (6.67%)  5 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  2 1/6 (16.67%)  2 0/3 (0.00%)  0 0/12 (0.00%)  0 1/9 (11.11%)  1
Aspartate aminotransferase increased † 1  3/7 (42.86%)  5 3/3 (100.00%)  3 0/2 (0.00%)  0 2/8 (25.00%)  3 1/2 (50.00%)  1 12/60 (20.00%)  17 12/60 (20.00%)  14 0/3 (0.00%)  0 3/4 (75.00%)  3 2/5 (40.00%)  4 3/6 (50.00%)  4 0/3 (0.00%)  0 6/12 (50.00%)  10 5/9 (55.56%)  8
Blood alkaline phosphatase increased † 1  1/7 (14.29%)  2 0/3 (0.00%)  0 0/2 (0.00%)  0 2/8 (25.00%)  2 0/2 (0.00%)  0 10/60 (16.67%)  18 12/60 (20.00%)  16 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 2/6 (33.33%)  2 0/3 (0.00%)  0 2/12 (16.67%)  2 3/9 (33.33%)  3
Blood bilirubin increased † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 1/8 (12.50%)  1 0/2 (0.00%)  0 1/60 (1.67%)  2 0/60 (0.00%)  0 0/3 (0.00%)  0 1/4 (25.00%)  1 0/5 (0.00%)  0 1/6 (16.67%)  1 0/3 (0.00%)  0 1/12 (8.33%)  1 0/9 (0.00%)  0
Blood cholesterol increased † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 3/60 (5.00%)  5 2/60 (3.33%)  2 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 2/9 (22.22%)  2
Blood creatine phosphokinase increased † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 1/2 (50.00%)  1 5/60 (8.33%)  9 6/60 (10.00%)  9 1/3 (33.33%)  1 0/4 (0.00%)  0 2/5 (40.00%)  2 3/6 (50.00%)  3 0/3 (0.00%)  0 1/12 (8.33%)  1 0/9 (0.00%)  0
Blood creatinine increased † 1  2/7 (28.57%)  4 0/3 (0.00%)  0 1/2 (50.00%)  2 0/8 (0.00%)  0 0/2 (0.00%)  0 5/60 (8.33%)  8 5/60 (8.33%)  6 0/3 (0.00%)  0 1/4 (25.00%)  1 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 2/12 (16.67%)  2 0/9 (0.00%)  0
Blood glucose increased † 1  1/7 (14.29%)  1 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 1/60 (1.67%)  1 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Blood iron decreased † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 1/8 (12.50%)  1 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Blood lactate dehydrogenase increased † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 1/8 (12.50%)  1 0/2 (0.00%)  0 0/60 (0.00%)  0 2/60 (3.33%)  3 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Blood potassium increased † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 0/9 (0.00%)  0
Blood uric acid increased † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 1/60 (1.67%)  1 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/9 (11.11%)  1
Body temperature increased † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 0/9 (0.00%)  0
C-reactive protein abnormal † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 0/9 (0.00%)  0
C-reactive protein increased † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 1/60 (1.67%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 0/9 (0.00%)  0
Ejection fraction decreased † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 1/2 (50.00%)  2 0/8 (0.00%)  0 0/2 (0.00%)  0 1/60 (1.67%)  1 2/60 (3.33%)  2 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Gamma-glutamyltransferase increased † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 1/8 (12.50%)  1 0/2 (0.00%)  0 7/60 (11.67%)  8 10/60 (16.67%)  14 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 2/12 (16.67%)  3 1/9 (11.11%)  1
International normalised ratio increased † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 1/2 (50.00%)  1 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 0/9 (0.00%)  0
Lipase increased † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 5/60 (8.33%)  7 2/60 (3.33%)  3 0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  2 1/6 (16.67%)  1 0/3 (0.00%)  0 1/12 (8.33%)  1 2/9 (22.22%)  3
Liver function test abnormal † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 1/3 (33.33%)  1 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Neutrophil count decreased † 1  2/7 (28.57%)  7 0/3 (0.00%)  0 0/2 (0.00%)  0 3/8 (37.50%)  4 0/2 (0.00%)  0 2/60 (3.33%)  7 2/60 (3.33%)  2 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 0/9 (0.00%)  0
Neutrophil count increased † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 0/9 (0.00%)  0
Platelet count decreased † 1  1/7 (14.29%)  1 0/3 (0.00%)  0 0/2 (0.00%)  0 2/8 (25.00%)  4 0/2 (0.00%)  0 1/60 (1.67%)  1 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/6 (16.67%)  1 0/3 (0.00%)  0 1/12 (8.33%)  1 0/9 (0.00%)  0
Procalcitonin increased † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 0/9 (0.00%)  0
Transaminases increased † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 1/8 (12.50%)  2 0/2 (0.00%)  0 2/60 (3.33%)  2 1/60 (1.67%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/9 (11.11%)  1
Troponin I increased † 1  1/7 (14.29%)  1 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Troponin increased † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  1 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Urobilinogen urine increased † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/6 (16.67%)  1 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Weight decreased † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 1/2 (50.00%)  1 1/8 (12.50%)  1 0/2 (0.00%)  0 6/60 (10.00%)  6 7/60 (11.67%)  8 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/6 (16.67%)  1 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Weight increased † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 2/60 (3.33%)  2 2/60 (3.33%)  2 0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  1 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
White blood cell count decreased † 1  2/7 (28.57%)  2 0/3 (0.00%)  0 0/2 (0.00%)  0 1/8 (12.50%)  2 0/2 (0.00%)  0 1/60 (1.67%)  2 1/60 (1.67%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Metabolism and nutrition disorders                             
Cachexia † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 1/4 (25.00%)  1 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Decreased appetite † 1  3/7 (42.86%)  4 2/3 (66.67%)  2 0/2 (0.00%)  0 2/8 (25.00%)  2 0/2 (0.00%)  0 13/60 (21.67%)  17 11/60 (18.33%)  11 0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  1 1/6 (16.67%)  1 1/3 (33.33%)  1 2/12 (16.67%)  2 0/9 (0.00%)  0
Dehydration † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 1/2 (50.00%)  1 0/8 (0.00%)  0 0/2 (0.00%)  0 2/60 (3.33%)  2 3/60 (5.00%)  3 0/3 (0.00%)  0 0/4 (0.00%)  0 2/5 (40.00%)  3 1/6 (16.67%)  1 0/3 (0.00%)  0 1/12 (8.33%)  1 0/9 (0.00%)  0
Hypercalcaemia † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 3/60 (5.00%)  4 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 0/9 (0.00%)  0
Hyperglycaemia † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 3/60 (5.00%)  3 3/60 (5.00%)  3 0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  1 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Hyperkalaemia † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 1/60 (1.67%)  1 0/3 (0.00%)  0 1/4 (25.00%)  1 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  3 0/9 (0.00%)  0
Hyperphosphataemia † 1  1/7 (14.29%)  1 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 1/60 (1.67%)  1 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Hypertriglyceridaemia † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 3/60 (5.00%)  3 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/6 (16.67%)  1 0/3 (0.00%)  0 1/12 (8.33%)  1 1/9 (11.11%)  1
Hyperuricaemia † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/9 (11.11%)  1
Hypoalbuminaemia † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 2/60 (3.33%)  5 4/60 (6.67%)  4 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Hypocalcaemia † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 1/8 (12.50%)  1 0/2 (0.00%)  0 2/60 (3.33%)  3 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Hypokalaemia † 1  1/7 (14.29%)  1 0/3 (0.00%)  0 0/2 (0.00%)  0 1/8 (12.50%)  1 1/2 (50.00%)  1 6/60 (10.00%)  8 3/60 (5.00%)  3 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Hypomagnesaemia † 1  1/7 (14.29%)  1 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 1/60 (1.67%)  1 1/60 (1.67%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  1 1/6 (16.67%)  2 0/3 (0.00%)  0 3/12 (25.00%)  3 1/9 (11.11%)  1
Hyponatraemia † 1  1/7 (14.29%)  1 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 1/2 (50.00%)  1 1/60 (1.67%)  1 4/60 (6.67%)  5 0/3 (0.00%)  0 2/4 (50.00%)  4 0/5 (0.00%)  0 1/6 (16.67%)  1 1/3 (33.33%)  1 0/12 (0.00%)  0 0/9 (0.00%)  0
Hypophagia † 1  1/7 (14.29%)  1 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Hypophosphataemia † 1  1/7 (14.29%)  1 0/3 (0.00%)  0 0/2 (0.00%)  0 1/8 (12.50%)  1 0/2 (0.00%)  0 2/60 (3.33%)  2 0/60 (0.00%)  0 1/3 (33.33%)  1 2/4 (50.00%)  3 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Polydipsia † 1  1/7 (14.29%)  1 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Musculoskeletal and connective tissue disorders                             
Arthralgia † 1  3/7 (42.86%)  6 2/3 (66.67%)  2 1/2 (50.00%)  1 4/8 (50.00%)  12 0/2 (0.00%)  0 24/60 (40.00%)  54 17/60 (28.33%)  34 0/3 (0.00%)  0 2/4 (50.00%)  2 1/5 (20.00%)  1 2/6 (33.33%)  2 0/3 (0.00%)  0 0/12 (0.00%)  0 2/9 (22.22%)  2
Arthritis † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 1/8 (12.50%)  1 0/2 (0.00%)  0 0/60 (0.00%)  0 2/60 (3.33%)  2 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Back pain † 1  2/7 (28.57%)  3 0/3 (0.00%)  0 1/2 (50.00%)  1 1/8 (12.50%)  1 1/2 (50.00%)  1 8/60 (13.33%)  9 3/60 (5.00%)  3 1/3 (33.33%)  1 0/4 (0.00%)  0 1/5 (20.00%)  1 2/6 (33.33%)  2 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Bone pain † 1  0/7 (0.00%)  0 1/3 (33.33%)  1 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Bursitis † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 1/60 (1.67%)  1 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/6 (16.67%)  1 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Flank pain † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 1/60 (1.67%)  1 0/3 (0.00%)  0 1/4 (25.00%)  1 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Joint instability † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 1/8 (12.50%)  1 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Limb discomfort † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  1 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Limb mass † 1  1/7 (14.29%)  1 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Muscle spasms † 1  1/7 (14.29%)  3 1/3 (33.33%)  1 0/2 (0.00%)  0 3/8 (37.50%)  5 0/2 (0.00%)  0 4/60 (6.67%)  8 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 2/6 (33.33%)  2 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Muscular weakness † 1  1/7 (14.29%)  1 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 1/60 (1.67%)  2 1/60 (1.67%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Musculoskeletal chest pain † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 1/8 (12.50%)  1 0/2 (0.00%)  0 2/60 (3.33%)  2 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Musculoskeletal stiffness † 1  1/7 (14.29%)  1 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 1/60 (1.67%)  1 1/60 (1.67%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Myalgia † 1  2/7 (28.57%)  2 1/3 (33.33%)  1 0/2 (0.00%)  0 3/8 (37.50%)  12 0/2 (0.00%)  0 16/60 (26.67%)  23 10/60 (16.67%)  17 0/3 (0.00%)  0 2/4 (50.00%)  3 1/5 (20.00%)  1 2/6 (33.33%)  2 0/3 (0.00%)  0 1/12 (8.33%)  1 0/9 (0.00%)  0
Neck mass † 1  1/7 (14.29%)  1 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 1/60 (1.67%)  1 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Neck pain † 1  2/7 (28.57%)  2 1/3 (33.33%)  1 0/2 (0.00%)  0 2/8 (25.00%)  2 0/2 (0.00%)  0 1/60 (1.67%)  1 2/60 (3.33%)  2 0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  1 1/6 (16.67%)  2 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Osteopenia † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 1/60 (1.67%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/9 (11.11%)  1
Pain in extremity † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 1/8 (12.50%)  2 1/2 (50.00%)  1 7/60 (11.67%)  11 3/60 (5.00%)  7 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 0/9 (0.00%)  0
Rotator cuff syndrome † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/6 (16.67%)  1 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Winged scapula † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/6 (16.67%)  1 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)                             
Basal cell carcinoma † 1  0/7 (0.00%)  0 1/3 (33.33%)  2 1/2 (50.00%)  1 0/8 (0.00%)  0 0/2 (0.00%)  0 4/60 (6.67%)  6 2/60 (3.33%)  3 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Cancer pain † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/9 (11.11%)  1
Melanocytic naevus † 1  1/7 (14.29%)  1 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 1/60 (1.67%)  1 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Nervous system disorders                             
Dizziness † 1  3/7 (42.86%)  3 0/3 (0.00%)  0 1/2 (50.00%)  1 1/8 (12.50%)  1 0/2 (0.00%)  0 7/60 (11.67%)  8 8/60 (13.33%)  10 0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  2 1/6 (16.67%)  2 1/3 (33.33%)  2 0/12 (0.00%)  0 0/9 (0.00%)  0
Dizziness postural † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/6 (16.67%)  1 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Dysgeusia † 1  1/7 (14.29%)  1 1/3 (33.33%)  1 0/2 (0.00%)  0 0/8 (0.00%)  0 1/2 (50.00%)  1 2/60 (3.33%)  3 3/60 (5.00%)  3 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 2/3 (66.67%)  2 0/12 (0.00%)  0 0/9 (0.00%)  0
External compression headache † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  1 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Head discomfort † 1  1/7 (14.29%)  1 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Headache † 1  5/7 (71.43%)  7 2/3 (66.67%)  4 0/2 (0.00%)  0 4/8 (50.00%)  6 0/2 (0.00%)  0 18/60 (30.00%)  29 13/60 (21.67%)  23 1/3 (33.33%)  1 1/4 (25.00%)  1 1/5 (20.00%)  1 2/6 (33.33%)  4 0/3 (0.00%)  0 4/12 (33.33%)  4 0/9 (0.00%)  0
Hyperaesthesia † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 1/8 (12.50%)  1 0/2 (0.00%)  0 0/60 (0.00%)  0 1/60 (1.67%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/6 (16.67%)  1 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Hypoaesthesia † 1  1/7 (14.29%)  1 1/3 (33.33%)  2 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 2/60 (3.33%)  3 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  1 1/6 (16.67%)  1 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Hyposmia † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 1/4 (25.00%)  1 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Migraine † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 1/8 (12.50%)  1 0/2 (0.00%)  0 3/60 (5.00%)  4 1/60 (1.67%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Neuralgia † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/9 (11.11%)  1
Neuropathy peripheral † 1  1/7 (14.29%)  1 1/3 (33.33%)  1 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 1/60 (1.67%)  1 1/60 (1.67%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Paraesthesia † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 1/8 (12.50%)  1 0/2 (0.00%)  0 1/60 (1.67%)  2 1/60 (1.67%)  2 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Peroneal nerve palsy † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/6 (16.67%)  1 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Seizure † 1  1/7 (14.29%)  1 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 1/60 (1.67%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Syncope † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 1/2 (50.00%)  1 2/60 (3.33%)  2 2/60 (3.33%)  3 0/3 (0.00%)  0 1/4 (25.00%)  1 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Taste disorder † 1  1/7 (14.29%)  1 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Tremor † 1  2/7 (28.57%)  2 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 1/60 (1.67%)  1 2/60 (3.33%)  2 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Psychiatric disorders                             
Anxiety † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 1/8 (12.50%)  1 0/2 (0.00%)  0 1/60 (1.67%)  1 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Confusional state † 1  2/7 (28.57%)  2 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 3/60 (5.00%)  3 1/60 (1.67%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  1 1/6 (16.67%)  1 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Depression † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 1/8 (12.50%)  1 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Insomnia † 1  1/7 (14.29%)  2 0/3 (0.00%)  0 2/2 (100.00%)  2 2/8 (25.00%)  2 0/2 (0.00%)  0 2/60 (3.33%)  3 2/60 (3.33%)  2 0/3 (0.00%)  0 1/4 (25.00%)  1 0/5 (0.00%)  0 2/6 (33.33%)  2 1/3 (33.33%)  1 0/12 (0.00%)  0 1/9 (11.11%)  1
Renal and urinary disorders                             
Bladder spasm † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/6 (16.67%)  1 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Dysuria † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 1/8 (12.50%)  1 0/2 (0.00%)  0 2/60 (3.33%)  2 2/60 (3.33%)  2 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 2/12 (16.67%)  2 0/9 (0.00%)  0
Haematuria † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 2/60 (3.33%)  2 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 1/3 (33.33%)  1 0/12 (0.00%)  0 0/9 (0.00%)  0
Hydronephrosis † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 1/2 (50.00%)  1 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Pollakiuria † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 1/8 (12.50%)  1 0/2 (0.00%)  0 1/60 (1.67%)  1 1/60 (1.67%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 2/5 (40.00%)  2 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Renal failure † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/9 (11.11%)  1
Urinary retention † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 1/60 (1.67%)  2 0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  1 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Urinary tract pain † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 1/4 (25.00%)  1 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Reproductive system and breast disorders                             
Adnexa uteri mass † 1  1/7 (14.29%)  1 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Benign prostatic hyperplasia † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 1/2 (50.00%)  1 0/8 (0.00%)  0 0/2 (0.00%)  0 1/60 (1.67%)  1 1/60 (1.67%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Erectile dysfunction † 1  0/7 (0.00%)  0 1/3 (33.33%)  1 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Vaginal haemorrhage † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  4 0/9 (0.00%)  0
Respiratory, thoracic and mediastinal disorders                             
Atelectasis † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 0/9 (0.00%)  0
Cough † 1  3/7 (42.86%)  3 0/3 (0.00%)  0 0/2 (0.00%)  0 5/8 (62.50%)  6 1/2 (50.00%)  1 10/60 (16.67%)  17 12/60 (20.00%)  12 1/3 (33.33%)  2 2/4 (50.00%)  2 1/5 (20.00%)  1 3/6 (50.00%)  3 1/3 (33.33%)  1 4/12 (33.33%)  6 1/9 (11.11%)  1
Dysphonia † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 1/60 (1.67%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  1 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Dyspnoea † 1  0/7 (0.00%)  0 2/3 (66.67%)  3 1/2 (50.00%)  1 1/8 (12.50%)  2 1/2 (50.00%)  1 9/60 (15.00%)  11 4/60 (6.67%)  4 0/3 (0.00%)  0 1/4 (25.00%)  1 0/5 (0.00%)  0 1/6 (16.67%)  1 0/3 (0.00%)  0 1/12 (8.33%)  2 1/9 (11.11%)  1
Dyspnoea exertional † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 1/60 (1.67%)  1 1/60 (1.67%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/6 (16.67%)  1 0/3 (0.00%)  0 0/12 (0.00%)  0 1/9 (11.11%)  1
Epistaxis † 1  1/7 (14.29%)  1 1/3 (33.33%)  2 0/2 (0.00%)  0 1/8 (12.50%)  2 0/2 (0.00%)  0 2/60 (3.33%)  3 0/60 (0.00%)  0 1/3 (33.33%)  1 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 2/12 (16.67%)  2 0/9 (0.00%)  0
Haemoptysis † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 0/9 (0.00%)  0
Laryngeal inflammation † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/9 (11.11%)  1
Lung consolidation † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/9 (11.11%)  1
Nasal congestion † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 2/8 (25.00%)  2 0/2 (0.00%)  0 2/60 (3.33%)  2 0/60 (0.00%)  0 1/3 (33.33%)  1 1/4 (25.00%)  1 0/5 (0.00%)  0 1/6 (16.67%)  1 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Nasal ulcer † 1  0/7 (0.00%)  0 1/3 (33.33%)  1 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Oropharyngeal pain † 1  1/7 (14.29%)  2 0/3 (0.00%)  0 1/2 (50.00%)  1 2/8 (25.00%)  3 0/2 (0.00%)  0 5/60 (8.33%)  5 8/60 (13.33%)  12 1/3 (33.33%)  1 0/4 (0.00%)  0 1/5 (20.00%)  1 0/6 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 0/9 (0.00%)  0
Painful respiration † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 1/3 (33.33%)  1 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/9 (11.11%)  1
Pleural effusion † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 1/60 (1.67%)  1 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 1/3 (33.33%)  2 1/12 (8.33%)  1 0/9 (0.00%)  0
Pneumonitis † 1  1/7 (14.29%)  1 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 1/2 (50.00%)  1 4/60 (6.67%)  6 1/60 (1.67%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 0/9 (0.00%)  0
Productive cough † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 2/60 (3.33%)  2 0/60 (0.00%)  0 0/3 (0.00%)  0 1/4 (25.00%)  1 1/5 (20.00%)  1 0/6 (0.00%)  0 2/3 (66.67%)  2 0/12 (0.00%)  0 0/9 (0.00%)  0
Pulmonary embolism † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 1/60 (1.67%)  1 0/60 (0.00%)  0 1/3 (33.33%)  1 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 1/3 (33.33%)  1 0/12 (0.00%)  0 0/9 (0.00%)  0
Rales † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 1/60 (1.67%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  2 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Respiratory distress † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 1/3 (33.33%)  1 0/12 (0.00%)  0 0/9 (0.00%)  0
Rhinalgia † 1  1/7 (14.29%)  1 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Rhinitis allergic † 1  1/7 (14.29%)  1 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 0/9 (0.00%)  0
Rhinitis atrophic † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 0/9 (0.00%)  0
Rhinorrhoea † 1  0/7 (0.00%)  0 1/3 (33.33%)  1 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 2/60 (3.33%)  2 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Sinus pain † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/6 (16.67%)  1 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Throat irritation † 1  1/7 (14.29%)  2 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Wheezing † 1  1/7 (14.29%)  1 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 1/60 (1.67%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  1 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Skin and subcutaneous tissue disorders                             
Acne † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 1/8 (12.50%)  1 0/2 (0.00%)  0 2/60 (3.33%)  2 3/60 (5.00%)  3 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/9 (11.11%)  1
Alopecia † 1  0/7 (0.00%)  0 1/3 (33.33%)  1 0/2 (0.00%)  0 1/8 (12.50%)  1 0/2 (0.00%)  0 5/60 (8.33%)  5 1/60 (1.67%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  1 1/6 (16.67%)  1 0/3 (0.00%)  0 1/12 (8.33%)  1 1/9 (11.11%)  1
Dermatitis † 1  1/7 (14.29%)  1 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 2/60 (3.33%)  6 3/60 (5.00%)  3 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 0/9 (0.00%)  0
Dermatitis acneiform † 1  2/7 (28.57%)  2 3/3 (100.00%)  4 0/2 (0.00%)  0 4/8 (50.00%)  5 0/2 (0.00%)  0 9/60 (15.00%)  9 4/60 (6.67%)  4 3/3 (100.00%)  4 3/4 (75.00%)  7 2/5 (40.00%)  5 5/6 (83.33%)  6 1/3 (33.33%)  1 3/12 (25.00%)  4 6/9 (66.67%)  7
Drug eruption † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  1 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Dry skin † 1  0/7 (0.00%)  0 1/3 (33.33%)  1 0/2 (0.00%)  0 2/8 (25.00%)  2 0/2 (0.00%)  0 7/60 (11.67%)  10 4/60 (6.67%)  4 1/3 (33.33%)  1 0/4 (0.00%)  0 2/5 (40.00%)  2 1/6 (16.67%)  2 1/3 (33.33%)  1 1/12 (8.33%)  1 1/9 (11.11%)  1
Eczema † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 1/8 (12.50%)  1 0/2 (0.00%)  0 0/60 (0.00%)  0 2/60 (3.33%)  2 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Erythema † 1  0/7 (0.00%)  0 1/3 (33.33%)  2 1/2 (50.00%)  1 1/8 (12.50%)  1 0/2 (0.00%)  0 7/60 (11.67%)  12 4/60 (6.67%)  4 0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  1 2/6 (33.33%)  2 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Erythema multiforme † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/6 (16.67%)  1 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Erythema nodosum † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 1/8 (12.50%)  1 0/2 (0.00%)  0 3/60 (5.00%)  4 2/60 (3.33%)  2 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Hyperhidrosis † 1  3/7 (42.86%)  10 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 4/60 (6.67%)  7 6/60 (10.00%)  10 0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  1 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Macule † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 2/60 (3.33%)  3 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  1 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Nail disorder † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/6 (16.67%)  1 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Night sweats † 1  3/7 (42.86%)  7 0/3 (0.00%)  0 0/2 (0.00%)  0 1/8 (12.50%)  1 0/2 (0.00%)  0 3/60 (5.00%)  3 1/60 (1.67%)  1 0/3 (0.00%)  0 1/4 (25.00%)  1 2/5 (40.00%)  2 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Pain of skin † 1  0/7 (0.00%)  0 1/3 (33.33%)  1 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Palmar erythema † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  1 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Palmar-plantar erythrodysaesthesia syndrome † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 1/8 (12.50%)  1 0/2 (0.00%)  0 2/60 (3.33%)  2 3/60 (5.00%)  3 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/9 (11.11%)  1
Pruritus † 1  2/7 (28.57%)  6 3/3 (100.00%)  5 1/2 (50.00%)  1 2/8 (25.00%)  2 1/2 (50.00%)  2 10/60 (16.67%)  17 9/60 (15.00%)  12 1/3 (33.33%)  1 1/4 (25.00%)  1 2/5 (40.00%)  3 2/6 (33.33%)  2 2/3 (66.67%)  3 6/12 (50.00%)  10 3/9 (33.33%)  3
Psoriasis † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 1/8 (12.50%)  1 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Purpura † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 0/9 (0.00%)  0
Rash † 1  3/7 (42.86%)  8 2/3 (66.67%)  5 1/2 (50.00%)  3 4/8 (50.00%)  5 1/2 (50.00%)  1 27/60 (45.00%)  50 18/60 (30.00%)  24 0/3 (0.00%)  0 2/4 (50.00%)  2 2/5 (40.00%)  3 2/6 (33.33%)  2 3/3 (100.00%)  5 6/12 (50.00%)  11 3/9 (33.33%)  6
Rash erythematous † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 1/8 (12.50%)  1 0/2 (0.00%)  0 1/60 (1.67%)  1 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Rash follicular † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/9 (11.11%)  1
Rash macular † 1  1/7 (14.29%)  1 1/3 (33.33%)  1 0/2 (0.00%)  0 0/8 (0.00%)  0 1/2 (50.00%)  1 2/60 (3.33%)  2 3/60 (5.00%)  3 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Rash maculo-papular † 1  1/7 (14.29%)  1 0/3 (0.00%)  0 1/2 (50.00%)  1 1/8 (12.50%)  1 0/2 (0.00%)  0 6/60 (10.00%)  9 3/60 (5.00%)  5 0/3 (0.00%)  0 1/4 (25.00%)  1 1/5 (20.00%)  1 0/6 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 0/9 (0.00%)  0
Rash pruritic † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 1/8 (12.50%)  1 0/2 (0.00%)  0 2/60 (3.33%)  4 1/60 (1.67%)  1 0/3 (0.00%)  0 1/4 (25.00%)  1 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 1/9 (11.11%)  1
Scab † 1  0/7 (0.00%)  0 1/3 (33.33%)  4 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Skin exfoliation † 1  0/7 (0.00%)  0 2/3 (66.67%)  3 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 3/60 (5.00%)  3 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  1 1/6 (16.67%)  2 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Skin fissures † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 1/60 (1.67%)  1 0/60 (0.00%)  0 1/3 (33.33%)  1 2/4 (50.00%)  2 1/5 (20.00%)  2 3/6 (50.00%)  4 0/3 (0.00%)  0 2/12 (16.67%)  2 1/9 (11.11%)  1
Skin haemorrhage † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 1/60 (1.67%)  1 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 1/6 (16.67%)  1 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Vitiligo † 1  1/7 (14.29%)  1 1/3 (33.33%)  1 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 12/60 (20.00%)  18 1/60 (1.67%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/9 (11.11%)  1
Xeroderma † 1  1/7 (14.29%)  1 1/3 (33.33%)  1 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Vascular disorders                             
Axillary vein thrombosis † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 1/3 (33.33%)  1 0/12 (0.00%)  0 0/9 (0.00%)  0
Deep vein thrombosis † 1  1/7 (14.29%)  1 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 1/3 (33.33%)  1 0/12 (0.00%)  0 0/9 (0.00%)  0
Flushing † 1  1/7 (14.29%)  1 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Hot flush † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 1/8 (12.50%)  2 0/2 (0.00%)  0 0/60 (0.00%)  0 1/60 (1.67%)  1 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Hypertension † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 4/60 (6.67%)  12 3/60 (5.00%)  4 0/3 (0.00%)  0 0/4 (0.00%)  0 1/5 (20.00%)  1 0/6 (0.00%)  0 1/3 (33.33%)  1 1/12 (8.33%)  1 1/9 (11.11%)  1
Hypertensive crisis † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 1/9 (11.11%)  1
Hypotension † 1  1/7 (14.29%)  2 1/3 (33.33%)  1 1/2 (50.00%)  1 0/8 (0.00%)  0 0/2 (0.00%)  0 6/60 (10.00%)  7 10/60 (16.67%)  13 1/3 (33.33%)  1 0/4 (0.00%)  0 0/5 (0.00%)  0 1/6 (16.67%)  1 0/3 (0.00%)  0 1/12 (8.33%)  1 0/9 (0.00%)  0
Lymphoedema † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 1/8 (12.50%)  1 0/2 (0.00%)  0 2/60 (3.33%)  2 2/60 (3.33%)  2 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 1/12 (8.33%)  1 0/9 (0.00%)  0
Phlebitis † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 1/4 (25.00%)  1 0/5 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/12 (0.00%)  0 0/9 (0.00%)  0
Thrombosis † 1  0/7 (0.00%)  0 0/3 (0.00%)  0 0/2 (0.00%)  0 0/8 (0.00%)  0 0/2 (0.00%)  0 0/60 (0.00%)  0 0/60 (0.00%)  0 0/3 (0.00%)  0 0/4 (0.00%)  0 0/5 (0.00%)  0 0/6 (0.00%)  0 1/3 (33.33%)  1 0/12 (0.00%)  0 0/9 (0.00%)  0
1
Term from vocabulary, MedDRA 24.0
†
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 trial 45 days prior to submission for publication/presentation. Any information identified by the Sponsor as confidential must be deleted prior to submission; this confidentiality does not include efficacy and safety results. 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 LLC
Phone: 1-800-672-6372
EMail: ClinicalTrialsDisclosure@merck.com
Publications of Results:
Ribas A, Lawrence D, Atkinson V, Agarwal S, Miller WH Jr, Carlino MS, Fisher R, Long GV, Hodi FS, Tsoi J, Grasso CS, Mookerjee B, Zhao Q, Ghori R, Moreno BH, Ibrahim N, Hamid O. Combined BRAF and MEK inhibition with PD-1 blockade immunotherapy in BRAF-mutant melanoma. Nat Med. 2019 Jun;25(6):936-940. doi: 10.1038/s41591-019-0476-5. Epub 2019 Jun 6. Erratum In: Nat Med. 2019 Aug;25(8):1319.
Ascierto PA, Ferrucci PF, Fisher R, Del Vecchio M, Atkinson V, Schmidt H, Schachter J, Queirolo P, Long GV, Di Giacomo AM, Svane IM, Lotem M, Bar-Sela G, Couture F, Mookerjee B, Ghori R, Ibrahim N, Moreno BH, Ribas A. Dabrafenib, trametinib and pembrolizumab or placebo in BRAF-mutant melanoma. Nat Med. 2019 Jun;25(6):941-946. doi: 10.1038/s41591-019-0448-9. Epub 2019 Jun 6.
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: NCT02130466    
Other Study ID Numbers: 3475-022
MK-3475-022 ( Other Identifier: Merck )
KEYNOTE-022 ( Other Identifier: Merck )
2015-000681-55 ( EudraCT Number )
First Submitted: May 1, 2014
First Posted: May 5, 2014
Results First Submitted: June 30, 2022
Results First Posted: August 1, 2022
Last Update Posted: August 1, 2022