Conditions: Melanoma Solid Tumors
Keywords: Programmed Cell Death-1 (PD1, PD-1) Programmed Death-Ligand 1 (PDL1, PD-L1) Programmed Cell Death 1 Ligand 2 (PDL2, PD-L2)
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 184
Healthy volunteers: no

Brief summary:
This is a 5-part dose-finding and preliminary efficacy study of pembrolizumab (Pembro) + dabrafenib (D) + trametinib (T) for participants with advanced melanoma and solid tumors.

Parts 1 and 2 are open-label to find and confirm the maximum tolerated dose (MTD)/maximum administered dose (MAD) for Pembro+D+T. The primary hypothesis (Parts 1 and 2) is that Pembro+D+T is sufficiently well-tolerated to permit clinical investigation.

Part 3 is a double-blind study of Pembro+D+T versus placebo+D+T. The primary study hypothesis (Part 3 only) is that the Pembro+D+T improves progression-free survival (PFS) compared with placebo+D+T.

Part 4 is nonrandomized and open-label and is designed to evaluate the safety and tolerability and identify the MTD or MAD of Pembro+T in participants who have v-raf murine sarcoma viral oncogene homolog B1 \[BRAF\] mutation-negative (without V600 E or K) melanoma or solid tumors \[irrespective of BRAF status\]. The primary hypothesis (Part 4) is that Pembro+T is sufficiently well-tolerated to permit clinical investigation.

Part 5 will confirm the dose(s) identified in Part 4 in participants BRAF wild type \[without V600E or K\] melanoma or solid tumors \[irrespective of BRAF status\] and will further evaluate the safety and preliminary efficacy (Objective Response Rate \[ORR\]) of Pembro+T in participants who have BRAF wild type \[without V600E or K\] melanoma or solid tumors \[irrespective of BRAF status\]. The primary hypotheses (Part 5) are that Pembro+T is sufficiently well-tolerated at the MTD/MAD to permit further clinical investigation and is effective in attaining objective responses based upon Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 by Investigator review in participants who have melanoma without BRAF V600 E or K mutations. With Amendment 5 (21-Mar-2019), the Part 5 expansion cohort will not be pursued following the completion of Part 5 dose confirmation.

Parts 1 and 2 of the study may also explore, if needed based on tolerability, the backup combinations of open-label Pembro+T (for BRAF mutation-negative participants) or Pembro+D (for BRAF mutation-positive participants). These will run concurrently with the Pembro+D+T arm.

Detailed description:

Arms:
arm 1: 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. arm 2: 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. arm 3: 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. arm 4: 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. arm 5: 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. arm 6: 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. arm 7: 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. arm 8: 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. arm 9: 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. arm 10: 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. arm 11: 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. arm 12: 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. arm 13: 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. arm 14: 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.

Interventions: intervention 1: Pembrolizumab intervention 2: Dabrafenib intervention 3: Trametinib intervention 4: Placebo
Intervention descriptions: intervention 1: IV infusion intervention 2: oral capsule intervention 3: oral tablet intervention 4: IV infusion

Protocol document:
Prot_SAP_000.pdf: 
Official Protocol Title: 
NCT number: 
Document Date: 
A Phase I/II Study to Assess the Safety and Efficacy of MK-3475 in 
Combination with Trametinib and Dabrafenib in Subjects with 
Advanced Melanoma
05-DEC-2019
NCT02130466


Product:  MK-3475 
1
Protocol/Amendment No.: 022-06 
MK-3475-022-06 Final Protocol
05-DEC-2019
Confidential
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., 
WHITEHOUSE STATION, NJ, U.S.A.
SPONSOR:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. 
(hereafter referred to as the Sponsor or Merck)
One Merck Drive
P.O. Box 100
Whitehouse Station, NJ 08889-0100, U.S.A.
Protocol-specific Sponsor Contact information can be found in the Investigator Trial File
Binder (or equivalent).
TITLE:
A Phase I/II Study to Assess the Safety and Efficacy of MK-3475 in Combination with 
Trametinib and Dabrafenib in Subjects with Advanced Melanoma
IND NUMBER:  110,080
EudraCT NUMBER:  2015-000681-55
 
 
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TABLE OF CONTENTS
DOCUMENT HISTORY ..................................................................................................... 14
SUMMARY OF CHANGES................................................................................................ 16
1.0
TRIAL SUMMARY.................................................................................................. 17
2.0
TRIAL DESIGN........................................................................................................ 19
Trial Design ........................................................................................................... 19
Trial Diagram........................................................................................................ 27
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 27
Primary Objective(s) & Hypothesis(es).............................................................. 27
Secondary Objective(s) & Hypothesis(es)........................................................... 30
Exploratory Objective(s)...................................................................................... 30
4.0
BACKGROUND & RATIONALE.......................................................................... 31
Background ........................................................................................................... 31
Pharmaceutical and Therapeutic Background .................................................... 31
Pembrolizumab ............................................................................................ 31
Trametinib and Dabrafenib.......................................................................... 33
Rationale................................................................................................................ 35
Rationale for the Trial and Selected Subject Population .................................... 35
Rationale for Dose Selection/Regimen/Modification......................................... 37
Starting Dose for This Trial......................................................................... 39
Maximum Dose/Exposure for This Trial..................................................... 40
Rationale for Dose Interval and Trial Design.............................................. 40
Rationale for Endpoints ...................................................................................... 40
Efficacy Endpoints....................................................................................... 40
4.2.3.1.1
Primary.................................................................................................. 40
4.2.3.1.2
Interim Analysis.................................................................................... 42
4.2.3.1.3
Secondary.............................................................................................. 42
Safety Endpoints.......................................................................................... 42
Pharmacokinetic Endpoints ......................................................................... 43
Patient Reported Outcomes.......................................................................... 43
 
 
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4.2.3.4.1
EuroQol (EQ-5D) ................................................................................. 43
4.2.3.4.2
EORTC (QLQ-C30) ............................................................................. 44
Biomarker Research..................................................................................... 44
Future Biomedical Research........................................................................ 44
5.0
METHODOLOGY ................................................................................................... 45
Entry Criteria........................................................................................................ 45
Diagnosis/Condition for Entry into the Trial ...................................................... 45
Subject Inclusion Criteria.................................................................................... 45
Subject Exclusion Criteria .................................................................................. 48
Trial Treatment(s) ................................................................................................ 51
Dose Selection/Modification .............................................................................. 53
Dose Selection ............................................................................................. 53
Dose Modification ....................................................................................... 53
5.2.1.2.1
Dose Modification and Toxicity Management Guidelines for 
Pembrolizumab..................................................................................... 53
5.2.1.2.2
Trametinib Dose Modification.............................................................. 57
5.2.1.2.3
Dabrafenib Dose Modification ............................................................. 57
Timing of Dose Administration.......................................................................... 57
Pembrolizumab Dose Administration.......................................................... 57
Trametinib and Dabrafenib Dose Administration........................................ 58
Trial Blinding/Masking....................................................................................... 58
Rules for Dose Escalation and Confirmation...................................................... 59
Dose Escalation............................................................................................ 59
5.2.4.1.1
Dose Escalation (Part 1) ....................................................................... 59
5.2.4.1.2
Dose Escalation (Part 4) ....................................................................... 60
Dose Confirmation....................................................................................... 63
5.2.4.2.1
Dose Confirmation (Part 2)................................................................... 63
5.2.4.2.2
Dose Confirmation (Part 5)................................................................... 65
Dose Limiting Toxicity................................................................................ 67
Treatment Duration............................................................................................. 68
Randomization or Treatment Allocation............................................................ 69
Stratification.......................................................................................................... 69
 
 
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Concomitant Medications/Vaccinations (allowed & prohibited)..................... 69
Acceptable Concomitant Medications ................................................................ 70
Prohibited Concomitant Medications.................................................................. 70
Medications to be Used with Caution................................................................. 72
Rescue Medications & Supportive Care............................................................. 74
Supportive Care Guidelines ................................................................................ 74
Pembrolizumab+Trametinib 
and/or 
Dabrafenib, 
or, 
Trametinib+Dabrafenib Combination Safety Management Guidelines ...... 75
5.6.1.1.1
Dose Level Reduction of Trametinib and/or Dabrafenib for 
Subjects beyond the DLT Period.......................................................... 75
5.6.1.1.2
Interruption or Discontinuation of Trametinib, Dabrafenib and/or 
Pembrolizumab..................................................................................... 75
5.6.1.1.3
Immune-related Adverse Events........................................................... 76
5.6.1.1.4
General Guidelines for Clinically Significant Toxicities ..................... 77
5.6.1.1.5
Diarrhea ................................................................................................ 79
5.6.1.1.6
Endocrine Events .................................................................................. 80
5.6.1.1.7
Vision Changes..................................................................................... 83
5.6.1.1.8
Pneumonitis .......................................................................................... 85
5.6.1.1.9
Renal Events ......................................................................................... 86
5.6.1.1.10 Skin Events ........................................................................................... 88
Rash.............................................................................................. 88
Hand-Foot Skin Reactions (HFSR).............................................. 91
New Malignancies........................................................................ 91
Severe Cutaneous Adverse Reactions.......................................... 91
5.6.1.1.11 Fever ..................................................................................................... 92
5.6.1.1.12 Cardiovascular Events .......................................................................... 93
Left Ventricular Ejection Fraction (LVEF).................................. 93
5.6.1.1.13 Hypertension......................................................................................... 94
Monitoring of Hypertension......................................................... 95
Management of Hypertension ...................................................... 95
5.6.1.1.14 Prolonged QTc...................................................................................... 96
5.6.1.1.15 Hepatic Laboratory Abnormalities ....................................................... 97
Liver Chemistry Stopping Criteria............................................... 99
 
 
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Liver Event Follow-up Assessments.......................................... 101
Liver Chemistry Monitoring Criteria ......................................... 102
Drug Restart/Rechallenge Following Liver Events that are 
Possibly Related to Study Treatment.................................................... 103
Drug Restart Following Transient Resolving Liver Events Not 
Related to Study Treatment................................................................... 103
5.6.1.1.16 Hematologic Events............................................................................ 104
5.6.1.1.17 Neurologic Events............................................................................... 105
5.6.1.1.18 Infusion Reactions .............................................................................. 106
Pembrolizumab Infusion Reaction Treatment Guidelines......................... 106
Supportive Care Guidelines for Adverse Events with an Immune-
Etiology (irAEs)......................................................................................... 108
Diet/Activity/Other Considerations................................................................... 109
Diet.................................................................................................................... 109
Contraception.................................................................................................... 109
Use in Pregnancy .............................................................................................. 109
Use in Nursing Women..................................................................................... 110
Subject Withdrawal/Discontinuation Criteria................................................. 110
Discontinuation of Treatment ........................................................................... 110
Withdrawal from the Trial ................................................................................ 112
Subject Replacement Strategy........................................................................... 112
Parts 1, 2, 4, and 5:  Subject Replacement Strategy - Dose Limiting Toxicity 112
Beginning and End of the Trial ......................................................................... 112
Clinical Criteria for Early Trial Termination ................................................. 113
6.0
TRIAL FLOW CHART ......................................................................................... 114
Treatment Phase ................................................................................................. 114
Parts 1 and 2:  Pembrolizumab Q3W Dosing with Trametinib and/or 
Dabrafenib......................................................................................................... 114
Part 3:  Pembrolizumab Q3W Dosing With Trametinib and Dabrafenib......... 118
Parts 4 and 5:  4-Week Monotherapy Trametinib + 6-Week Treatment 
Cycle(s) of Pembrolizumab Q3W Dosing With Trametinib ............................ 123
Parts 4 and 5:  2-Week Monotherapy Trametinib + 6-Week Treatment 
Cycle(s) of Pembrolizumab Q3W Dosing With Trametinib ............................ 128
 
 
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Post-Treatment Follow-Up ONLY for Subjects Who Discontinue 
Pembrolizumab Due to SD, PR or CR and Continue on Dabrafenib 
and/or Trametinib............................................................................................... 133
Post-Treatment:  Follow-Up .............................................................................. 135
7.0
TRIAL PROCEDURES ......................................................................................... 137
Trial Procedures ................................................................................................. 137
Administrative Procedures................................................................................ 137
Informed Consent....................................................................................... 137
7.1.1.1.1
General Informed Consent.................................................................. 137
7.1.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................. 138
Inclusion/Exclusion Criteria ...................................................................... 138
Subject Identification Card ........................................................................ 138
Medical History ......................................................................................... 138
Prior and Concomitant Medications Review............................................. 138
7.1.1.5.1
Prior Medications................................................................................ 138
7.1.1.5.2
Concomitant Medications................................................................... 138
Assignment of Screening Number............................................................. 139
Assignment of Randomization Number..................................................... 139
Trial Compliance (Medication/Diet/Activity/Other) ................................. 139
Clinical Procedures/Assessments...................................................................... 140
Adverse Event (AE) Monitoring................................................................ 140
Physical Exam............................................................................................ 140
7.1.2.2.1
Full Physical Exam ............................................................................. 140
7.1.2.2.2
Directed Physical Exam...................................................................... 140
Dermatologic Exam...................................................................... 140
Vital Signs.................................................................................................. 141
12-Lead Electrocardiogram (ECG)............................................................ 141
Echocardiogram (ECHO)........................................................................... 141
Eastern Cooperative Oncology Group (ECOG) Performance Scale ......... 141
Tumor Imaging and Assessment of Disease.............................................. 141
Laboratory Procedures/Assessments ................................................................ 141
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) 142
 
 
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Pharmacokinetic/Pharmacodynamic Evaluations...................................... 143
7.1.3.2.1
Blood Collection for PK Serum MK-3475......................................... 143
7.1.3.2.2
Blood Collection for PK Plasma Trametinib...................................... 143
7.1.3.2.3
Blood Collection for PK Plasma Dabrafenib and Metabolites 
(Hydroxy- and Desmethyl-dabrafenib)............................................... 143
7.1.3.2.4
Anti-MK-3475 Antibodies.................................................................. 143
Future Biomedical Research...................................................................... 143
Other Procedures............................................................................................... 143
Withdrawal/Discontinuation...................................................................... 143
7.1.4.1.1
Withdrawal From Future Biomedical Research ................................. 144
Blinding/Unblinding .................................................................................. 144
Visit Requirements............................................................................................ 145
Screening.................................................................................................... 145
Treatment Period........................................................................................ 145
Post-Treatment Follow-up Phase............................................................... 145
Survival Status ........................................................................................... 146
Treatment After the End of the Study........................................................ 146
Assessing and Recording Adverse Events ........................................................ 146
Definition of an Overdose for This Protocol and Reporting of Overdose to 
the Sponsor........................................................................................................ 147
Reporting of Pregnancy and Lactation to the Sponsor ..................................... 148
Immediate Reporting of Adverse Events to the Sponsor.................................. 149
Serious Adverse Events ............................................................................. 149
Events of Clinical Interest.......................................................................... 150
Protocol-Specific Exceptions to Serious Adverse Event Reporting.......... 151
Evaluating Adverse Events............................................................................... 151
Sponsor Responsibility for Reporting Adverse Events .................................... 154
TRIAL GOVERNANCE AND OVERSIGHT................................................. 154
Data Monitoring Committee............................................................................. 154
8.0
STATISTICAL ANALYSIS PLAN ...................................................................... 154
Statistical Analysis Plan Summary ................................................................... 154
Parts 1 and 2:  Pembrolizumab in Combination with Trametinib and 
Dabrafenib......................................................................................................... 154
 
 
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Parts 1, 2, 4, and 5:  Pembrolizumab in Combination With Trametinib........... 155
Part 3:  Pembrolizumab in Combination with Trametinib and Dabrafenib...... 156
Final Efficacy Analyses ............................................................................. 156
8.1.3.1.1
Power of the Final Efficacy Analysis of Part 3 .................................. 157
Safety Analyses of Part 3........................................................................... 157
Interim Analysis of Part 3.......................................................................... 157
Subgroup Analyses ........................................................................................... 158
Statistical Analysis Plan ..................................................................................... 158
Responsibility for Analysis/In-House Blinding................................................ 158
Hypotheses/Estimation ..................................................................................... 159
Analysis Endpoints ........................................................................................... 160
Efficacy Endpoints..................................................................................... 160
8.2.3.1.1
Primary Endpoint................................................................................ 160
8.2.3.1.2
Secondary Endpoints .......................................................................... 160
8.2.3.1.3
Exploratory Endpoints ........................................................................ 160
Safety Endpoints........................................................................................ 162
Analysis Populations......................................................................................... 162
Efficacy Analysis Populations ................................................................... 162
Safety Analysis Populations ...................................................................... 162
Statistical Methods............................................................................................ 163
Statistical Methods for Efficacy Analyses................................................. 163
Pharmacokinetic Analysis.......................................................................... 166
Biomarker Analysis ................................................................................... 166
Statistical Methods for Safety Analyses .................................................... 166
Summaries of Baseline Characteristics, Demographics, and Other 
Analyses..................................................................................................... 168
Multiplicity ....................................................................................................... 168
Sample Size and Power Calculations................................................................ 168
Subgroup Analyses and Effect of Baseline Factors.......................................... 169
Interim Analyses ............................................................................................... 169
Primary Endpoint for the Interim Analysis................................................ 169
Analysis of the Primary Endpoint for the Interim Analysis ...................... 169
 
 
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8.2.9.2.1
Interim Decision Rules ....................................................................... 169
8.2.9.2.2
Power of the Interim Analysis ............................................................ 170
8.2.9.2.3
Secondary and Exploratory Endpoints at the Interim Analysis.......... 171
Compliance (Medication Adherence)............................................................... 172
Extent of Exposure............................................................................................ 172
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ............................................................................................................... 172
Investigational Product ...................................................................................... 172
Packaging and Labeling Information ............................................................... 173
Clinical Supplies Disclosure............................................................................... 173
Storage and Handling Requirements................................................................ 174
Returns and Reconciliation................................................................................ 174
Standard Policies................................................................................................. 174
10.0
ADMINISTRATIVE AND REGULATORY DETAILS..................................... 174
Confidentiality..................................................................................................... 174
Confidentiality of Data ..................................................................................... 174
Confidentiality of Subject Records................................................................... 174
Confidentiality of Investigator Information...................................................... 175
Confidentiality of IRB/IEC Information........................................................... 175
Compliance with Financial Disclosure Requirements..................................... 175
Compliance with Law, Audit and Debarment ................................................. 176
Compliance with Trial Registration and Results Posting Requirements ...... 178
Quality Management System............................................................................. 178
Data Management............................................................................................... 178
Publications ......................................................................................................... 179
11.0
LIST OF REFERENCES....................................................................................... 180
12.0
APPENDICES......................................................................................................... 189
Merck Code of Conduct for Clinical Trials...................................................... 189
Collection and Management of Specimens for Future Biomedical 
Research............................................................................................................... 191
Pharmacogenetics 
Informational 
Brochure 
for 
IRBs/IECs 
& 
Investigational Site StaffUnderstanding the Intent, Scope and Public 
 
 
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Health Benefits of Exploratory Biomarker Research: A Guide for
IRBs/IECs and Investigational Site Staff.......................................................... 197
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1....................... 208
Common Terminology Criteria for Adverse Events (CTCAE) v4.0.............. 209
ECOG Performance Status................................................................................ 210
CCG Formula...................................................................................................... 211
NYHA Functional Classification System.......................................................... 212
Sample Patient Daily Dosing Diary................................................................... 213
List of Abbreviations .......................................................................................... 214
Past Medical History Related to Dermatologic Event..................................... 217
Presentation of the Dermatologic Event ........................................................... 219
Focused Skin Examination................................................................................. 221
Contraceptive Guidance..................................................................................... 222
Definitions ................................................................................................. 222
Contraception Requirements...................................................................... 223
13.0
SIGNATURES......................................................................................................... 224
Sponsor's Representative ................................................................................... 224
Investigator.......................................................................................................... 224
 
 
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LIST OF TABLES
Table 1
Study Treatment Combinations.............................................................................. 19
Table 2
Parts 1 and 2: (MK+D+T) Study Treatment Arm.................................................. 20
Table 3
Parts 1 and 2: (MK+T) Study Treatment Arm(s)................................................... 20
Table 4
Parts 1 and 2:  (MK+D) Study Treatment Arm...................................................... 21
Table 5
Parts 1 and 2:  (MK+D+T) Dose Level Minus (-1) Options.................................. 21
Table 6
Parts 4 and 5:  Concurrent (MK+T) Study Treatment Arm(s) and 
Escalation/De-Escalation Algorithm...................................................................... 23
Table 7
Parts 4 and 5:  Intermittent (MK+T) Study Treatment Arm(s) and 
Escalation/De-Escalation Algorithm...................................................................... 24
Table 8
Inclusion Criteria Laboratory Parameters .............................................................. 47
Table 9
Trial Treatment....................................................................................................... 52
Table 10 Dose Modification and Toxicity Management Guidelines for Immune-related 
AEs Associated with Pembrolizumab.................................................................... 54
Table 11 Part 2 Dose Confirmation Rules............................................................................. 64
Table 12 mTPI Dosing Sequences ........................................................................................ 65
Table 13 Part 5 Dose Confirmation Rules............................................................................. 66
Table 14 Prohibited Concomitant Medications..................................................................... 71
Table 15 Medications to be used with Caution ..................................................................... 73
Table 16 Dose Level Reduction Guidelines.......................................................................... 75
Table 17 Dose Modification Guidelines for Events Considered Related to Study 
Treatment................................................................................................................ 78
Table 18 Management and Dose Modification Guidelines for Diarrhea .............................. 79
Table 19 Management and Dose Modification Guidelines for Endocrine AEs.................... 82
Table 20 Management and Dose Modification Guidelines for Visual Changes and/or 
Ophthalmic Examination Findings......................................................................... 84
Table 21 Recommended Dose Modifications for Trametinib for Retinal Pigment
Epithelial Detachments (RPED)............................................................................. 85
Table 22 Management and Dose Modification Guidelines for Pneumonitis ........................ 86
Table 23 Management and Dose Modification Guidelines for Renal Insufficiency............. 87
Table 24 Guidelines for Supportive Care of Rash................................................................. 88
Table 25 Management and Dose Modification Guidelines for Rash .................................... 90
Table 26 Management and Dose Modification Guidelines for Fever ................................... 92
Table 27 Dose Modification Guidelines and Stopping Criteria for LVEF Decrease............ 94
Table 28 Management and Dose Modification Guidelines for Hypertension....................... 96
Table 29 Withholding and Stopping Criteria for QTc-Prolongation..................................... 97
Table 30 Management and Dose Modification Guidelines for Hepatic Laboratory 
Abnormalities......................................................................................................... 98
Table 31 Management and Dose Modification Guidelines for Hematologic Adverse 
Events ................................................................................................................... 104
Table 32 Management and Dose Modification Guidelines for Neutropenia ...................... 105
Table 33 Management and Dose Modification Guidelines for Neurologic Adverse 
Events ................................................................................................................... 105
 
 
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Table 34 Pembrolizumab Infusion Reaction Dose Modification and Treatment 
Guidelines............................................................................................................. 107
Table 35 General Approach to Handling irAEs .................................................................. 109
Table 36 Laboratory Tests................................................................................................... 142
Table 37 Evaluating Adverse Events .................................................................................. 152
Table 38 Analysis Strategy for Primary and Secondary Efficacy Endpoints in Part 3 ....... 157
Table 39 Summary of Interim Analysis Strategy................................................................ 158
Table 40 Analysis Strategy for Primary and Secondary Efficacy Endpoints in Part 3 ....... 163
Table 41 Censoring Rules for Primary and Sensitivity Analyses of PFS ........................... 164
Table 42 Analysis Strategy for Safety Parameters.............................................................. 168
Table 43 Product Descriptions ............................................................................................ 173
 
 
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LIST OF FIGURES
Figure 1 Trial Diagram: Part 3.............................................................................................. 27
Figure 2 Flow Diagram: Part 4 Concurrent (cDL) and Intermittent (iDL) Dose 
Levels ..................................................................................................................... 61
 
 
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 6
05-DEC-2019
Revised to add dose modification 
requirements for cases of severe cutaneous 
adverse reactions (SCARs) that have been 
reported during treatment with dabrafenib 
in combination with trametinib.
Amendment 5
21-MAR-2019
Enrollment for Part 5 Dose expansion 
phase removed from the protocol in 
Amendment 05.  Updated language for 
contraception requirements and rash 
management.
Amendment 4
18-MAY-2018
Update protocol operation after the final 
analysis of Part 3 including unblinding
Amendment 3
13-DEC-2017
To implement a safety update regarding 
myocarditis, and update for compliance 
with latest dose modification guidance;
To increase clarity and ensure alignment 
with study specific dose modification 
guidelines;
To ensure the collection of survivor 
information throughout and following 
study participation regardless of 
discontinuation of treatment
 
 
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Document
Date of Issue
Overall Rationale
Amendment 2
4-OCT-2016
Additional dose levels were added, as a
tolerable dose level for (MK+T) was not 
identified in BRAF wild-type melanoma 
subjects in Part 1 of the study.
Amendment 1
10-NOV-2014
Implementation of the monotherapy 
dose/schedule for MK-3475 at 2 mg/kg 
Q3W
Original Protocol
31-JAN-2014
Not applicable
 
 
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SUMMARY OF CHANGES
PRIMARY REASON(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title(s)
Description of Change (s)
Rationale
5.6.1.1.4
General Guidelines for 
Clinically Significant 
Toxicities
Table 17 - Added language and 
footnote related to Severe 
Cutaneous Adverse Reactions
Alignment with updated 
Investigator Brochure for 
dabrafenib and trametinib 
combination therapy
5.6.1.1.10.4
Severe Cutaneous Adverse 
Reactions
Added language related to 
Severe Cutaneous Adverse 
Reactions
Alignment with updated 
Investigator Brochure for 
dabrafenib and trametinib 
combination therapy
12.10
List of Abbreviations
Added SCARs definition
Update Abbreviations Table
ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
No additional changes.
 
 
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1.0 TRIAL SUMMARY
Abbreviated Title
Phase I Study of MK-3475 in Combination with Trametinib and 
Dabrafenib
Trial Phase
I/II
Clinical Indication
The treatment of subjects with advanced or metastatic melanoma in all 
parts of the trial.  Additionally, the treatment of subjects with advanced 
(unresectable and/or metastatic) solid tumors in Parts 4 and 5 dose 
escalation and confirmation only.
Trial Type
Interventional
Type of control
No treatment control in Parts 1, 2, 4, and 5.  Placebo (standard, active 
therapy with a placebo add-on) in Part 3.
Route of administration
Intravenous Pembrolizumab (MK-3475)
Oral (trametinib)
Oral (dabrafenib)
Trial Blinding
Parts 1, 2, 4, 5:  Unblinded Open Label
Part 3:  Double-blind
Treatment Groups
In Part 1 (3+3 design), a cohort of 3 or 6 subjects with BRAF mutant 
[V600 E or K] melanoma will receive pembrolizumab 2 mg/kg q3weeks 
in combination with trametinib 2 mg QD and dabrafenib 150 mg BID.  
Additionally in Part 1 (3+3 design), a cohort of 3 or 6 subjects with 
BRAF wild type [without V600 E or K] melanoma will receive
pembrolizumab 2 mg/kg q3weeks in combination with trametinib 2 mg 
QD.
Approximately 12 subjects will be enrolled in Part 1 (~6 for the
pembrolizumab + dabrafenib + trametinib (MK+D+T) combination 
therapy and ~6 for the pembrolizumab + trametinib (MK+T)
combination therapy).
In Part 1, and only in the event the (MK+D+T) combination therapy is 
not tolerable, a cohort of 3 or 6 subjects with BRAF mutant [V600 E]
melanoma will receive pembrolizumab 2 mg/kg q3weeks in combination 
with dabrafenib 150 mg BID (3+3 design).
Approximately 6 subjects will be enrolled for the pembrolizumab + 
dabrafenib (MK+D) combination therapy, but only if the (MK+D+T)
combination therapy is not tolerable.
Part 2 will expand cohort(s) from Part 1 for dose confirmation.   
Approximately 45 subjects will be enrolled in Part 2, ~11 for (MK+D+T)
and ~34 for (MK+T).
 
 
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In Part 3, approximately 120 subjects with BRAF mutant [V600 E or K] 
melanoma will be randomized 1:1 to either: (a) pembrolizumab 2 mg/kg 
q3weeks, trametinib 2 mg QD, dabrafenib 150 mg BID, or, (b) placebo 
(saline IV), trametinib 2 mg QD, dabrafenib 150 mg BID.  Note:  The 
triplet dose combination of all treatments used in Part 3 will be 
confirmed by Parts 1 and 2 of the study. 
In Part 4 (3+3 design), a cohort of 3 or 6 subjects with BRAF wild type 
[without V600E or K] melanoma or solid tumors [irrespective of BRAF 
status] will receive pembrolizumab 200 mg q3weeks in combination with 
either trametinib 2 mg QD or 1.5 mg QD after receiving a 2-week or 4-
week monotherapy run-in with trametinib in either a concurrent or 
intermittent dosing regimen.  Approximately 24 subjects total are 
estimated for enrollment in Part 4 for the (MK+T) combination therapy, 
~6-24 subjects for the concurrent dosing regimen and ~6-18 subjects for 
the intermittent dosing regimen.  
Part 5 will confirm the dose(s) identified in Part 4 in BRAF wild type 
[without V600E or K] melanoma or solid tumors [irrespective of BRAF 
status] in subjects.  
Number of trial subjects
Approximately 77 subjects will be enrolled in the investigation of the 
(MK+D+T) combination therapy (this total includes 17 subjects from
specific arms in Parts 1 and 2, and 60 subjects in the blinded active 
(MK+D+T) arm from Part 3).  Additionally, 60 subjects will receive 
PBO (saline IV) + (D+T) in Part 3 of the study.  ~ Approximately 50
subjects will be enrolled in the investigation of the (MK+T) combination 
therapy (Parts 1, 2, 4, and 5).  In the overall study, ~Approximately 190
subjects will be enrolled.
Estimated duration of trial
The sponsor estimates that the trial will require approximately 48
months from the time the first subject signs the informed consent until 
the last subject’s last visit.
Duration of Participation
Each subject will participate in the trial from the time the subject signs 
the Informed Consent Form (ICF) through the final protocol-specified 
contact.  After a screening phase of up to 28 days, eligible subjects will 
receive assigned treatment on Day 1 of the dosing cycle.  Treatment with 
pembrolizumab, trametinib, and/or dabrafenib will continue until 
documented disease progression, unacceptable adverse event(s), 
intercurrent illness that prevents further administration of treatment, 
investigator’s decision to withdraw the subject, subject withdraws 
consent, pregnancy of the subject, noncompliance with trial treatment or 
procedure requirements, or administrative reasons or completion of 24 
months of trial treatment.  In Parts 4 and 5 treatment with 
pembrolizumab and trametinib will discontinue at 24 months. 
pembrolizumab treated subjects who attain a complete response after at 
least 6 months of study treatment may consider stopping pembrolizumab
treatment (at the discretion of the investigator after receiving at least two 
doses beyond the initial determination of complete response), while 
continuing on treatment with trametinib and/or dabrafenib.  After the end 
of all treatments, each subject will be followed for a minimum of 30 days 
for adverse event monitoring (serious adverse events will be collected for 
up to 90 days after the end of treatment).  Subjects will have post-
treatment follow-up for disease status, including initiating a non-study 
 
 
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cancer treatment and experiencing disease progression, until death, 
withdrawing consent, or becoming lost to follow-up.  
Once the subject has achieved the study objective or the study has ended, 
the subject is discontinued from this study and may be enrolled in an 
extension study to continue protocol-defined assessments and treatment.
Randomization Ratio
Part 3:  1:1
A list of abbreviations used in this document can be found in Section 12.10.
2.0 TRIAL DESIGN
Trial Design
This study (KEYNOTE 022) is a multi-center, worldwide, Phase I/II 5-part trial of 
intravenous (IV) pembrolizumab (MK-3475) in combination with oral dabrafenib and/or
trametinib in subjects with advanced or metastatic melanoma (or solid tumors in Parts 4 and 
5) to be conducted in conformance with Good Clinical Practices.  Approximately 190
subjects evaluable for safety, tolerability, and efficacy will be enrolled in the overall study.  
The final number will depend on empirical safety data and observed Dose Limiting 
Toxicities (DLTs).
Due to the various combinations of treatment evaluated in the 5 parts of this study, the 
following abbreviations will be utilized to clarify the combinations (Table 1) when discussed 
within protocol text.
Table 1
Study Treatment Combinations
Part 1 is a nonrandomized, multi-site, open-label portion of the study using a traditional 3+3 
design to evaluate safety, tolerability, and dosing of pembrolizumab in combination with 
dabrafenib and trametinib (MK+D+T) in BRAF mutation-positive (V600 E or K) melanoma 
subjects.  A cohort of 3-6 subjects will be enrolled with the dose combination listed in Table 
2 for the duration of the study. Dose modifications based upon observed toxicities and in 
accordance with the criteria outlined in the protocol are allowed but may meet DLT criteria if 
made during the DLT evaluation period.
Drug Combination
Abbreviation
When Combination is Active in Study
MK-3475 + dabrafenib + trametinib
(MK+D+T)
Parts 1, 2, & 3
MK-3475 + dabrafenib
(MK+D)
Activated only if triplet combination does not move forward in 
Parts 1 & 2
MK-3475 + trametinib
(MK+T)
Parts 1, 2, 4 & 5
Placebo (saline IV) + dabrafenib + trametinib
(PBO+D+T)
Part 3 only
 
 
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Table 2
Parts 1 and 2: (MK+D+T) Study Treatment Arm
Dose Level
Pembrolizumab
Dabrafenib
Trametinib
1
2 mg/kg Q3W
150 mg BID
2 mg QD
Approximately 6 subjects (range 3-12) will be enrolled in the (MK+D+T) combination dose 
evaluation portion of the study.  Subjects will be evaluated for DLTs for 6 weeks.  Subjects 
who withdraw from the study for reasons other than DLT or subjects who are not evaluable 
for DLTs before the completion of 6 weeks of treatment may be replaced.  See Section 5.9
for additional information.  
Additionally, in Part 1, dosing of pembrolizumab in combination with trametinib only 
(MK+T) will be explored in BRAF mutation-negative (without V600 E or K) melanoma 
subjects, to evaluate safety, tolerability, and efficacy of (MK+T) in Part 2 (Table 3) in this 
population.  In the event that DL1 for (MK+T) in Part 1 is not tolerable, the Dose Level 
Minus (-1) option (DL-1) will be selected and opened as listed in Table 3.  A cohort of 3-6 
subjects will be enrolled sequentially at the (MK+T) dose combination. Approximately 6 
subjects (range 3-12) will be enrolled in the (MK+T) combination dose evaluation portion of 
the study, resulting in a total of ~12 subjects overall in Part 1 of the study.  In the event that 
DL-1 for (MK+T) is not tolerable, additional dosing level combination(s) will be further 
explored in Parts 4 and 5.
Table 3
Parts 1 and 2: (MK+T) Study Treatment Arm(s)
Dose Level
Pembrolizumab
Trametinib
1
2 mg/kg Q3W
2 mg QD
DL -1
2 mg/kg Q3W
1.5 mg QD
In the event that Dose Level 1 (DL1) for (MK+D+T) in Part 1 is not tolerable, a Dose Level 
Minus (-1) option (DL-1) will be selected and opened (a single DL-1 will be chosen from the 
options listed in Table 5 based on clinically observed toxicity; e.g. pyrexia attributed to 
dabrafenib would open DL-1b, or rash due to trametinib would open DL-1a). In addition, if 
one of the DL-1 options for MK+D+T is opened, the back-up combination of pembrolizumab
and dabrafenib 150 mg BID (MK+D) will be explored in Part 1 (and Part 2 if the (MK+D+T) 
combination DL-1 is not tolerated) in BRAF mutation-positive (V600 E) melanoma subjects. 
Approximately 6 subjects will be enrolled if this portion of the study must be activated.  A 
cohort of 3-6 subjects will be enrolled sequentially at the dose combination listed in Table 4.  
Additional lower doses of this combination (MK+D) may be enrolled based on the 
tolerability of the DL1 in Part 1 (and/or Part 2 if necessary).  Please refer to Section 5.2.4.1 
for the rules utilized in determining when DLTs will trigger enrollment of patients at DL-1.
In the event that DL-1 for (MK+D+T) in Part 1 or Part 2 is not tolerable, this combination 
will not be further explored in Part 3.
 
 
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Table 4
Parts 1 and 2:  (MK+D) Study Treatment Arm
Dose Level
Pembrolizumab
Dabrafenib
1
2 mg/kg Q3W
150 mg BID
Table 5
Parts 1 and 2:  (MK+D+T) Dose Level Minus (-1) Options
For kinase-inhibitor related AEs:
Dose Levels
Pembrolizumab
Dabrafenib
Trametinib
DL -1a
2 mg/kg Q3W
150 mg BID
1.5 mg QD
DL -1b
2 mg/kg Q3W
100 mg BID
2 mg QD
DL -1c
2 mg/kg Q3W
100 mg BID
1.5 mg QD
For immune-related AEs:
Dose Levels
Pembrolizumab
Dabrafenib
Trametinib
DL -1
1 mg/kg Q3W
150 mg BID
2 mg QD
Unclear cause of AEs:
Dose Levels
Pembrolizumab
Dabrafenib
Trametinib
DL -1
1 mg/kg Q3W
100 mg BID
1.5 mg QD
Part 2 is a nonrandomized, multi-site, open-label portion of the study using an expansion 
cohort to further evaluate safety and confirm dose of (MK+D+T).  Approximately 11
subjects will be enrolled in the Part 2 (MK+D+T) dose confirmation.
Also in Part 2, an expansion cohort will be used to further evaluate safety and preliminary 
efficacy in the (MK+T) combination.  After 14 subjects are enrolled on the (MK+T) dose 
confirmed in Part 2 (including subjects from both Parts 1 and 2), 26 additional subjects will 
be enrolled at the same dose, resulting in a total of 40 patients in Parts 1 and 2 on the 
(MK+T) combination.  Approximately 34 subjects will be enrolled in (MK+T) Part 2 of the 
study.  In Part 2, for the (MK+D+T) and (MK+T) cohorts, ~a total of ~45 subjects will be 
enrolled.   In the event that DL1 and DL-1 for (MK+T) in Part 1 is not tolerable, Part 2 for 
this combination will not open, and instead the combination will be further explored in Parts 
4 and 5.
 
 
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Part 3 is a randomized (1:1), active-controlled, multi-site, two-arm study of the confirmed 
dose of the triplet combination (MK+D+T) versus placebo in combination with D+T 
(PBO+D+T).  Approximately 120 subjects will be enrolled in Part 3.  Subjects will be 
stratified by Eastern Cooperative Oncology Group (ECOG) Performance Scale (0 vs. 1) and
Lactate Dehydrogenase (LDH) level (>1.1 x ULN vs. ≤1.1 x ULN).
Part 4 is a nonrandomized, multi-site, open-label portion of the study using a traditional 3+3 
design to evaluate pembrolizumab in combination with trametinib only (MK+T) in BRAF 
mutation-negative (without V600 E or K) melanoma or solid tumor [irrespective of BRAF 
status] subjects.  A cohort of 3-6 subjects will be enrolled in the initial combination (DL1) 
proposed for both the concurrent and intermittent dosing regimens in Table 6 and Table 7 . It 
should be noted that the concurrent and intermittent dosing regimens in these tables have 
been named such based on the initial proposed dose within each regimen:  cDL1 and iDL1, 
respectively.  There is, in fact, a potential for intermittent dosing within the concurrent 
dosing regimen table (Table 6) if, and only if, dose(s) must de-escalate (e.g., cDL1 is not 
tolerated).  The choice of the dosing regimen for a new subject will be determined using 1:1 
randomization whenever both regimens are opened for enrollment. Dose escalation or de-
escalation will occur for each dosing regimen as outlined in Table 6 and Table 7, following 
the algorithms provided in each respective table.  The escalation and de-escalation for 
(MK+T) in the concurrent and intermittent dosing regimens will occur simultaneously in Part 
4 until a dose has been identified for each regimen.  Subjects will be evaluated for DLTs for 
a period of 6 weeks, commencing with the initial dose of pembrolizumab in Cycle 1.   
Subjects who withdraw from the study for reasons other than DLT or subjects who are not 
evaluable for DLTs before the completion of 6 weeks of combination treatment may be 
replaced.  See Section 5.9 for additional information.  
Dose modifications based upon observed toxicities and in accordance with the criteria 
outlined in the protocol are allowed but may meet DLT criteria if made during the DLT 
evaluation period.  Approximately 24 subjects are estimated for enrollment in the (MK+T) 
combination dose evaluation in Part 4, with anywhere from 6-24 subjects for the concurrent 
dosing regimen and 6-18 subjects for the intermittent dosing regimen.
Upon identification of a preliminary maximum tolerated dose for both the concurrent and 
intermittent dosing regimens, each regimen will proceed to Part 5 for dose confirmation
using a modified TPI (mTPI) design. In the event that tolerable concurrent and intermittent 
dosing regimens are identified, the Sponsor may choose to pursue one or both for dose 
confirmation in Part 5.  For each regimen, a total of 14 subjects evaluable for DLT will be 
treated with the identified dose across Part 4 and 5 by the end of the dose confirmation.  In 
the event that a tolerable dose for either dosing regimen of (MK+T) cannot be identified in 
Part 4, that particular dosing regimen will not be further explored in Part 5.
In Part 5, the expansion cohort(s) will be used to further evaluate safety and preliminary 
efficacy in the (MK+T) combination(s). Dose expansion requires only BRAF wild type 
[without V600E or K] melanoma to be enrolled.  During the study it was found that the 
accrual of BRAF wild type melanoma subjects was limited, reflecting recent changes in the 
standard of care for these patients which include checkpoint inhibition in combination with 
 
 
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other drugs not compatible with this study design.  The expansion cohort will not be pursued 
further following the completion of Part 5 dose confirmation.  
Table 6
Parts 4 and 5:  Concurrent (MK+T) Study Treatment Arm(s)
and 
Escalation/De-Escalation Algorithm
Dose 
Level
Trametinib 
Monotherapy Run-
In
Pembrolizumab
Trametinib
Dosing Regimen
cDL3
2 Weeks 2 mg QD
200 mg Q3W
2 mg QD
Concurrent dosing of 
pembrolizumab and trametinib 
starting at Week 3
cDL2b
4 Weeks 2 mg QD
200 mg Q3W
2 mg QD
Concurrent dosing of 
pembrolizumab and trametinib 
starting at Week 5
cDL2a
2 Weeks 1.5 mg QD
200 mg Q3W
1.5 mg QD
Concurrent dosing of 
pembrolizumab and trametinib 
starting at Week 3
cDL1
4 Weeks 1.5 mg QD
200 mg Q3W
1.5 mg QD
Concurrent dosing of 
pembrolizumab and trametinib 
starting at Week 5
cDL-1b
4 Weeks 2 mg QD
200 mg Q3W
2 mg QD
pembrolizumab dosing starting at 
Week 5 with intermittent 2 weeks 
OFF trametinib/2 weeks ON 
trametinib
cDL-1a
4 Weeks 1.5 mg QD
200 mg Q3W
1.5 mg QD
pembrolizumab dosing starting at 
Week 5 with intermittent 2 weeks 
OFF trametinib/2 weeks ON 
trametinib
Start at cDL1.
If cDL1 is tolerated, test cDL2a and cDL2b concurrently.
          If cDL2a and cDL2b both tolerated, test cDL3.
               If cDL3 is tolerated, preliminary MTD is cDL3.
               If cDL3 is not tolerated, preliminary MTD is cDL2a.
          If cDL2a is tolerated and cDL2b is not tolerated, preliminary MTD is cDL2a.
          If cDL2b is tolerated and cDL2a is not tolerated, preliminary MTD is cDL2b.
          If cDL2a and cDL2b both not tolerated, preliminary MTD is cDL1.
If cDL1 is not tolerated, test cDL-1a.
          If cDL-1a is tolerated, test cDL-1b.
               If cDL-1b is tolerated, preliminary MTD is cDL-1b.
               If cDL-1b is not tolerated, preliminary MTD is cDL-1a.
       If cDL-1a is not tolerated, no tolerable dose for the regimen is identified.
 
 
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Table 7
Parts 4 and 5:  Intermittent (MK+T) Study Treatment Arm(s) and 
Escalation/De-Escalation Algorithm
Dose 
Level
Trametinib 
Monotherapy Run-
In
Pembrolizumab
Trametinib
Dosing Regimen
iDL2
2 Weeks 2 mg QD
200 mg Q3W
2 mg QD
pembrolizumab dosing starting at 
Week 3 with intermittent 1 week 
OFF trametinib/2 weeks ON 
trametinib
iDL1
2 Weeks 1.5 mg QD
200 mg Q3W
1.5 mg QD
pembrolizumab dosing starting at 
Week 3 with intermittent 1 week 
OFF trametinib/2 weeks ON 
trametinib
iDL-1b
2 Weeks 2 mg QD
200 mg Q3W
2 mg QD
pembrolizumab dosing starting at 
Week 3 with intermittent 2 weeks 
OFF trametinib/2 weeks ON 
trametinib
iDL-1a
2 Weeks 1.5 mg QD
200 mg Q3W
1.5 mg QD
pembrolizumab dosing starting at 
Week 3 with intermittent 2 weeks 
OFF trametinib/2 weeks ON 
trametinib
Start at iDL1.
If iDL1 is tolerated, test iDL2.
          If iDL2 is tolerated, preliminary MTD is iDL2.
          If iDL2 is not tolerated, preliminary MTD is iDL1.
If iDL1 is not tolerated, test iDL-1a.
          If iDL-1a is tolerated, test iDL-1b.
                    If iDL-1b is tolerated, preliminary MTD is iDL-1b.
                    If iDL-1b is not tolerated, preliminary MTD is iDL-1a.
          If iDL-1a is not tolerated, no tolerable dose for the regimen is identified.
After radiological assessment at screening, the first radiological assessment will be 
performed following 2 cycles of study treatment (±7 days), unless there is clinical indication 
(based on Investigator’s assessment) warranting earlier radiologic imaging.  The same 
imaging technique as used at screening should be used throughout the study.   After the first 
on-treatment imaging assessment, subjects will be evaluated every six (6) weeks up to Month 
18 with radiographic imaging to assess response to treatment.  Following Month 18, imaging 
assessment will occur every twelve (12) weeks.  Investigators will make all treatment-based 
decisions using modified Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 
criteria.  Imaging from Parts 1, 2, 4, and 5 for (MK+D+T) and (MK+T) and Part 3 (non-
inclusive of IA) will be investigator-assessed using RECIST 1.1 for determination of 
endpoints (including ordinal response), but also collected and held, and may be centrally-read 
later by independent radiologists, retrospectively.  Imaging for the first 80 patients up to 
Week 36 in Part 3 (subjects included in the interim analysis) will be centrally-read using 
RECIST 1.1 for determination of efficacy endpoints.  Refer to Section 8.2.3 for additional 
information on endpoints.  RECIST 1.1 will be adapted as described in Section 4.2.3.1 due to 
the tumor response patterns seen with pembrolizumab treatment (e.g., tumor flare), and this 
 
 
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adapted RECIST will be used by the sites for treatment decisions. Adverse events will be 
monitored throughout the trial and graded in severity according to the guidelines outlined in 
the NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0.  In 
general, study treatment will continue until documented disease progression, unacceptable 
adverse event(s), intercurrent illness that prevents further administration of treatment, 
investigator’s decision to withdraw the subject, subject withdraws consent, pregnancy of the 
subject, noncompliance with trial treatment or procedure requirements, or administrative 
reasons.  Subjects who attain an investigator-determined confirmed complete response (CR) 
per RECIST after at least 6 months of pembrolizumab treatment could potentially stop trial 
treatment of pembrolizumab and continue treatment with trametinib and/or dabrafenib, in 
accordance with standard care, until disease progression or the end of study, whichever 
comes first.  
Subjects in Part 3 who remain on study treatment with pembrolizumab and who have not 
progressed after 24 months will discontinue pembrolizumab treatment and may continue 
treatment with trametinib and/or dabrafenib, off study and in accordance with standard care.  
Please refer to Section 5.2.5 and Section 7.1.5.4 for additional details.
Subjects in Parts 4 and 5 who have not progressed after 24 months will discontinue 
pembrolizumab and trametinib treatment. They may continue treatment with pembrolizumab
or trametinib off study and in accordance with standard of care.  After the end of treatment, 
each subject will be followed for a minimum of 30 days for adverse event monitoring 
(serious adverse events will be collected for up to 90 days after the end of treatment).  
Subjects who stop study treatment for reasons other than disease progression should continue 
to have disease assessments until progression is documented.  Subjects will have post-
treatment follow-up for disease status, including initiating a non-study cancer treatment and 
experiencing disease progression, until death, withdrawing consent, or becoming lost to 
follow-up.  
A primary objective of the trial is to assess safety and tolerability of (MK+D+T) and confirm 
the maximum tolerated dose (MTD) or maximum administered dose (MAD) in subjects with 
advanced melanoma with BRAF V600 E or K mutations, and the primary safety analysis will 
include descriptive tables that summarize the number and percentage of subjects who
experience dose limiting toxicity (DLT) at each dose level for (MK+D+T).  Safety and 
tolerability will also be assessed for (MK+T) therapy in subjects with advanced melanoma 
without BRAF V600 E or K mutations and solid tumors [irrespective of BRAF status].  As a 
back-up strategy in the event Dose Level 1 (DL1) of (MK+D+T) is not tolerable, safety and 
tolerability will also be evaluated for (MK+D) in subjects with advanced melanoma with 
BRAF V600 E mutations.  
A primary efficacy evaluation of (MK+T) in Part 2, Part 4 and Part 5 will include the 
analysis of the overall response rate (ORR) per RECIST 1.1 by investigator-assessment in 
subjects with solid tumors or advanced melanoma without BRAF V600 mutations taking 
(MK+T), in order to establish whether this combination therapy is active and warrants further 
investigation.  An efficacy evaluation of (MK+D+T) with respect to progression-free 
survival (PFS) will also be performed.
 
 
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The database will be locked for (MK+D+T) analysis of Parts 1 and 2 approximately six
months after the enrollment of the last (MK+D+T) subject in Part 2.  The database will be 
locked for (MK+T) analysis of Parts 1 and 2, or, Part 4 and 5, approximately six months after 
the enrollment of the last (MK+T) subject in Part 2 or Part 5.  Part 3 will not be unblinded 
when these analyses take place. Details are described in Section 8.2.1.
Key pharmacokinetic (PK) properties of (MK+D+T) and (MK+T) will be investigated as a 
secondary objective. 
In Part 3, the primary objective of the randomized, double-blind Phase II portion of the study 
is to compare the progression free survival (PFS) of (MK+D+T) to (PBO+D+T) in subjects 
with BRAF V600 E or K mutations.  In addition, assessment of ORR, response duration, and 
overall survival (OS) will also be evaluated as secondary endpoints.
An Interim Analysis (IA) of Part 3 will be conducted to inform a potential early Go/No Go 
decision for initiation of Phase III before the completion of Part 3.   The IA will be 
performed when the first 80 subjects randomized into this part of the study have completed 
their Week 36 visit and have their central radiology assessment at Week 36 available, or, 
have discontinued prior to Week 36.  The primary endpoint for the IA is the ordinal response 
at Week 36 including the following five categories (consistent with RECIST 1.1 definitions, 
with the exception of PR being divided into MPR and VGPR based on the degree of tumor 
shrinkage): Complete Response (CR), Very Good Partial Response (VGPR), Moderate 
Partial Response (MPR), Stable Disease (SD), and Progressive Disease (PD).  These 
categories are further defined in Section 8.1.    Subjects who discontinued prior to Week 36 
will be assigned to one of these categories for Week 36 according to the reason for 
discontinuation (see the endpoint definition).  Secondary and exploratory endpoints including 
the use of tumor kinetic parameters for the IA are further defined in Section 8.2.
As exploratory objectives in this study, key candidate biomarkers will be evaluated in tumor 
tissue and peripheral blood that may correlate with clinical response to treatment and/or with 
the development of disease progression, and to further explore the relationship between study
treatment and pharmacodynamic response.  Subgroup analyses are summarized in Section 
8.1.4.
Part 3 of this trial will use a standing internal Data Monitoring Committee (siDMC) to 
monitor safety information and efficacy in the study.  The siDMC will oversee the conduct of 
the study in accordance with Good Clinical Practice (GCP) and as described in the siDMC 
charter. The siDMC will also evaluate the data at the planned IA and make recommendations 
of stopping or continuing the study according to the siDMC charter.  In addition, the trial 
may be stopped early at the recommendation of the siDMC if the risk/benefit ratio to the trial 
population as a whole is unacceptable.  Details are described in Section 8.0 – Statistical 
Analysis Plan.
Specific procedures to be performed during the trial, as well as their prescribed times and 
associated visit windows, are outlined in the Trial Flow Chart - Section 6.0. Details of each 
procedure are provided in Section 7.0 – Trial Procedures.
 
 
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Trial Diagram
Following the dose confirmation and dose expansion portions of the trial (Parts 1 and 2), Part 
3 will evaluate the clinical efficacy of the confirmed triplet dose (MK+D+T) as compared to 
(PBO+D+T).  The trial design for Part 3 is depicted in Figure 1.
Figure 1
Trial Diagram: Part 3
3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
Primary Objective(s) & Hypothesis(es)
Parts 1 and 2:
(1a) Objective:  To evaluate the safety and tolerability and identify the maximum tolerated 
dose (MTD) or maximum administered dose (MAD) of pembrolizumab administered 
intravenously in combination with oral dabrafenib and trametinib in subjects with 
advanced (unresectable or metastatic) melanoma with BRAF V600 E or K mutations.
Hypothesis:  Pembrolizumab dosed intravenously on a q3week schedule combined 
with twice daily oral dabrafenib and once daily oral trametinib is sufficiently well-
tolerated based on assessment of clinical and laboratory adverse events (AEs) to permit 
clinical investigation.
(1b) Objective:  To evaluate the safety and tolerability and identify the maximum tolerated 
dose (MTD) or maximum administered dose (MAD) of pembrolizumab administered 
intravenously in combination with oral trametinib in subjects with advanced 
(unresectable or metastatic) melanoma without BRAF V600 E or K mutations.
Hypothesis:  Pembrolizumab dosed intravenously on a q3week schedule combined 
with once daily oral trametinib is sufficiently well-tolerated based on assessment of 
clinical and laboratory adverse events (AEs) to permit clinical investigation.
(1c) Objective:  To evaluate the safety and tolerability and identify the maximum tolerated 
dose (MTD) or maximum administered dose (MAD) of pembrolizumab administered 
intravenously in combination with oral dabrafenib in subjects with advanced 
(unresectable or metastatic) melanoma with BRAF V600 E mutations. (Note: this 
objective will only be evaluated if DL1 of the MK+D+T triplet (objective 1a) is not 
tolerated).
 
 
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Hypothesis:  Pembrolizumab dosed intravenously on a q3week schedule combined 
with twice daily oral dabrafenib is sufficiently well-tolerated based on assessment of 
clinical and laboratory adverse events (AEs) to permit clinical investigation.
Part 2:
(2)
Objective:  To confirm the safety and tolerability of the preliminary maximum 
tolerated dose (MTD) or maximum administered dose (MAD) of pembrolizumab
administered intravenously in combination with oral dabrafenib and trametinib in 
subjects with advanced (unresectable or metastatic) melanoma with BRAF V600 E or 
K mutations.
Hypothesis:  Pembrolizumab dosed intravenously on a q3week schedule combined 
with twice daily oral dabrafenib and once daily oral trametinib is sufficiently well-
tolerated at the MTD/MAD based on assessment of clinical and laboratory adverse 
events (AEs) to permit further clinical investigation.
(3)
Objective:  To confirm the safety and tolerability of the preliminary maximum 
tolerated dose (MTD) or maximum administered dose (MAD) of pembrolizumab
administered intravenously in combination with oral trametinib in subjects with 
advanced (unresectable or metastatic) melanoma without BRAF V600 E or K
mutations.
Hypothesis:  Pembrolizumab dosed intravenously on a q3week schedule combined 
with once daily oral trametinib is sufficiently well-tolerated at the MTD/MAD based on 
assessment of clinical and laboratory adverse events (AEs) to permit further clinical 
investigation.
(4)
Objective: To evaluate the efficacy of pembrolizumab administered intravenously in 
combination with oral trametinib in subjects with advanced (unresectable or metastatic) 
melanoma without BRAF V600 E or K mutations with respect to Objective Response 
Rate (ORR).
Hypothesis:  Pembrolizumab dosed intravenously on a q3week schedule combined 
with once daily oral trametinib is effective in attaining objective responses based upon 
RECIST 1.1 by the investigator review in subjects with melanoma without BRAF V600
E or K mutations.
Part 3:
(5)
Objective: To evaluate the efficacy with respect to progression-free survival (PFS) of 
pembrolizumab administered intravenously in combination with oral dabrafenib and 
trametinib in subjects with advanced (unresectable or metastatic) melanoma with 
BRAF V600 E or K mutations, compared with placebo administered intravenously in 
combination with oral dabrafenib and trametinib alone. 
 
 
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Hypothesis:  Pembrolizumab dosed intravenously combined with twice daily oral 
dabrafenib and once daily oral trametinib (at doses determined in Parts 1 & 2 of the 
study) improves progression-free survival (PFS) based upon RECIST 1.1 by the 
investigator review compared with placebo dosed intravenously combined with oral 
dabrafenib and trametinib treatment.
Part 4:
(6)    Objective:  To evaluate the safety and tolerability and identify the maximum tolerated 
dose (MTD) or maximum administered dose (MAD) of pembrolizumab administered 
intravenously in combination with oral trametinib in subjects with advanced 
(unresectable or metastatic) melanoma without BRAF V600 E or K mutations or 
advanced (metastatic and/or unresectable) solid tumors, irrespective of BRAF status.
Hypothesis:  Pembrolizumab dosed intravenously on a q3week schedule combined 
with oral trametinib is sufficiently well-tolerated based on assessment of clinical and 
laboratory adverse events (AEs) to permit clinical investigation.
Part 5:
(7)
Objective:  To confirm the safety and tolerability of the preliminary maximum 
tolerated dose (MTD) or maximum administered dose (MAD) of pembrolizumab
administered intravenously in combination with oral trametinib in subjects with 
advanced (unresectable or metastatic) melanoma without BRAF V600 E or K mutations 
or advanced (metastatic and/or unresectable) solid tumors, irrespective of BRAF status.
Hypothesis:  Pembrolizumab dosed intravenously on a q3week schedule combined 
with oral trametinib is sufficiently well-tolerated at the MTD/MAD based on 
assessment of clinical and laboratory adverse events (AEs) to permit further clinical 
investigation.
(8)
Objective:  To evaluate the efficacy of pembrolizumab administered intravenously in 
combination with oral trametinib in subjects with advanced (unresectable or metastatic) 
melanoma without BRAF V600 E or K mutations or advanced (metastatic and/or 
unresectable) solid tumors, irrespective of BRAF status with respect to Objective 
Response Rate (ORR).
Hypothesis:  Pembrolizumab dosed intravenously on a q3week schedule combined 
with oral trametinib is effective in attaining objective responses based upon RECIST 
1.1 by the investigator review in subjects with melanoma without BRAF V600 E or K 
mutations.
 
 
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Secondary Objective(s) & Hypothesis(es)
Parts 1 and 2:
(1)
Objective:  To evaluate the efficacy of pembrolizumab administered intravenously in 
combination with oral dabrafenib and trametinib in subjects with advanced 
(unresectable or metastatic) melanoma with BRAF V600 E or K mutations with respect 
to Objective Response Rate (ORR).
Parts 1, 2, 3, 4, and 5:
(2)
Objective:  To evaluate the pharmacokinetics (PK) of pembrolizumab, dabrafenib, 
and/or trametinib when pembrolizumab is administered intravenously in combination 
with oral dabrafenib and/or trametinib.
Part 3:
(3)
Objective: To evaluate the efficacy of pembrolizumab administered intravenously in 
combination with oral dabrafenib and trametinib in subjects with advanced 
(unresectable or metastatic) melanoma with BRAF V600 E or K mutations with respect 
to Objective Response Rate (ORR), Response Duration, and overall survival (OS), 
compared with oral dabrafenib and trametinib alone. 
Exploratory Objective(s)
(1)
Objective:  To evaluate key biomarkers (via tumor biopsy and peripheral blood 
sample) at baseline and 10-14 days after administration of oral dabrafenib and/or 
trametinib in combination with intravenously administered pembrolizumab, and 
determine the relationship between key biomarkers and clinical response.
(2) 
Objective:  To evaluate key biomarkers (via tumor biopsy and peripheral blood 
sample) at the time of progression after administration of oral dabrafenib and/or 
trametinib in combination with intravenously administered pembrolizumab, and 
determine the relationship between key biomarkers and clinical progression.
(3)
Objective: To evaluate the use of tumor kinetic parameters including time to growth 
(TTG) modeling and simulation to evaluate the effect of pembrolizumab administered 
intravenously in combination with oral dabrafenib and trametinib in subjects with 
advanced (unresectable or metastatic) melanoma with BRAF V600 E or K mutations.  
These tumor kinetics parameters may be correlated with clinical outcomes.
(4)
Objective: To evaluate the efficacy of pembrolizumab administered intravenously in 
combination with oral dabrafenib and trametinib in subjects with advanced 
(unresectable or metastatic) melanoma with BRAF V600 E or K mutations with respect 
to Best Overall Response, 5-Category Best Overall Response, 5-Category Ordinal 
Response by Week,  Percentage of Subjects with Complete Response, Percentage of 
Subjects with Partial Response, Percentage of Subjects with Deep Response, Best 
 
 
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Target Lesion Response,  Time to Confirmed Response, Percentage of Subjects with 
Sustained Response at Week 36 (see Section 8.2.3.1 for endpoint definitions), EuroQol
(EQ-5D), and EORTC (QLQ-C30) compared with oral dabrafenib and trametinib alone
in Part 3.
(5)
Objective: To evaluate the potential for development of anti-drug antibodies (ADA) 
after administration of pembrolizumab.
4.0 BACKGROUND & RATIONALE
Background
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody 
(mAb) with high specificity of binding to the programmed cell death 1 (PD 1) receptor, thus 
inhibiting its interaction with programmed cell death ligand 1 (PD-L1) and programmed cell 
death ligand 2 (PD-L2).  Based on preclinical in vitro data, pembrolizumab has high affinity 
and potent receptor blocking activity for PD 1.  Pembrolizumab has an acceptable preclinical 
safety profile and is in clinical development as an intravenous (IV) immunotherapy for 
advanced malignancies.  Keytruda™ (pembrolizumab) is indicated for the treatment of 
patients across a number of indications. Refer to the appropriate Investigator’s Brochure 
(IB)/approved labeling for detailed background information on MK-3475, trametinib or 
dabrafenib.
Pharmaceutical and Therapeutic Background
Pembrolizumab
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades [1]. Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies [2-37].  In particular, the presence of CD8+ T-cells and the ratio of 
CD8+ effector T-cells / FoxP3+ regulatory T-cells seems to correlate with improved 
prognosis and long-term survival in solid malignancies such as ovarian, colorectal and 
pancreatic cancer, hepatocellular carcinoma, malignant melanoma (MEL) and renal cell 
carcinoma (RCC). TILs can be expanded ex vivo and re-infused, inducing durable objective 
tumor responses in cancers such as MEL [38; 39].
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control. The normal function of PD-1, expressed on the cell surface of activated
T-cells under healthy conditions, is to down -modulate unwanted or excessive immune 
responses, including autoimmune reactions.  PD-1 (encoded by the gene Pdcd1) is an Ig 
superfamily member related to CD28 and CTLA-4 which has been shown to negatively
regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2) 
[40; 41] The structure of murine PD-1 has been resolved [42]. PD-1 and family members are 
type I transmembrane glycoproteins containing an Ig Variable-type (V-type) domain 
responsible for ligand binding and a cytoplasmic tail which is responsible for the binding of 
 
 
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signaling molecules.  The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling 
motifs, an immunoreceptor tyrosine-based inhibition motif (ITIM) and an immunoreceptor 
tyrosine-based switch motif (ITSM).  Following T-cell stimulation, PD-1 recruits the tyrosine 
phosphatases SHP-1 and SHP-2 to the ITSM motif within its cytoplasmic tail, leading to the 
dephosphorylation of effector molecules such as CD3ζ, PKCθ and ZAP70 which are 
involved in the CD3 T-cell signaling cascade [40; 43-45]. The mechanism by which PD-1 
down modulates T-cell responses is similar to, but distinct from that of CTLA-4 as both 
molecules regulate an overlapping set of signaling proteins [46; 34]. PD-1 was shown to be 
expressed on activated lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells,
T-regs and Natural Killer cells [47; 48]. Expression has also been shown during thymic 
development on CD4-CD8- (double negative) T-cells as well as subsets of macrophages and 
dendritic cells [30]. 
The ligands for PD-1 (PD-L1 and PD-L2) are constitutively
expressed or can be induced in a variety of cell types, including non-hematopoietic tissues as
well as in various tumors [49; 50; 46; 51]. Both ligands are type I transmembrane receptors
containing both IgV- and IgC-like domains in the extracellular region and contain short 
cytoplasmic regions with no known signaling motifs. Binding of either PD-1 ligand to
PD-1 inhibits T-cell activation triggered through the T-cell receptor. PD-L1 is expressed at
low levels on various non-hematopoietic tissues, most notably on vascular endothelium,
whereas PD-L2 protein is only detectably expressed on antigen-presenting cells found in
lymphoid tissue or chronic inflammatory environments. 
PD-L2 is thought to control
immune
T-cell
activation in lymphoid organs, whereas PD-L1 serves to dampen
unwarranted T-cell function in peripheral tissues [49]. Although healthy organs express
little (if any) PD-L1, a variety of cancers were demonstrated to express abundant levels of 
this T-cell inhibitor.  High expression of PD-L1 on tumor cells (and to a lesser extent of PD-
L2) has been found to correlate with poor prognosis and survival in various cancer types, 
including renal cell carcinoma (RCC) [52], pancreatic carcinoma [53], hepatocellular
carcinoma [54], and ovarian carcinoma [55]. Furthermore, PD-1 has been suggested to
regulate tumor-specific T-cell expansion in subjects with MEL [56].
The observed correlation of clinical prognosis with PD-L expression in multiple cancers 
suggests that the PD-1/PD-L1 pathway plays a critical role in tumor immune evasion and 
should be considered as an attractive target for therapeutic intervention.
Therapeutic studies in mouse models have shown that administration of antibodies blocking 
PD-1/PD-L1 interaction enhances infiltration of tumor-specific CD8+ T-cells and leads 
ultimately to tumor rejection, either as a mono-therapy or in combination with other 
treatment modalities. Anti-mouse PD-1 or anti-mouse PD-L1 antibodies have demonstrated 
anti-tumor responses as a monotherapy in models of squamous cell carcinoma, pancreatic 
carcinoma, MEL and colorectal carcinoma.  Blockade of the PD-1 pathway effectively 
promoted CD8+ T-cell infiltration into the tumor and the presence of IFN-, granzyme B
and perforin, indicating that the mechanism of action involved local infiltration and
activation of effector T-cell function in vivo [57; 58; 59; 53; 60; 61].  In addition, the
combination of gemcitabine and anti-PD-L1 mAb demonstrated synergy in the rejection of 
pancreatic mouse tumors [53]. In-house experiments have confirmed the in vivo efficacy of
PD -1 blockade as a mono-therapy as well as in combination with chemotherapy in
syngeneic mouse tumor models (see the IB).
 
 
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Pembrolizumab (previously known as SCH 900475) is a potent and highly selective 
humanized monoclonal antibody (mAb) of the IgG4/kappa isotype designed to directly block 
the interaction between PD-1 and its ligands, PD-L1 and PD-L2.  The first clinical results for 
pembrolizumab based on a total of 135 subjects with advanced melanoma were reported in 
the NEJM.  The confirmed response rate across all dose cohorts, evaluated by central 
radiologic review according to the Response Evaluation Criteria in Solid Tumors (RECIST) 
version 1.1, was 38% (95% confidence interval [CI], 25 to 44), with the highest confirmed 
response rate observed in the cohort that received 10 mg per kilogram every 2 weeks (52%; 
95% CI, 38 to 66).  The response rate did not differ significantly between subjects who had 
received prior ipilimumab treatment and those who had not (confirmed response rate, 38% 
[95% CI, 23 to 55] and 37% [95% CI, 26 to 49], respectively).  Responses were durable in 
the majority of subjects (median follow-up, 11 months among subjects who had a response); 
81% of the subjects who had a response (42 of 52) were still receiving treatment at the time 
of analysis in March 2013.  The overall median progression-free survival among the 135 
subjects was longer than 7 months.  Common adverse events attributed to treatment were 
fatigue, rash, pruritus, and diarrhea; most of the adverse events were low grade [62].
Trametinib and Dabrafenib
The mitogen-activated protein kinase pathway (also known as MAPK-pathway) is a critical 
signal transduction pathway in normal and cancer cells.  The MAPK pathway is a 
three-tiered kinase cascade consisting of the rapidly-activated fibrosarcoma kinase (RAF 
kinase), mitogen-activated extracellular signal-related kinase (MEK kinase), and extracellular 
signaling-regulated kinase (ERK or MAPK).
BRAF, one of three structurally related RAF-kinase isoforms (A-, B-, and C-RAF or RAF-1), 
is part of the MAPK-signal transduction pathway which controls cell cycle progression, 
differentiation, and survival.  Under physiological conditions, signal transduction through the 
MAPK-pathway is tightly regulated through multiple negative feedback mechanisms.  
However, constitutive pathway activation through multiple genetic alterations is a hallmark 
of malignant tumors.  For the serine-threonine kinase RAF alone over 45 cancer-associated 
mutations [63-65] are currently known.  Most of these mutations constitutively activate the 
RAF-kinase.  In melanoma, more than 80% of the BRAF mutations cause a substitution of 
the amino acid glutamate (E) for valine (V) at position 600 (V600E) of the BRAF protein, 
whereas approximately 3-20% of melanoma mutations are a substitution of lysine (K) for 
valine at position 600 (V600K) [66-71].  The BRAF V600E mutation occurs at a high 
frequency in specific cancers, including approximately 60% of melanoma [63], 30 to 50% of 
papillary thyroid, 5 to 20% of colorectal, and approximately 30% of ovarian cancer [65].  
Although BRAF-mutations were initially identified in premalignant, benign cutaneous nevi, 
there is overwhelming pre-clinical and clinical evidence that these mutations confer 
‘oncogenic addiction’ to melanoma cells and are thus a key driver of advanced and metastatic 
disease and a prime target for therapeutic intervention with targeted small-molecule 
inhibitors [72].  While the introduction of BRAF inhibitors represent a significant advance in 
the treatment of BRAF V600 mutation-positive metastatic melanoma subjects [73], 
limitations of this novel therapy have already been identified. As has been the pattern with 
other highly selective small molecule kinase inhibitors (e.g. imatinib in bcr-abl chronic 
 
 
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myelogenous leukemia; erlotinib and gefitinib in epidermal growth factor receptor-mutant 
non-small cell lung cancer [NSCLC]) the rapid onset of drug resistance restricts the efficacy 
of vemurafenib and limits the median duration of response to only 6.7 months (data from the 
vemurafenib Phase III study BRIM3).  Understanding the specific mechanisms of resistance 
to BRAF-inhibitors is critical for the development of more effective strategies to inhibit the 
MAPK-pathway in order to delay or prevent the onset of resistance in BRAF-mutant 
melanoma. 
In a majority of cell models and melanoma samples, acquired resistance to BRAF inhibitors 
was associated with a reactivation of the MAPK-pathway indicating that the ‘addiction’ to 
this pathway remains unchanged [74].  In these resistant BRAF mutant melanomas, the 
MAPK-pathway can be reactivated through secondary activating mutations of the upstream 
NRAS- or the downstream MEK1-kinase or an overexpression of the RAF1- and 
COT-kinase.  In addition, activation of further upstream RTKs most probably due to 
alterations 
in 
molecular 
feedback 
loops 
affecting 
in 
particular 
the 
IGF-IR 
(insulin-like-growth factor receptor) and the PDGFR (platelet-derived growth factor) have 
also been detected.  Although all of these molecular events enable the melanoma cell to 
circumvent BRAF-inhibition in order to re-activate the MAPK-pathway, this activation 
renders most of the BRAF-inhibitor resistant tumors susceptible to an inhibition of the 
downstream MEK-kinase.  Experimental data generated with a BRAF- and MEK-inhibitor 
combination therapy in BRAF-mutant melanoma cell lines in vitro and xenografts in vivo 
support this concept by demonstrating activity of the combination therapy in models of 
acquired BRAF resistance.  More importantly, superior anti-tumor activity of the BRAF- and 
MEK inhibitor combination as compared to each agent as monotherapy was also observed in 
BRAF-sensitive models. These data clearly indicate that a concomitant and more potent 
inhibition of the MAPK-pathway at the critical level of the BRAF- and MEK-kinases leads to 
a more pronounced tumor inhibition, thus significantly delaying the onset of resistance.  In 
addition, pre-clinical safety data obtained with this combination therapy in a rat-model 
indicate that the potential for proliferative skin lesions and secondary cutaneous malignancies 
is reduced in comparison to treatment with a BRAF-inhibitor alone [75].
Dabrafenib (GSK2118436), a 4-(3-aminosulfonylphenyl)-5-(pyrimidin-3-yl) thiazole, is a 
potent and selective inhibitor of B-RAF kinase activity with a mode of action consistent with 
adenosine triphosphate (ATP)-competitive inhibition, and is approved as monotherapy in 
BRAF V600E-mutant advanced/metastatic melanoma.  Trametinib (GSK1120212), a 
pyrido-pyrimidine derivative, is a potent and highly selective allosteric non-competitive 
inhibitor of MEK1/MEK2 activation and kinase activity [76] has been approved as 
monotherapy in BRAF (V600E)-mutant and BRAF (V600K)-mutant melanoma.  The safety, 
tolerability, PK and clinical activity of trametinib + dabrafenib combination therapy has been 
evaluated in subjects with BRAF-mutant melanoma in a Phase I/II study [77], and 
demonstrated good efficacy with 76% ORR and 9.4 month median PFS at the highest dose 
combination.
 
 
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Rationale
Rationale for the Trial and Selected Subject Population
Pembrolizumab (previously known as SCH 900475) is a potent and highly-selective 
humanized mAb of the IgG4/kappa isotype designed to directly block the interaction between 
PD-1 and its ligands, PD-L1 and PD-L2.  Pembrolizumab contains the S228P stabilizing 
mutation and has no antibody-dependent cell-mediated cytotoxicity (ADCC) or complement-
dependent cytotoxicity (CDC) activity.  Pembrolizumab strongly enhances T lymphocyte 
immune responses in cultured blood cells from healthy human donors, cancer subjects, and 
primates.  In T- cell activation assays using human donor blood cells, the EC50 was in the 
range of 0.1 to 0.3 nM.  Pembrolizumab also modulates the level of interleukin-2 (IL-2), 
tumor necrosis factor alpha (TNFα), interferon gamma (IFNγ), and other cytokines.  The 
antibody potentiates existing immune responses only in the presence of antigen and does not 
nonspecifically activate T- cells.  A one-month repeat dose GLP-toxicity study with four 
months observation post dosing revealed no major safety findings.  The no observed adverse 
event level (NOAEL) was ≥200 mg/kg. (For details on the pre-clinical data of 
pembrolizumab, see the IB).  Based on the preliminary clinical data, PD-1 inhibitors such as 
pembrolizumab appear to be attractive therapeutic candidates.  Recently, the first clinical 
results from an ongoing study of pembrolizumab in subjects with advanced melanoma
reported a confirmed response rate of 38% (95% confidence interval [CI], 25 to 44) across all 
tested dose cohorts.
Pharmacologic inhibition of the mitogen-activated protein kinase (MAPK) pathway has 
proved to be a significant advance in the treatment of metastatic melanoma. The use of 
vemurafenib and dabrafenib, agents that inhibit BRAF and block MAPK signaling in 
subjects with melanoma and the BRAF V600E mutation, has been associated with prolonged 
survival and progression-free survival, respectively, in randomized phase 3 trials involving 
subjects with previously untreated melanoma [78-83].  Trametinib mediates blockade of 
MAPK kinase at the level of MEK, which is downstream of BRAF in the MAPK pathway 
and has been associated with improved progression-free and overall survival in BRAF V600 
melanoma (comprising both V600E and V600K mutations) [84; 85].  In spite of these 
advances, 50% of subjects who are treated with BRAF or MEK inhibitors have disease 
progression within 6 to 7 months after the initiation of treatment [80; 83].
In preclinical models, rapid recovery of MAPK pathway signaling has been associated with 
BRAF inhibitor resistance, and complete inhibition of the MAPK pathway is needed to 
induce cell death in BRAF V600 melanoma [86; 87]. This can be achieved by combining a 
BRAF inhibitor with a MEK inhibitor [86; 87]. The emergence of cutaneous squamous cell 
carcinoma early in the course of BRAF-inhibitor therapy has been associated with 
paradoxical MAPK pathway activation during BRAF inhibition [88].
In an experimental 
model of squamous cell carcinoma, the addition of a MEK inhibitor to a BRAF inhibitor 
reduced this effect [88].
In an attempt to delay resistance to BRAF inhibition and explore the safety of combination 
therapy with BRAF and MEK inhibition, a Phase I/II open-label study involving 247 subjects
 
 
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investigating the combination of the BRAF inhibitor dabrafenib and the MEK inhibitor 
trametinib in subjects with metastatic BRAF V600 melanoma was recently reported [85].  
Subjects were randomly assigned to receive combination therapy with dabrafenib (150 mg
twice daily) plus trametinib (1 or 2 mg once daily) or dabrafenib monotherapy.  Dose-
limiting toxic effects were infrequently observed in subjects receiving combination therapy 
with the highest tested dose of 150 mg of dabrafenib twice daily and 2 mg of trametinib once 
daily (combination 150/2), with only 1/24 subjects treated at this dose experiencing a DLT 
(recurrent neutrophilic panniculitis).  Cutaneous squamous-cell carcinoma was seen in 7% of 
subjects receiving combination 150/2 and in 19% receiving monotherapy (P = 0.09), whereas 
pyrexia was more common in the combination 150/2 group than in the monotherapy group 
(71% vs. 26%).  Median progression-free survival in the combination 150/2 group was 
9.4 months, as compared with 5.8 months in the monotherapy group (hazard ratio for 
progression or death, 0.39; 95% confidence interval, 0.25 to 0.62; P<0.001).  The rate of 
complete or partial response with combination 150/2 therapy was 76%, as compared with 
54% with monotherapy (P = 0.03).
While the benefit of combination MAPK pathway inhibition has been demonstrated, 
progression-free survival was still limited at 9.4 months (although this does represent a 
significant improvement on previously reported PFS), and complete responses (CR) were 
rare (<10%).  Therefore, treatment with dabrafenib and trametinib can be characterized as 
having high response rate with modest duration of response.  Conversely, the response rates 
from early clinical data of anti PD-1 therapies are generally <40%, but responses appear to be 
durable [62].  It would therefore be desirable to combine the high response rate of MAPK 
inhibition, either singly or in combination (dabrafenib + trametinib) with the duration of 
response of pembrolizumab, which could present a new standard of care for subjects with 
advanced or metastatic melanoma with BRAF V600 mutations.
Early reports of attempts at combining MAPK inhibitors with immunotherapies have 
produced unexpected toxicity.  Ribas et al. reported that ipilimumab combined with 
vemurafenib in a planned Phase I trial resulted in unexpected hepatotoxicity, leading to the 
discontinuation of the trial by the sponsors.  Other immunotherapy combinations with 
tyrosine kinase inhibitors (TKIs) or other immunotherapies are ongoing, and clinical results 
remain preliminary.  However, in light of the possibility of unacceptable toxicity for a 3-drug 
combination (pembrolizumab + dabrafenib + trametinib), a contingency cohort of 
pembrolizumab + dabrafenib (without the MEK inhibitor trametinib) is planned to be 
initiated in case the starting dose of the MK+D+T triplet combination cohort is not tolerable.
The data for MAPK pathway inhibition in melanoma without BRAF mutations (BRAF ‘wild 
type’) is limited.  Neither dabrafenib nor trametinib are indicated for the treatment of BRAF 
unmutated melanoma.  However, trametinib has demonstrated modest clinical activity in 
BRAF wild type melanoma [84], and preclinical data reporting synergy in BRAF unmutated 
melanoma cell lines when MEK inhibitors are administered with anti-PD1 therapy suggest 
that some synergy may be seen clinically when combining these two treatment modalities 
[103].
In addition, it has recently been reported that treatment of melanoma with either 
BRAF inhibitor alone or BRAF + MEK inhibitor was associated with an increased 
expression of melanoma antigens, an increase in CD8+ T-cell infiltrate, and an increase in 
 
 
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expression of PD-1 and PD-L1, as well as a decrease in immunosuppressive cytokines 
[interleukin (IL)-6 and IL-8] [89].
Based on this preclinical and translational data, this study will plan to evaluate the safety, 
tolerability, and preliminary efficacy of pembrolizumab in combination with trametinib in 
subjects with advanced or metastatic melanoma without BRAF mutations (BRAF wild type).
Details regarding specific benefits and risks for subjects participating in this clinical trial may 
be found in the accompanying Investigators Brochure (IB) and Informed Consent documents.
Rationale for Dose Selection/Regimen/Modification
In the first-in-human study (PN001, refer to IB), pembrolizumab showed evidence of target 
engagement and objective evidence of tumor size reduction at all dose levels (1 mg/kg, 
3 mg/kg and 10 mg/kg Q2W).  PK data analysis of pembrolizumab administered in Q2W 
showed slow systemic clearance, limited volume of distribution, and a long half-life (refer to 
IB).  Pharmacodynamic data (IL-2 release assay) suggested that peripheral target engagement 
is durable (>21 days).  This early PK and pharmacodynamic data provides scientific rationale 
for testing Q2W and Q3W dosing schedules.
Two randomized cohort evaluations of melanoma subjects in PN001 receiving 
pembrolizumab at a dose of 2 mg/kg versus 10 mg/kg Q3W have been completed, and one 
randomized cohort evaluating of 10 mg/kg Q3W versus 10 mg/kg Q2W has also been 
completed.  The clinical efficacy and safety data demonstrate a lack of clinically important 
differences in efficacy response or safety profile at these doses.  For example, in Cohort B2, 
advanced melanoma subjects who had received prior ipilimumab therapy were randomized to 
receive pembrolizumab at 2 mg/kg versus 10 mg/kg Q3W.  The ORR was 26% (21/81) in the 
2mg/kg group and 26% (25/79) in the 10 mg/kg group (FAS).  The proportion of subjects 
with drug-related AE, grade 3-5 drug-related AE, serious drug-related AE, death or 
discontinuation due to an AE was comparable between groups or lower in the 10 mg/kg 
group.  In Cohort B3, advanced melanoma subjects (irrespective of prior ipilimumab therapy) 
were randomized to receive pembrolizumab at 10 mg/kg Q2W versus 10 mg/kg Q3W.  The 
ORR was 30.9% (38/123) in the 10 mg/kg Q2W group and 24.8% (30/121) in the 10 mg/kg 
Q3W group (APaT).  The proportion of subjects with drug-related AE, grade 3-5 drug-
related AE, serious drug-related AE, death or discontinuation due to an AE was comparable 
between groups.
Available pharmacokinetic results in subjects with melanoma, NSCLC, and other solid tumor 
types support a lack of meaningful difference in pharmacokinetic exposures obtained at a 
given dose among tumor types.   Moreover, population PK analysis has been performed and 
has confirmed the expectation that intrinsic factors do not affect exposure to pembrolizumab
to a clinically meaningful extent. Importantly, the analysis revealed no significant impact of 
tumor burden on exposure.  Taken together, these data support the use of lower doses 
(2 mg/kg Q3W) in all solid tumor indications.
 
 
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An integrated body of evidence suggests that 200 mg every 3 weeks (Q3W) is expected to
provide similar response to 2 mg/kg Q3W, 10 mg/kg Q3W and 10 mg/kg Q2W. Previously,
a flat pembrolizumab exposure-response relationship for efficacy and safety has been found
in subjects with melanoma in the range of doses between 2 mg/kg and 10 mg/kg. Exposures
for 200 mg Q3W are expected to lie within this range and will be close to those obtained with
2 mg/kg Q3W dosing.
A population pharmacokinetic (PK) model, which characterized the influence of body weight
and other patient covariates on exposure, has been developed. The PK profile of
pembrolizumab is consistent with that of other humanized monoclonal antibodies, which
typically have a low clearance and a limited volume of distribution.
The distribution of
exposures from the 200 mg fixed dose are predicted to considerably overlap those obtained
with the 2 mg/kg dose and importantly will maintain individual patient exposures within the
exposure range established in melanoma as associated with maximal clinical response. PK
properties of pembrolizumab, and specifically the weight-dependency in clearance and
volume of distribution are consistent with no meaningful advantage to weight-based dosing
relative to fixed dosing.
In translating to other tumor indications, similarly flat exposure-response relationships for
efficacy and safety as observed in subjects with melanoma can be expected, as the anti-tumor
effect of pembrolizumab is driven through immune system activation rather than through a
direct interaction with tumor cells, rendering it independent of the specific tumor type. In
addition, available PK results in subjects with melanoma, NSCLC, and other tumor types
support a lack of meaningful difference in pharmacokinetic exposures obtained at tested
doses among tumor types. Thus the 200 mg Q3W fixed-dose regimen is considered an
appropriate fixed dose for other tumor indications as well.
A fixed dose regimen will simplify the dosing regimen to be more convenient for physicians
and to reduce potential for dosing errors. A fixed dosing scheme will also reduce complexity
in the logistical chain at treatment facilities and reduce wastage. In summary, the existing
data support 200 mg Q3W as the appropriate dose for pembrolizumab in Parts 4 and 5 of this 
protocol.
Dabrafenib and trametinib have been evaluated in combination in a recent [85] Phase I/II 
study in which the highest tested dose combination consisted of oral dabrafenib 150mg twice 
daily with oral trametinib 2 mg once daily (full single-agent dose of both agents).  In 
comparison with subjects receiving dabrafenib monotherapy, subjects receiving combination 
therapy had more frequent and more severe pyrexia and chills (71% vs 26% all grades, 5% vs 
0% grade 3 or 4); they also had more frequent gastrointestinal toxic effects (e.g., nausea and 
vomiting), but most of these events were grade 1 or 2.  Pyrexia was generally manageable 
with antipyretic agents.  However, recurrent fevers required the use of low dose oral 
glucocorticoids.  
Frequency of grade 3 or 4 AE's was reported as 58% in the 150/2 dabrafenib/trametinib 
combination cohort vs 43% in the dabrafenib monotherapy cohort.  An intermediate cohort, 
150mg twice daily dabrafenib with 1mg daily trametinib, was also evaluated, and reported 
 
 
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48% grade 3 or 4 AEs, with 9% grade 3 or 4 pyrexia.  However, dose-limiting toxic effects 
were only observed at the highest tested dose (combination 150/2), with only 1/24 subjects
treated at this dose experiencing a DLT (recurrent neutrophilic panniculitis).
Median PFS for dabrafenib monotherapy was reported as 5.8 months (4.6-7.4), for the 150/1 
combination 9.2 months (6.4-11.0), and for the 150/2 combination 9.4 months (8.6-16.7).  
Overall response rate was highest for the 150/2 combination of dabrafenib and trametinib, 
which reported 76% (62-86) complete or partial responses, vs 50% (36-64) for the 150/1 
combination and 54% (40-67) for dabrafenib monotherapy.
Therefore, while the rate of grade 3 or 4 AEs was higher in the 150/2 combination cohort vs 
dabrafenib monotherapy or the 150/1 combination cohort, the response rate and PFS of the 
150/2 combination was superior to either of the other groups (and only reported a ~4% DLT 
rate), and will be used as the starting dose levels for this protocol (in both the triplet 
combination cohorts, and the doublet cohorts, with the option to down-dose one or both of 
dabrafenib and/or trametinib if toxicities in the combination arise).
Starting Dose for This Trial
The starting dose of pembrolizumab will be 2 mg per kg body weight administered 
intravenously every 3 weeks.  This was the lowest tested dose from the ongoing PN 001 
which recently reported results from an interim analysis showing efficacy at this dose level 
with 25% confirmed objective response rate and tolerable AE profile.  This lowest tested 
dose for pembrolizumab was chosen as a starting dose due to the potential for unforeseen or 
additive toxicity when administered in combination with MAPK inhibitors dabrafenib and 
trametinib, whose AE profile when administered in combination with each other has been 
investigated in a Phase I/II trial.  In addition, given the recently reported hepatotoxicity when 
another immunotherapy/MAPK inhibitor combination was tested - ipilimumab and 
vemurafenib in combination [62] – the lowest tested dose of pembrolizumab was selected for 
this combination protocol.
The starting dose of dabrafenib will be the FDA/EMA-approved dose of 150 mg orally twice 
daily (for triplet combination cohort, and if needed, (MK+D) cohort).
The starting dose of trametinib will be the FDA-approved dose of 2 mg orally once daily (for 
both the triplet combination cohort and the (MK+T) cohort).
The starting doses of dabrafenib and trametinib are based on the approved single agent doses, 
as well as Phase I/II data showing that combination therapy with the full single-agent doses 
of both drugs resulted in the maximum efficacy (76% PR+CR), with a tolerable side effect 
profile (58% grade 3-4 AEs) [85].  This dose combination is currently under study in a 
Phase 3 study (MEK115306; NCT01584648).
 
 
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Maximum Dose/Exposure for This Trial
In Parts 1, 2, and 3 of this trial, the maximum dose of pembrolizumab will be 2 mg per kg 
body weight administered intravenously every 3 weeks.  In Parts 4 and 5, the maximum dose 
of pembrolizumab will be 200 mg.
The maximum dose of dabrafenib will be 150 mg orally twice daily (for triplet combination 
cohort, and if needed, (MK+D) cohort).
The maximum dose of trametinib will be 2 mg orally once daily (for both the triplet 
combination cohort and the (MK+T) cohort).
The maximum doses of dabrafenib and trametinib are based on the approved single agent 
doses, as well as the highest doses tested in combination in the Phase I/II trial (full 
single-agent doses for each drug).
Rationale for Dose Interval and Trial Design
Pembrolizumab will initially be evaluated at the lowest tested dose (2 mg/kg IV Q3W) from 
the ongoing PN 001 which recently reported interim analysis data.  
The MAPK inhibitors dabrafenib (150 mg orally BID) and trametinib (2 mg PO QD) will 
start at their full single-agent doses in Part 1 (for both the triplet combination cohort and the 
doublet cohorts).  This dose combination was shown to be the maximally efficacious 
combination in the Phase I/II trial, with an acceptable AE profile, and represents the 
approved single-agent dose for both drugs.  No data on higher dose combinations have been 
reported to date.
Given the potential for additive, overlapping, or unforeseen AEs when the agents are used in 
combination, down-dosing of one, two, or all three agents (in the case of the triple 
combination) is allowed, based on clinical observation of the AE profile.  Down dosing of 
the compounds is outlined in Section 5.2.1.
Rationale for Endpoints
Efficacy Endpoints
4.2.3.1.1
Primary
The primary efficacy endpoint of the trial is Progression Free Survival (PFS) in Part 3.  PFS 
is an acceptable scientific endpoint to demonstrate superiority of a new antineoplastic 
therapy, especially if it is believed that the median time to Overall Survival (OS) with the 
new therapy may be significantly longer than that seen with standard of care.  RECIST 1.1 
will be used to determine the dates of progression as this methodology is accepted by 
regulatory authorities.  Images will be read by investigators and collected and held for 
potential central-read by independent radiologists later, as determined by the Sponsor.
 
 
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For the (MK+T) cohort, the primary efficacy endpoint of the study is objective response rate 
(ORR) based on a best overall response (BOR) analysis in subjects with advanced or 
metastatic melanoma without BRAF mutation.  Modified RECIST 1.1 (see discussion below)
will be used to assess response rate by investigators/sites and collected and held for potential 
central-read by independent radiologists later, as determined by the Sponsor. 
RECIST 1.1 will be adapted to account for the unique tumor response characteristics seen
with treatment of pembrolizumab. Immunotherapeutic agents such as pembrolizumab may 
produce antitumor effects by potentiating endogenous cancer-specific immune responses. 
The response patterns seen with such an approach may extend beyond the typical time course 
of responses seen with cytotoxic agents and can manifest a clinical response after an initial
increase in tumor burden or even the appearance of new lesions. Standard RECIST may not
provide an accurate
response assessment of immunotherapeutic agents such as 
pembrolizumab. Therefore, RECIST 1.1 will be used with the following adaptations:
If radiologic imaging shows initial PD, tumor assessment should be repeated ≥4 weeks later
in order to confirm PD with the option of continuing treatment per below while awaiting
radiologic confirmation of progression. If repeat imaging shows a reduction in the tumor
burden compared to the initial scan demonstrating PD, treatment may be continued /
resumed. If repeat imaging confirms progressive disease, subjects will be discontinued from
study therapy. In determining whether or not the tumor burden has increased or decreased, 
investigators should consider all target lesions as well as non-target lesions (please refer to
the Site Imaging Manual).
In subjects who have initial evidence of radiological PD, it is at the discretion of the treating
physician whether to continue a subject on study treatment until repeat imaging is obtained a
minimum of 4 weeks later. This clinical judgment decision should be based on the subject’s 
overall clinical condition, including performance status, clinical symptoms, and laboratory
data. Subjects may receive pembrolizumab treatment while waiting for confirmation of PD if 
they are clinically stable as defined by the following criteria:
• Absence of signs and symptoms indicating disease progression
• No decline in ECOG performance status
• Absence of rapid progression of disease
• Absence of progressive tumor at critical anatomical sites (e.g., cord compression) requiring 
urgent alternative medical intervention
When feasible, subjects should not be discontinued until progression is confirmed. This
allowance to continue treatment despite initial radiologic progression takes into account the
observation that some subjects can have a transient tumor flare in the first few months after
the start of immunotherapy, but with subsequent disease response. Subjects who are deemed
clinically unstable are not required to have repeat imaging for confirmation of progressive
disease.
 
 
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4.2.3.1.2
Interim Analysis
An interim analysis of Part 3 will be conducted to inform a potential early Go/No Go 
decision for initiation of Phase III before the completion of Part 3, as well as assess for 
futility.  It will be conducted when the first 80 subjects randomized into the study will have 
completed 36 weeks (if not discontinued earlier) and have the respective data based on a
central radiology assessment available.  The primary endpoint for the interim analysis is the 
ordinal response at Week 36 with the following categories (consistent with RECIST 1.1 
definitions, with the exception of PR being divided into MPR and VGPR based on the degree 
of tumor shrinkage): Complete Response (CR), Very Good Partial Response (VGPR) defined 
as partial response with Percent Change from Baseline (maximum reduction in tumor line 
length >60%), Moderate Partial Response (MPR) defined as partial response that is not 
VGPR, Stable Disease (SD), and Progressive Disease (PD).  As this interim analysis is 
planned for a landmark in time, responses may or may not represent confirmed responses at 
the time of the analysis.  The interim analysis will only include subjects randomized in Part 3 
of the study.
The IA of ordinal response will be based on central-read of images. Additionally, a 
sensitivity analysis of 36-week ordinal response, BOR classified by ordinal response, and 
summaries of the ordinal response by time, will be based on investigator-read data.  
Investigators will be required to collect ordinal response data when RECIST 1.1 data is 
collected.
Ordinal response analysis was selected as the primary endpoint for the interim analysis as it 
relies on seeing more tumor shrinkage with addition of pembrolizumab
to the 
dabrafenib+trametinib combination alone (versus improving RECIST 1.1-defined response 
rate based on a 30% decrease in the sum of longest tumor dimensions).  When applied at a 
landmark in time at Week 36, there is significant “attrition” of responses to 
dabrafenib+trametinib doublet.  The ordinal analysis at Week 36 integrates a degree of tumor 
shrinkage with the durability of tumor shrinkage; in addition, improvement in this endpoint 
will detect the ability of pembrolizumab to prevent tumor progression compared to the 
dabrafenib+trametinib doublet alone.  
4.2.3.1.3
Secondary
Secondary endpoints include evaluation of pharmacokinetic properties of pembrolizumab, 
dabrafenib, and/or trametinib, when used in combination.  Pharmacokinetic endpoints are 
further discussed in Section 4.2.3.3.  
Safety Endpoints
The primary safety objective of this study is to characterize the safety and tolerability of
different combinations of pembrolizumab and/or trametinib and/or dabrafenib in adult
subjects with advanced melanoma. The primary safety analysis will be based on subjects 
who experienced toxicities as defined by CTCAE Version 4.0 criteria. Safety will be 
assessed by quantifying the toxicities and grades experienced by subjects who have received 
 
 
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pembrolizumab and/or trametinib and/or dabrafenib, including serious adverse events (SAEs) 
and events of clinical interest (ECIs).  
Safety will be assessed by reported adverse experiences using CTCAE Version 4.0. The
attribution to drug, time-of-onset, duration of the event, its resolution, and any concomitant
medications administered will be recorded. AEs will be analyzed including but not limited to
all AEs, SAEs, fatal AEs, and laboratory changes. Furthermore, AEs of potentially 
immunologic etiology (AEs of special interest [AEOSI]) will be identified using a 
pre-specified list of terms and summarized.
Other safety endpoints include laboratory safety assessments, ECOG performance status, 
vital signs and physical examinations.
Pharmacokinetic Endpoints
The accumulation of robust PK and ADA data has allowed for the adequate characterization 
the clinical pharmacology of pembrolizumab across indications. Therefore, the collection of 
PK and ADA samples are being discontinued for subjects enrolled under Amendment 
04. Blood samples for PK and ADA collected prior to Amendment 04 may be stored. 
Analysis will be performed only if required. Plasma samples will be obtained to characterize 
the pharmacokinetics of dabrafenib and its metabolites including hydroxy- and desmethyl-
dabrafenib and trametinib when given in combination with pembrolizumab using a sparse 
sampling approach.  The population pharmacokinetic parameters of dabrafenib and 
trametinib including oral clearance (CL/F), volume of distribution (Vc/F) and other 
parameters as appropriate, will be determined using previously validated pharmacokinetic 
models.  Dabrafenib and trametinib exposure such as average concentration (Cavg) and/or 
minimum concentration (Cmin) will be derived.
Patient Reported Outcomes
The EuroQol EQ5D and EORTC QLQ-C30 are not pure efficacy or safety endpoints because 
they are affected by both disease progression and treatment tolerability.  The subject reported 
outcomes will only be utilized in Part 3 of the study.  Electronic EORTC QLQ-C30 and 
EuroQol EQ-5D will be completed by the subject prior to all other study procedures.  It is 
most relevant and strongly recommended that ePROs are administered prior to drug 
administration, adverse event evaluation and disease status notification.
4.2.3.4.1
EuroQol (EQ-5D)
The EuroQol-5D (EQ-5D) is a standardized instrument for use as a measure of health 
outcome.  The EQ-5D will provide data for use in economic models and analyses including 
developing health utilities or QALYs.  The five health state dimensions in this instrument 
include the following: mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression (5).  Each dimension is rated on a three point scale from 1 (extreme 
problem) to 3 (no problem).  The EQ-5D also includes a graded (0 to 100) vertical visual 
analog scale on which the subject rates his or her general state of health at the time of the 
 
 
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assessment.  The EQ-5D will always be completed by subjects first before completing the
EORTC QLQ-C30.
4.2.3.4.2
EORTC (QLQ-C30)
The EORTC-QLQC30 is the most widely used cancer specific HRQoL instrument, which 
contains 30 items and measures five functional dimensions (physical, role, emotional, 
cognitive, and social), three symptom items (fatigue, nausea/vomiting, and pain), six single 
items (dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, and financial impact), 
and a global health and quality of life scale. This instrument is translated and validated into 
more than 80 languages.  
Biomarker Research
Additional biomarker research to identify factors important for pembrolizumab therapy will
be pursued.  Pre- and post-treatment tumor and blood samples from Parts 1,2, 4, and 5
(required, optional in Part 3) of this study may undergo proteomic, genomic and 
transcriptional analyses (both DNA and RNA analyses).  Additional research may evaluate
factors important for predicting responsiveness or resistance to pembrolizumab therapy and 
other immunologic targets.
Expression of candidate biomarkers in tumor tissue will be 
evaluated both at baseline and 10-14 days after initiation of therapy with pembrolizumab in 
combination with dabrafenib and/or trametinib, including immune signaling markers on the 
surface of tumor cells, phenotypic and functional immune cell markers on TIL (which may 
include PD-1, PD-L1, CD8, and possibly other biomarkers), and DNA/RNA changes. These 
and other additional biomarker or genomic research to identify factors important for 
pembrolizumab therapy (for example, HLA genotype) may also be pursued.
Future Biomedical Research
The Sponsor may conduct Future Biomedical Research on specimens routinely and 
specifically collected during this clinical trial. This research may include genetic analyses 
(DNA), gene expression profiling (RNA), proteomics, metabolomics (serum, plasma) and/or 
the measurement of other analytes.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main trial) and will only be conducted on specimens from 
appropriately consented subjects. The objective of collecting specimens for Future 
Biomedical Research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. For instance, exploratory 
pharmacogenetic 
(PGt) 
studies 
may 
be 
performed 
if
significant 
Pharmacokinetic/Pharmacodynamic (PK/PD) relationships are observed or adverse events 
are identified.  Genomic markers of disease may also be investigated.  Such retrospective 
pharmacogenetic studies will be conducted with appropriate biostatistical design and analysis 
and compared to PK/PD results or clinical outcomes. Any significant PGt relationships to 
outcome would require validation in future clinical trials. The overarching goal is to use such 
information to develop safer, more effective drugs/vaccines, and/or to ensure that subjects 
 
 
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receive the correct dose of the correct drug/vaccine at the correct time.  The details of this 
Future Biomedical Research sub-trial are presented in Section 12.2 - Collection and 
Management of Specimens for Future Biomedical Research.  Additional informational 
material for institutional review boards/ethics committees (IRBs/ERCs) and investigational 
site staff is provided in Section 12.3.
5.0 METHODOLOGY
Entry Criteria
Diagnosis/Condition for Entry into the Trial
Male/Female subjects of at least 18 years of age with advanced or metastatic melanoma (or
solid tumor in Parts 4 and 5) will be enrolled in this trial.
Subject Inclusion Criteria
In order to be eligible for participation in this trial, the subject must:
1. Have a histologically confirmed diagnosis of advanced (unresectable Stage III) or 
metastatic (Stage IV) melanoma or a histologically or cytologically-documented, 
locally-advanced or metastatic solid malignancy, and have at least one measurable 
lesion as defined by RECIST 1.1 on imaging studies (CT or MRI). Cutaneous lesions 
and other superficial lesions that are detectable only by physical examination and 
subcutaneous lesions detectable by CT are not considered measurable lesions for the 
purposes of this protocol, but may be considered as non-target lesions.

Mucosal or ocular melanoma are excluded.

For solid tumors other than melanoma, the subject must be a participant in Part 4 or 
5 (dose confirmation only), have a malignancy that is incurable and has either: (a) 
failed prior standard therapy, (b) for which no standard therapy exists, or (c) 
standard therapy is not considered appropriate by the patient and treating 
physician. There is no limit to the number of prior treatment regimens, but prior 
treatment(s) should not include compounds targeting PD-1, PD-L1, BRAF, or 
MEK.  Treatment must end at least 4 weeks prior to randomization.  
2. Be willing and able to provide written informed consent for the trial.  The subject 
may also provide consent for Future Biomedical Research.  However, the subject may 
participate in the main trial without participating in Future Biomedical Research.
3. Be ≥ 18 years of age on day of signing the informed consent.
4. Have BRAF mutation testing as determined at a local laboratory and either:
a.
Have a BRAF mutation-positive (V600 E or K) tumor to be eligible for 
treatment with pembrolizumab+trametinib+dabrafenib, trametinib+dabrafenib 
 
 
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or pembrolizumab+dabrafenib (if this part of the study is performed).  If a 
subject’s initial specimen does not test BRAF mutation-positive, a newly 
obtained specimen (different from the sample previously submitted) may be 
submitted for testing.  If the newer specimen tests BRAF mutation-positive, 
the subject meets this eligibility criterion.
b. Have a BRAF mutation-negative (wild type) tumor to be eligible for treatment 
with pembrolizumab+trametinib.

Criterion 4a is applicable only to enrollment of melanoma subjects in Parts 1, 
2, and 3 of the trial design.  Criterion 4b is applicable only to enrollment of 
melanoma subjects in Parts 1, 2, 4, and 5 of the trial design.  The inclusion 
criterion does not apply to solid tumor subjects in Parts 4 and 5 (dose 
confirmation only).
Note:  Local laboratory testing for BRAF mutation is acceptable provided the 
methodology can detect both V600E and V600K mutations.
5. For BRAF mutation-negative (wild type) subjects who have received prior therapy 
for metastatic or advanced melanoma, must have documented progression of at least 
one measurable lesion by RECIST 1.1 on imaging studies (CT or MRI).
6. Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group 
(ECOG) Performance Scale.
7. Have an anticipated life expectancy of at least 3 months.
8. Be able to swallow and retain oral medication and must not have any clinically 
significant gastrointestinal abnormalities that may alter absorption such as 
malabsorption syndrome or major resection of the stomach or bowels.
 
 
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9. Have adequate organ function as defined in Table 8 below:
Table 8
Inclusion Criteria Laboratory Parameters
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
≥1,500 /mcL
Platelets
≥100,000 / mcL
Hemoglobin
≥9 g/dL or ≥5.6 mmol/L
Renal
Serum creatinine
≤1.5 X upper limit of normal (ULN)
Calculated creatinine clearancea
50 mL/min
Hepatic
Serum total bilirubin
≤  1.5 X ULN OR
Direct bilirubin ≤ ULN for subjects with total bilirubin 
levels > 1.5 X ULN
AST (SGOT) and ALT (SGPT)
≤2.5 X ULN
Alkaline Phosphatase
If > 2.5 X ULN, then liver fraction should be ≤ 2.5 X ULN 
Albumin
2.5 g/dL
Coagulation
International Normalized Ratio (INR) 
or Prothrombin Time (PT)
Activated Partial Thromboplastin Time 
(aPTT)
≤1.5 X ULN unless the subject is receiving anticoagulant 
therapy as long as PT or aPTT is within therapeutic range 
of intended use of anticoagulants 
≤1.5 X ULN unless the subject is receiving anticoagulant 
therapy as long as PT or aPTT is within therapeutic range 
of intended use of anticoagulants
a Calculate creatinine clearance using standard Cockcroft-Gault formula (Appendix 12.7). 
Creatinine clearance must be 50 mL/min to be eligible. 
10. Have provided tissue for biomarker analysis from a newly or recently-obtained 
biopsy (within 90 days of Study Day 1) of a tumor lesion not previously irradiated.
Note:  Study Day 1=First dose(s) of study treatment.  Vendor acknowledgment of 
evaluability does not need to be obtained prior to allocation.
11. Female subjects of childbearing potential should have a negative urine or serum 
pregnancy test within 72 hours prior to receiving the first dose of study medication.  
If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test 
will be required.  The serum pregnancy test must be negative for the subject to be 
eligible.
12. A female participant is eligible to participate if she is not pregnant (see Appendix 
12.14), not breastfeeding, and at least one of the following conditions applies:  
a. Not a woman of childbearing potential (WOCBP) as defined in Appendix 12.14
OR 
b. A WOCBP who agrees to follow the contraceptive guidance in Appendix 12.14
 
 
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during the treatment period and for at least 120 days after the last dose of study 
treatment.
13. Male subjects should agree to use an adequate method of contraception as outlined in 
Appendix 12.14 starting with the first dose of study medication through 120 days 
after the last dose of study medication.
Subject Exclusion Criteria
The subject must be excluded from participating in the trial if the subject:
1. Is currently participating and receiving study therapy or has participated in a study of 
an investigational agent and received study therapy or used an investigation device
within 4 weeks of the first dose of treatment.
2. Is either:
1) BRAF mutation-positive and has received prior systemic therapy for metastatic or 
advanced melanoma.
Note:  Prior adjuvant or neoadjuvant therapy is allowed (i.e., does not count as prior 
systemic therapy) as long as that therapy did not include compounds targeting PD-1, 
PD-L1, BRAF, or MEK. Treatment must end at least 4 weeks prior to randomization. 
Prior adjuvant therapy with anti-CTLA-4 will only be permitted if relapse did not 
occur during treatment or within 6 months of treatment discontinuation.
or
2) BRAF mutation-negative and has received >1 prior systemic therapy for metastatic 
melanoma.  
Note:  Prior adjuvant or neoadjuvant therapy does not count as prior line of systemic 
therapy, but should not include compounds targeting PD-1, PD-L1, BRAF, or MEK.  
Treatment must end at least 4 weeks prior to randomization.  

The BRAF exclusion criterion does not apply to solid tumor subjects in Parts 4 
and 5 (dose confirmation only).
3. Has received prior therapy with compounds targeting the PD-1, PD-L1, BRAF, MEK 
or other molecules in the MAPK pathway.
Note:  Examples of BRAF inhibitors include, but are not limited to, dabrafenib and 
vemurafenib.  An example of a MEK inhibitor includes, but is not limited to, 
trametinib.
4. Is BRAF mutation-positive and has received prior systemic therapy with ipilimumab 
or other CTLA-4 blocking antibodies.
 
 
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5. Has had chemotherapy, radioactive, or biological cancer therapy within four weeks 
prior to the first dose of trial treatment, or who has not recovered to CTCAE Grade 1 
or better from the clinically significant AEs due to cancer therapeutics administered 
more than four weeks prior to the first dose of trial treatment.
6. Is expected to require any other form of systemic or localized antineoplastic therapy 
while in study.
7. Has a known additional malignancy that is progressing or requires active treatment. 
Exceptions include early stage cancers (carcinoma in situ or stage 1) treated with 
curative intent, basal cell carcinoma of the skin, squamous cell carcinoma of the skin, 
in situ cervical cancer, or in situ breast cancer that has undergone potentially curative 
therapy. For dabrafenib-containing treatment regimens in this study, subjects with any 
malignancy with confirmed activating RAS mutation are excluded. 
Note: Prospective RAS testing is not required. However, if the results of previous 
RAS testing are known, they must be used in assessing eligibility.
8. Has known active central nervous (CNS) metastases and/or carcinomatous 
meningitis.  Subjects with previously treated brain metastases may participate 
provided they are stable (without evidence of progression by MRI for at least four 
weeks prior to the first dose of trial treatment and any neurologic symptoms have 
returned to baseline), have no evidence of new or enlarging brain metastases, and are 
off systemic steroids for at least two weeks.  
9. Has an active infection requiring systemic therapy.
10. Has an active autoimmune disease, or a documented history of autoimmune disease, 
or a syndrome that requires systemic steroids or immunosuppressive agents.  Subjects 
with vitiligo or resolved childhood asthma/atopy would be exception to this rule.  
Subjects that require intermittent use of bronchodilators or local steroid injections are 
not excluded from the study.  Subjects with hypothyroidism stable on hormone 
replacement are not excluded from the study.
11. Has previously had a severe hypersensitivity reaction to treatment with another 
monoclonal antibody (mAb). 
12. Is on chronic systemic steroid therapy (>10 mg/day prednisone or equivalent) within 
two weeks before the planned date for first dose of study treatment or on any other 
form of immunosuppressive medication.  (Subjects that are expected to require 
premedication with corticosteroid for pembrolizumab will not be eligible for this 
study.)
13. Currently uses a prohibited medication as described in Section 5.5.2.
 
 
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14. Has history or evidence of cardiovascular risk including any of the following:
1) Current LVEF < LLN as determined by echocardiogram;
2) A QT interval corrected for heart rate using the Bazett’s formula (QTcB; [90]) 
480 msec;
3) A history or evidence of current clinically significant uncontrolled 
arrhythmias;
Exception:  Subjects with atrial fibrillation controlled for > 30 days prior to 
randomization are eligible.
4) A history (within 6 months prior to randomization) of acute coronary 
syndromes (including myocardial infarction or unstable angina), coronary 
angioplasty or stenting;
5) A history or evidence of current Class II congestive heart failure as defined 
by the New York Heart Association (NYHA) guidelines [91];
6) Treatment refractory hypertension defined as a blood pressure of systolic> 
140 mmHg and/or diastolic > 90 mm Hg which cannot be controlled by anti-
hypertensive therapy;
7) Subjects with intra-cardiac defibrillators;
8) Abnormal 
cardiac 
valve 
morphology 
(≥grade 
2) 
documented 
by 
echocardiogram 
(subjects 
with 
grade 
1
abnormalities 
[i.e., 
mild 
regurgitation/stenosis] can be entered on study).  Subjects with moderate 
valvular thickening should not be entered in study.
15. Has uncorrectable electrolyte abnormalities (e.g. hypokalaemia, hypomagnesaemia, 
hypocalcaemia), long QT syndrome or taking medicinal products known to prolong 
the QT interval.
16. Has known history of prior or current retinal vein occlusion (RVO).
Note:  In the event history of RVO is not known, an ophthalmic exam is required.
17. Has known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs 
chemically related to the study treatments, their excipients, and/or dimethyl sulfoxide 
(DMSO).  
18. Has had an allogeneic tissue/solid organ transplant, prior stem cell or bone marrow 
transplant.
 
 
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19. Has a history of (non-infectious) pneumonitis that required steroids or current 
pneumonitis.
20. Has known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
21. Has a known history of or is positive for Hepatitis B (HBsAg reactive) or Hepatitis C
(HCV RNA [qualitative] is detected).
Note:  In those countries, where standard of care uses only Hepatitis C antibody 
testing as evidence of status of Hepatitis C, HCV RNA testing is not required. 
22. Has received a live vaccine within 30 days prior to first dose.
23. Has a known psychiatric or substance abuse disorder that would interfere with the 
subject’s ability to cooperate with the requirements of the trial.
24. Has a clinical history suggestive of a condition which could impact the safety or 
efficacy of the subject in the study.  
25. Is, at the time of signing informed consent, a regular user (including “recreational 
use”) of any illicit drugs or had a recent history (within the last year) of substance 
abuse (including alcohol).
26. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the screening visit (Visit 1) through 
120 days after the last dose of trial treatment.
27. Is or has an immediate family member (spouse or children) who is investigational site 
or sponsor staff directly involved with this trial, unless prospective IRB approval (by 
chair or designee) is given allowing exception to this criterion for a specific subject.
Trial Treatment(s)
The treatments to be used in this trial are outlined below in.  A cycle of treatment in this 
protocol is defined as six weeks, except as noted in the table.
 
 
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Table 9
Trial Treatment
Drug
Dose/Potency
Dose 
Frequency
Route of 
Administration
Regimen/Treatment 
Period
Use
Pembrolizu
mab
1mg/kg*
Q3W
IV infusion
Days 1 and 22 of each 
cycle in Parts 1, 2, or 3
Experimental
Pembrolizu
mab
2mg/kg
Q3W
IV infusion
Days 1 and 22 of each 
cycle in Parts 1, 2, or 3
Experimental
Pembrolizu
mab
200 mg
Q3W
IV infusion
Days 1 and 22 of each 
cycle in Parts 4 or 5, 
with the exception of 
Cycle 1**
Experimental
Placebo 
(saline IV)
--
Q3W 
IV infusion
Days 1 and 22 of each 
cycle
Experimental
Trametinib
1.5mg*
1.5mg QD
Oral
Day 1 up until study 
treatment discontinuation 
Experimental
Trametinib
2mg
2mg QD
Oral
Day 1 up until study 
treatment discontinuation 
Experimental
Dabrafenib
150mg*
75mg BID
Oral
Day 1 up until study 
treatment discontinuation
Experimental
Dabrafenib
200mg*
100mg 
BID
Oral
Day 1 up until study 
treatment discontinuation
Experimental
Dabrafenib
300mg
150mg 
BID
Oral
Day 1 up until study 
treatment discontinuation
Experimental
*Dose/Potency activated only in the event dose reduction required.
**Cycle 1 in Parts 4 and 5 are longer in length due to trametinib run-in of two or four weeks.  
For dosing regimens initiating with four weeks of trametinib monotherapy, pembrolizumab
dosing occurs on Days 29 and 50.  For dosing regimens initiating with two weeks of 
trametinib monotherapy, pembrolizumab dosing occurs on Days 15 and 36.
Please note, the term ‘study treatment’ is used throughout the protocol to describe any 
combination of products received by the subject as per the protocol design. Study treatment 
may therefore refer to the individual study treatments or a combination of those study 
treatments.
Trial treatment should begin on the day of randomization or as close as possible to the date 
on which the subject is allocated/assigned.
 
 
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Dose Selection/Modification
Dose Selection
The rationale for selection of doses to be used in this trial is provided in Section 4.0 –
Background & Rationale.
In Parts 1, 2, and 3 of this trial, the dose amount required to prepare the pembrolizumab
infusion solution will be based on the subject’s weight in kilograms (kg).  In Parts 4 and 5, a 
flat dose (independent of the subject’s weight) for pembrolizumab infusion is required.  
Details on the dose calculation, preparation and administration are provided in the Pharmacy
Manual.
Trametinib and dabrafenib will be administered as per the approved product labels.
Dose Modification
It should be noted that for dose modifications in Part 3 of the study, changes could occur for 
either pembrolizumab or placebo (saline IV) in combination with trametinib and dabrafenib, 
depending on the study arm assignment. Detailed dose modification and toxicity 
management guidelines for each study treatment are provided in Section 5.6 (Table 16 to 
Table 35).
5.2.1.2.1
Dose 
Modification
and 
Toxicity 
Management 
Guidelines 
for 
Pembrolizumab
Dose modification and toxicity management for immune-related AEs associated with 
pembrolizumab
AEs associated with pembrolizumab exposure may represent an immunologic etiology. 
These immune-related AEs (irAEs) may occur shortly after the first dose or several months 
after the last dose of pembrolizumab treatment and may affect more than one body system 
simultaneously. Therefore, early recognition and initiation of treatment is critical to reduce 
complications.  Based on existing clinical study data, most irAEs were reversible and could 
be managed with interruptions of pembrolizumab, administration of corticosteroids and/or
other supportive care. For suspected irAEs, ensure adequate evaluation to confirm etiology or 
exclude other causes. Additional procedures or tests such as bronchoscopy, endoscopy, skin 
biopsy may be included as part of the evaluation. Based on the severity of irAEs, withhold or 
permanently discontinue pembrolizumab and administer corticosteroids. Dose modification 
and toxicity management guidelines for irAEs associated with pembrolizumab are provided
in Table 10 below and in Section 5.6. See Section 5.6 for detailed supportive care guidelines, 
including use of corticosteroids for specific AEs.
 
 
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Table 10
Dose Modification and Toxicity Management Guidelines for Immune-related AEs Associated with Pembrolizumab
General instructions:
1.
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks.
2.
For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and 
corticosteroid has been tapered. Pembrolizumab must be permanently discontinued if AE does not resolve within 12 weeks of last dose or 
corticosteroids cannot be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks. 
3.
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive treatment 
should be initiated if irAEs cannot be controlled by corticosteroids.
Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with 
corticosteroid and/or other 
therapies 
Monitor and follow-up 
Pneumonitis 
(see also Table
22)
Grade 2
Withhold 

Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper

Monitor participants for signs and 
symptoms of pneumonitis

Evaluate participants with suspected 
pneumonitis with radiographic imaging and 
initiate corticosteroid treatment

Add prophylactic antibiotics for 
opportunistic infections
Grade 3 or 4, or 
recurrent Grade 2
Permanently 
discontinue
Diarrhea / Colitis
(see also Table
18)
Grade 2 or 3
Withhold

Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper

Monitor participants for signs and symptoms 
of enterocolitis (ie, diarrhea, abdominal 
pain, blood or mucus in stool with or 
without fever) and of bowel perforation 
(ie, peritoneal signs and ileus).

Participants with ≥ Grade 2 diarrhea 
suspecting colitis should consider GI 
consultation and performing endoscopy to 
rule out colitis. 

Participants with diarrhea/colitis should be 
advised to drink liberal quantities of clear 
fluids.  If sufficient oral fluid intake is not 
feasible, fluid and electrolytes should be 
substituted via IV infusion.
Grade 4
Permanently 
discontinue
 
 
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Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with 
corticosteroid and/or other 
therapies 
Monitor and follow-up 
AST / ALT 
elevation or 
Increased 
bilirubin
See also Section 
5.6.1.1.15
Grade 2
Withhold
See also Table 30

Administer corticosteroids (initial 
dose of 0.5-1 mg/kg prednisone or 
equivalent) followed by taper

Monitor with liver function tests (consider 
weekly or more frequently until liver 
enzyme value returned to baseline or is 
stable
Grade 3 or 4 
Permanently 
discontinue
Note: For Grade 3 
events see Table 30
for detailed
management and 
dose modification 
guidelines based on 
specific hepatic 
laboratory 
abnormalities

Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper
Type 1 diabetes 
mellitus (T1DM) 
or 
Hyperglycemia
See also Section 
5.6.1.1.6
Newly onset 
T1DM or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -cell 
failure
Withhold

Initiate insulin replacement 
therapy for participants with 
T1DM 

Administer anti-hyperglycemic in 
participants with hyperglycemia 

Monitor participants for hyperglycemia or 
other signs and symptoms of diabetes.
Hypophysitis
See also Table 19
Grade 2
Withhold

Administer corticosteroids and 
initiate hormonal replacements as 
clinically indicated.  

Monitor for signs and symptoms of 
hypophysitis (including hypopituitarism and 
adrenal insufficiency)
Grade 3 or 4 
Withhold or 
permanently 
discontinue1
Hyperthyroidism 
See also Section 
5.6.1.1.6
Grade 2
Continue 

Treat with non-selective beta-
blockers (eg, propranolol) or 
thionamides as appropriate 

Monitor for signs and symptoms of thyroid 
disorders. 
Grade 3 or 4 
Withhold or 
permanently 
discontinue1
 
 
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Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with 
corticosteroid and/or other 
therapies 
Monitor and follow-up 
Hypothyroidism
See also Section 
5.6.1.1.6
Grade 2-4
Continue 

Initiate thyroid replacement 
hormones (eg, levothyroxine or 
liothyronine) per standard of care

Monitor for signs and symptoms of thyroid 
disorders. 
Nephritis and 
Renal 
dysfunction
See also Table 23
Grade 2
Withhold 

Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by taper.

Monitor changes of renal function
Grade 3 or 4 
Permanently 
discontinue
Myocarditis
See also Section 
5.6.1.1.12
Grade 1 or 2
Withhold

Based on severity of AE 
administer corticosteroids

Ensure adequate evaluation to confirm 
etiology and/or exclude other causes
Grade 3 or 4
Permanently 
discontinue
All other 
immune-related 
AEs
See also Section 
5.6.1.3 and Table
35
Intolerable/ 
persistent Grade 2
Withhold

Based on type and severity of AE 
administer corticosteroids 

Ensure adequate evaluation to confirm 
etiology and/or exclude other causes
Grade 3
Withhold or 
discontinue based 
on the type of 
event.  Events that 
require 
discontinuation 
include and not 
limited to:  
Guillain-Barre 
Syndrome, 
encephalitis
Grade 4 or 
recurrent Grade 3 
Permanently 
discontinue
1.
Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.  
NOTE: 
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may be resumed 
when AE resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM).  
 
 
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With investigator and Sponsor agreement, subjects with a laboratory adverse event still at 
Grade 2 after 12 weeks may continue treatment in the trial only if asymptomatic and 
controlled.  For information on the management of adverse events, see Section 5.6.1.  
For subjects who experience a recurrence of the same AE(s) at the same grade or greater with 
rechallenge of pembrolizumab, a consultation between the Sponsor and investigator should 
occur to determine whether the subject should continue in the trial.  However, for a subject 
who experiences a recurrence of the same serious adverse event at the same grade or 
greater with rechallenge of 
pembrolizumab, the subject must discontinue 
pembrolizumab.
Dose increase of pembrolizumab will not be permitted in individual subjects unless a dose 
level of pembrolizumab is dropped during the trial.  If this occurs then those subjects who 
were assigned the dropped dose may switch to the remaining dose level at the discretion of 
the investigator.
Dose modification and toxicity management of infusion-reactions related to 
pembrolizumab
See Section 5.6.1.2
Other allowed dose interruption for pembrolizumab 
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as 
medical / surgical events or logistical reasons not related to study therapy. Participants should 
be placed back on study therapy within 3 weeks of the scheduled interruption, unless 
otherwise discussed with the Sponsor. The reason for interruption should be documented in 
the patient's study record.
5.2.1.2.2
Trametinib Dose Modification
Please refer to Section 5.6.1.1.4.
5.2.1.2.3
Dabrafenib Dose Modification
Please refer to Section 5.6.1.1.4.
Timing of Dose Administration
A maximum of 28 days has been provided to screen subjects prior to first dose.
Pembrolizumab Dose Administration
Pembrolizumab should be administered every 21 days (for Q3W schedule) after all 
procedures and assessments have been completed except for the post-infusion PK sample 
time points listed in the Study Flow Chart.  Pembrolizumab may be administered within 72 
hours before or after the planned date of treatment for administrative reasons only (e.g., 
scheduling an infusion around a holiday).
 
 
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The specific time of pembrolizumab administration (e.g., time of the week for first 
administration; time of the day for each administration) should take into consideration PK 
sampling time points and study visit procedures.  
Pembrolizumab will be administered as a 30 minute IV infusion Q3W.  Sites should make 
every effort to target infusion timing to be as close to 30 minutes as possible.  However, 
given the variability of infusion pumps from site to site, a window of -5 minutes and +10 
minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min).  Subjects do not 
need to be observed for any specific period of time after the infusion, but should be provided 
instructions to notify study personnel if symptoms of infusion reaction occur after any 
pembrolizumab infusion.
The Procedures/Pharmacy Manuals contain specific instructions for pembrolizumab dose 
calculation, preparation of the infusion fluid, and administration. 
Trametinib and Dabrafenib Dose Administration
Both trametinib and dabrafenib should be administered in the morning at approximately the 
same time every day.  The second dose of dabrafenib should be administered approximately 
12 hours after the morning dose.  Study medication should be taken orally with 
approximately 200 mL of water under fasting conditions, either 1 hour before or 2 hours after 
a meal.
The specific time of trametinib and dabrafenib administration should take into consideration 
PK sampling time points and study visit procedures.
If a subject vomits after taking study medication, the subject should be instructed not to 
retake the dose and should take the next dose as originally scheduled.
If a subject misses a dose of dabrafenib, the subject may take the dose immediately if the 
next dose is scheduled for at least 6 hours later. If the next scheduled dose is due in less than 
6 hours, the subject should skip the dose and resume dosing at the next scheduled dose.  
If a subject misses a dose of trametinib, the subject may take the dose immediately if the next 
dose is scheduled for at least 12 hours later. If the next scheduled dose is due in less than 12 
hours, the subject should skip the dose and resume dosing at the next scheduled dose.  
Subjects should start treatment as soon as possible after randomization but no later than 72 
hours post-randomization.
Trial Blinding/Masking
Parts 1, 2, 4, and 5 are open-label in the trial; therefore, the Sponsor, investigator and subject 
will know the treatment administered.
In Part 3, a double-blind/masking technique will be used.  Pembrolizumab and placebo will 
be dispensed in a blinded fashion by an unblinded pharmacist or qualified trial site personnel.  
 
 
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The subject, the investigator and Sponsor personnel or delegate(s) who are involved in the 
treatment or clinical evaluation of the subjects are unaware of the group assignments.
Rules for Dose Escalation and Confirmation
Dose Escalation
5.2.4.1.1
Dose Escalation (Part 1)
Dose limiting toxicities (DLTs) observed in Cycle 1 (i.e., Cycle 1, initiated with the first 
pembrolizumab dose) will be used to determine escalation to the next dose level. The study is 
using a 3+3 design followed by dose confirmation based on the TPI method [92] and has 2 
parts: a dose escalation part, and a dose confirmation part according to the TPI approach. The 
guidelines used for dose escalation and dose confirmation are shown in Table 11.
The rules applied for the dose escalation part are as follows:
An initial cohort of 3 subjects is enrolled at Dose Level 1. 

If 0/3 subjects develops a DLT, then dose escalation will terminate with this finding, 
Dose Level 1 will be considered the preliminary MTD/MAD, and the study will 
proceed to the dose confirmation stage. 

If 1/3 subjects develops a DLT, another 3 subjects will be enrolled at this dose level.
o
If ≤1 of the 3 new subjects develops a DLT (for a total of ≤2/6 subjects with a 
DLT at this dose level), then dose escalation will terminate with this finding, 
Dose Level 1 will be considered the preliminary MTD/MAD, and the study 
will proceed to the dose confirmation stage.
o
If >1 of the 3 new subjects develop a DLT (for a total of >2/6 subjects with a 
DLT at this dose level), 3 subjects will be enrolled at Dose Level -1.

If 0/3 subjects develops a DLT at Dose Level -1, then dose escalation 
will terminate with this finding, Dose Level -1 will be considered the 
preliminary MTD/MAD, and the study will proceed to the dose 
confirmation stage.

If 1/3 subjects develops a DLT at Dose Level -1, another 3 subjects 
will be enrolled at Dose Level -1. If ≤2/6 subjects develop a DLT at 
Dose Level -1, then dose escalation will terminate with this finding, 
Dose Level -1 will be considered the preliminary MTD/MAD, and the 
study will proceed to the dose confirmation stage. 

If ≥2/3 subjects or >2/6 subjects develop a DLT at Dose Level -1, the 
dose escalation part of the study will terminate and the combination 
will not be studied further. 
 
 
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
If ≥2/3 subjects develop a DLT, 3 subjects will be enrolled in Dose Level -1.
o
If 0/3 subjects develops a DLT at Dose Level -1, then dose escalation will 
terminate with this finding, Dose Level -1 will be considered the preliminary 
MTD/MAD, and the study will proceed to the dose confirmation stage.
o
If 1/3 subjects develops a DLT at Dose Level -1, another 3 subjects will be 
enrolled at Dose Level -1. If ≤2/6 subjects develop a DLT at Dose Level -1, 
then dose escalation will terminate with this finding, Dose Level -1 will be 
considered the preliminary MTD/MAD, and the study will proceed to the dose
confirmation stage. 
o
If ≥2/3 subjects of >2/6 subjects develop a DLT at Dose Level -1, the dose 
escalation part will terminate and the combination will not be studied further.
It is conceptually acceptable to de-escalate to an intermediate, not pre-defined and not 
previously-studied dose, if evaluation of toxicity at such a dose is desired in lieu of 
proceeding directly to the dose confirmation stage of the study. If this approach is taken, 3 
new subjects should be enrolled at the new intermediate dose, and the aforementioned rules 
should be used to determine further enrollment at this dose level. 
There may be >3 or >6 subjects enrolled at any given dose cohort due to replacement of 
subjects who were not evaluable or further evaluation of safety or pharmacokinetics at a dose 
level.
5.2.4.1.2
Dose Escalation (Part 4)
Dose limiting toxicities (DLTs) observed in Cycle 1 (i.e., following the trametinib run-in 
period in Cycle 1, initiated with the first pembrolizumab dose) will be used to determine 
escalation to the next dose level. The study is using a 3+3 design followed by dose 
confirmation based on the modified Toxicity Probability Interval (mTPI) method [104] and 
has 2 parts: a dose escalation part, and a dose confirmation part according to the mTPI 
approach. The guidelines used for dose escalation (Table 6 and Table 7) and dose 
confirmation (Table 12 and Table 13) are provided.  A flow diagram for the concurrent and 
intermittent regimens is included in Figure 2.
 
 
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Figure 2
Flow Diagram: Part 4 Concurrent (cDL) and Intermittent (iDL) Dose Levels
Each treatment regimen (concurrent and intermittent) will be tested simultaneously, and 
subjects will be assigned to these treatment arms using 1:1 randomization whenever both 
regimens are open for enrollment.  For each regimen, an initial cohort of 3 subjects is 
enrolled at Dose Level 1. The dose levels for the concurrent and intermittent treatment arms 
are shown in Table 6 and Table 7, respectively.  Of note, for the concurrent dosing regimen, 
Dose Levels 2a and 2b will be tested simultaneously, and to proceed to Dose Level 3, both 
Dose Level 2a and 2b must be found to be tolerable.
The rules applied for the dose escalation part are as follows:

If 0/3 subjects develop a DLT, then dose escalation will advance to the next Dose 
Level(s).

If 1/3 subjects develop a DLT, another 3 subjects will be enrolled at this dose level.
o
If ≤1 of the 3 new subjects develops a DLT (for a total of ≤2/6 subjects with a 
DLT at this dose level), then dose escalation will advance to the next Dose 
Level(s).  If this occurs at Dose Level 3 (concurrent regimen) or Dose Level 2 
(intermittent regimen), then dose escalation will terminate with this finding, 
 
 
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the respective Dose Level will be considered the MTD/MAD, and the study 
will proceed to the dose confirmation stage.
o
If >1 of the 3 new subjects develop a DLT at Dose Level 1 (for a total of >2/6 
subjects with a DLT), 3 subjects will be enrolled at Dose Level -1a. If this 
occurs at any other dose level for either regimen, then dose escalation will 
terminate with this finding, the previous lower dose level will be considered 
the preliminary MTD, and the study will proceed to the dose confirmation 
stage.

If 0/3 subjects develop a DLT at Dose Level -1a, then dose escalation 
will advance to Dose Level -1b.

If 1/3 subjects develops a DLT at Dose Level -1a, another 3 subjects 
will be enrolled at Dose Level -1a.  If ≤2/6 subjects develop a DLT at 
Dose Level -1a, then dose escalation will advance to Dose Level -1b. 
Of note, if Dose Level -1b is subsequently found to be tolerable, the 
dose escalation will terminate with this finding, Dose Level -1b will be 
considered the preliminary MTD, and the study will proceed to the 
dose confirmation stage.

If ≥2/3 subjects or >2/6 subjects develop a DLT at Dose Level -1a, the 
dose escalation part of the study will terminate and the dosing regimen 
will not be studied further. 

If ≥2/3 subjects develop a DLT at Dose Level 1, 3 subjects will be enrolled in Dose 
Level -1a.
o
If 0/3 subjects develop a DLT at Dose Level -1a, then dose escalation will 
advance to Dose Level -1b. Of note, if Dose Level -1b is subsequently found 
to be tolerable, the dose escalation will terminate with this finding, Dose 
Level -1b will be considered the preliminary MTD, and the study will proceed 
to the dose confirmation stage.
o
If 1/3 subjects develop a DLT at Dose Level -1a, another 3 subjects will be 
enrolled at Dose Level -1a. If ≤2/6 subjects develop a DLT at Dose Level -1a, 
then dose escalation will advance to Dose Level -1b. Of note, if Dose Level -
1b is subsequently found to be tolerable, the dose escalation will terminate 
with this finding, Dose Level -1b will be considered the preliminary MTD, 
and the study will proceed to the dose confirmation stage.
o
If ≥2/3 subjects or >2/6 subjects develop a DLT at Dose Level -1a, the dose 
escalation part will terminate and the combination will not be studied further.
It is conceptually acceptable to de-escalate to an intermediate, not pre-defined and not 
previously-studied dose, if evaluation of toxicity at such a dose is desired in lieu of 
proceeding directly to the dose confirmation stage of the study. If this approach is taken, 3 
 
 
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new subjects should be enrolled at the new intermediate dose, and the aforementioned rules 
should be used to determine further enrollment at this dose level. 
There may be >3 or >6 subjects enrolled at any given dose cohort due to replacement of 
subjects who were not evaluable or further evaluation of safety or pharmacokinetics at a dose 
level.
Patients who experience a DLT will be allowed to remain on study if they meet the following 
criteria: (1) the investigator believes it is appropriate for patients to remain on study, and (2) 
the event has resolved and no longer meets the definition of DLT.
Dose Confirmation
5.2.4.2.1
Dose Confirmation (Part 2)
The objective of dose confirmation is to refine the estimate of the MTD.  Dose confirmation 
involves the expansion of at least 1 dose combination studied in the dose escalation stage of 
the study. 
Dose confirmation will begin with expansion of the preliminary MTD identified in the dose 
escalation stage described above. The dose confirmation part will continue based on the TPI 
method [92] until 14 subjects are studied at the selected dose (combined from dose escalation 
and dose confirmation) with ≤5 of 14 subjects experiencing a DLT.  As subjects become 
evaluable for DLT assessment, the number of subjects who are evaluable for DLT versus the 
number of subjects who developed a DLT will be continuously assessed and de-escalation 
and re-escalation to eligible doses will occur as shown in Table 11.
 
 
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Table 11
Part 2 Dose Confirmation Rules
Target MTD = 25%
a=1; b=1; k1=1.5; k2=0.5; pow=1.1 per [92]
If de-escalation to Dose Level -1 is required, but Dose Level -1 was not studied in the Part 1 
of the study, 3+3 design rules described in Section 5.2.4.1 will be applied to Dose Level -1 
before 0/3 or ≤2/6 DLTs are observed at this dose and Dose Level -1 enters the dose 
confirmation stage with the rules shown in Table 11.
Subjects may be enrolled continuously (i.e., without waiting for Cycle 1 completion of 
subjects who have received the first dose) unless a DLT is observed at the particular dose.  
Once a DLT is observed, the number of subjects who are enrolled at that dose but are not yet 
fully evaluable for DLT assessment may not exceed the number of remaining subjects who 
are at risk of developing a DLT before the dose would be considered unacceptably toxic 
(denoted as DU in Table 11).  For example, if 3/8 subjects have experienced a DLT at a 
given dose level, no more than an additional 2 subjects should be enrolled at this dose level 
until additional DLT data are available. This is because this dose level would be considered 
unacceptably toxic if all 2 additional subjects experience a DLT (i.e., 5/10 subjects with DLT 
in Table 11). To find out how many more subjects can be enrolled, one can count steps in 
diagonal direction (down and to the right) from the cell (8 subjects, 3 toxicities) to the first 
cell marked DU.
 
 
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If enrollment expands to 14 subjects for a dose level, and ≤5 of the 14 subjects develop a 
DLT, then the dose confirmation will stop.  If enrollment expands to 14 subjects for a dose 
level and >5/14 subjects develop a DLT, then the next lower dose may be expanded to 
further explore the dose-response relationship. Note that while 25% has been the target 
toxicity rate used to generate the guidelines in Table 11, the observed rate of subjects with 
DLT at the MTD may be slightly above or below 25%.
5.2.4.2.2
Dose Confirmation (Part 5)
The objective of dose confirmation is to refine the estimate of the MTD.  Dose confirmation 
involves the expansion of at least 1 dose combination studied in the dose escalation stage of 
the study. 
Dose confirmation will begin with expansion of the preliminary MTD identified in the dose 
escalation stage described above. As in Part 4, each treatment arm (concurrent and 
intermittent) will be tested simultaneously, and subjects will be assigned to these treatment 
arms using 1:1 randomization whenever both regimens are open for enrollment. The dose 
confirmation part will continue based on the mTPI method [104] with a target DLT rate of 
30% until 14 subjects are studied at the selected dose (combined from dose escalation and 
dose confirmation) with ≤6 of 14 subjects experiencing a DLT.  As subjects become 
evaluable for DLT assessment, the number of subjects who are evaluable for DLT versus the 
number of subjects who developed a DLT will be continuously assessed and de-escalation 
and re-escalation to eligible doses will occur as shown in Table 12.  Table 12 outlines the 
dose escalation and de-escalation sequences depending on the preliminary MTD defined in 
Part 4 for the concurrent and intermittent dosing regimens.
If, for example, de-escalation to Dose Level -1a is required, but Dose Level -1a was not 
studied in Part 4, the 3+3 design rules described in Section 5.2.4.1.2 will be applied to Dose 
Level -1a before (1) 0/3 or ≤2/6 DLTs are observed at this dose, and, (2) Dose Level -1a 
enters the dose confirmation stage with the rules shown in Table 13.
Table 12
mTPI Dosing Sequences
Concurrent Dosing Regimen
Intermittent Dosing Regimen
Preliminary 
MTD from 
Part 4
Sequence
Preliminary 
MTD from 
Part 4
Sequence
cDL-1a
cDL-1a -> cDL-1b -> cDL1 -> 
cDL2a -> cDL3
iDL-1a
iDL-1a -> iDL-1b -> iDL1 -> iDL2
cDL-1b
cDL-1a <- cDL-1b -> cDL1 -> 
cDL2a -> cDL3
iDL-1b
iDL-1a <- iDL-1b -> iDL1 -> iDL2
cDL1
cDL-1a <- cDL1 -> cDL2a -> cDL3
iDL1
iDL-1a <- iDL1 -> iDL2
cDL2a
cDL-1a <- cDL1 <- cDL2a -> cDL3
iDL2
iDL-1a <- iDL1 <- iDL2
cDL2b
cDL-1a <- cDL1 <- cDL2b -> cDL3
cDL3
cDL-1a <- cDL1 <- cDL2a <- cDL3
 
 
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Subjects may be enrolled continuously (i.e., without waiting for Cycle 1 completion of 
subjects who have received the first dose) unless a DLT is observed at the particular dose.  
Once a DLT is observed, the number of subjects who are enrolled at that dose but are not yet 
fully evaluable for DLT assessment may not exceed the number of remaining subjects who 
are at risk of developing a DLT before the dose would be considered unacceptably toxic 
(denoted as DU in Table 13).  For example, if 3/8 subjects have experienced a DLT at a 
given dose level, no more than an additional 3 subjects should be enrolled at this dose level 
until additional DLT data are available. This is because this dose level would be considered 
unacceptably toxic if all 3 additional subjects experience a DLT (i.e., 6/11 subjects with DLT 
in Table 13). To find out how many more subjects can be enrolled, one can count steps in 
diagonal direction (down and to the right) from the cell (8 subjects, 3 toxicities) to the first 
cell marked DU. 
If enrollment expands to 14 subjects for a dose level, and ≤6 of the 14 subjects develop a 
DLT, then the dose confirmation will stop.  If enrollment expands to 14 subjects for a dose 
level and >6/14 subjects develop a DLT, then the next lower dose may be expanded to 
further explore the dose-response relationship. Note that while 30% has been the target 
toxicity rate used to generate the guidelines in Table 13, the observed rate of subjects with 
DLT at the MTD may be slightly above or below 30%.
Table 13
Part 5 Dose Confirmation Rules
Number of subjects treated at current dose
Number of toxicities
3
4
5
6
7
8
9
10
11
12
13
14
0
E
E
E
E
E
E
E
E
E
E
E
E
1
S
S
S
E
E
E
E
E
E
E
E
E
2
D
S
S
S
S
S
S
S
E
E
E
E
3
DU
DU
D
S
S
S
S
S
S
S
S
S
4
DU
DU
DU
D
D
S
S
S
S
S
S
5
DU
DU
DU
DU
DU
D
S
S
S
S
6
DU
DU
DU
DU
DU
DU
D
S
S
7
DU
DU
DU
DU
DU
DU
DU
D
8
DU
DU
DU
DU
DU
DU
DU
9
DU
DU
DU
DU
DU
DU
10
DU
DU
DU
DU
DU
11
DU
DU
DU
DU
12
DU
DU
DU
13
DU
DU
14
DU
E = Escalate to the next higher dose
S = Stay at the current dose
D = De-escalate to the next lower dose
DU = The current dose is unacceptably toxic
Target toxicity rate = 30%
Flat non-informative prior Beta (1,1) is used as a prior and ε1=ε2=0.05 [104].
 
 
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Dose Limiting Toxicity
Toxicities will be graded using National Cancer Institute (NCI) CTCAE Version 4.0.  A DLT 
evaluable subject is defined as a subject who receives treatment for the 6-week dose-limiting 
toxicity (DLT) observation period and who receives at least 66% of all planned treatments. 
A subject who does not receive at least 66% of planned treatment due to AEs that are 
unrelated to study treatment will not be considered evaluable for DLTs and may be replaced 
as needed during dose escalation or dose confirmation. More than 3 or 6 subjects may be 
enrolled to a given dose level if needed to replace subjects who are not evaluable for DLT or 
to ensure a thorough evaluation of a given dose level during the dose escalation part of the 
study.  An event will be considered a dose-limiting toxicity (DLT) if it occurs during the first 
cycle of treatment in dose identification and confirmation subjects (first 6 weeks after 
initiating pembrolizumab treatment) and meets at least one of the following criteria:
• Clinically significant hematologic toxicity (e.g. grade 4 neutropenia lasting more than 7
days or accompanied by neutropenic fever, or Grade 4 thrombocytopenia of any duration)
• Clinically significant Grade ≥3 non-hematologic toxicity that has not been previously 
identified for either pembrolizumab or dabrafenib/trametinib and cannot be controlled with 
routine supportive measures (e.g. anti-emetics)
• Clinically significant Grade ≥3 non-hematologic toxicities that are known to occur with 
either pembrolizumab or dabrafenib/trametinib but that cannot be controlled using the 
recommended product-specific supportive measures (e.g. steroids for pembrolizumab-related 
immune toxicities)
• Drug-related toxicity, regardless of CTCAE grade, that results in an interruption of any 
component of study therapy during Cycle 1 for more than 21 consecutive days and cannot be 
controlled within 2 weeks from its onset
• Any other Grade 2 or greater non-hematological toxicity that in the judgment of the 
investigator and Sponsor is dose limiting, with the exception of mild or moderate immune-
mediated adverse reactions or symptomatic endocrinopathy attributable to pembrolizumab
• Liver chemistries meeting stopping guidelines (as outlined in Section 5.6.1.1.15):
1. ALT or AST 3xULN and bilirubin 2xULN (>35% direct bilirubin) (or 
ALT/AST3xULN and INR>1.5, if INR measured)
NOTE: If serum bilirubin fractionation is not immediately available, study treatment 
should be discontinued if ALT or AST 3xULN and bilirubin 2xULN. Serum 
bilirubin fractionation should be performed if testing is available.  If testing is 
unavailable, record presence of detectable urinary bilirubin on dipstick, indicating 
direct bilirubin elevations suggest liver injury.
 
 
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2. ALT or AST 8xULN
3. ALT or AST 5xULN but <8 xULN persists for 2 weeks
4. ALT or AST 3xULN if associated with the appearance or worsening of symptoms 
of hepatitis or hypersensitivity such as fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, pyrexia, rash or eosinophilia.
5. ALT or AST 5xULN but <8 xULN and cannot be monitored weekly for >2 weeks.
The following will NOT be considered a DLT for the purposes of this protocol:
• Clinically insignificant laboratory values of any grade (i.e. asymptomatic amylase, lipase 
elevations).
• Cutaneous squamous cell carcinoma (cuSCC), basal cell carcinoma, and new primary 
melanomas which are manageable with surgical excision alone.
Note: Dose reduction of pembrolizumab is prohibited during Cycle 1 of Parts 1, 2, 4, and 5 
(excluding the subjects enrolled into the MK+T cohort after MTD/MAD is confirmed in 
Parts 2 and 5 of the MK+T arms).  Dose reduction of dabrafenib and trametinib during all 
parts of the trial should follow the label instructions or protocol guidance where appropriate.
Treatment Duration
Subjects who have a confirmed complete response after at least 6 months of study treatment 
and 2 doses of pembrolizumab treatment beyond CR may stop pembrolizumab at the 
investigator’s discretion.  Trametinib and/or dabrafenib treatment may be continued until PD 
or unacceptable toxicity or until completion of 24 months of treatment.   
All subjects who continue pembrolizumab treatment to 24 months and who did not 
discontinue prior to 24 months due to PD or unacceptable toxicity will discontinue 
pembrolizumab at that time. Beyond 24 months, trametinib and/or dabrafenib treatment may 
be continued off study as per standard of care.  
The Part 3 final analysis did not demonstrate a statistically significant increase in PFS in the 
experimental arm compared to the control arm. Subjects in the Part 3 experimental arm 
experienced a higher rate of Grade 3-5 AEs, SAEs, and discontinuations due to AEs 
compared to the control arm. Therefore, there is no further rationale to offer re-challenge 
with triplet therapy and Second Course treatment will not be offered to any subject in 
KEYNOTE-022. In exceptional cases and upon Sponsor consultation and approval, 
trametinib and/or dabrafenib may be continued on study after completion of 24 months of 
treatment with pembrolizumab combined with trametinib and dabrafenib or placebo 
combined with trametinib and dabrafenib. These subjects can continue in accordance with 
the flow chart in Section 6.2 until the study is closed by the Sponsor.  At the time of study 
closure, the subjects would move to local supply and continue care under their local treating 
physician.
 
 
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In the event a Part 3 subject discontinued study treatment due to documented disease 
progression, and the unblinding of treatment alters a subject’s eligible therapy options 
outside of the trial, a PI may request to have the subject’s treatment assignment unblinded 
after discussion with Sponsor. All precautions will be taken to ensure the Sponsor and 
blinded site personnel remain blinded to the subject’s treatment.
After completion of pembrolizumab and/or trametinib at 24 months in Part 4 and 5, subjects 
will be discontinued from the trial.  Subjects who are discontinued from the trial may move 
to followup until progression or survival follow-up if they opt to continue on any oncologic 
therapy.  This would include pembrolizumab or trametinib and would be sourced locally as 
per standard of care. At the time of study closure, the subjects would move to local supply 
and continue care under their local treating physician. 
Randomization or Treatment Allocation
Randomization will occur centrally using an interactive voice response system / integrated 
web response system (IVRS/IWRS). There are 2 arms.  Subjects will be assigned randomly 
in an 1:1 ratio to (1) the confirmed triplet dose of pembrolizumab, trametinib 2 mg QD, 
dabrafenib 150 mg BID,  or, (2) placebo of pembrolizumab (saline IV), trametinib 2 mg QD, 
dabrafenib 150 mg BID, respectively.  Randomization will occur only in Part 3 of the trial in 
the blinded portion of the study.  Subjects in Parts 1 and 2 of the study (open label) will be 
assigned study treatment without randomization. Subjects in Parts 4 and 5 of the study (open 
label), will be assigned study treatment (concurrent vs. intermittent dosing regimen) in a 1:1 
fashion whenever more than one regimen is open for enrollment.
Stratification
Randomization will be stratified according to the following factors:
1. Eastern Cooperative Oncology Group Performance Status (0 vs. 1)
2. Lactate Dehydrogenase (LDH) level (>1.1 x ULN vs. ≤1.1 x ULN)
Stratification is applicable only to Part 3 of this study.  No stratification is utilized in Parts 1,
2, 4, and 5.
Concomitant Medications/Vaccinations (allowed & prohibited)
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  Listed below are some specific restrictions for concomitant therapy 
or vaccination during the course of the trial.  If there is a clinical indication for one of these 
or other medications or vaccinations specifically prohibited during the trial, discontinuation 
from trial therapy or vaccination may be required.  The investigator should discuss any 
questions regarding this with the Sponsor Clinical Monitor.  The final decision on any 
supportive therapy or vaccination rests with the investigator and/or the subject's primary 
physician.  However, the decision to continue the subject on trial therapy or vaccination 
schedule requires the mutual agreement of the investigator, the Sponsor and the subject.
 
 
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Acceptable Concomitant Medications
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care. All concomitant medication will be recorded on the case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications 
and fluids. If changes occur during the trial period, documentation of drug dosage, frequency, 
route, and date may also be included on the CRF.
Use of anticoagulants such as warfarin is permitted; however, caution should be exercised 
and additional International Normalized Ratio (INR) monitoring is recommended when 
dabrafenib is used concomitantly with warfarin.  See Section 5.5.3 Medications to be Used 
with Caution.
All concomitant medications received within 28 days before the first dose of trial treatment 
and 30 days after the last dose of trial treatment should be recorded. Concomitant 
medications administered after 90 days after the last dose of trial treatment should be 
recorded for SAEs and ECIs as defined in Section 7.2.
Prohibited Concomitant Medications
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phases of this trial:

Antineoplastic systemic chemotherapy or biological therapy. 

Immunotherapy not specified in this protocol.

Chemotherapy not specified in this protocol.

Investigational agents other than pembrolizumab, trametinib, and dabrafenib.

Radiation therapy.

Live vaccines within 30 days prior to the first dose of study therapy and while 
participating in study. Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, and 
typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are allowed; however intranasal influenza vaccines (e.g. Flu-Mist) are 
live attenuated vaccines, and are not allowed.

Antiretroviral drugs
Note:  Subjects with known HIV are ineligible for study participation.

Herbal remedies (e.g., St. John’s wort).
 
 
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
Glucocorticoids for any purpose other than to manage adverse events.

Dabrafenib is metabolized primarily by Cytochrome P450 (CYP) 2C8 and CYP3A4.  
Co-administration of dabrafenib with ketoconazole, a CYP3A4 inhibitor, or with 
gemfibrozil, a CYP2C8 inhibitor, resulted in increases in dabrafenib AUC of 71% 
and 47%, respectively.  Drugs that are strong inhibitors or inducers of CYP3A and 
CYP2C8 (see list in Table 14) may only be used under special circumstances (e.g., as 
a single use for a procedure) while treatment with study drug is interrupted as they 
may alter dabrafenib concentrations; consider therapeutic substitutions for these 
medications.  Approval of the medical monitor is required in these situations. The list 
may be modified based on emerging data.
Table 14
Prohibited Concomitant Medications
PROHIBITED – strong inducers of CYP3A or CYP2C8, since concentrations of dabrafenib 
may be decreased
Class/Therapeutic Area
Drugs/Agents
Antibiotics
rifamycin class agents (e.g., rifampin, rifabutin, rifapentine)
Anticonvulsant
carbamazepine, oxcarbazepine phenobarbital, phenytoin, s-mephenytoin 
Miscellaneous
bosentan, St-John’s wort
PROHIBITED – Strong inhibitors of CYP3A, or CYP2C8 since concentrations of 
dabrafenib may be increased
Class/Therapeutic Area
Drugs/Agents
Antibiotics
clarithromycin, telithromycin, troleandomycin
Antidepressant
Nefazodone
Antifungals
itraconazole, ketoconazole, posaconazole, voriconazole
Hyperlipidemia
gemfibrozil
Antiretroviral
ritonavir, saquinavir, atazanavir
Miscellaneous
conivaptan 
Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial.  
Subjects may receive other medications that the investigator deems to be medically 
necessary.
The Exclusion Criteria describes other medications which are prohibited in this trial.
There are no prohibited therapies during the Post-Treatment Follow-up Phase.
 
 
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Medications to be Used with Caution
The following medications should be used with caution during the Screening and Treatment 
Phases of this trial, as their concentrations may be altered by dabrafenib or they may alter 
dabrafenib concentrations:

Drugs that are moderate inhibitors or inducers of CYP3A and CYP2C8 as they may 
alter concentrations of dabrafenib.

Dabrafenib has been shown to induce CYP3A4 and CYP2C9 in vivo using 
midazolam (CYP3A4 substrate) and S-warfarin (CYP2C9 substrate).  Dabrafenib is 
an in vitro inducer of CYP2B6 and other enzymes such as CYP2C8, CYP2C19, 
UDP-glucuronyl transferases. Transporters may also be affected.  Co-administration 
of dabrafenib and medications which are affected by the induction of these enzymes 
(including warfarin) and transporters may result in loss of efficacy.  If co-
administration of these medications is necessary, investigators should monitor 
subjects for loss of efficacy or consider substitutions of these medications. A partial 
list of these medications is provided in Table 15.

Therapeutic level dosing of warfarin can be used with approval by the medical 
monitor and close monitoring of PT/INR by the site.  Warfarin exposure has been 
shown to decrease (37% decrease) due to dabrafenib-mediated enzyme induction. 
Conversely, if dabrafenib dosing is reduced, interrupted, or discontinued, warfarin 
exposure may be increased. Thus, warfarin dosing may need to be adjusted based on 
PT/INR during and after treatment with dabrafenib. Prophylactic low dose warfarin 
may be given to maintain central catheter patency.

Dabrafenib solubility is pH-dependent with decreased solubility at higher pH. Drugs 
such as proton pump inhibitors that inhibit gastric acid secretion to elevate gastric pH 
may decrease the solubility of dabrafenib and reduce its bioavailability. No clinical 
study has been conducted to evaluate the effect of pH on dabrafenib 
pharmacokinetics. In an ad-hoc analysis, no differences in Cmax and AUC were noted 
between subjects who reported taking pH-elevating products relative to other 
subjects. Due to the theoretical risk that pH-elevating agents may decrease oral 
bioavailability and exposure to dabrafenib, these medicinal products that increase 
gastric pH should be used with caution when administered with dabrafenib.
 
 
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Table 15
Medications to be used with Caution
USE WITH CAUTION: Moderate  inhibitors of CYP3A, or CYP2C8 since concentrations of 
dabrafenib may be increased
Class/Therapeutic Area
Moderate CYP3A and CYP2C8 Inhibitors
Antiarrhythmics
diltiazem, verapamil
Antibiotic
Erythromycin
Antifungal
Fluconazole
Miscellaneous
Aprepitant
USE WITH CAUTION: Co-administration of these drugs with study treatment may result in loss of 
efficacy.  Monitor subjects for loss of efficacy or substitute with another medication.
Class/Therapeutic Area
CYP3A4, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or Transporter 
Substrates that May be Affected by Induction 
Analgesics
alfentanil, buprenorphine, celecoxib, codeine, fentanyl, methadone, 
oxycodone
Antiarrhythmics
disopyramide, dronedarone, mexiletine, propafenone, quinidine
Antibiotics
chloramphenicol, doxycycline, erythromycin, moxifloxacin 
Anticoagulants/ 
Antiplatelets
cilostazole, warfarin
Anticonvulsants
divalproex, lamotrigine, valproate, zonisamide
Antidepressants and 
Antipsychotics
aripiprazole, bupropion, buspirone, desipramine, haloperidol, mirtazapine, 
pimozide, quetiapine, trazodone, amitriptyline, clomipramine, imipramine
Antidiabetics
glyburide, saxagliptin, tolbutamide, nateglinide, pioglitazone, repaglinide,
rosiglitazone
Antifungals
caspofungin, fluconazole, terbinafine
Antihistamines
astemizole, chlorpheniramine, ebastine
Antihypertensives
amlodipine, diltiazem, felodipine, nifedipine, nilvadipine, nisoldipine, 
verapamil
Antimigraine Agents
diergotamine, eletriptan, ergotamine
Corticosteroids
dexamethasone, methylprednisolone, oral budesonide
Erectile Dysfunction Agents
sildenafil, tadalafil, vardenafil
HMG-CoA Reductase 
Inhibitors
atorvastatin, lovastatin, simvastatin, rosuvastatin, pravastatin
Hypnotics and Sedatives
alprazolam, brotizolam, diazepam, estazolam, midazolam, triazolam, 
zolpidem, zopiclone
Immunosuppressants
everolimus, sirolimus, tacrolimus
Miscellaneous
aprepitant, cisapride, darifenacin, digoxin, disopyramide, leflunomide, 
methohexital, oral contraceptives, quinine, ranitidine, solifenacin, 
sulfasalazine, tramadol, tolvaptan, chloroquine, zopiclone
Selective Aldosterone Blockers
Eplerenone
USE WITH CAUTION: Co-administration of drugs that increase gastric pH should be used with 
caution when administered with dabrafenib as exposure to dabrafenib may be decreased
pH altering agents
dexlansoprazole. esomeprazole, famotidine, ilaprazole, lansoprazole, 
omeprazole, pantoprazole, rabeprazole, ranitidine
Abbreviations: CYP = cytochrome P450; HMG-CoA = 3-hydroxy-3-methylglutaryl-coenzyme A.
Questions regarding concomitant medications should be directed to the medical monitor for 
clarification.
 
 
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Rescue Medications & Supportive Care
Supportive Care Guidelines
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of AEs with 
potential immunologic etiology associated with pembrolizumab are outlined along with the 
dose modification guidelines in Section 5.2.1.2, Table 10. Additional toxicity management 
guidelines are provided below in Table 16 to Table 35.  Where appropriate, these guidelines 
include the use of oral or IV treatment with corticosteroids, as well as additional anti-
inflammatory agents if symptoms do not improve with administration of corticosteroids.  
Note that several courses of steroid tapering may be necessary as symptoms may worsen 
when the steroid dose is decreased.  For each disorder, attempts should be made to rule out 
other causes such as metastatic disease or bacterial or viral infection, which might require 
additional supportive care.  The treatment guidelines are intended to be applied when the 
Investigator determines the events to be related to study treatment. 
Note: If after the evaluation of the event, it is determined not to be related to pembrolizumab, 
the Investigator does not need to follow the treatment guidance.  Refer to Table 10 in Section 
5.2.1.2 for guidelines regarding dose modification and supportive care. 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event. 
Adverse Event Management Guidelines, including dose modification algorithms, are 
provided in this section for subjects treated with:

Trametinib+dabrafenib

Pembrolizumab (or saline IV)+trametinib and/or dabrafenib

Pembrolizumab
Note:  Dose modification guidelines for a given toxicity (e.g., hepatotoxicity) may not be 
identical for each treatment; therefore it is important to refer to the algorithm described for 
the combination treatment or specific single-agent.  An overview of the available dose 
modification guidelines is presented in Table 16 along with the location of the toxicity- and 
treatment-specific guidance.
All AEs are to be graded according to NCI-CTCAE v4 (http://ctep.cancer.gov).  All dose 
modifications and the reason for the dose modification must be documented in the eCRF.
Investigators should refer to the
appropriate
IB for trametinib, dabrafenib
and 
pembrolizumab for additional information regarding the background of each drug and the 
management of other AEs or potential safety-related issues.
 
 
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Events of Clinical Interest (ECIs) are selected non-serious and serious adverse experiences 
that must be reported to Merck within 24 hours regardless of attribution to trial treatment.  
Pembrolizumab+Trametinib and/or Dabrafenib, or, Trametinib+Dabrafenib 
Combination Safety Management Guidelines
Dose modifications and stopping criteria for the management of toxicities are presented in 
this section for subjects treated with the combination of dabrafenib and/or trametinib +/-
pembrolizumab. Toxicities common to dabrafenib, trametinib, and pembrolizumab include, 
but are not limited to, ocular toxicities, skin-related toxicities, diarrhea, pneumonitis, and 
pyrexia.  Therefore, it is possible that these and/or other toxicities may be exacerbated when 
dabrafenib, trametinib, and pembrolizumab are combined.  For this reason, it is important to 
note that the management guidelines for the combination of dabrafenib + trametinib + 
pembrolizumab may differ for a given AE from the management guidelines for single-agent 
dabrafenib, single-agent trametinib, combination of dabrafenib+trametinib, or single-agent 
pembrolizumab.
5.6.1.1.1
Dose Level Reduction of Trametinib and/or Dabrafenib for Subjects
beyond the DLT Period
The dose level reductions for subjects beyond the DLT evaluation period for dabrafenib and
trametinib for this study are provided in Table 5 and Table 16.  
Table 16
Dose Level Reduction Guidelines
Dose Level
Dabrafenib
Dose/Schedule
Trametinib
Dose/Schedule
Starting Dose
150 mg BID
2 mg once daily
-1 (1st Dose reduction)
100 mg BID
1.5 mg once daily
-2 (2nd Dose reduction)
75 mg BID
1.0 mg once daily
Abbreviation: BID = twice daily
If an AE resolves to grade 1 or baseline at the reduced dose level, and no additional toxicities 
are seen after 4 weeks of study treatment at the reduced dose, the dose may be increased to 
the previous dose level after discussion with the Sponsor.  Please refer to Section 5.2.1.2.1
and Section 5.6.1.1 for additional information on dose modification and associated 
supportive care guidelines for pembrolizumab, trametinib, and/or dabrafenib.
5.6.1.1.2
Interruption or Discontinuation of Trametinib,
Dabrafenib
and/or 
Pembrolizumab
If a subject’s study treatment has been interrupted for more than 21 days for dabrafenib, 
trametinib, and/or 2 doses of pembrolizumab have been withheld, the investigator must 
contact the Sponsor to review the subject’s condition in order to resume the treatment.
Subjects being treated on combination therapy who require discontinuation of one or more 
medications for toxicity may continue the remaining treatment(s). 
The reason for 
 
 
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discontinuation must be recorded.  For subsequent management of toxicities on the 
remaining treatment(s), please refer to the relevant IB for the medication. 
5.6.1.1.3
Immune-related Adverse Events
Adverse events of special interest of a potential immunologic etiology may be defined as an 
adverse event associated with drug exposure and consistent with an immune phenomenon. 
irAEs may be predicted based on the nature of the pembrolizumab compound, its mechanism 
of action, and reported experience with immunotherapies that have a similar mechanism of 
action. Special attention should be paid to AEs that may be suggestive of potential irAEs. 
An irAE can occur shortly after the first dose or several months after the last dose of 
treatment.
General principles of irAE identification and evaluation: 
Before each dose investigators are to review a subject's AEs, concomitant medications and 
clinical evaluation results e.g., vital signs, laboratory results, physical exam findings, etc., as 
outlined in Section 7.1 to monitor for new or worsening irAEs and ensure continued dosing is 
appropriate.
Early recognition of irAEs and initiation of treatment are critical to reduce the risk of 
complications, since the majority of irAEs are reversible with the use of steroids and other 
immune suppressants [93-95]. If an irAE is suspected, the subject should return to the study 
site as soon as possible instead of waiting for their next scheduled visit. Subjects who 
experience a new or worsening irAE should be contacted and/or evaluated at the study site 
more frequently.
If an irAE is suspected, a thorough evaluation should be conducted in an effort to possibly 
rule out neoplastic, infectious, metabolic, toxin or other etiologic causes before diagnosing an 
irAE.  Serological, immunological, and histological (biopsy) data should be considered to 
support the diagnosis of an immune-related toxicity. Higher grade and persistent lower grade 
irAEs typically necessitate interrupting or permanently discontinuing treatment and 
administration of systemic steroids or other immunosuppressive agents (such as TNF 
blockers) when systemic steroids are not effective.  
Identification and treatment of irAEs: Based on literature review and consideration of 
mechanism of action of pembrolizumab, guidelines have been developed regarding how to 
identify, evaluate and manage irAEs that may occur in subjects receiving pembrolizumab
(see Section 5.2.1.2.1). It is possible that irAEs other than those listed in this document may 
be observed in subjects receiving pembrolizumab, therefore all AEs of unknown etiology 
associated with drug exposure should be evaluated to determine if it is possibly immune-
related. This section is meant to be a general guidance; therefore, recommendations in the 
current document might not be all inclusive. As such investigators are encouraged to contact 
the Sponsor as needed to discuss cases that warrant separate discussion outside of the scope 
of current guidelines.  Permanent discontinuation of pembrolizumab, trametinib, and/or 
 
 
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dabrafenib due to an irAE may be the subject of discussion between the Sponsor and treating 
investigator.  
Subjects should be followed to resolution. The Adverse Experience eCRF should be updated 
with information regarding duration and clinical course of the event. Information obtained 
from the consulting specialist, including diagnosis, should be recorded in the appropriate AE 
fields. Free-text fields should be used to record narrative information: 
–
Clinical course of the event 
–
Course of treatment 
–
Evidence supporting recovery 
–
Follow-up to the clinical course 
Any treatments administered for the event should also be entered in the Concomitant 
Medication eCRF. 
5.6.1.1.4
General Guidelines for Clinically Significant Toxicities
General guidelines regarding management and dose reduction for adverse events that are 
considered by the investigator to be related to study treatment and which do not have specific 
guidelines are provided in Table 17.
 
 
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Table 17
Dose Modification Guidelines for Events Considered Related to Study 
Treatment
CTCAE Grade
Action and Dose Modification
Grade 
1 
or 
Grade 
2 
(tolerable)

Continue study treatment at current dose level

Monitor closely 

Provide supportive care according to institutional standards
Grade 2 (Intolerable)

Interrupt study treatment if clinically indicated

Monitor closely 

Provide supportive care according to institutional standards
-
If treatment was interrupted, when toxicity resolves to grade 1 or 
baseline, restart study treatment:
dose-reduced for 1st or 2nd
occurrence (dabrafenib and/or trametinib only)
-
if > 2 dose-reductions are required, permanently discontinue 
study treatment
Grade 3 

Interrupt study treatment 

Monitor closely 

Provide supportive care according to institutional standards

When toxicity resolves to grade 1 or baseline, restart study treatment 
reduced by one dose level or discontinue at investigator’s discretion 
after discussion with sponsor

If the grade 3 toxicity recurs, interrupt study treatment

When toxicity resolves to grade 1 or baseline, restart study treatment 
reduced by another dose level or discontinue at investigator’s 
discretion after discussion with sponsor

Discontinue study treatment at next occurrence
Grade 4 

Interrupt study treatment 

Permanently discontinue pembrolizumab

Monitor closely 

Provide supportive care according to institutional standards

May restart dabrafenib and/or trametinib reduced by one dose level
once toxicity resolves to grade 1 or baseline, or discontinue at 
investigator’s discretion

If the grade 4 toxicity recurs, either permanently discontinue all study 
treatment or, if the subject is clinically benefiting, discuss continuation 
of study treatment with the Sponsor.  
Any Gradea

Any signs of symptoms of Severe Cutaneous Adverse Reactions
(SCARs), permanently discontinue dabrafenib and trametinib 
immediately
a.
Cases of SCARs, including Stevens-Johnson syndrome, and drug reaction with eosinophilia and systemic 
symptoms, which can be life-threatening or fatal, have been reported during treatment with dabrafenib in 
combination with trametinib. Before initiating treatment, patients should be advised of the signs and 
symptoms and monitored closely for skin reactions. If signs and symptoms suggestive of SCARs appear, 
dabrafenib and trametinib should be permanently discontinued.
Note: With the exception of cases of SCARs, when an individual subject’s adverse reactions 
are effectively managed, dose re-escalation following the same dosing steps as de-escalation 
may be considered.
 
 
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5.6.1.1.5
Diarrhea
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such as 
diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of bowel 
perforation (such as peritoneal signs and ileus).
All subjects who experience diarrhea/colitis should be advised to drink liberal quantities of 
clear fluids. If sufficient oral fluid intake is not feasible, fluid and electrolytes should be 
substituted via IV infusion. For Grade 2 or higher diarrhea, consider GI consultation and 
endoscopy to confirm or rule out colitis.
All attempts should be made to rule out other causes such as metastatic disease, bacterial or 
parasitic infection, viral gastroenteritis, or the first manifestation of an inflammatory bowel 
disease by examination for stool leukocytes, stool cultures, and a Clostridium difficile titer.
Episodes of diarrhea have occurred in subjects receiving dabrafenib, trametinib, or both 
therapies in combination, as well as in subjects receiving pembrolizumab. Other, frequent 
causes for diarrhea including concomitant medications (e.g., stool softeners, laxatives, 
antacids, etc.), infections by C. difficile or other pathogens, partial bowel obstruction, etc., 
should be clinically excluded.
Guidelines regarding management and dose reduction for diarrhea considered to be related to 
study treatment by the investigator are provided in Table 10 and Table 18.
Table 18
Management and Dose Modification Guidelines for Diarrhea
CTCAE Grade
Adverse Event Management
Action and Dose Modification
Uncomplicated 
Diarrheaa
Grade 1 or 2

Diet:
stop all lactose containing products; eat 
small meals, ADA colitis diet recommended

Hydration:
8-10 large glasses of clear liquids 
per day (e.g., Gatorade or broth)

Consider GI consultation and endoscopy to 
evaluate for colitis for Grade 2 diarrhea 
persisting > 1 week

If symptoms worsen or persist > 3 days, treat as 
Grade 3

Loperamidec: initially 4 mg, followed by 2 mg 
every four hours or after every unformed stool; 
maximum 16 mg/day. Continue until diarrhea 
free for 12 hours.

Diarrhea > 24h: loperamide 2 mg every two 
hours; maximum 16 mg/day.  Consider adding 
oral antibiotics.

Diarrhea > 48h: loperamide 2 mg every two 
hours; maximum 16 mg/day. Add budesonide 
(9mg/day) 
or 
other 
second-line 
therapies 
(octreotide, oral diphenoxylate hydrochloride, 
atropine sulfate four times daily, or tincture of 
opium) and oral antibiotics

Grade 2 diarrhea with diffuse ulceration and 
bleeding seen on endoscopy or lasting >1 week
may require oral steroids with prolonged taper 
and represent an increased risk for the 
development of bowel perforation.

When symptoms improve to Grade 1 or less, 
steroid taper should be started and continued 
over no less than 4 weeks.

Continue study treatment, unless:

If diarrhea is grade 2 for > 48h:  interrupt 
study treatment until diarrhea resolves to 
grade ≤1.

Restart study treatment at the same dose 
level.
 
 
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CTCAE Grade
Adverse Event Management
Action and Dose Modification
Uncomplicated 
Diarrheaa
Grade 3 or 4
OR
Any 
Complicated 
Diarrheab

Clinical evaluation mandatory; rule out bowel 
perforation

Consider consultation with Gastroenterologist 
and confirmation biopsy with endoscopy

Loperamidec: initially 4 mg, followed by 2 mg 
every four hours or after every unformed stool; 
maximum 16 mg/day. Continue until diarrhea 
free for 12 hours

Hydration:
intravenous fluids if clinically 
indicated

Antibiotics (oral or intravenous) if clinically 
indicated

Intervention should be continued until the 
subject is diarrhea free for ≥ 24 hours

In addition to symptomatic treatment and 
hydration, immediate treatment with intravenous 
steroids (methylprednisolone 125 mg) followed 
by high dose oral steroids (prednisone 1 to 2 
mg/kg once per day or dexamethasone 4 mg 
every 4 hours) is recommended.  When 
symptoms improve to ≤Grade 1, steroid taper 
should be started and continued over no less 
than 4 weeks.  Taper over 6 to 8 weeks in 
subjects with diffuse and severe ulceration 
and/or bleeding.

If IV steroids followed by high dose oral 
steroids do not reduce initial symptoms within 
48 to 72 hours, consider alternative treatment.  
Discontinue 
alternative 
treatment
upon 
symptom relief and initiate a prolonged steroid 
taper over 45 to 60 days. If symptoms worsen 
during steroid reduction, initiate a re-tapering of 
steroids starting at a higher dose of 80 or 100 
mg followed by a more prolonged taper and 
administer infliximab.  .

If symptoms persist despite the above treatment 
a surgical consult should be obtained.

Intervention may require hospitalization for 
subjects at risk of life-threatening complications
Grade 3

Interrupt all study treatment until diarrhea 
resolves to grade  ≤1

pembrolizumab
may be restarted after 
diarrhea resolves to grade ≤1 and steroid 
taper (if initiated) is completed

Restart 
dabrafenib 
and/or 
trametinib
reduced by one dose leveld

If dabrafenib and/or trametinib was 
already 
dose 
reduced 
twice, 
permanently 
discontinue 
dabrafenib and/or trametinib.
Grade 4

Permanently discontinue pembrolizumab

Follow Grade 3 rules for dabrafenib and/or 
trametinib.
Abbreviation:  CTCAE = Common Terminology Criteria for Adverse Events
a.
Uncomplicated diarrhea defined by the absence of  symptoms such as, cramping, nausea/vomiting ≥grade 2, decreased 
performance status, pyrexia, sepsis, neutropenia grade ≥3, frank bleeding, and/or dehydration requiring intravenous fluid 
substitution
b.
Complicated diarrhea defined by the presence of symptoms such as, cramping, nausea/vomiting ≥grade 2, decreased 
performance status, pyrexia, sepsis, neutropenia grade ≥3, frank bleeding, and/or dehydration requiring intravenous fluid 
substitution
c.
Loperamide should be made available prior to start of study treatment so loperamide administration can begin at the first signs of 
diarrhea
d.
Escalation of study treatment to previous dose level is allowed after consultation with the Sponsor and in the absence of another 
episode of complicated or severe diarrhea in the 4 weeks subsequent to dose reduction.
5.6.1.1.6
Endocrine Events
Subjects should be carefully monitored for signs and symptoms of endocrine events (such as 
adrenal insufficiency, hypophysitis, hyperthyroidism, hypothyroidism). If symptoms (such 
as hypotension or arrhythmia) indicate possible new or worsening cardiac abnormalities, 
additional testing and/or a cardiology consultation should be considered.  All attempts should 
be made to rule out other causes such as brain metastases, sepsis and/or infection.  An 
endocrinology consultation is recommended.
 
 
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Thyroid disorders can occur at any time during treatment. Monitor patients for changes in 
thyroid function (at the start of treatment, periodically during treatment, and as indicated 
based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders.
Guidelines regarding management and dose reduction for endocrine events considered to be 
related to study treatment by the investigator are provided in Table 10 and Table 19.
For Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or >
Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic acidosis (DKA)

Insulin replacement therapy is recommended for Type 1 diabetes mellitus and for 
Grade 3-4 hyperglycemia associated with metabolic acidosis or ketonuria.

Evaluate patients with serum glucose and a metabolic panel, urine ketones, 
glycosylated hemoglobin, and C-peptide.
 
 
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Table 19
Management and Dose Modification Guidelines for Endocrine AEs
CTCAE Grade
Adverse Event Management
Action and Dose Modification
Grade 1 or 2

Monitor thyroid function or other hormonal 
level 
tests 
and 
serum 
chemistries 
more 
frequently until returned to baseline values

If 
hypophysitis
or 
other 
symptomatic 
endocrinopathy 
(other 
than 
hypo-
or 
hyperthyroidism) is considered, pituitary gland 
imaging should be considered (MRIs with 
gadolinium and selective cuts of the pituitary 
can show enlargement or heterogeneity and 
confirm the diagnosis).

For Grade 2 hypophysitis or other symptomatic 
endocrinopathy 
other 
than 
hypo-
or 
hyperthyroidism, treat with prednisone 40 mg 
p.o. or equivalent per day.  When symptoms 
improve to grade 1 or less, initiate steroid taper 
over no less than 4 weeks.  Replacement of 
appropriate hormones may be required as the 
steroid dose is tapered.

Thyroid hormone and/or steroid replacement 
therapy to manage adrenal insufficiency.

In hyperthyroidism, non-selective beta-blockers 
(e.g. propranolol) are suggested as initial 
therapy. 

In 
hypothyroidism, 
thyroid 
hormone 
replacement therapy, with levothyroxine or 
liothyronine, is indicated per standard of care. 

Consultation with an endocrinologist may be 
considered.

Continue study treatment

Interrupt pembrolizumab for Grade 2 events 
other 
than hypo-
or 
hyperthyroidism 
(treatment 
may 
be 
continued 
while 
treatment for ≤Grade 2 thyroid disorder is 
initiated)
Symptomatic pan-
hypopituitarism 
OR
Grade 3-4

Consider Endocrinology consultation

Rule out infection and sepsis with appropriate 
cultures and imaging.

Treat with an initial dose of methylprednisolone 
1 to 2 mg/kg intravenously followed by oral 
prednisone 1 to 2 mg/kg per day.  When 
symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no
less than 4 weeks. Replacement of appropriate 
hormones may be required as the steroid dose is 
tapered. 

Hypophysitis with clinically significant adrenal 
insufficiency and hypotension, dehydration, and 
electrolyte abnormalities (such as hyponatremia 
and hyperkalemia) constitutes adrenal crisis. 
Hospitalization, endocrine consultation, and
intravenous 
methylprednisolone 
should 
be 
initiated.

Interrupt pembrolizumab until AE resolves 
to grade  ≤1

Restart pembrolizumab.

If 2 interruptions of pembrolizumab are 
clinically 
indicated, 
permanently 
discontinue study pembrolizumab

NOTE: 
Interrupt 
or 
permanently 
discontinue 
pembrolizumab
is 
at 
the 
discretion of the investigator or treating 
physician.

NOTE: pembrolizumab may be continued 
for Grade 3-4 hypothyroidism if thyroid 
replacement is initiated.
Abbreviation:  CTCAE = Common Terminology Criteria for Adverse Events
Note: Hyperglycemia (≥Grade 3) requiring an increase in the dose of, or initiation of insulin or oral therapy can occur with dabrafenib. 
Monitor serum glucose levels as clinically appropriate during treatment with dabrafenib in subjects with pre-existing diabetes or 
hyperglycemia. Advise patients to report symptoms of severe hyperglycemia such as excessive thirst or any increase in the 
volume or frequency of urination.
 
 
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5.6.1.1.7
Vision Changes
Subjects should be carefully monitored for signs and symptoms of vision changes (such as 
uveitis, iritis, retinal pigment epithelial detachment [RPED], and Retinal Vein Occlusion 
[RVO]). Symptoms may include (but not limited to):  blurred vision, diffuse erythema and a 
prominent blush on the sclerae, dryness of the eyes, pain, or photophobia.  All attempts 
should be made to rule out other causes such as metastatic disease, infection or other ocular 
disease (e.g. glaucoma or cataracts).
Episodes of visual changes have been observed in subjects receiving dabrafenib, trametinib 
or the combination of both therapies, as well as in subjects receiving pembrolizumab.  In 
addition, ocular AEs are known to be related to trametinib. The causal relationship between 
a change in vision and the study treatment should be carefully explored and an 
ophthalmologist should be consulted.  However, if the visual changes are clearly unrelated to 
study treatment (e.g., allergic conjunctivitis), then close monitoring is acceptable and it may 
be reasonable to defer ophthalmic examination. Special attention should be given to retinal 
(e.g., RPED) or retinovascular abnormalities (e.g., branch or central RVO). For events of 
visual changes regardless of severity for which an ophthalmic examination is conducted, a 
blood sample for PK analysis must be drawn as close as possible to the time of the event.
Guidelines regarding management and dose reduction for visual changes and/or ophthalmic 
examination findings considered to be related to study treatment are provided in Table 20.
Management guidelines for Retinal Pigment Epithelial Detachment (RPED) are provided 
separately in Table 21.
 
 
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Table 20
Management and Dose Modification Guidelines for Visual Changes and/or 
Ophthalmic Examination Findings
CTCAE 
Gradea
Adverse Event Management
Action and Dose Modification
Grade 1

Consult ophthalmologist within 7 days of onset 
(preferably prior to next dose of pembrolizumab)

Treat with topical steroids such as 1% prednisolone 
acetate suspension and iridocyclitics as appropriate.

If dilated fundoscopic
examination cannot be 
performed within 7 days of onset, interrupt 
trametinib until RPED and RVO can be excluded by 
retinal specialist/ophthalmologist.  

If RPED and RVO excluded, continue (or restart) 
trametinib at same dose level

If RPED suspected or diagnosed: see RPED dose 
modification table below; report as SAE.

If RVO diagnosed:  Permanently discontinue 
trametinib and report as SAE.  Uveitis: Interrupt 
pembrolizumab and consider interrupting dabrafenib
until symptoms resolve and exam shows resolution

Non-RPED/RVO: Discontinue pembrolizumab if 
symptoms persist despite treatment with topical and 
systemic immunosuppressive therapy.
Grade 2 
and
Grade 3

Consult ophthalmologist immediately

Treat with topical steroids such as 1% prednisolone 
acetate suspension and iridocyclitics as appropriate.

For Grade 3 visual changes, consider treatment with 
systemic corticosteroids such as prednisone at a dose of 
1 to 2 mg/kg per day as appropriate.  When symptoms 
improve to ≤Grade 1, steroid taper should be started and 
continued over no less than 4 weeks.

Interrupt pembrolizumab and trametinib until signs 
and symptoms resolve to baseline

If RPED and RVO excluded, restart trametinib at 
same dose level

If RPED diagnosed, see RPED dose modification 
table below; report as SAE.

If RVO diagnosed:
Permanently discontinue 
trametinib and report as SAE

Non-RPED/RVO: Discontinue pembrolizumab if 
symptoms persist despite treatment with topical and 
systemic immunosuppressive therapy.

Uveitis: Interrupt pembrolizumab and dabrafenib, 
treat with topical steroids until symptoms resolve 
and exam shows resolution
Grade 4

Consult ophthalmologist immediately

Report as SAE

Management as per Grade 3 above

Interrupt trametinib

Permanently discontinue pembrolizumab

If RPED and RVO excluded, may consider 
restarting trametinib at same or reduced dose after 
discussion with study medical monitor 

If RVO or RPED diagnosed, permanently 
discontinue trametinib
Abbreviations:  RPED = Retinal Pigment Epithelial Detachment; CTCAE = Common Terminology Criteria for Adverse Events; 
RVO = retinal vein occlusion; SAE = serious adverse event
a.     Refers to CTCAE Version 4.0 ‘Eye disorders – Other, specify
 
 
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Table 21
Recommended Dose Modifications for Trametinib for Retinal Pigment 
Epithelial Detachments (RPED)
CTCAE Grade
Action and Dose Modification
Grade 1 RPEDa (Asymptomatic; clinical 
or
diagnostic observations only)

Continue 
treatment 
with 
retinal 
evaluation monthly until resolution. If 
RPED worsens follow instructions below
Grade 2-3 RPEDa (Symptomatic with
mild to moderate decrease in visual 
acuity; limiting instrumental ADL)

Interrupt trametinib 

Retinal evaluation monthly 

If improved to ≤ Grade 1, restart 
trametinib at lower dose (reduced by 0.5 
mg) or discontinue in patients taking 
trametinib 1 mg daily
a) Refers to CTCAE Version 4.0 ‘Retinopathy’
5.6.1.1.8
Pneumonitis
Subjects should be carefully monitored for signs and symptoms of pneumonitis, interstitial 
lung disease, or acute interstitial pneumonitis.  If symptoms (such as chest pain and/or 
tightness or dyspnea) indicate possible new or worsening cardiac abnormalities, additional 
testing and/or a cardiology consultation should be considered.  All attempts should be made 
to rule out other causes such as metastatic disease, bacterial or viral infection. 
Pneumonitis has been observed in subjects receiving trametinib, as well as in subjects 
receiving pembrolizumab. To reduce the risk of pneumonitis, subjects will be monitored 
closely for symptoms, evaluated with imaging and functional tests. Dose modification and 
supportive care guidelines for pneumonitis are described in Table 10 and Table 22.
It is important that patients with a suspected diagnosis of pneumonitis be managed as 
per the guidance below until treatment-related pneumonitis is excluded.  Treatment of 
both a potential infectious etiology and pneumonitis in parallel may be warranted.  
Management of the treatment of suspected pneumonitis with steroid treatment should 
not be delayed for a therapeutic trial of antibiotics.  If an alternative diagnosis is 
established, the patient does not require management as below; however the AE should 
be reported regardless of etiology.
 
 
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Table 22
Management and Dose Modification Guidelines for Pneumonitis
CTCAE Grade
Adverse Event Management
Action and Dose Modification
Grade 1

CT 
scan 
(high-resolution 
with 
lung 
windows) 
recommended, with serial imaging to monitor for 
resolution or progression

Clinical evaluation and laboratory work-up for 
infection

Monitoring 
of 
oxygenation 
via 
pulse-oximetry 
recommended 

Consultation of pulmonologist recommended

Continue study treatment at current dose
Grade 2

CT scan (high-resolution with lung windows)

Consider frequent Chest X-ray for monitoring

Clinical evaluation and laboratory work-up for 
infection

Consult pulmonologist, consider Infectious Disease 
consultation

Conduct in-person evaluation approximately twice per 
week

Bronchoscopy with biopsy and/or BAL recommended

Treat with systemic corticosteroids at a dose of 1 to 2 
mg/kg/day prednisone or equivalent.  

When symptoms improve to Grade 1 or less, steroid 
taper (if systemic corticosteroids initiated) should be 
started and continued over no less than 4 weeks.

Interrupt study all treatment until recovery to 
grade ≤1

Treatment with pembrolizumab
may be 
resumed if the event improves to ≤ Grade 1 
within 12 weeks and corticosteroids have been 
reduced 
to 
the 
equivalent 
of 
methylprednisolone 10 mg PO daily or less.  
Repeat chest imaging monthly as clinically 
indicated.

Treatment with dabrafenib and trametinib at 
one dose level reduction may be resumed if the 
event improves to ≤  Grade 1 within 4 weeks; 
escalation to previous dose level after 4 weeks 
may be possible after discussion with sponsor

If no recovery to grade ≤1 within 4 weeks or 
second episode of
Grade 2 or higher
pneumonitis on re-challenge, permanently 
discontinue all study treatment
Grade 3

Hospitalize patient

CT scan (high-resolution with lung windows)

Clinical evaluation and laboratory work-up for 
infection

Consult pulmonologist

Bronchoscopy with biopsy and/or BAL if possible

Immediate 
treatment
with 
intravenous 
steroids 
(methylprednisolone 
125 
mg). 
When 
symptoms 
improve to ≤ Grade 1, a high dose oral steroid 
(prednisone 1
to 2 mg/kg once per day or 
dexamethasone 4 mg every 4 hours) taper should be 
started and continued over no less than 4 weeks.

If IV steroids followed by high dose oral steroids does 
not reduce initial symptoms within 48 to 72 hours, 
consider alternate therapy (treat with additional anti-
inflammatory measures). Discontinue alternate therapy 
upon symptom relief and initiate a prolonged steroid 
taper over 45 to 60 days. If symptoms worsening 
during steroid reduction, initiate a retapering of steroids 
starting at a higher dose of 80 or 100 mg followed by a 
more prolonged taper and consider alternate therapy as 
needed.

Permanently discontinue pembrolizumab

Interrupt dabrafenib and trametinib until 
recovery to ≤ Grade 1

After consultation with Sponsor, dabrafenib
and trametinib may be restarted reduced by 
one dose level

If no recovery to grade ≤1 within 4 weeks, 
permanently discontinue dabrafenib and 
trametinib
Grade 4

Same as grade 3

Permanently 
discontinue 
all 
study 
treatment
Abbreviations:  BAL= bronchoalveolar lavage; CT = computed tomography; CTCAE = Common Terminology Criteria for Adverse Events
5.6.1.1.9
Renal Events
Subjects should be carefully monitored for signs and symptoms of renal insufficiency (such 
as nephritis, renal failure, or creatinine elevations).  All attempts should be made to rule out 
 
 
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other causes such as obstructive uropathy, progression of disease, or injury to other 
chemotherapy agents.  A renal consultation is recommended.
Cases of renal insufficiency have occurred in subjects receiving dabrafenib and the 
combination of dabrafenib and trametinib, as well as in subjects receiving pembrolizumab.  
Prior to start of study treatment, concomitant medications should be reviewed for the 
potential risk of inducing nephrotoxicity and concomitant medications should be modified if 
clinically possible. 
Guidelines regarding management and dose reduction for renal insufficiency considered to 
be related to study treatment by the investigator are provided in Table 10 and Table 23.
Table 23
Management and Dose Modification Guidelines for Renal Insufficiency
Serum Creatinine Level
Adverse Event Management
Action and Dose Modification
Serum 
creatinine 
increase 
>0.2 mg/dL (18 umol/L)
but
0.5 mg/dL (44 umol/L) above 
baseline

Recheck serum creatinine within 1 week

Serum creatinine increase > 1 week: 
contact Sponsor

For Grade 2 creatinine elevations, treat 
with prednisone 1-2 mg/kg p.o. daily 
(when symptoms improve to Grade 1 or 
less, steroid taper should be started and 
continued over no less than 4 weeks)

If pyrexia is present, treat pyrexia as per 
guidelinesa

Continue study treatment at the same 
dose level

For Grade 2 creatinine elevations, 
interrupt pembrolizumab
Serum creatinine increase >0.5 
mg/dL 
(44 
umol/L) 
above 
baseline 
or 
serum creatinine >2 mg/dL (> 
177 umol/L)

Monitor serum creatinine ≥ 2-times per 
week 

Hospitalization may be necessary
if 
serum creatinine cannot be monitored 
frequently

If pyrexia is present, treat pyrexia per 
guidelinesa

Consult 
nephrologist 
if 
clinically 
indicated

Perform ultrasound and/or renal biopsy if 
clinically indicated, for example:
1.
Renal insufficiency persists despite 
volume repletion
2.
Subject has new rash or signs of 
hypersensitivity (such as elevated 
eosinophil count)

For ≥Grade 3 creatinine elevations, treat
with systemic corticosteroids at a dose of 
1 to 2 mg/kg prednisone or equivalent 
once per day.  

When symptoms improve to Grade 1 or 
less, steroid taper should be started and 
continued over no less than 4 weeks.

Interrupt study treatment until serum 
creatinine recovers to baseline

Restart study treatmentb

For Grade 3-4 creatinine elevations, 
permanently 
discontinue 
pembrolizumab
Abbreviations:  NSAIDS = non-steroidal anti-inflammatory drugs
a.
NSAIDs can induce renal insufficiency, especially in subjects with dehydration; encourage oral fluids or consider intravenous
fluids as clinically indicated. See guidelines for pyrexia.
b.
Investigator may restart at either the same (pembrolizumab, dabrafenib and/or trametinib) or a reduced dose level (dabrafenib 
and/or trametinib).  Escalation of study treatment to previous dose level is allowed if another episode of renal insufficiency does 
not occur after 4 weeks of dose reduction.  Consultation with Sponsor is required before restarting study treatment if there is 
evidence of thrombotic microangiopathy.
 
 
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5.6.1.1.10
Skin Events
Subjects should be carefully monitored for signs and symptoms of skin AEs, such as pruritis 
or rash.  All attempts should be made to rule out other causes such as metastatic disease, 
infection or allergic dermatitis.
Rash
Rash is a frequent AE observed in subjects receiving trametinib, dabrafenib, or the 
combination of both therapies, as well as in subjects receiving pembrolizumab. Guidelines 
for rash management are based on experience with other MEK inhibitors and EGFR 
inhibitors [96, 97] and are provided below (Table 24 and Table 25).
Table 24
Guidelines for Supportive Care of Rash
Type of Care
Action
Prevention/Prophylaxis:
Start from Day 1

Avoid unnecessary exposure to sunlight
Apply broad-spectrum sunscreen (containing titanium dioxide or zinc 
oxide) with a skin protection factor (SPF) ≥15 at least twice daily.  
Sunscreen should be used during the day when exposed to the sun; 
emollient cream should be used at night or when not being exposed to 
the sun. Sunscreens should not be applied concomitantly with 
moisturizers such as emollient cream.

Use thick, alcohol-free emollient cream (eg, glycerine and 
cetomacrogol cream) on dry areas of the body at least twice daily.
Symptomatic Care 
(rash):
Start from Day 1 of rash 
and implement for a total 
of 6 weeks

Topical steroids and antibiotics should be applied once daily and more 
often as needed from Day 1.  

Use mild-strength topical steroid (hydrocortisone 1% cream) 
and

topical antibiotic (eg, clindamycin) or oral antibiotics (eg, doxycycline 
100 mg BID, minocycline 100 mg BID)
Symptomatic Care
(other) a

Pruritic lesions: cool compresses and oral antihistamine therapies 

Fissuring lesions: Monsel’s solution, silver nitrate, or zinc oxide cream 

Desquamation: thick emollients and mild soap 

Paronychia: antiseptic bath, local potent corticosteroids in addition to 
oral antibiotics; if no improvement, consult dermatologist or surgeon 

Infected lesions: appropriate bacterial/fungal culture-driven systemic or 
topical antibiotics 
Abbreviations:  BID = twice daily; SPF = sun protection factor
a.
Subjects who develop rash/skin toxicities should be seen by a qualified physician and should receive 
evaluation for symptomatic/supportive care management 
Immediate Evaluation for Potential Skin ECIs
A. Photographs: 
Every attempt should be made to get a photograph of the actual skin lesion or rash as soon as 
possible. Obtain appropriate consent for subject photographs if a consent form addendum is 
required by your IRB/ERC. 
 
 
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–
Take digital photographs of: 
o
the head (to assess mucosal or eye involvement), 
o
the trunk and extremities, and 
o
a close-up of the skin lesion/rash. 
–
If possible, a ruler should be placed alongside the site of a skin occurrence as a fixed 
marker of distance. 
–
The time/date stamp should be set in the 'ON' position for documentation purposes. 
–
Photographs should be stored with the subject’s study records. 
–
The Sponsor may request copies of photographs. The local study contact (e.g., CRA) 
will provide guidance to the site, if needed. 
B. Past Medical History: 
Collect past medical history relevant to the event, using the questions in Appendix 12.11
(Past Medical History Related to Dermatologic Event) as a guide. Any preexisting conditions
not previously reported (e.g., drug allergy) should be entered into the Medical History eCRF. 
C. Presentation of the Event: 
Collect information on clinical presentation and potential contributing factors using the 
questions in Appendix 12.12 (Presentation of the Dermatologic Event) as a guide. This
information should be summarized and entered in narrative format in the AE eCRF. Please 
use the available free-text fields, such as Signs and Symptoms. Note pertinent negatives 
where applicable to reflect that the information was collected. Any treatments administered 
should be entered on the Concomitant Medication eCRF. 
D. Vitals Signs and Standard Laboratory Tests: 
Measure vital signs (pulse, sitting BP, oral temperature, and respiratory rate) and record on 
the Vital Signs eCRF.  Perform standard laboratory tests (CBC with manual differential and 
serum chemistry panel, including LFTs). 
E. Focused Skin Examination: 
Perform a focused skin examination using the questions in Appendix 12.13 (Focused Skin 
Examination) as a guide. Information should be summarized and entered on the Adverse
Experience eCRF as part of the narrative. 
F. Dermatology Consult 
Refer the subject to a dermatologist as soon as possible. 
 
 
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–
For a “severe rash”, the subject must be seen within 1-2 days of reporting the event. 
–
For clinically significant rash, the subject should be seen within 3-5 days. 
The dermatologist should submit a biopsy sample to a certified dermatopathology laboratory 
or to a pathologist experienced in reviewing skin specimens. 
The site should provide the dermatologist with all relevant case history, including copies of 
clinical photographs and laboratory test results.
Guidelines for management and dose reduction for rash considered to be related to study 
treatment are provided in Table 25.
Table 25
Management and Dose Modification Guidelines for Rash
CTCAE Grade
Adverse Event Management
Action and Dose Modification (apply to both 
Dabrafenib and Trametinib for Part 3 and 
to Trametinib only for Part 4 and 5)
Grade 1

Initiate 
prophylactic 
and 
symptomatic 
treatment measures.

Consider use of topical glucocorticosteroids 
(eg, 
betamethasone 
0.1% 
cream 
or 
hydrocortisone 1%) or urea-containing creams 
in combination with oral antipruritics (eg, 
diphenhydramine HCl or hydroxyzine HCl) or 
moderate strength topical steroida 

Reassess after 2 weeks

If tolerable, continue study treatment at 
the same dose.

If intolerable despite best supportive 
care, 
reduce 
dabrafenib 
and/or
trametinib by one dose levelc
Grade 2

Initiate 
prophylactic 
and 
symptomatic 
treatment measures

Use moderate strength topical steroida

Reassess after 2 weeks

Treatment with oral steroids at the physician’s 
discretion

If tolerable, continue study treatment at 
the same dose. 

If intolerable despite best supportive 
care, 
reduce 
dabrafenib 
and/or 
trametinib by one dose level. If rash 
recovers to ≤Grade 1 within 2 weeks, 
resume dabrafenib and/or trametinib 
at previous dose level c

If intolerable despite dose reduction 
interrupt 
dabrafenib 
and/or 
trametinib until recovery to ≤Grade 1, 
then restart at the reduced dose b

Consider holding pembrolizumab
Grade 3

Use moderate strength topical steroidsa PLUS 
oral steroids (eg, methyl-prednisolone dose 
pack, 1 mg/kg prednisone or equivalent once 
per day, or dexamethasone 4 mg four times 
orally daily).  When symptoms improve to 
Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks.

Consult dermatologist, consider biopsy

Interrupt all study treatments until rash 
recovers to Grade ≤1

Restartb
pembrolizumab
(after 
appropriate steroid tapering) and reduce 
dabrafenib and/or trametinib by one 
dose levelc

If no recovery to Grade ≤2 within 4 
weeks, 
permanently 
discontinue 
dabrafenib and/or trametinib

Consider discontinuing pembrolizumab
Grade 4

Same as Grade 3

Permanently discontinue all study 
treatment
Abbreviations:  CTCAE = Common Terminology Criteria for Adverse Events.
a.     Moderate-strength topical steroids: hydrocortisone 2.5% cream or fluticasone propionate 0.5% cream
b.     Approval of Sponsor is required to restart study treatment after ≥21 days of interruption.
c.     Escalation of study treatment to previous dose level may be considered if either improvement of Grade 1 rash per investigators’ 
judgment or no rash is evident 4 weeks after dose reduction or after restarting study treatment.
 
 
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Hand-Foot Skin Reactions (HFSR)
Episodes of Hand-foot Skin Reaction (HFSR) have been observed in subjects receiving 
dabrafenib. Guidelines for management of HFSR are based on experience with other kinase 
inhibitors [98, 99].  
Lifestyle modification: avoidance of hot water, traumatic activity, constrictive footwear, or 
excessive friction on the skin and the use of thick cotton socks and gloves, and shoes with 
padded insoles
Symptomatic treatments: apply moisturizing creams frequently, topical keratolytics (e.g. 
urea 20-40 % cream, salicylic acid 6%, tazarotene 0.1% cream, fluorouracil 5% cream), 
clobetasol propionate 0.05% ointment for erythematous areas, topical lidocaine 2%, and / or 
systemic pain medication such as non-steroidal anti-inflammatory drugs, codeine, and 
pregabalin for pain.
Dose modification may also be required.  Refer to Table 24 for rash guidelines.
New Malignancies
Cutaneous squamous cell carcinoma and keratoacanthoma have been observed in subjects 
treated with dabrafenib and the combination of dabrafenib and trametinib (see dabrafenib and 
trametinib combination IB). These treatment-related cuSCC should be surgically removed 
according to institutional practice.  Dose modifications or interruptions of the study treatment 
are not required for cuSCC.  Occurrence of cuSCC must be reported as an SAE. 
New cutaneous and non-cutaneous malignancies that are reported to the Investigator should 
be reported as a SAE, excluding basal cell carcinoma.  A biopsy of the new malignancy 
should be taken, where possible, and submitted for further analyses.  Testing of these 
biopsies may include RAS mutation testing and analysis of proteins related to the action of 
dabrafenib.  Genomic alterations, which include but not limited to DNA, RNA and protein 
analysis of these biopsy specimens may be performed, and would be restricted to the analysis 
of pathway mutations known to be associated with, and relevant to, BRAF-mutant tumors or 
pathway activation.  Following discontinuation of dabrafenib, monitoring for non-cutaneous 
secondary/recurrent malignancies should continue every 3 months for up to 6 months or until 
initiation of another anti-neoplastic therapy.
Severe Cutaneous Adverse Reactions
Cases of Severe Cutaneous Adverse Reactions (SCARs), including Stevens-Johnson 
syndrome, and Drug Reaction with Eosinophilia and Systemic Symptoms, which can be life-
threatening or fatal, have been reported during treatment with dabrafenib in combination with 
trametinib. Before initiating treatment, subjects should be advised of the signs and symptoms 
and monitored closely for skin reactions. If signs and symptoms suggestive of SCARs 
appear, dabrafenib and trametinib should be permanently discontinued.
 
 
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5.6.1.1.11
Fever
Subjects should be carefully monitored for signs and symptoms of fever, chills, or pyrexia.  
All attempts should be made to rule out other causes such as metastatic disease,
hypersensitivity, bacterial or viral infection. 
Episodes of fever have been observed in subjects receiving dabrafenib monotherapy or in 
combination with trametinib (see dabrafenib and dabrafenib + trametinib combination IBs), 
as well as in subjects receiving pembrolizumab. In a minority of cases the fever which 
occurred with dabrafenib and trametinib was accompanied by symptoms such as severe 
chills, dehydration, hypotension, dizziness or weakness. 
Fever accompanied by hypotension, dehydration requiring IV fluids, renal insufficiency, or
severe (≥Grade 3) rigors/chills, in the absence of an obvious infectious cause should be 
reported as an SAE. 
Subjects should be instructed on the importance of immediately reporting febrile episodes.  
In the event of a fever, the subject should be instructed to take non-steroidal anti-pyretics as 
appropriate to control fever.  In subjects experiencing fever associated with rigors, severe 
chills, dehydration, hypotension, etc., renal function should be monitored carefully. 
Guidelines regarding management and dose reduction for fever considered to be related to 
study treatment are provided in Table 26.
Table 26
Management and Dose Modification Guidelines for Fever
Adverse 
Event
Adverse Event Management
Action and Dose Modification
Fevera
1st Eventb:

Clinical 
evaluation 
for 
infection 
and 
hypersensitivityc

Laboratory work-upc

Hydration as requiredd

Administer anti-pyretic treatment if clinically 
indicated and continue prophylactic treatment e,f
2nd Eventg

Clinical 
evaluation 
for 
infection 
and 
hypersensitivityc

Laboratory work-upc

Hydration as requiredd

Within 3 days of onset of fever
•        Optimize anti-pyretic therapye
1st Event: 

Interrupt dabrafenib

Continue 
trametinib 
and 
pembrolizumab

If fever does not resolve within 48 
hours, 
hold 
trametinib 
and 
pembrolizumab

Once fever resolves to baseline, restart 
study treatment at the same dose level
•  If fever was associated with 
dehydration, hypotension, or 
renal insufficiency, reduce 
dabrafenib by one dose level
2nd Event:

Interrupt dabrafenib

Continue 
trametinib 
and 
pembrolizumab

If fever does not resolve within 48 
hours, 
hold 
trametinib 
and 
pembrolizumab

Once fever resolves to baseline, restart 
study treatment at the same dose level
•        If fever was associated with 
dehydration, hypotension, or 
 
 
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Adverse 
Event
Adverse Event Management
Action and Dose Modification
Subsequent Events: 

Clinical 
evaluation 
for 
infection 
and 
hypersensitivityc

Laboratory work-upc

Hydration as requiredd

Within 3 days of onset of fever:
•        Consider oral corticosteroids (i.e., 
prednisone 10 mg) for at least 5 days or as 
clinically indicatedf
•       Optimize oral corticosteroid dose as 
clinically indicated for recalcitrant feverg
•        If corticosteroids have been tapered and 
fever recurs, restart steroids 
•        If corticosteroids cannot be tapered consult 
Sponsor
renal insufficiency, reduce 
dabrafenib by one dose level
Subsequent Events:

Interrupt 
dabrafenib 
and 
pembrolizumab

Continue trametinib

Once fever resolves to baseline, restart 
pembrolizumab at the same dose level, 
restart dabrafenib reduced by one 
dose levelg

If dabrafenib must be reduced to <75 
mg BID, permanently discontinue 
dabrafenib
a.
Fever is defined as a body temperature equal to or above 38.5 Celsius or 101.3○Fahrenheit. 
b.
For subjects experiencing fever complicated by rigors, severe chills, etc., a clinical evaluation and laboratory 
work-up is mandatory for each event; anti-pyretic treatment should be started immediately at the first occurrence 
and prophylactic anti-pyretic treatment is recommended.  For subjects experiencing rigors/chills without fever, 
work-up and supportive care, including interruption of study treatment, are recommended.
c.
Thorough clinical examination for signs and symptoms of infection or hypersensitivity is required; laboratory 
work-up should include full-blood-count, electrolytes, creatinine, BUN, CRP, liver-function tests, blood culture, 
and urine culture.
d.
Oral hydration should be encouraged in subjects without evidence of dehydration.  Intravenous hydration is 
recommended in subjects experiencing fever complicated by dehydration/hypotension.
e.
Anti-pyretic treatment may include ibuprofen, or suitable anti-pyretic medication according to institutional 
standards. Acetaminophen should be used with caution, especially in subjects with elevated liver enzymes.  
Prophylactic anti-pyretic treatment may be discontinued after three days in the absence of fever.
f.
In subject experiencing fever complicated by rigors, severe chills, etc., which cannot be controlled with anti-
pyretic medication, oral corticosteroids may be started at the 2nd event and doses should be gradually increased for 
subsequent events.
g.
Dabrafenib should be reduced by one dose level after three episodes of fever complicated by rigors, severe chills, 
etc., which cannot be managed by best supportive care and increasing doses of oral steroids.  Escalation of 
dabrafenib is allowed if no episode of fever is observed in the 4 weeks subsequent to dose reduction.
5.6.1.1.12
Cardiovascular Events
Cardiovascular adverse events have been seen in subjects receiving either dabrafenib, 
trametinib or both in combination.  See the IBs for additional information. Pembrolizumab
dose modification guidance and stopping criteria for myocarditis are provided in Table 10.
Left Ventricular Ejection Fraction (LVEF)
Decreases of the left-ventricular-ejection-fraction (LVEF) have been observed in subjects 
receiving trametinib monotherapy and in combination with dabrafenib. Therefore, ECHOs 
must be performed to assess cardiac ejection fraction in regular intervals as outlined in the 
protocol. All ECHOs will be collected.  
 
 
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Dose modification guidance and stopping criteria for LVEF decrease are provided in 
Table 27.
Table 27
Dose Modification Guidelines and Stopping Criteria for LVEF Decrease
Clinic
LVEF-drop (%) or
CTCAE grade
Action and Dose Modification
Asymptomatic
Absolute decrease of >10% in 
LVEF compared to baseline and
ejection 
fraction 
below 
the 
institution’s  LLN

Interrupt dabrafenib and trametinib and repeat 
ECHO within 2 weeksa

If the LVEF recovers within 4 weeks (defined 
as LVEF ≥LLN and absolute decrease ≤10% 
compared to baseline) 
•       Consult with the Sponsor and request 
approval for restart 
•       Restart treatment with trametinib reduced 
by one dose level
•       Restart dabrafenib at previous dose levelb
•       Repeat ECHO 2, 4, 8 and 12 weeks after 
re-start; continue in intervals of 12 weeks 
thereafter

If LVEF does not recover within 4 weeks
•       Consult with cardiologist
•       Permanently discontinue trametinib
•       Repeat ECHO after 2, 4, 8, 12, and 16 
weeks or until resolution
•       Consult with Sponsord
Symptomaticc
Grade 3: resting LVEF 39-20% 
or >20% absolute reduction 
from baseline

Permanently discontinue trametinib

Discontinue dabrafenib

Report as SAE

Consult with cardiologist

Repeat ECHO after 2, 4, 8, 12, and 16 weeks 
or until resolutione

Consult with Sponsorc
Grade 4: resting LVEF <20%
Abbreviations:  CTCAE = Common Terminology Criteria for Adverse Events; ECHO = echocardiogram; 
LLN = lower limit of normal; LVEF = left ventricular ejection fraction; 
a.
If ECHO does not show LVEF recovery after 2 weeks, repeat ECHO 2 weeks later.
b.
If recurrent episodes of LVEF reduction occur with dabrafenib treatment, consult medical monitor.
c.
Symptoms may include: dyspnea, orthopnea, and other signs and symptoms of pulmonary congestion 
and edema.
d.
Once LVEF recovers, restarting dabrafenib can be considered in consultation with Sponsor. 
e.
Once LVEF recovers, including resolution of symptoms, restart of dabrafenib only, can be considered 
in consultation with Sponsor.
5.6.1.1.13
Hypertension
Increases in blood pressure have been observed in subjects receiving trametinib.
 
 
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Monitoring of Hypertension
All blood pressure assessments should be performed under the following optimal conditions:
1. the subject has been seated with back support, ensuring that legs are uncrossed and 
flat on the floor
2. the subject is relaxed comfortably for at least 5 minutes
3. restrictive clothing has been removed from the cuff area and the right cuff size has 
been selected
4. the subjects arm is supported so that the middle of the cuff is at heart level
5. the subject remains quiet during the measurement. 
In subjects with an initial blood pressure reading within the hypertensive range, a second 
reading should be taken at least 1 minute later, with the 2 readings averaged to obtain a final 
blood pressure measurement.  The averaged value should be recorded in the eCRF.
Persistent hypertension is defined as an increase of systolic blood pressure (SBP) > 140 mm 
Hg and/or diastolic blood pressure (DBP) > 90 mm Hg in three consecutive visits with blood 
pressure assessments from two readings collected as described above.  Visits to monitor 
increased blood pressure can be scheduled independently from the per-protocol visits 
outlined in Study Procedures.  Ideally, subsequent blood pressure assessments should be 
performed within one week. 
Asymptomatic hypertension is defined as an increase of SBP >140 mm Hg and/or DBP >90 
mm Hg in the absence of headache, light-headedness, vertigo, tinnitus, episodes of fainting 
or other symptoms indicative of hypertension.
Management of Hypertension
For subjects experiencing an increase in systolic and/or diastolic blood pressure that is 
persistent and may be associated with the study treatment, recommendations for the clinical 
management of hypertension are described in Table 28.
 
 
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Table 28
Management and Dose Modification Guidelines for Hypertension
Hypertension
Action and Dose Modification
(Scenario A)

Asymptomatic and persistenta SBP of ≥140 and 
<160 mmHg, or DBP ≥90 and <100 mmHg, 
or 

Clinically significant increase in DBP of 20 mmHg 
(but still below 100 mmHg).

Continue study treatment at the current dose 

Adjust 
current 
or 
initiate 
new 
antihypertensive medication

Titrate antihypertensive medication(s) during 
the next 2 weeks as indicated to achieve well-
controlledb BP

If BP is not well controlled within 2 weeks, 
consider referral to a specialist and go to 
scenario (B).
(Scenario B)

Asymptomatic 
SBP 
≥160 
mmHg, 
or 
DBP 
≥100 mmHg, 

or 

Failure to achieve well-controlled BP within 2 
weeks in Scenario A

Interrupt 
dabrafenib 
and 
trametinib
if 
clinically indicated

Adjust 
current 
or 
initiate 
new 
antihypertensive medication(s)

Titrate antihypertensive medication(s) during 
the next 2 weeks as indicated to achieve well-
controlled BP

Once BP is well controlledb, restart study 
treatment reduced by one dose level
(Scenario C)

Symptomaticc hypertension 
or 

Persistent SBP ≥160 mmHg, or DBP ≥100 mmHg, 
despite antihypertensive medication and dose 
reduction of study treatment

Interrupt dabrafenib and trametinib

Adjust 
current 
or 
initiate 
new 
antihypertensive medication(s)

Titrate antihypertensive medication during 
the next 2 weeks as indicated to achieve well-
controlled BP

Referral to a specialist for further evaluation 
and follow-up is recommended

Once BP is well controlled, restart study 
treatment reduced by one dose level
(Scenario D)

Refractory hypertension unresponsive to above 
interventions or hypertensive crisis.

Permanently discontinue dabrafenib and 
trametinib

Continue follow-up per protocol.
Abbreviations:  BP = blood pressure; DBP = diastolic blood pressure; mmHg = millimetres mercury; SBP = 
systolic blood pressure;
a.
Hypertension detected in two separate readings during up to three consecutive visits
b.
Well-controlled blood pressure defined as SBP ≤140 mm Hg and DBP ≤90 mm Hg in two separate 
readings during up to three consecutive visits.
c.
Symptomatic hypertension defined as hypertension aggravated by symptoms (e.g., headache, light-
headedness, vertigo, tinnitus, episodes of fainting) that resolve after the blood pressure is controlled within 
the normal range.
5.6.1.1.14
Prolonged QTc
Guidelines for dose modification and stopping criteria due to QTC-prolongation are provided 
in Table 29. 
 
 
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Table 29
Withholding and Stopping Criteria for QTc-Prolongation
QTc-Prolongationa
Action and Dose Modification

QTcB ≥501 msec, OR

uncorrected QT>600 msec, OR

QTcB>530 msec for subjects with 
bundle branch block

Interrupt 
dabrafenib 
and 
trametinib
until 
QTcB 
prolongation resolves to grade 1 or baseline

Test serum potassium, calcium, phosphorus, and 
magnesium.  If <LLN correct with supplements to within 
normal limits

Review concomitant medication usage for a prolonged 
QTc

If event resolves, restart dabrafenib and trametinib at 
current dose levelb

If event does not resolve, permanently discontinue 
study treatment

If event recurs, permanently discontinue study 
treatment
Abbreviations:  msec = milliseconds; QTcB = QT interval on electrocardiogram corrected using the Bazett’s 
formula
a.
Based on average QTc value of triplicate ECGs.  For example, if an ECG demonstrates a prolonged QT 
interval, obtain two or more ECGs over a brief period, and then use the averaged QTc values of the three 
ECGs to determine if study treatments should be interrupted or discontinued.
If the QTc prolongation resolves to grade 1 or baseline, the subject may resume dabrafenib and/or 
trametinib if the investigator and Sponsor agree that the subject will benefit from further treatment.
b.
If the QTc prolongation resolves to grade 1 or baseline, the subject may resume dabrafenib and/or 
trametinib if the investigator and Sponsor agree that the subject will benefit from further treatment.
5.6.1.1.15
Hepatic Laboratory Abnormalities
The following AE terms, if considered ≥ Grade 2 or if requiring dose modification or use of 
systemic corticosteroids for treatment of the AE, are considered ECIs and should be reported 
to the Sponsor within 24 hours of the event:  
–
Hepatitis 
–
Hepatitis, Autoimmune
–
Transaminase elevations
–
Bilirubin abnormalities
–
Any increase in Liver Function Tests (LFTs) ≥ grade 3 or any increase from grade 0 
to grade 2
Subjects should be carefully monitored for signs and symptoms of elevations in AST, ALT, 
total bilirubin, fever, malaise and/or upper quadrant abdominal pain.  All attempts should be 
made to rule out other causes such as metastatic disease, progressive liver disease, viral 
hepatitis, alternative drug toxicity, infectious causes and/or myositis.
 
 
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Drug Induced Liver Injury (DILI)
In addition, the event must be reported as a Drug Induced Liver Injury (DILI) ECI, if the 
patient meets the laboratory criteria for potential DILI defined as:

An elevated alanine transaminase (ALT) or aspartate transaminase (AST) lab value 
that is greater than or equal to three times (3X) the upper limit of normal (ULN) and 

An elevated total bilirubin lab value that is greater than or equal to two times (2X) 
ULN and

At the same time, an alkaline phosphatase (ALP) lab value that is less than 2X ULN, 

As a result of within-protocol-specific testing or unscheduled testing.
Note that any hepatic immune ECI meeting DILI criteria should only be reported once as a 
DILI event. Dose modification guidance and stopping criteria for hepatic laboratory 
abnormalities are provided in Table 10 (for pembrolizumab) and Table 30 (all study drugs).
Table 30
Management and Dose Modification Guidelines for Hepatic Laboratory 
Abnormalities
Event
Adverse Event Management
Action and Dose Modification
AST or ALT > 5.0x ULN

Monitor hepatic laboratory tests more 
frequently until returned to baseline 
values (consider weekly)

For Grade 2 AST, ALT, or bilirubin 
elevations, treat with 0.5-1 mg/kg/day 
methylprednisolone or oral equivalent 
and when LFT returns to grade 1 or 
baseline, taper steroids over at least 1 
month, 
consider 
prophylactic 
antibiotics 
for 
opportunistic 
infections 

Hold 
pembrolizumab
when 
AST or ALT >3.0x to 5.0x 
ULN and/or total bilirubin 
>1.5x to 3.0x ULN

Resume pembrolizumab when 
LFT returns to ≤Grade 1 or 
baseline 

Permanently 
discontinue 
pembrolizumab for patients 
with liver metastasis who 
begin treatment with Grade 
2 elevation of AST or ALT, 
and AST or ALT increases 
≥50% relative to baseline and 
lasts ≥1 week
 
 
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Event
Adverse Event Management
Action and Dose Modification
AST or ALT >5.0xULN to 
8.0xULN without bilirubin 
elevation (defined as total 
bilirubina
2.0xULN, 
or 
direct bilirubin 35%)

Consider appropriate consultation and 
liver biopsy to establish etiology of 
hepatic injury, if necessary

Treat
with high-dose intravenous 
glucocorticosteroids for 24 to 48 
hours.  When symptoms improve to 
Grade 1 or less, a steroid taper with 
dexamethasone 4 mg every 4 hours or 
prednisone at 1 to 2 mg/kg should be 
started and continued over no less 
than 4 weeks. 

If serum transaminase levels do not 
decrease 48 hours after initiation of 
systemic steroids, oral mycophenolate 
mofetil 500 mg every 12 hours may 
be 
given. 
Infliximab 
is 
not 
recommended due to its potential for 
hepatotoxicity.

Several courses of steroid tapering 
may be necessary as symptoms may 
worsen when the steroid dose is 
decreased.

Discontinue pembrolizumab
if AST/ALT >5.0x ULN 
and/or 
total 
bilirubin 
>3.0xULN

Hold 
dabrafenib, 
and/or
trametinib if (any criteria are 
met):  
- AST/ALT >5.0x ULN
- AST/ALT >3x ULN AND
total 
bilirubin 
>2x 
ULN
- Total bilirubin > 3x ULN

Interrupt
dabrafenib 
and/or 
trametinib until recovery to 
Grade ≤1

After 
consultation 
with 
Sponsor, dabrafenib and/or 
trametinib may be restarted
reduced by one dose level

If no recovery to grade ≤1 
within 
2 
weeks, 
permanently 
discontinue 
study treatment
AST or ALT >3.0 x ULN 
with concomitant elevation 
in bilirubin (defined as total 
bilirubina 2.0 x ULN with 
direct bilirubin >35%)  OR 
meeting any liver chemistry 
stopping 
criteria 
(see 
5.6.1.1.15.1)

Same as grade 3

Permanently discontinue all
study treatment
Abbreviations:  CTCAE = Common Terminology Criteria for Adverse Events
a. Serum bilirubin fractionation should be performed if testing is available.  If testing is unavailable and a 
subject meets the criterion of total bilirubin flix ULN, then the event should be promptly reported as an SAE.
Note: in the event of a drug-induced liver injury (DILI) adverse event (as outlined in the 
study protocol), please follow the DILI guidance outlined in the site Administrative Binder. 
Liver Chemistry Stopping Criteria 
These liver chemistry stopping and follow-up criteria have been designed to assure subject 
safety and evaluate liver event etiology in alignment with the FDA Guidance for Industry –
Drug-Induced Liver Injury: Premarketing Clinical Evaluation (July 2009, www.fda.gov).  
Liver chemistry stopping criteria 1-5 are defined as:
1. AST/ALT 
3xULN 
and bilirubin 
2xULN (>35% direct bilirubin) (or 
AST/ALT3xULN and INR>1.5, if INR measured)
 
 
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NOTE: If serum bilirubin fractionation is not immediately available, study treatment 
should be discontinued if AST/ALT 3xULN and bilirubin 2xULN. Serum 
bilirubin fractionation should be performed if testing is available.  If testing is 
unavailable, record presence of detectable urinary bilirubin on dipstick, indicating 
direct bilirubin elevations and suggesting liver injury.
2. AST/ALT 8xULN
3. AST/ALT 5xULN but <8 xULN persists for 2 weeks
4. AST/ALT 3xULN if associated with the appearance or worsening of symptoms of 
hepatitis or hypersensitivity such as fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, pyrexia, rash or eosinophilia.
5.
AST/ALT 5xULN but <8 xULN and cannot be monitored weekly for >2 weeks.
When any of the liver chemistry stopping criteria 1 - 5 is met, do the following:

Immediately discontinue subject from study treatment 

Report the event to Sponsor within 24 hours of learning its occurrence

Complete the liver event CRF and SAE data collection tool if the event also meets the 
criteria for an SAE  
•
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) (or 
ALT3xULN and INR>1.5, if INR measured; INR measurement is not required and 
the threshold value stated will not apply to subjects receiving anticoagulants), termed 
‘Hy’s Law’, must be reported as an SAE.
•
NOTE: if serum bilirubin fractionation is not immediately available, study treatment 
should be discontinued if ALT 3xULN and bilirubin 2xULN. Serum bilirubin 
fractionation should be performed if testing is available. If testing is unavailable, 
record presence of detectable urinary bilirubin on dipstick, indicating direct 
bilirubin elevations and suggesting liver injury

Complete the liver imaging and/or liver biopsy CRFs if these tests are performed

Perform liver event follow up assessments, and monitor the subject until liver 
chemistries resolve, stabilize, or return to baseline values as described below

Follow up for overall survival is required following discontinuation from study 
treatment. 

Do not rechallenge with study treatment.
 
 
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In addition, for subjects meeting liver stopping criterion 1: 

Make every reasonable attempt to have subjects return to clinic within 24 hours for 
repeat liver chemistries, liver event follow up assessments, and close monitoring

A specialist or hepatology consultation is recommended

Monitor subjects twice weekly until liver chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) resolve, stabilize or return to within baseline values.
For subjects meeting any of the liver stopping criteria 2 – 5:

Make every reasonable attempt to have subjects return to clinic within 24-72 hrs for 
repeat liver chemistries and liver event follow up assessments

Monitor subjects weekly until liver chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) resolve, stabilize or return to within baseline values; 

Subjects meeting criterion 5 should be monitored as frequently as possible.
Liver Event Follow-up Assessments
For subjects meeting any of the liver chemistry stopping criteria 1 – 5, make every attempt to 
carry out the liver event follow up assessments described below:

Viral hepatitis serology including:
•
Hepatitis A IgM antibody
•
Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM) 
•
Hepatitis C RNA 
•
Cytomegalovirus IgM antibody  
•
Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain heterophile 
antibody or monospot testing)  
•
Hepatitis E IgM antibody.

Blood sample for pharmacokinetic (PK) analysis, obtained within 10 days of last dose.  
Record the date/time of the PK blood sample draw and the date/time of the last dose of 
study treatment prior to blood sample draw on the CRF.  If the date or time of the last 
dose is unclear, provide the subject’s best approximation.  If the date/time of the last 
dose cannot be approximated OR a PK sample cannot be collected in the time period 
indicated above, do not obtain a PK sample.  Instructions for sample handling and 
shipping are in the SPM. 

Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH).
 
 
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
Fractionate bilirubin, if total bilirubin 2xULN.

Obtain complete blood count with differential to assess eosinophilia.

Record the appearance or worsening of clinical symptoms of hepatitis, or 
hypersensitivity, such as fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, pyrexia, rash or eosinophilia as relevant on the AE form. Please note that 
treatment with trametinib often associates with rash which is usually acneiform and 
affects the scalp, face, neck, chest, and upper back. Discuss with Sponsor as needed.

Record use of concomitant medications such as acetaminophen, herbal remedies, other 
over the counter medications, or putative hepatotoxins, on the concomitant medications
form.
The following assessments are required for subjects with ALT 3xULN and bilirubin 
2xULN (>35% direct) but are optional for other abnormal liver chemistries:

Anti-nuclear antibody, anti-smooth muscle antibody, and Type 1 anti-liver kidney 
microsomal antibodies and quantitative total immunoglobulin G (IgG or gamma 
globulins).

Liver imaging (ultrasound, magnetic resonance, or computerized tomography) to 
evaluate liver disease.

Serum acetaminophen adduct assay (quantifies potential acetaminophen contribution to 
liver injury, detectable by HPLC assay more than 1 week following acetaminophen use).

Only in those with underlying chronic hepatitis B at study entry (identified by positive 
hepatitis B surface antigen):  quantitative hepatitis B DNA and hepatitis delta antibody.
NOTE:  if hepatitis delta antibody assay cannot be performed, it can be replaced with a 
PCR 
of 
hepatitis 
D 
RNA 
virus 
(where 
needed) 
–
as 
outlined 
in: 
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1153793/.
Liver Chemistry Monitoring Criteria
For subjects with ALT 3xULN but <8xULN which exhibit a decrease to ALT 3xULN, but 
<5xULN and bilirubin <2xULN, without hepatitis symptoms or rash, and who can be 
monitored weekly for 4 weeks, the following actions should be taken:
•
Notify the Sponsor within 24 hours of learning of the abnormality to discuss subject 
safety
•
Continue study treatment
•
Return weekly for repeat liver chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilize or return to within baseline values 
 
 
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•
If at any time the subject meets any of the liver chemistry stopping criteria 1 – 5, 
proceed as described above
•
If, after 4 weeks of monitoring, ALT <3xULN and bilirubin <2xULN, monitor 
subjects twice monthly until liver chemistries normalize or return to within baseline 
values. 
Drug Restart/Rechallenge Following Liver Events that are Possibly 
Related to Study Treatment
Approval by Sponsor for study treatment restart can be considered where:
The subject is receiving compelling benefit, benefit of drug restart exceeds risk, and no 
effective alternative therapy is available. Ethics Committee or Institutional Review Board 
approval of study treatment restart/rechallenge must be obtained, as required.
If the restart/rechallenge is approved by Sponsor in writing, the subject must be provided 
with a clear description of the possible benefits and risks of drug administration, including 
the possibility of recurrent, more severe liver injury or death.
The subject must also provide signed informed consent specifically for the study treatment 
restart/rechallenge.  Documentation of informed consent must be recorded in the study chart.
Study treatment must be administered at the dose specified by Sponsor.
Subjects approved by the Sponsor for restart/rechallenge of study treatment must return to 
the clinic twice a week for liver chemistry tests until stable liver chemistries have been 
demonstrated and then laboratory monitoring may resume as per protocol. 
Drug Restart Following Transient Resolving Liver Events Not Related to 
Study Treatment
Approval by Sponsor for drug restart can be considered where:
•
Liver chemistries have a clear underlying cause (e.g., biliary obstruction, 
hypotension and liver chemistries have improved to normal or are within 1.5 x 
baseline and ALT <3xULN).  Ethics Committee or Institutional Review Board 
approval of study treatment restart/rechallenge must be obtained, as required.
•
If restart of study treatment is approved by Sponsor in writing, the subject must be 
provided with a clear description of the possible benefits and risks of drug 
administration, including the possibility of recurrent, more severe liver injury or 
death.  
•
The subject must also provide signed informed consent specifically for the restart.  
Documentation of informed consent must be recorded in the study chart.
•
Study treatment must be administered at the dose specified by Sponsor.
Subjects approved by the Sponsor for restarting study treatment must return to the clinic once 
a week for liver chemistry tests until stable liver chemistries have been demonstrated and 
 
 
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then laboratory monitoring may resume as per protocol. If protocol defined stopping criteria 
for liver chemistry elevations are met, study treatment must be stopped.
A dose reduction below 75 mg BID for dabrafenib and 1 mg once daily for trametinib is not 
allowed.  If a dose reduction below 75 mg BID for dabrafenib is required, dabrafenib will be 
permanently discontinued, but the subjects will be allowed to continue trametinib.  If a dose 
reduction below 1 mg once daily for trametinib is required, then trametinib will be 
permanently discontinued, but these subjects will be allowed to continue dabrafenib.
Note: Approval from the Sponsor is required to restart study treatment after ≥21 days 
of interruption. 
5.6.1.1.16
Hematologic Events
Subjects should be carefully monitored for signs and symptoms of hematologic events (such 
as autoimmune hemolytic anemia, aplastic anemia, disseminated intravascular coagulation 
(DIC), or neutropenia).  All attempts should be made to rule out other causes such as 
metastases, sepsis and/or infection.   Relevant diagnostic studies such as peripheral blood 
smear, reticulocyte count, LDH, haptoglobin, bone marrow biopsy or Coomb’s test, etc., 
should be considered to confirm the diagnosis. However the AE should be reported 
regardless of etiology.
Dose modification and supportive care guidelines for hematologic adverse events are 
described in Table 31.  Guidelines for dose modification for neutropenia are provided in 
Table 32.
Table 31
Management and Dose Modification Guidelines for Hematologic Adverse 
Events 
CTCAE Grade
Adverse Event Management
Action and Dose Modification
Grade 2

Consider Hematology consultation

Consider systemic corticosteroids at a dose of 1 to 2 
mg/kg/day prednisone or equivalent.  

When symptoms improve to Grade 1 or less, steroid 
taper (if systemic corticosteroids initiated) should be 
started and continued over no less than 4 weeks.

Interrupt pembrolizumab until improvement to 
≤Grade 1

Consider interruption of dabrafenib and/or 
trametinib
Grade 3

Hematology consultation

Treat with methylprednisolone 125mg IV or prednisone 
1-2 mg/kg p.o. (or equivalent) as appropriate.  

When symptoms improve to Grade 1 or less, steroid 
taper (if systemic corticosteroids initiated) should be 
started and continued over no less than 4 weeks.

Interrupt all study treatment until improvement 
to ≤Grade 1

Restart dabrafenib and/or trametinib at reduced 
dose
Grade 4

Same as grade 3

Permanently 
discontinue 
all 
study 
treatment
Abbreviations:  CTCAE = Common Terminology Criteria for Adverse Events
 
 
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Table 32
Management and Dose Modification Guidelines for Neutropenia  
CTCAE Grade
Action and Dose Modification
Grade 2

Consider interrupting dabrafenib and/or trametinib if clinically indicated

Monitor closely

Provide supportive care according to institutional standards

When toxicity resolves to ≤Grade 1, restart study treatment at current dose level
Grade 3

Interrupt dabrafenib and/or trametinib

Monitor closely

Provide supportive care according to institutional standards

When toxicity resolves to ≤Grade 1, restart dabrafenib and/or trametinib at reduced dose. May titrate dose 
up to previous level if tolerated
Grade 4

Interrupt all study treatment

Monitor closely

Provide supportive care according to institutional standards

When toxicity resolves to ≤Grade 1, restart pembrolizumab at current dose. Restart dabrafenib and/or 
trametinib at reduced dose. May titrate dose up to previous level if tolerated

If the Grade 4 toxicity recurs, either permanently discontinue all study treatment or, if the subject is 
clinically benefitting, discuss continuation of treatment with the Sponsor
Abbreviations:  CTCAE = Common Terminology Criteria for Adverse Events
5.6.1.1.17
Neurologic Events
Subjects should be carefully monitored for signs and symptoms of neurologic events.  All 
attempts should be made to rule out other causes such as metastatic disease, other 
medications or infectious causes. However the AE should be reported regardless of etiology.
Dose modification and supportive care guidelines for neurologic adverse events are described 
in Table 33.
Table 33
Management and Dose Modification Guidelines for Neurologic Adverse 
Events
CTCAE Grade
Adverse Event Management
Action and Dose Modification
Grade 2

Consider Neurology consultation and possible biopsy 
for diagnosis

Consider systemic corticosteroids at a dose of 1 to 2 
mg/kg/day prednisone or equivalent.  

When symptoms improve to Grade 1 or less, steroid 
taper (if systemic corticosteroids initiated) should be 
started and continued over no less than 4 weeks.

Consider interrupting pembrolizumab
Grade 3

Neurology consultation and consider biopsy for 
diagnosis

Treat with systemic corticosteroids prednisone 1-2 
mg/kg p.o. (or equivalent).  If condition worsens 
consider IVIG or other immunosuppressive therapies as 
per local guidelines.

When symptoms improve to Grade 1 or less, steroid 
taper (if systemic corticosteroids initiated) should be 
started and continued over no less than 4 weeks.

Permanently discontinue pembrolizumab

Consider 
interrupting 
dabrafenib 
and/or 
trametinib
Grade 4

Same as grade 3

Permanently discontinue pembrolizumab

Consider 
interrupting 
dabrafenib 
and/or 
trametinib
Abbreviations:  CTCAE = Common Terminology Criteria for Adverse Events
 
 
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5.6.1.1.18
Infusion Reactions
Subjects should be carefully monitored for signs and symptoms of infusion reaction (such as 
allergic reaction, anaphylaxis, cytokine release syndrome, or serum sickness).  The AE 
should be reported regardless of etiology.
Signs and symptoms usually develop during or shortly after drug infusion and generally 
resolve completely within 24 hours of completion of infusion.
Pembrolizumab Infusion Reaction Treatment Guidelines
Pembrolizumab may cause severe or life-threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion. 
Dose modification and toxicity management guidelines on pembrolizumab associated 
infusion reaction are provided in Table 34.
Pembrolizumab subjects should receive appropriate supportive care measures as deemed 
necessary by the treating investigator including but not limited to the items outlined below:

Management of Infusion Reactions: acute infusion reactions (which can include 
cytokine release syndrome, angioedema, or anaphylaxis) are different from 
allergic/hypersensitive reactions, although some of the manifestations are common to 
both AEs. Signs and symptoms usually develop during or shortly after drug infusion 
and generally resolve completely within 24 hours of completion of infusion. 
Signs/symptoms may include: allergic reaction/hypersensitivity (including drug 
fever); arthralgia (joint pain); bronchospasm; cough; dizziness; dyspnea (shortness of 
breath); Fatigue (asthenia, lethargy, malaise); Headache; Hypertension; hypotension; 
myalgia (muscle pain); nausea; pruritis/itching; rash/desquamation; rigors/chills; 
sweating (diaphoresis); tachycardia; tumor pain (onset or exacerbation of tumor pain 
due to treatment); urticaria (hives, welts, wheals); vomiting.
 
 
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Table 34
Pembrolizumab Infusion Reaction Dose Modification and Treatment 
Guidelines
NCI CTCAE Grade
Treatment
Premedication at 
Subsequent Dosing
Grade 1
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion 
of the investigator.
None
Grade 2
Requires infusion interruption 
but responds promptly to 
symptomatic treatment (e.g., 
antihistamines, NSAIDS, 
narcotics, IV fluids); 
prophylactic medications 
indicated for ≤24 hrs
Stop Infusion.
Additional appropriate medical therapy 
may include but is not limited to:
IV fluids
Antihistamines
NSAIDS
Acetaminophen
Narcotics
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion 
of the investigator.
If symptoms resolve within 1 hour of 
stopping drug infusion, the infusion 
may be restarted at 50% of the original 
infusion rate (e.g. from 100 mL/hr to 
50 mL/hr).  Otherwise dosing will be 
held until symptoms resolve and the 
subject should be premedicated for the 
next scheduled dose.
Subjects who develop Grade 2 toxicity 
despite adequate premedication should be 
permanently discontinued from further 
trial treatment administration.
Subject may be 
premedicated 1.5h (± 30 
minutes) prior to infusion of 
pembrolizumab with:
Diphenhydramine 50 mg po 
(or equivalent dose of 
antihistamine).
Acetaminophen 500-1000 
mg po (or equivalent dose 
of analgesic).
 
 
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NCI CTCAE Grade
Treatment
Premedication at 
Subsequent Dosing
Grades 3 or 4
Grade 3:
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial improvement; 
hospitalization indicated for 
other clinical sequelae (e.g., 
renal impairment, pulmonary 
infiltrates)
Grade 4:
Life-threatening; pressor or 
ventilatory support indicated
Stop Infusion.
Additional appropriate medical therapy 
may include but is not limited to:
IV fluids
Antihistamines
NSAIDS
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Epinephrine**
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion 
of the investigator.
Hospitalization may be indicated.
**In cases of anaphylaxis, epinephrine 
should be used immediately.
Subject is permanently discontinued from 
further trial treatment administration.
No subsequent dosing
Appropriate resuscitation equipment should be available at the bedside and a physician readily available 
during the period of drug administration.
For Further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 
(CTCAE) at http://ctep.cancer.gov
IV=intravenous; NSAIDs= non-steroidal anti-inflammatory drugs; PO=oral administration.
Supportive Care Guidelines for Adverse Events with an Immune-Etiology 
(irAEs)
Adverse events of a potential immunologic etiology (irAEs) may be defined as an adverse 
event of unknown etiology, associated with drug exposure and is consistent with an immune 
phenomenon. irAEs may be predicted based on the nature of the pembrolizumab compound, 
its mechanism of action, and reported experience with immunotherapies that have a similar 
mechanism of action. Special attention should be paid to AEs that may be suggestive of 
potential irAEs. An irAE can occur shortly after the first dose or several months after the last 
dose of treatment.
If an irAE is suspected, efforts should be made to rule out neoplastic, infectious, metabolic,
toxin or other etiologic causes prior to labeling an adverse event as an irAE. Subjects who 
develop a Grade 2 or higher irAE should be discussed immediately with the Sponsor.
Recommendation to evaluate and manage irAEs are provided in Section 5.6.1.1.3 and 
Section 5.2.1.2.1, Table 10.  Recommendations to managing irAEs that are not detailed 
elsewhere in the protocol are detailed in Table 35.
 
 
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Table 35
General Approach to Handling irAEs
irAE
Withhold/Discontinue 
Pembrolizumab?
Supportive Care
Grade 1
No action
Provide symptomatic treatment
Grade 2
May 
withhold 
pembrolizumab
Consider systemic corticosteroids in addition 
to appropriate symptomatic treatment
Grade 3 and Grade 4
Withhold pembrolizumab
Discontinue if grade 4 or 
grade 3 and
unable to 
reduce corticosteroid dose 
to < 10 mg per day 
prednisone 
equivalent 
within 12 weeks of toxicity
Systemic corticosteroids are indicated in 
addition to appropriate symptomatic treatment.  
May utilize 1 to 2 mg/kg prednisone or 
equivalent per day.
Steroid taper should be considered once 
symptoms improve to Grade 1 or less and 
tapered over at least 4 weeks.
Diet/Activity/Other Considerations
Diet
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting.  
Contraception
Pembrolizumab and other study medications may have adverse effects on a fetus in utero.  
Refer to Appendix 12.14 for approved methods of contraception.
Participants should be informed that taking the study medication may involve unknown risks 
to the fetus (unborn baby) if pregnancy were to occur during the study.  In order to 
participate in the study, participants of childbearing potential must adhere to the 
contraception requirement (Appendix 12.14) from the day of study medication initiation 
throughout the study period up to 120 days after the last dose of study medication.  If there is 
any question that a participant of childbearing potential will not reliably comply with the 
requirements for contraception, that participant should not be entered into the study. 
Use in Pregnancy
If a female subject inadvertently becomes pregnant while on treatment with pembrolizumab
or trametinib or dabrafenib, the subject will immediately be removed from the study.  The 
site will contact the subject at least monthly and document the subject’s status until the 
pregnancy has been completed or terminated.  The outcome of the pregnancy will be reported 
to the Sponsor without delay and within 24 hours if the outcome is a serious adverse 
 
 
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experience (e.g., death, abortion, congenital anomaly, or other disabling or life-threatening 
complication to the mother or newborn).  The study investigator will make every effort to 
obtain permission to follow the outcome of the pregnancy and report the condition of the 
fetus or newborn to the Sponsor.  If a male subject impregnates his female partner the study 
personnel at the site must be informed immediately and the pregnancy reported to the 
Sponsor and followed as described above and in Section 7.2.2.
Use in Nursing Women
It is unknown whether pembrolizumab or trametinib or dabrafenib is excreted in human milk.  
Since many drugs are excreted in human milk, and because of the potential for serious 
adverse reactions in the nursing infant, subjects who are breast-feeding are not eligible for 
enrollment.
Subject Withdrawal/Discontinuation Criteria
Discontinuation of Treatment
Discontinuation of treatment does not represent withdrawal from the trial.
As certain data on clinical events beyond treatment discontinuation may be important to the 
study, they must be collected through the subject’s last scheduled follow-up, even if the
subject has discontinued treatment.  Therefore, all subjects who discontinue trial treatment
prior to completion of the treatment will still continue to participate in the trial as specified in 
Section 6.0 - Trial Flow Chart and Section 7.1.5.3 – Post-Treatment Follow-Up Phase.
Subjects may discontinue treatment at any time for any reason or be dropped from treatment
at the discretion of the investigator should any untoward effect occur.  In addition, a subject 
may be discontinued from treatment by the investigator or the Sponsor if treatment is 
inappropriate, the trial plan is violated, or for administrative and/or other safety reasons.  
Specific details regarding procedures to be performed at treatment discontinuation are 
provided in Section 7.1.4 – Other Procedures.
A subject must be discontinued from treatment but continue to be monitored in the trial for 
any of the following reasons:
o
The subject or legal representative (such as parent or legal representative) withdraws 
consent.
o
The subject’s treatment assignment has been unblinded by the investigator, Merck 
subsidiary or through the emergency unblinding call center. 
o
The subject has a medical condition or personal circumstance which, in the opinion of the 
investigator and/or sponsor, placed the subject at unnecessary risk from continued 
administration of study drug/vaccine
 
 
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o
The subject has a confirmed positive serum pregnancy test.
o
Documented disease progression
Note: If a subject has confirmed progression of disease, i.e., persistent tumor increase of 
20% or greater compared to nadir and/or worsening or increased number of new lesions, 
(via a second scan at least 28 days from the date of the scan showing initial radiological 
progression by RECIST 1.1), the subject should not receive further trial treatment on 
study.  If a subject has unconfirmed progression of disease and is clinically stable, it is 
at the discretion of the investigator to continue treating the subject with the assigned 
treatment per protocol until progression of disease is confirmed at least 28 days from the 
date of the scan suggesting progression of disease. Clinical Stability is defined as:
1)
Absence of symptoms and signs indicating clinically significant progression of 
disease (including worsening of laboratory values) indicating disease progression.
2)
No decline in ECOG performance status.
3) Absence of rapid progression of disease or progressive tumor at critical 
anatomical sites (e.g., cord compression) requiring urgent alternative medical 
intervention. 
o
Unacceptable adverse experiences as described in Section 5.2.1.2 and Section 5.6
o
Intercurrent illness that prevents further administration of treatment
o
Investigator’s decision to withdraw the subject
o
Noncompliance with trial treatment or procedure requirements
o
The subject is lost to follow-up
o
Administrative reasons
The End of Treatment and Follow-up visit procedures are listed in Section 6 - Trial Flow 
Chart and Section 7.1.5 - Visit Requirements. After the end of treatment, each subject will 
be followed for a minimum of 30 days for adverse event monitoring (serious adverse events 
will be collected for up to 90 days after the end of treatment as described in Section 7.2.3.1). 
Subjects will have post-treatment follow-up for disease status until disease progression, 
initiating a non-study cancer treatment, withdrawing consent, or becoming lost to follow-
up. After documented disease progression each subject will be followed for overall survival 
until death or withdrawal of consent, or the end of the study, whichever occurs first.
Discontinuation of pembrolizumab after CR
Discontinuation of pembrolizumab may be considered for subjects who have attained a 
confirmed response per RECIST 1.1 that have been treated for at least 6 months and had at 
least two doses of pembrolizumab treatment beyond the date when the initial CR was 
declared. See Section 5.2.5 for more information.
 
 
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For subjects who are discontinued from treatment but continue to be monitored in the trial, 
all visits and procedures, as outlined in the trial flowchart, should be completed.
Subjects may be allowed to begin treatment again if deemed medically appropriate..
Withdrawal from the Trial
Subjects may withdraw from the trial at any time for any reason.  If a subject withdraws from 
the trial, they will no longer receive treatment or be followed at scheduled protocol visits.
A subject must be withdrawn from the trial if:
o
The subject or legal representative (such as parent or legal representative) withdraws 
consent from the trial.
o
The subject is lost to follow-up
Specific details regarding procedures to be performed at the time of withdrawal from the trial 
including specific details regarding withdrawal from Future Biomedical Research are 
outlined in Section 7.1.4 – Other Procedures.
Subject Replacement Strategy
In Parts 1, 2, 4, and 5, additional subjects may be enrolled in a given cohort to ensure that the 
required number of evaluable subjects in each cohort is achieved. A subject who discontinues 
the trial for progressive disease or a drug-related AE will not be replaced and will be counted 
in the evaluable population of subjects for the respective cohort. Further details are provided 
in Section 8.2.4.2.
Parts 1, 2, 4, and 5:  Subject Replacement Strategy - Dose Limiting Toxicity
Any subject who does not complete the 6-week DLT evaluation period in Parts 1, 2, 4, or 5
(i.e., Cycle 1, initiated with the first pembrolizumab dose) and does not experience any DLT 
will be replaced, except those who discontinue due to non-DLT toxicity that is nevertheless 
drug-related (or suspected to be drug-related).  In addition, any subject who misses ≥50% of 
PK or PD samples or misses 3 consecutive doses of study medication immediately prior to 
PK blood sampling may be replaced at the discretion of the Sponsor. In Parts 4 and 5, any 
subject who discontinues trametinib during the trametinib monotherapy run-in period is not 
considered evaluable for DLTs for the MK+T combination, even if the subject discontinued 
due to a DLT, and will be replaced.
Beginning and End of the Trial
The overall trial begins when the first subject signs the informed consent form.  The overall 
trial ends when the last subject completes the last trial visit, discontinues from the trial or is 
lost to follow-up (i.e. the subject is unable to be contacted by the investigator).
 
 
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Clinical Criteria for Early Trial Termination
Early trial termination will be the result of the criteria specified below:
1. Quality or quantity of data recording is inaccurate or incomplete.
2. Poor adherence to protocol and regulatory requirements.
3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential
health hazard to subjects
4. Plans to modify or discontinue the development of the study drug(s).
Statistical criteria for stopping the trial are provided in Section 8.0 – Statistical Analysis Plan.
Enrollment will not be halted during the planned interim analysis.
In the event of Sponsor decision to no longer supply study drug, ample notification will be
provided so that appropriate adjustments to subject treatment can be made.
Further recruitment in the trial or at (a) particular trial site(s) may be stopped due to 
insufficient compliance with the protocol, GCP and/or other applicable regulatory 
requirements, procedure-related problems or the number of discontinuations for 
administrative reasons is too high.
 
 
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6.0 TRIAL FLOW CHART
Treatment Phase
Parts 1 and 2:  Pembrolizumab Q3W Dosing with Trametinib and/or Dabrafenib
Trial Period:
Screening9
Treatment (6-Week Cycle)
End of Treatment
Visit Number:
1
2
3
4
5
6
7
8
9
> 10
Discontinuation23
Days
(-28 to -1)
1
8
15
22
29
36
1
22
1,22
Cycle
1
2
> 3
Scheduling Window (Days)
±3
±3
±3
±3
±3
±3
±3
±3
±3
Administrative Procedures
Informed Consent1
X
Informed Consent for Future Biomedical Research (optional)
X
Inclusion/Exclusion Criteria
X
Subject Identification Card
X
Demographics and Medical History2
X
Prior and Concomitant Medication Review3
X
X
X
X
X
X
X
X
X
X
X
Treatment Assignment
X
Survival status 28
Clinical Procedures / Assessments
Full Physical Examination27
X
X
X
X24
Directed Physical Examination
X
X
X
X
X
X
X24
X
Vital Signs and Weight4
X
X
X
X
X
X
X
X
X
X
X
12-Lead Electrocardiogram (ECG)5
X
X
X
X25
ECHO
X
X
X25
Review Adverse Events6,7,8
X
X
X
X
X
X
X
X
X
X
ECOG Performance Status
X
X
X
X25
X
 
 
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Trial Period:
Screening9
Treatment (6-Week Cycle)
End of Treatment
Visit Number:
1
2
3
4
5
6
7
8
9
> 10
Discontinuation23
Days
(-28 to -1)
1
8
15
22
29
36
1
22
1,22
Cycle
1
2
> 3
Scheduling Window (Days)
±3
±3
±3
±3
±3
±3
±3
±3
±3
Laboratory Procedures / Assessments9
Pregnancy Test - Urine or Serum -HCG10
X
CBC with Differential11
X
X
X
X
X
X
X
X
X
X25
X
Comprehensive Chemistry Panel11
X
X
X
X
X
X
X
X
X
X25
X
Urinalysis11
X
X
X
X
X
X
X
X
X
X25
X
PT/INR and aPTT12
X
As clinically indicated
Calculated Creatinine Clearance
X
T3, FT4 and TSH11,13
X
X
X
X13
X
Hepatitis B and C14
X
Blood for Future Biomedical Research15 (optional)
X
Drug Dispensation, Administration, and Associated Analyses
pembrolizumab Administration (30-minute infusion)
X
X
X
X
X
Pharmacokinetics of pembrolizumab16
X
X
X
X25
Anti-pembrolizumab Antibodies17
X
X
X25
Dispensation of Drug Kit
X
X
X
X
X25
Pharmacokinetics of Dabrafenib and/or Trametinib18
X
X
X25
X
Efficacy Measurements
Tumor Imaging19
X
X25
X
Tissue Collection and Pharmacodynamic Assessment
BRAF Testing20
X
Tumor Tissue Collection21
X
X21
X26
Correlative Blood Sample21
X
X
X
X
Blood for Genetics22
X
1  Written consent must be obtained prior to performing any protocol-specific procedure. Results of a test performed prior to the subject signing consent as part of routine clinical management 
are acceptable in lieu of a screening test if performed within the specified time frame (e.g. within 28 days prior to Day 1). Assign Baseline number when the study informed consent is signed.
2  Includes history of treatment for the primary diagnosis, including prior systemic, radiation treatment and surgical treatment, and best response to prior systemic treatments.  Date of last prior 
cancer treatment must be documented.  Radiographic studies performed prior to study entry may be collected for review by the investigator.
3  Prior Medications - Report all medications taken within 30 days of Visit 1 and all treatments for a prior cancer even if taken greater than 30 days prior to Visit 1.  Concomitant Medications -
Enter new medications started during the trial through the Safety Follow-Up visit.  After the Safety Follow-Up visit, record all medications taken for SAEs and ECIs as defined in Section 7.2.
4  Vital signs to include temperature, pulse, respiratory rate and blood pressure. If a patient's baseline weight does not fluctuate by more than 10%, this weight can be used to calculate dose.  
Height will be measured at Visit 1 only.
5  Electrocardiogram (12-lead ECG) should be performed at Screening and post-infusion at visits indicated in the flow chart.  
6  Adverse experiences and laboratory safety measurements will be graded per NCI CTCAE version 4.0. All adverse experiences, whether gradable by CTCAE or not, will also be evaluated for 
seriousness.
7  Any adverse experience of unknown etiology associated with trial treatment exposure should be evaluated to determine if it is possibly an Event of Clinical Interest (ECI).
 
 
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8  Evaluate patients for symptoms or clinical signs of non-cutaneous, new primary/recurrent malignancies before initiation of treatment, periodically during treatment, or as clinically indicated. 
Following discontinuation of dabrafenib, monitoring for non-cutaneous secondary/recurrent malignancies should continue for up to 6 months or until initiation of another anti-neoplastic therapy. 
Abnormal findings should be managed according to clinical practices.
9  Routine laboratory tests (chemistry; hematology) for screening should be performed  within 10 days prior to the first dose of trial treatment.  See Section 7.1.3 for details regarding laboratory 
tests.
10  For women of reproductive potential, a urine pregnancy test will be performed within 72 hours prior to first dose of trial treatment.  If urine pregnancy results cannot be confirmed as 
negative, a serum pregnancy test, performed by the local study site laboratory, will be required.  Pregnancy tests (serum and/or urine tests) should be repeated if required by local guidelines.
11  After Cycle 1, lab samples can be collected up to 48 hours prior to the scheduled time point.  Laboratory results must be known and acceptable prior to dosing.  See Section 7.1.3 for details 
regarding laboratory tests.
12  Coagulation factors (PT/INR and aPTT) should be monitored closely throughout the trial for any subject receiving anticoagulant therapy.
13  Thyroid function tests will be performed by a central laboratory only if the local laboratory is unable to perform this service.  Following Cycle 4, testing will be performed every other cycle.  
In countries where T3 results are not available, FT3 results may be reported.  See Section 7.1.3 for details regarding laboratory tests. 
14  Testing will be performed by the local laboratory at Screening.  Hepatitis B and Hepatitis C serologies should be obtained for subjects without a known history of Hepatitis B or C.  Those 
with a known history are ineligible.  Include HCV RNA (qualitative) and HBsAg.  
15  Informed consent for Future Biomedical Research (FBR) samples must be obtained before the DNA sample is drawn.  DNA sample for analysis should be obtained predose, on Day 1 (or 
with the next scheduled blood draw), as the last sample drawn, on allocated subjects only, or at a later date as soon as the informed consent is obtained. This sample should only be taken once 
from each subject.  See Section 12.2 for guidance regarding the collection and management of specimens for FBR.
16  Pre-dose and post-dose serum samples for PK of pembrolizumab will be collected on Day 1 and Day 22 of Cycle 1 and Day 1 of Cycle 2.  Thereafter, only pre-dose (Ctrough) PK serum 
samples will be collected at Day 1 of every alternate cycle (i.e., Day 1 of Cycle 3, Day 1 of Cycle 5, etc.).  All pre-dose (Ctrough) samples should be collected within 24 hours before the start of 
infusion of pembrolizumab and, if blood is collected for anti-pembrolizumab antibodies, at the same time blood sample for anti-pembrolizumab antibodies is collected.  All post-dose PK samples 
should be collected within 30 minutes after the end of infusion of pembrolizumab.  One additional post-dose sample should be collected between 24 and 96 hours following C1D1.  Procedures 
for collection of samples are described in the Procedures Manual.
17  Blood for anti-pembrolizumab antibodies should be collected on Day1of Cycles 1, 2, 3 and every other cycle thereafter (Cycle 5, Cycle 7, etc.).  During pembrolizumab treatment, all samples 
should be drawn within 24 hours before infusion of pembrolizumab at the same time as blood collection for pre-dose (Ctrough) PK serum samples of pembrolizumab.
18  On C1D22, both pre-dose and post-dose plasma samples for PK of trametinib and dabrafenib will be collected.  On C1D22, morning dose(s) should be withheld until after PK (pre-dose) 
sample has been drawn.  On C1D22, post-dose PK samples for trametinib and/or dabrafenib should be drawn (1) at the same time as when the post-dose pembrolizumab PK sample is drawn (the 
end of infusion), and, (2) at approximately 4-6 hours post-dose.  On C2D1, subjects should take their morning dose at home.  A post-dose sample will be obtained during study visit.  Thereafter, 
PK plasma samples will be collected at Day 1 of every alternate cycle (i.e., Day 1 of Cycle 3, Day 1 of Cycle 5, etc.) during study visit.  If visit is in the morning, subjects will be asked to 
withhold their morning dose; if visit is in the afternoon, subjects will be asked to take their morning dose as usual. Procedures for collection of samples are described in the Procedures Manual.
19  The initial tumor imaging will be performed within 28 days prior to the date of allocation.  Scans performed as part of routine clinical management are acceptable for use as the screening 
scan if they are of diagnostic quality and performed within 28 days prior to the first dose of trial treatment.  CT scans are the required modality for measurable disease unless a subject has a 
clinical condition, e.g., severe contrast allergy.  The same imaging technique has to be used for the subject throughout the study.  The visit window for subsequent imaging is +/- 7 days.  If there 
is progressive disease, radiologic assessment/tumor imaging should be obtained at least four weeks from scan date for confirmation.  CT timing should follow calendar days and should not be 
adjusted for delays in cycle starts.  The process for collection of CT images is described in the Procedures Manual.  Tumor imaging will be performed every 6 weeks (or whenever clinically 
indicated) starting at Week 13 while the subject remains on study therapy; after 18 months, tumor imaging will be performed every 12 weeks (or whenever clinically indicated) while the subject 
remains on study therapy.  Per the modified RECIST 1.1 used in this protocol, if imaging shows progressive disease, the imaging assessment should be repeated at a minimum of 4 weeks later in 
order to confirm progressive disease as described in Section 4.2.3.1.  
20  BRAF V600 E or K mutation analysis should be performed by sites during screening in subjects without documented BRAF status.  This specimen may be collected any time from the initial 
diagnosis to the study entry and may be an archival tissue sample (within 6 months of study entry).  BRAF analysis may be performed at a local laboratory, provided that the methodology is able 
to detect V600E and/or V600K mutations.  A sample from the originally-tested tissue block must be collected and stored at the central laboratory for possible assay at a later date (i.e., in the 
event that BRAF status must be confirmed).  Detailed instructions for tissue collection, processing and shipment are provided in the Procedures Manual.  
 
 
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21  In order to be eligible for the study, all subjects must provide a tumor tissue specimen for biomarker analysis and blood samples for pharmacodynamic assessment.  The tissue specimen may 
be collected any time from the initial diagnosis to the study entry and may be an archival tissue sample (within 9o days of Study Day 1=first dose(s) of study treatment) if it is not feasible to 
obtain a fresh biopsy not previously irradiated.  Site documentation that the sample has been shipped to the biomarker analysis laboratory is sufficient evidence to meet eligibility criterion.  If a 
tumor biopsy was obtained of a target lesion during eligibility assessment, it is preferred to obtain a new baseline scan.  Biopsy of lesions on study should be limited to non-target lesions or new 
lesions if their pathologic etiology is ambiguous.  The tissue sample should have proper size to enable multiple planned biomarker analyses, but not artificially decrease the longest diameter of 
the lesion.  Additionally, a fresh biopsy should be obtained 10-14 days following initiation of study treatment for Parts 1 and 2 of the study.  The fresh biopsy at 10-14 days following initiation of 
study treatment is optional in Part 3 of the study.  Detailed instructions for blood sample collection, tissue collection, processing and shipment are provided in the Laboratory and Procedures 
Manual, respectively. Any leftover blood or tumor tissue may be stored for future research if the subject signs the optional FBR consent.  
22  Blood for genetics sample will be collected to explore host genetics and to identify genetic predictors which may have a role in therapeutic response to pembrolizumab.
23  The discontinuation visit should be scheduled at the time of permanent discontinuation of all treatments (pembrolizumab, trametinib, and/or dabrafenib).  The window for this visit is +10 
days.  Required assessments for this visit are identified in the study flow chart; additional assessments that are not flagged as required may be performed if clinically indicated (e.g., coagulation 
tests, thyroid function tests, etc.).
24  Perform a full physical examination on the first day of each cycle and a directed physical examination on Day 22 of each cycle.  Example:  full physical exam on C3D1, directed physical 
exam on C3D22, full physical exam on C4D1, directed physical exam on C4D22, etc.
25  Day 1 and 22 of Cycle 3:  CBC with Differential, Comprehensive Chemistry Panel, Urinalysis
Day 1 ONLY from C4D1 onwards:  CBC with Differential, Comprehensive Chemistry Panel, Urinalysis
Day 1 ONLY of every cycle (e.g., C3D1, C4D1, C5D1, etc.):  ECOG Performance Status
Day 1 and 22 of every cycle (e.g., C3D1, C3D22, C4D1, C4D22, etc.):  Dispensation of Drug Kit
Day 1 ONLY of every cycle (e.g., C3D1, C4D1, C5D1, etc.) until 18 months, then Day 1 ONLY of every other cycle:  Tumor Imaging
Day 1 ONLY of every alternate cycle, as indicated (e.g., C3D1, C5D1, C7D1, etc.):  ECG, ECHO, Pharmacokinetics of pembrolizumab and/or trametinib and/or dabrafenib, Anti-pembrolizumab Antibodies testing
26  pembrolizumab treated subjects in the Treatment Phase – Additional optional biopsy at disease progression is highly desired when feasible.   Detailed instructions for tissue collection, 
processing and shipment are provided in the Procedures Manual.
27  Dermatological examination will be part of full physical examination on the first day of each cycle. 
28  Updated survival status may be requested by the Sponsor at any time during the course of the study. Upon Sponsor notification, all participants who do not/will not have a scheduled study 
visit or study contact during the Sponsor defined time period will be contacted for their survival status (excluding participants who have a death event previously recorded).
 
 
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Part 3:  Pembrolizumab Q3W Dosing With Trametinib and Dabrafenib
Trial Period:
Screening9
Treatment (6-Week Cycle)24,25
End of Treatment
Visit Number:
1
2
3
4
5
> 6
Discontinuation25
Days
(-28 to -1)
1
22
1
22
1,22
Cycle
1
2
> 3
Scheduling Window (Days)
±3
±3
±3
±3
±3
Administrative Procedures
Informed Consent1
X
Informed Consent for Future Biomedical Research 
(optional)
X
Inclusion/Exclusion Criteria
X
Subject Identification Card
X
Demographics and Medical History2
X
Prior and Concomitant Medication Review3
X
X
X
X
X
X
X
Treatment Assignment
X
Survival Status 30
Clinical Procedures / Assessments
Full Physical Examination29
X
X
X
X26
Directed Physical Examination
X
X
X26
X
Vital Signs and Weight4
X
X
X
X
X
X
X
12-Lead Electrocardiogram (ECG)5
X
X
X
X27
ECHO
X
X
X27
Review Adverse Events6,7,8
X
X
X
X
X
X
ECOG Performance Status
X
X
X
X27
X
Laboratory Procedures / Assessments9
Pregnancy Test - Urine or Serum -HCG10
X
CBC with Differential11
X
X
X
X
X
X27
X
 
 
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Confidential
Trial Period:
Screening9
Treatment (6-Week Cycle) 24,25
End of Treatment
Visit Number:
1
2
3
4
5
> 6
Discontinuation25
Days
(-28 to -1)
1
22
1
22
1,22
Cycle
1
2
> 3
Scheduling Window (Days)
±3
±3
±3
±3
±3
Laboratory Procedures / Assessments9
Comprehensive Chemistry Panel11
X
X
X
X
X
X27
X
Urinalysis11
X
X
X
X27
X
PT/INR and aPTT12
X
As clinically indicated
Calculated Creatinine Clearance
X
T3, FT4 and TSH11,13
X
X
X
X13
X
Hepatitis B and C14
X
Blood for Future Biomedical Research15 (optional)
X
Drug Dispensation, Administration, and Associated Analyses
pembrolizumab Administration (30-minute infusion)
X
X
X
X
X
Pharmacokinetics of pembrolizumab16
X
X
X
X27
Anti-pembrolizumab Antibodies17
X
X
X27
Dispensation of Drug Kit
X
X
X
X
X27
Pharmacokinetics of Dabrafenib and/or Trametinib18
X
X
X27
X
Efficacy Measurements
Tumor Imaging19
X
X27
X
Patient Reported Outcomes (PRO)
EuroQol EQ-5D20
X
X
X
X
EORTC QLQ-C3020
X
X
X
X
 
 
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Confidential
Trial Period:
Screening9
Treatment (6-Week Cycle) 24,25
End of Treatment
Visit Number:
1
2
3
4
5
> 6
Discontinuation25
Days
(-28 to -1)
1
22
1
22
1,22
Cycle
1
2
> 3
Scheduling Window (Days)
±3
±3
±3
±3
±3
Tissue Collection and Pharmacodynamic Assessment
BRAF Testing21
X
Tumor Tissue Collection22
X
X22
X28
Correlative Blood Sample22
X
X
X
X
Blood for Genetics23
X
1  Written consent must be obtained prior to performing any protocol-specific procedure. Results of a test performed prior to the subject signing consent as part of routine 
clinical management are acceptable in lieu of a screening test if performed within the specified time frame (e.g. within 28 days prior to Day 1). Assign Baseline number 
when the study informed consent is signed.
2  Includes history of treatment for the primary diagnosis, including prior systemic, radiation treatment and surgical treatment, and best response to prior systemic 
treatments.  Date of last prior cancer treatment must be documented.  Radiographic studies performed prior to study entry may be collected for review by the investigator.
3  Prior Medications - Report all medications taken within 30 days of Visit 1 and all treatments for a prior cancer even if taken greater than 30 days prior to Visit 1.  
Concomitant Medications - Enter new medications started during the trial through the Safety Follow-Up visit.  After the Safety Follow-Up visit, record all medications 
taken for SAEs and ECIs as defined in Section 7.2.
4  Vital signs to include temperature, pulse, respiratory rate and blood pressure. If a subject's baseline weight does not fluctuate by more than 10%, this weight can be used 
to calculate dose.  Height will be measured at Visit 1 only.
5  Electrocardiogram (12-lead ECG) should be performed at Screening and post-infusion at visits indicated in the flow chart.  
6  Adverse experiences and laboratory safety measurements will be graded per NCI CTCAE version 4.0.  All adverse experiences, whether gradable by CTCAE or not, will 
also be evaluated for seriousness.
7  Any adverse experience of unknown etiology associated with trial treatment exposure should be evaluated to determine if it is possibly an Event of Clinical Interest 
(ECI).
8  Evaluate subjects for symptoms or clinical signs of non-cutaneous, new primary/recurrent malignancies before initiation of treatment, periodically during treatment, or as 
clinically indicated. Following discontinuation of dabrafenib, monitoring for non-cutaneous secondary/recurrent malignancies should continue for up to 6 months or until 
initiation of another anti-neoplastic therapy. Abnormal findings should be managed according to clinical practices.
9  Routine laboratory tests (chemistry; hematology) for screening should be performed  within 10 days prior to the first dose of trial treatment.  See Section 7.1.3 for details 
regarding laboratory tests
10  For women of reproductive potential, a urine pregnancy test will be performed within 72 hours prior to first dose of trial treatment.  If urine pregnancy results cannot be 
confirmed as negative, a serum pregnancy test, performed by the local study site laboratory, will be required. Pregnancy tests (serum and/or urine tests) should be repeated 
if required by local guidelines.
11  After Cycle 1, lab samples can be collected up to 48 hours prior to the scheduled time point.  Laboratory results must be known and acceptable prior to dosing.  LDH 
analysis required (stratification factor).  See Section 7.1.3 for details regarding laboratory tests.  
12  Coagulation factors (PT/INR and aPTT) should be monitored closely throughout the trial for any subject receiving anticoagulant therapy.
 
 
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MK-3475-022-06 Final Protocol
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Confidential
13  Thyroid function tests will be performed by a central laboratory only if the local laboratory is unable to perform this service.  Following Cycle 4, testing will be 
performed every other cycle.  In countries where T3 results are not available, FT3 results may be reported.
14  Testing will be performed by the local laboratory at Screening.  Hepatitis B and Hepatitis C serologies should be obtained for subjects without a known history of 
Hepatitis B or C.  Those with a known history are ineligible.  Include HCV RNA (qualitative) and HBsAg.  See Section 7.1.3 for details regarding laboratory tests.
15  Informed consent for Future Biomedical Research (FBR) samples must be obtained before the DNA sample is drawn.  DNA sample for analysis should be obtained 
predose, on Day 1 (or with the next scheduled blood draw), as the last sample drawn, on allocated subjects only, or at a later date as soon as the informed consent is 
obtained. This sample should only be taken once from each subject.  See Section 12.2 for guidance regarding the collection and management of specimens for FBR.
16  Pre-dose and post-dose serum samples for PK of pembrolizumab will be collected on Day 1 and Day 22 of Cycle 1 and Day 1 of Cycle 2.  Thereafter, only pre-dose 
(Ctrough) PK serum samples are collected at Day 1 of every alternate cycle (i.e., Day 1 of Cycle 3, Day 1 of Cycle 5, etc.).  All pre-dose (Ctrough) samples should be collected 
within 24 hours before the start of infusion of pembrolizumab and, if blood is collected for anti-pembrolizumab antibodies, at the same time blood sample for anti-
pembrolizumab antibodies is collected.  All post-dose PK samples should be collected within 30 minutes after the end of infusion of pembrolizumab.  One additional post-
dose pembrolizumab sample should be collected between 24 and 96 hours following C1D1.  Procedures for collection of samples are described in the Procedures Manual. 
17  Blood for anti-pembrolizumab antibodies should be collected on Day1 of Cycles 1, 2, 3 and every other cycle thereafter (Cycle 5, Cycle 7, etc.).  During 
pembrolizumab treatment, all samples should be drawn within 24 hours before infusion of pembrolizumab at the same time as blood collection for pre-dose (Ctrough) PK 
serum samples of pembrolizumab.
18  On C1D22, both pre-dose and post-dose plasma samples for PK of trametinib and dabrafenib will be collected.  On C1D22, morning dose(s) should be withheld until 
after PK (pre-dose) sample has been drawn.  On C1D22, post-dose PK samples for trametinib and/or dabrafenib should be drawn (1) at the same time as when the post-dose 
pembrolizumab PK sample is drawn (the end of infusion), and, (2) at approximately 4-6 hours post-dose.  On C2D1, subjects should take their morning dose at home.  A 
post-dose sample will be obtained during study visit. Thereafter, PK plasma samples will be collected at Day 1 of every alternate cycle (i.e., Day 1 of Cycle 3, Day 1 of 
Cycle 5, etc.) during study visit.  If visit is in the morning, subjects will be asked to withhold their morning dose; if visit is in the afternoon, subjects will be asked to take 
their morning dose as usual.  Procedures for collection of samples are described in the Procedures Manual.
19  The initial tumor imaging will be performed within 28 days prior to the date of allocation.  Scans performed as part of routine clinical management are acceptable for 
use as the screening scan if they are of diagnostic quality and performed within 28 days prior to the first dose of trial treatment.  CT scans are the required modality for 
measurable disease unless a subject has a clinical condition, e.g., severe contrast allergy.  The same imaging technique has to be used for the subject throughout the study.  
The visit window for subsequent imaging is ± 7 days. If there is progressive disease, radiologic assessment/tumor imaging should be obtained at least four weeks from scan 
date for confirmation.  CT timing should follow calendar days and should not be adjusted for delays in cycle starts.  Response status will be assessed by the investigator.  
The process for collection of CT images is described in the Procedures Manual.  Tumor imaging will be performed every 6 weeks (or whenever clinically indicated) 
starting at Week 13 while the subject remains on study therapy; after 18 months, tumor imaging will be performed every 12 weeks (or whenever clinically indicated) while 
the subject remains on study therapy.  Per the modified RECIST 1.1 used in this protocol, if imaging shows progressive disease, the imaging assessment should be repeated 
at a minimum of 4 weeks later in order to confirm progressive disease as described in Section 4.2.3.1.  
20  Patient Reported Outcomes (PROs) are to be administered by trained site personnel and completed electronically by subjects prior to all other study procedures in the 
following order:  EuroQol EQ-5D first, followed by EORTC QLQ-C30.  EuroQol EQ-5D and EORTC QLQ-C30 are to be performed at C1D1, C2D1, C3D1 and Day 1 of 
every other cycle thereafter (C5D1, C7D1, etc.) as well as the End of Treatment, and 30-day Safety Follow-up visit.  Subjects that complete 24 months on trial and opt to 
continue dabrafenib and trametinib will not be required to complete PROs at the 30-Day Safety follow up visit.  It is most relevant and strongly recommended that ePROs 
are administered prior to drug administration, adverse event evaluation and disease status notification.
21  BRAF V600 E or K mutation analysis should be performed by sites during screening in subjects without documented BRAF status.  This specimen may be collected 
any time from the initial diagnosis to the study entry and may be an archival tissue sample (within 6 months of study entry).  BRAF analysis may be performed at a local 
laboratory, provided that the methodology is able to detect V600E and/or V600K mutations.  A sample from the originally-tested tissue block must be collected and stored
at the central laboratory for possible assay at a later date (i.e., in the event that BRAF status must be confirmed).  Detailed instructions for tissue collection, processing and 
shipment are provided in the Procedures Manual.  
 
 
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Confidential
22  In order to be eligible for the study, all subjects must provide a tumor tissue specimen for biomarker analysis and blood samples for pharmacodynamic assessment.  The 
tissue specimen may be collected any time from the initial diagnosis to the study entry and may be an archival tissue sample (within 90 days of Study Day 1=first dose(s) of 
study treatment) if it is not feasible to obtain a fresh biopsy not previously irradiated.  Site documentation that the sample has been shipped to the biomarker analysis 
laboratory is sufficient evidence to meet eligibility criterion. If a tumor biopsy was obtained of a target lesion during eligibility assessment, it is preferred to obtain a new 
baseline scan.  Biopsy of lesions on study should be limited to non-target lesions or new lesions if their pathologic etiology is ambiguous.  The tissue sample should have 
proper size to enable multiple planned biomarker analyses, but not artificially decrease the longest diameter of the lesion.  Additionally, a fresh biopsy should be obtained 
10-14 days following initiation of study treatment for Parts 1 and 2 of the study.  The fresh biopsy at 10-14 days following initiation of study treatment is optional in Part 3 
of the study.  Detailed instructions for blood sample collection, tissue collection, processing and shipment are provided in the Laboratory and Procedures Manual, 
respectively.  Any leftover blood or tumor tissue will be stored for future research if the subject signs the optional FBR consent.    
23  Blood for genetics sample will be collected to explore host genetics and to identify genetic predictors which may have a role in therapeutic response to pembrolizumab.
24  Telephone Contact at Days 8, 15, 29, and 36 of Cycle 1 only.  Review Adverse Events and Concomitant Medications.
25  The discontinuation visit should be scheduled at the time of permanent discontinuation of all treatments (pembrolizumab, trametinib, and/or dabrafenib).  The window 
for this visit is +10 days.  Required assessments for this visit are identified in the study flow chart; additional assessments that are not flagged as required may be performed 
if clinically indicated (e.g., coagulation tests, thyroid function tests, etc.).
26  Perform a full physical examination on the first day of each cycle and a directed physical examination on Day 22 of each cycle.  Example:  full physical exam on C3D1, 
directed physical exam on C3D22, full physical exam on C4D1, directed physical exam on C4D22, etc.
27  Day 1 and 22 of Cycle 3:  CBC with Differential, Comprehensive Chemistry Panel
Day 1 ONLY from C3D1 onwards:  Urinalysis
Day 1 ONLY from C4D1 onwards:  CBC with Differential, Comprehensive Chemistry Panel
Day 1 ONLY of every cycle (e.g., C3D1, C4D1, C5D1, etc.):  ECOG Performance Status
Day 1 and 22 of every cycle (e.g., C3D1, C3D22, C4D1, C4D22, etc.):  Dispensation of Drug Kit
Day 1 ONLY of every cycle (e.g., C3D1, C4D1, C5D1, etc.) until 18 months, then Day 1 ONLY of every other cycle:  Tumor Imaging
Day 1 ONLY of every alternate cycle (e.g., C3D1, C5D1, C7D1, etc.):  ECG, ECHO, Pharmacokinetics of pembrolizumab and/or trametinib and/or dabrafenib, Anti-
pembrolizumab Antibodies testing
28  Additional optional biopsy at disease progression is highly desired when feasible.   Detailed instructions for tissue collection, processing and shipment are provided in 
the Procedures Manual.
29  Dermatological examination will be part of full physical examination on the first day of each cycle.
30  Updated survival status may be requested by the Sponsor at any time during the course of the study. Upon Sponsor notification, all participants who do not/will not have 
a scheduled study visit or study contact during the Sponsor defined time period will be contacted for their survival status (excluding participants who have a death event 
previously recorded).
 
 
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Parts 4 and 5:  4-Week Monotherapy Trametinib + 6-Week Treatment Cycle(s) of Pembrolizumab Q3W Dosing With 
Trametinib
Trial Period:
Screening9
4-Week Monotherapy Trametinib + 6-Week Combination 
Treatment Cycle(s)
End of 
Treatment
Visit Number:
1
2
3
4
5
6
7
8
9
10
11
12
13
> 14
Discontinuation23
Days
(-28 to -1)
1
8
15
22
29
36
43
50
57
64
1
22
1,22
Cycle
1
2
> 3
Scheduling Window (Days)
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Administrative Procedures
Informed Consent1
X
Informed Consent for Future Biomedical Research 
(optional)
X
Inclusion/Exclusion Criteria
X
Subject Identification Card
X
Demographics and Medical History2
X
Prior and Concomitant Medication Review3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Treatment Assignment
X
Survival Status30
Clinical Procedures / Assessments
Full Physical Examination27
X
X
X
X
X24
Directed Physical Examination
X
X
X
X
X
X
X
X
X
X24
X
Vital Signs and Weight4
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-Lead Electrocardiogram (ECG)5
X
X
X
X25
ECHO
X
X
X25
Review Adverse Events6,7,8
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECOG Performance Status
X
X
X
X
X25
X
 
 
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Confidential
Trial Period:
Screening9
4-Week Monotherapy Trametinib + 6-Week Combination 
Treatment Cycle(s)
End of 
Treatment
Visit Number:
1
2
3
4
5
6
7
8
9
10
11
12
13
> 14
Discontinuation23
Days
(-28 to -1)
1
8
15
22
29
36
43
50
57
64
1
22
1,22
Cycle
1
2
> 3
Scheduling Window (Days)
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Laboratory Procedures / Assessments9
Pregnancy Test - Urine or Serum -HCG10
X
CBC with Differential11
X
X
X
X
X
X
X
X
X
X
X
X
X
X25
X
Comprehensive Serum Chemistry Panel11
X
X
X
X
X
X
X
X
X
X
X
X
X
X25
X
Urinalysis11
X
X
X
X
X
X
X
X
X
X
X
X
X
X25
X
PT/INR and aPTT12
X
As clinically indicated
Calculated Creatinine Clearance
X
T3, FT4 and TSH11,13
X
X
X
X
X
X
Hepatitis B and C14
X
Blood for Future Biomedical Research15 (optional)
X
Drug Dispensation, Administration, and Associated Analyses
pembrolizumab Administration (30-minute infusion) 28,29
X
X
X
X
X
Pharmacokinetics of pembrolizumab16
X
X
X
X25
Anti-pembrolizumab Antibodies17
X
X
X25
Dispensation of pembrolizumab
X
X
X
X
X25
Dispensation of Trametinib
X
X
X
X
X
X25
Dosing Regimen Trametinib (cDL1, cDL2b regimens 
only)28
X
X
X
X
X
X
X
X
X
X
X
X
X
Dosing Regimen Trametinib (cDL-1b, cDL-1a regimens 
only)29
X
X
X
X
X
X
X
X
X
Pharmacokinetics of Trametinib18
X
X
X25
X
 
 
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Product:  MK-3475 
125
Protocol/Amendment No.: 022-06 
MK-3475-022-06 Final Protocol
05-DEC-2019
Confidential
Trial Period:
Screening9
4-Week Monotherapy Trametinib + 6-Week Combination 
Treatment Cycle(s)
End of 
Treatment
Visit Number:
1
2
3
4
5
6
7
8
9
10
11
12
13
> 14
Discontinuation23
Days
(-28 to -1)
1
8
15
22
29
36
43
50
57
64
1
22
1,22
Cycle
1
2
> 3
Scheduling Window (Days)
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Efficacy Measurements
Tumor Imaging19
X
X25
X
Tissue Collection and Pharmacodynamic Assessment
BRAF Testing20
X
Tumor Tissue Collection21
X
X
X26
Correlative Blood Sample21
X
X
X
X
Blood for Genetics22
X
1 Written consent must be obtained prior to performing any protocol-specific procedure. Results of a test performed prior to the subject signing consent as part of routine clinical 
management are acceptable in lieu of a screening test if performed within the specified time frame (e.g. within 28 days prior to Day 1). Assign Baseline number when the study informed 
consent is signed.
2 Includes history of treatment for the primary diagnosis, including prior systemic, radiation treatment and surgical treatment, and best response to prior systemic treatments.  Date of last 
prior cancer treatment must be documented.  Radiographic studies performed prior to study entry may be collected for review by the investigator.
3 Prior Medications - Report all medications taken within 30 days of Visit 1 and all treatments for a prior cancer even if taken greater than 30 days prior to Visit 1.  Concomitant Medications 
- Enter new medications started during the trial through the Safety Follow-Up visit.  After the Safety Follow-Up visit, record all medications taken for SAEs and ECIs as defined in Section 
7.2. 
4 Vital signs to include temperature, pulse, respiratory rate and blood pressure. If a patient's baseline weight does not fluctuate by more than 10%, this weight can be used to calculate dose.  
Height will be measured at Visit 1 only.
5 Electrocardiogram (12-lead ECG) should be performed at Screening and post-infusion at visits indicated in the flow chart.  
6 Adverse experiences and laboratory safety measurements will be graded per NCI CTCAE version 4.0. All adverse experiences, whether gradable by CTCAE or not, will also be evaluated 
for seriousness.
7 Any adverse experience of unknown etiology associated with trial treatment exposure should be evaluated to determine if it is possibly an Event of Clinical Interest (ECI).
8 Evaluate patients for symptoms or clinical signs of non-cutaneous, new primary/recurrent malignancies before initiation of treatment, periodically during treatment, or as clinically 
indicated. Following discontinuation of dabrafenib, monitoring for non-cutaneous secondary/recurrent malignancies should continue for up to 6 months or until initiation of another anti-
neoplastic therapy. Abnormal findings should be managed according to clinical practices.
9 Routine laboratory tests (chemistry; hematology) for screening should be performed  within 10 days prior to the first dose of trial treatment.  See Section 7.1.3 for details regarding 
laboratory tests.
10  For women of reproductive potential, a urine pregnancy test will be performed within 72 hours prior to first dose of trial treatment.  If urine pregnancy results cannot be confirmed as 
negative, a serum pregnancy test, performed by the local study site laboratory, will be required.  Pregnancy tests (serum and/or urine tests) should be repeated if required by local guidelines.
11  After Cycle 1, lab samples can be collected up to 48 hours prior to the scheduled time point.  Laboratory results must be known and acceptable prior to dosing.  See Section 7.1.3 for 
details regarding laboratory tests.
12  Coagulation factors (PT/INR and aPTT) should be monitored closely throughout the trial for any subject receiving anticoagulant therapy.
13 Thyroid function tests will be performed by a central laboratory only if the local laboratory is unable to perform this service.  Following Cycle 4, testing will be performed every other 
cycle.  In countries where T3 results are not available, FT3 results may be reported.  See Section 7.1.3 for details regarding laboratory tests.
 
 
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Confidential
14  Testing will be performed by the local laboratory at Screening.  Hepatitis B and Hepatitis C serologies should be obtained for subjects without a known history of Hepatitis B or C.  Those 
with a known history are ineligible.  Include HCV RNA (qualitative) and HBsAg.  
15  Informed consent for Future Biomedical Research (FBR) samples must be obtained before the DNA sample is drawn.  DNA sample for analysis should be obtained predose, on Day 1 (or 
with the next scheduled blood draw), as the last sample drawn, on allocated subjects only, or at a later date as soon as the informed consent is obtained. This sample should only be taken once 
from each subject.  See Section 12.2 for guidance regarding the collection and management of specimens for FBR.
16  Pre-dose and post-dose serum samples for PK of pembrolizumab will be collected on Day 29 and Day 50 of Cycle 1 and Day 1 of Cycle 2.  Thereafter, only pre-dose (Ctrough) PK serum 
samples will be collected at Day 1 of every alternate cycle (i.e., Day 1 of Cycle 3, Day 1 of Cycle 5, etc.).  All pre-dose (Ctrough) samples should be collected within 24 hours before the start of 
infusion of pembrolizumab and, if blood is collected for anti-pembrolizumab antibodies, at the same time blood sample for anti-pembrolizumab antibodies is collected.  All post-dose PK 
samples should be collected within 30 minutes after the end of infusion of pembrolizumab.  One additional post-dose sample should be collected between 24 and 96 hours following C1D29.  
Procedures for collection of samples are described in the Procedures Manual.
17  Blood for anti-pembrolizumab antibodies should be collected on Day 29 of Cycle 1 and Day 1 of Cycle 2, 3, and every other cycle thereafter (Cycle 5, Cycle 7, etc.).  During 
pembrolizumab treatment, all samples should be drawn within 24 hours before infusion of pembrolizumab at the same time as blood collection for pre-dose (Ctrough) PK serum samples of 
pembrolizumab.
18  On C1D50, both pre-dose and post-dose plasma samples for PK of trametinib will be collected.  On C1D50, morning dose(s) should be withheld until after PK (pre-dose) sample has been 
drawn.  On C1D50, post-dose PK samples for trametinib should be drawn (1) at the same time as when the post-dose pembrolizumab PK sample is drawn (the end of infusion), and, (2) at 
approximately 4-6 hours post-dose.  On C2D1, subjects should take their morning dose at home.  A post-dose sample will be obtained during study visit.  Thereafter, PK plasma samples will 
be collected at Day 1 of every alternate cycle (i.e., Day 1 of Cycle 3, Day 1 of Cycle 5, etc.) during study visit.  If visit is in the morning, subjects will be asked to withhold their morning 
dose; if visit is in the afternoon, subjects will be asked to take their morning dose as usual. Procedures for collection of samples are described in the Procedures Manual.
19  The initial tumor imaging will be performed within 28 days prior to the date of allocation.  Scans performed as part of routine clinical management are acceptable for use as the screening 
scan if they are of diagnostic quality and performed within 28 days prior to the first dose of trial treatment.  CT scans are the required modality for measurable disease unless a subject has a 
clinical condition, e.g., severe contrast allergy.  The same imaging technique has to be used for the subject throughout the study.  The visit window for subsequent imaging is +/- 7 days.  If 
there is progressive disease, radiologic assessment/tumor imaging should be obtained at least four weeks from scan date for confirmation.  CT timing should follow calendar days and should 
not be adjusted for delays in cycle starts.  The process for collection of CT images is described in the Procedures Manual.  Tumor imaging will be performed every 6 weeks (or whenever 
clinically indicated) starting at Week 17 while the subject remains on study therapy; after 18 months, tumor imaging will be performed every 12 weeks (or whenever clinically indicated) 
while the subject remains on study therapy.  Per the modified RECIST 1.1 used in this protocol, if imaging shows progressive disease, the imaging assessment should be repeated at a 
minimum of 4 weeks later in order to confirm progressive disease as described in Section 4.2.3.1.  
20  BRAF mutation testing is only required for melanoma subjects; BRAF mutation testing is not required for solid tumor subjects.  BRAF V600 E or K mutation analysis should be 
performed by sites during screening in subjects without documented BRAF status.  This specimen may be collected any time from the initial diagnosis to the study entry and may be an 
archival tissue sample (within 6 months of study entry).  BRAF analysis may be performed at a local laboratory, provided that the methodology is able to detect V600E and/or V600K 
mutations.  A sample from the originally-tested tissue block must be collected and stored at the central laboratory for possible assay at a later date (i.e., in the event that BRAF status must be 
confirmed).  Detailed instructions for tissue collection, processing and shipment are provided in the Procedures Manual.
21  In order to be eligible for the study, all subjects must provide a tumor tissue specimen for biomarker analysis and blood samples for pharmacodynamic assessment.  The tissue specimen 
may be collected any time from the initial diagnosis to the study entry and may be an archival tissue sample (within 90 days of Study Day 1=first dose(s) of study treatment) if it is not 
feasible to obtain a fresh biopsy not previously irradiated.  Site documentation that the sample has been shipped to the biomarker analysis laboratory is sufficient evidence to meet eligibility 
criterion.  If a tumor biopsy was obtained of a target lesion during eligibility assessment, it is preferred to obtain a new baseline scan.  Biopsy of lesions on study should be limited to non-
target lesions or new lesions if their pathologic etiology is ambiguous.  The tissue sample should have proper size to enable multiple planned biomarker analyses, but not artificially decrease 
the longest diameter of the lesion.  Additionally, a fresh biopsy should be obtained 10-14 days following initiation of pembrolizumab study treatment for Parts 4 and 5 of the study.  Detailed 
instructions for blood sample collection, tissue collection, processing and shipment are provided in the Laboratory and Procedures Manual, respectively. Any leftover blood or tumor tissue 
may be stored for future research if the subject signs the optional FBR consent.
22  Blood for genetics sample will be collected to explore host genetics and to identify genetic predictors which may have a role in therapeutic response to pembrolizumab
23  The discontinuation visit should be scheduled at the time of permanent discontinuation of all treatments (pembrolizumab and trametinib). The window for this visit is +10 days. All study 
treatments must be discontinued after 24 months.   Required assessments for this visit are identified in the study flow chart; additional assessments that are not flagged as required may be 
performed if clinically indicated (e.g., coagulation tests, thyroid function tests, etc.).
24  Perform a full physical examination on the first day of each cycle and a directed physical examination on Day 22 of each cycle.  Example:  full physical exam on C3D1, directed physical 
exam on C3D22, full physical exam on C4D1, directed physical exam on C4D22, etc
 
 
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Confidential
25  Day 1 and 22 of Cycle 3:  CBC with Differential, Comprehensive Chemistry Panel, Urinalysis
Day 1 ONLY from C4D1 onwards:  CBC with Differential, Comprehensive Chemistry Panel, Urinalysis
Day 1 ONLY of every cycle (e.g., C3D1, C4D1, C5D1, etc.):  ECOG Performance Status
Day 1 and 22 of every cycle (e.g., C3D1, C3D22, C4D1, C4D22, etc.):  Dispensation of Drug Kit
Day 1 ONLY of every cycle (e.g., C3D1, C4D1, C5D1, etc.) until 18 months, then Day 1 ONLY of every other cycle:  Tumor Imaging
Day 1 ONLY of every alternate cycle, as indicated (e.g., C3D1, C5D1, C7D1, etc.):  ECG, ECHO, Pharmacokinetics of pembrolizumab and/or trametinib and/or dabrafenib, Anti-pembrolizumab Antibodies testing
26  pembrolizumab treated subjects in the Treatment Phase – Additional optional biopsy at disease progression is highly desired when feasible.   Detailed instructions for tissue collection, 
processing and shipment are provided in the Procedures Manual.
27  Dermatological examination will be part of full physical examination on the first day of each cycle.
28  The following dosing regimens reflect the intended dosing of the subject at study initiation.  The original dosing code should be utilized to determine when the subject should be dosed
during the study.  The dose timing associated with the original dosing code should continue to be used to bring the patient back into the schedule (1) if the patient ultimately dose reduced
(e.g., due to AE) or (2) following study treatment interruption:
cDL1 = Subject allocated to study on 4 weeks of 1.5 mg QD trametinib, pembrolizumab 200 mg Q3W dosed at week 5 (Day 29) and week 8 (Day 50) with continuous dosing of trametinib in 
Cycle 1.  Cycle 2 and beyond:  pembrolizumab dosed at week 1 (Day 1) and week 4 (Day 22) with continuous dosing of trametinib in the cycle.
cDL2b = Subject allocated to study on 4 weeks of 2 mg QD trametinib, pembrolizumab 200 mg Q3W dosed at week 5 (Day 29) and week 8 (Day 50) with continuous dosing of trametinib in 
Cycle 1.  Cycle 2 and beyond:  MK-347 dosed at week 1 (Day 1) and week 4 (Day 22) with continuous dosing of trametinib in the cycle.
29  The following dosing regimens reflect the intended dosing of the subject at initiation and the original dosing code should be utilized to determine when the patient should be dosed during 
the study The dose timing associated with the original dosing code should continue to be used to bring the patient back into the schedule (1) if the patient ultimately dose reduced (e.g., due to 
AE) or (2) following study treatment interruption:
cDL-1a =  Subject allocated to study on 4 weeks of 1.5 mg QD trametinib, pembrolizumab 200 mg Q3W dosed week 5 (Day 29) and week 8 (Day 50) with no dosing of trametinib during 
weeks 5 and 6 (Days 29-42), dosing of trametinib during weeks 7 and 8 (Days 43-56), and no dosing of trametinib during weeks 9 and 10 (Days 57-70) of Cycle 1.  Cycles 2, 4, and even-
numbered cycles:  pembrolizumab dosed at week 1 (Day 1) and week 4 (Day 22), with dosing of trametinib during weeks 1 and 2 (Days 1-14), no dosing of trametinib during weeks 3 and 4 
(Days 15-28), and dosing of trametinib during weeks 5 and 6 (Days 29-42).  Cycles 3, 5, and subsequent odd-numbered cycles:  pembrolizumab dosed at week 1 (Day 1) and week 4 (Day 
22), with no dosing of trametinib during weeks 1 and 2 (Days 1-14), dosing of trametinib during weeks 3 and 4 (Days 15-28), and no dosing of trametinib during weeks 5 and 6 (Days 29-42).  
cDL-1b = Subject allocated to study on 4 weeks of 2 mg QD trametinib, pembrolizumab 200 mg Q3W dosed week 5 (Day 29) and week 8 (Day 50) with no dosing of trametinib during 
weeks 5 and 6 (Days 29-42), dosing of trametinib during weeks 7 and 8 (Days 43-56), and no dosing of trametinib during weeks 9 and 10 (Days 57-70) of Cycle 1.  Cycles 2, 4, and even-
numbered cycles:  pembrolizumab dosed at week 1 (Day 1) and week 4 (Day 22), with dosing of trametinib during weeks 1 and 2 (Days 1-14), no dosing of trametinib during weeks 3 and 4 
(Days 15-28), and dosing of trametinib during weeks 5 and 6 (Days 29-42).  Cycles 3, 5, and subsequent odd-numbered cycles:  pembrolizumab dosed at week 1 (Day 1) and week 4 (Day 
22), with no dosing of trametinib during weeks 1 and 2 (Days 1-14), dosing of trametinib during weeks 3 and 4 (Days 15-28), and no dosing of trametinib during weeks 5 and 6 (Days 29-42). 
30  Updated survival status may be requested by the Sponsor at any time during the course of the study. Upon Sponsor notification, all participants who do not/will not have a scheduled 
study visit or study contact during the Sponsor defined time period will be contacted for their survival status (excluding participants who have a death event previously recorded).
 
 
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Parts 4 and 5:  2-Week Monotherapy Trametinib + 6-Week Treatment Cycle(s) of Pembrolizumab Q3W Dosing With 
Trametinib
Trial Period:
Screening9
2-Week Monotherapy Trametinib + 6-Week Combination 
Treatment Cycle(s)
End of 
Treatment
Visit Number:
1
2
3
4
5
6
7
8
9
10
11
> 12
Discontinuation23
Days
(-28 to -1)
1
8
15
22
29
36
43
50
1
22
1,22
Cycle
1
2
> 3
Scheduling Window (Days)
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Administrative Procedures
Informed Consent1
X
Informed Consent for Future Biomedical Research 
(optional)
X
Inclusion/Exclusion Criteria
X
Subject Identification Card
X
Demographics and Medical History2
X
Prior and Concomitant Medication Review3
X
X
X
X
X
X
X
X
X
X
X
X
X
Treatment Assignment
X
Survival Status31
Clinical Procedures / Assessments
Full Physical Examination27
X
X
X
X
X24
Directed Physical Examination
X
X
X
X
X
X
X
X24
X
Vital Signs and Weight4
X
X
X
X
X
X
X
X
X
X
X
X
X
12-Lead Electrocardiogram (ECG)5
X
X
X
X25
ECHO
X
X
X25
Review Adverse Events6,7,8
X
X
X
X
X
X
X
X
X
X
X
X
ECOG Performance Status
X
X
X
X
X25
X
 
 
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Product:  MK-3475 
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Protocol/Amendment No.: 022-06 
MK-3475-022-06 Final Protocol
05-DEC-2019
Confidential
Trial Period:
Screening9
2-Week Monotherapy Trametinib + 6-Week Combination 
Treatment Cycle(s)
End of 
Treatment
Visit Number:
1
2
3
4
5
6
7
8
9
10
11
> 12
Discontinuation23
Days
(-28 to -1)
1
8
15
22
29
36
43
50
1
22
1,22
Cycle
1
2
> 3
Scheduling Window (Days)
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Laboratory Procedures / Assessments9
Pregnancy Test - Urine or Serum -HCG10
X
CBC with Differential11
X
X
X
X
X
X
X
X
X
X
X
X25
X
Comprehensive Serum Chemistry Panel11
X
X
X
X
X
X
X
X
X
X
X
X25
X
Urinalysis11
X
X
X
X
X
X
X
X
X
X
X
X25
X
PT/INR and aPTT12
X
As clinically indicated
Calculated Creatinine Clearance
X
T3, FT4 and TSH11,13
X
X
X
X
X
X
Hepatitis B and C14
X
Blood for Future Biomedical Research15 (optional)
X
Drug Dispensation, Administration, and Associated Analyses
pembrolizumab Administration (30-minute infusion) 28,29,30
X
X
X
X
X
Pharmacokinetics of pembrolizumab16
X
X
X
X25
Anti-pembrolizumab Antibodies17
X
X
X25
Dispensation of pembrolizumab
X
X
X
X
X25
Dispensation of Trametinib
X
X
X
X
X
X25
Dosing Regimen Trametinib (cDL2a, cDL3 regimens 
only)28
X
X
X
X
X
X
X
X
X28
X28
X
Dosing Regimen Trametinib (iDL1, iDL2 regimens only)29
X
X
X
X
X
X
X29
X29
X
Dosing Regimen Trametinib (iDL-1b, iDL-1a regimens 
only)30
X
X
X
X
X30
X30
X
Pharmacokinetics of Trametinib18
X
X
X25
X
 
 
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Product:  MK-3475 
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MK-3475-022-06 Final Protocol
05-DEC-2019
Confidential
Trial Period:
Screening9
2-Week Monotherapy Trametinib + 6-Week Combination 
Treatment Cycle(s)
End of 
Treatment
Visit Number:
1
2
3
4
5
6
7
8
9
10
11
> 12
Discontinuation23
Days
(-28 to -1)
1
8
15
22
29
36
43
50
1
22
1,22
Cycle
1
2
> 3
Scheduling Window (Days)
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Efficacy Measurements
Tumor Imaging19
X
X25
X
Tissue Collection and Pharmacodynamic Assessment
BRAF Testing20
X
Tumor Tissue Collection21
X
X
X26
Correlative Blood Sample21
X
X
X
X
Blood for Genetics22
X
1  Written consent must be obtained prior to performing any protocol-specific procedure. Results of a test performed prior to the subject signing consent as part of routine clinical 
management are acceptable in lieu of a screening test if performed within the specified time frame (e.g. within 28 days prior to Day 1). Assign Baseline number when the study informed 
consent is signed.
2  Includes history of treatment for the primary diagnosis, including prior systemic, radiation treatment and surgical treatment, and best response to prior systemic treatments.  Date of last 
prior cancer treatment must be documented.  Radiographic studies performed prior to study entry may be collected for review by the investigator.
3  Prior Medications - Report all medications taken within 30 days of Visit 1 and all treatments for a prior cancer even if taken greater than 30 days prior to Visit 1.  Concomitant 
Medications - Enter new medications started during the trial through the Safety Follow-Up visit.  After the Safety Follow-Up visit, record all medications taken for SAEs and ECIs as 
defined in Section 7.2. 
4  Vital signs to include temperature, pulse, respiratory rate and blood pressure. If a patient's baseline weight does not fluctuate by more than 10%, this weight can be used to calculate dose.  
Height will be measured at Visit 1 only.
5  Electrocardiogram (12-lead ECG) should be performed at Screening and post-infusion at visits indicated in the flow chart.  
6  Adverse experiences and laboratory safety measurements will be graded per NCI CTCAE version 4.0. All adverse experiences, whether gradable by CTCAE or not, will also be 
evaluated for seriousness.
7  Any adverse experience of unknown etiology associated with trial treatment exposure should be evaluated to determine if it is possibly an Event of Clinical Interest (ECI).
8  Evaluate patients for symptoms or clinical signs of non-cutaneous, new primary/recurrent malignancies before initiation of treatment, periodically during treatment, or as clinically 
indicated. Following discontinuation of dabrafenib, monitoring for non-cutaneous secondary/recurrent malignancies should continue for up to 6 months or until initiation of another anti-
neoplastic therapy. Abnormal findings should be managed according to clinical practices.
9  Routine laboratory tests (chemistry; hematology) for screening should be performed  within 10 days prior to the first dose of trial treatment.  See Section 7.1.3 for details regarding 
laboratory tests.
10  For women of reproductive potential, a urine pregnancy test will be performed within 72 hours prior to first dose of trial treatment.  If urine pregnancy results cannot be confirmed as 
negative, a serum pregnancy test, performed by the local study site laboratory, will be required.  Pregnancy tests (serum and/or urine tests) should be repeated if required by local guidelines.
11  After Cycle 1, lab samples can be collected up to 48 hours prior to the scheduled time point.  Laboratory results must be known and acceptable prior to dosing.  See Section 7.1.3 for 
details regarding laboratory tests.
12  Coagulation factors (PT/INR and aPTT) should be monitored closely throughout the trial for any subject receiving anticoagulant therapy.
 
 
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13  Thyroid function tests will be performed by a central laboratory only if the local laboratory is unable to perform this service.  Following Cycle 4, testing will be performed every other 
cycle.  In countries where T3 results are not available, FT3 results may be reported.  See Section 7.1.3 for details regarding laboratory tests.  
14  Testing will be performed by the local laboratory at Screening.  Hepatitis B and Hepatitis C serologies should be obtained for subjects without a known history of Hepatitis B or C.  
Those with a known history are ineligible.  Include HCV RNA (qualitative) and HBsAg.  
15  Informed consent for Future Biomedical Research (FBR) samples must be obtained before the DNA sample is drawn.  DNA sample for analysis should be obtained predose, on Day 1 
(or with the next scheduled blood draw), as the last sample drawn, on allocated subjects only, or at a later date as soon as the informed consent is obtained. This sample should only be taken 
once from each subject.  See Section 12.2 for guidance regarding the collection and management of specimens for FBR.
16  Pre-dose and post-dose serum samples for PK of pembrolizumab will be collected on Day 15 and Day 36 of Cycle 1 and Day 1 of Cycle 2.  Thereafter, only pre-dose (Ctrough) PK serum 
samples will be collected at Day 1 of every alternate cycle (i.e., Day 1 of Cycle 3, Day 1 of Cycle 5, etc.).  All pre-dose (Ctrough) samples should be collected within 24 hours before the start 
of infusion of pembrolizumab and, if blood is collected for anti-pembrolizumab antibodies, at the same time blood sample for anti-pembrolizumab antibodies is collected.  All post-dose PK 
samples should be collected within 30 minutes after the end of infusion of pembrolizumab.  One additional post-dose sample should be collected between 24 and 96 hours following 
C1D15.  Procedures for collection of samples are described in the Procedures Manual.
17  Blood for anti-pembrolizumab antibodies should be collected on Day 15 of Cycle 1 and Day 1 of Cycle 2, 3, and every other cycle thereafter (Cycle 5, Cycle 7, etc.).  During 
pembrolizumab treatment, all samples should be drawn within 24 hours before infusion of pembrolizumab at the same time as blood collection for pre-dose (Ctrough) PK serum samples of 
pembrolizumab.
18  PK for trametinib on C1D36:
cDL2a, cDL3, iDL-1a , iDL-1b:  both pre-dose and post-dose plasma samples will be collected. On C1D36, morning dose(s) should be withheld until after PK (pre-dose) sample has been 
drawn.  On C1D36, post-dose PK samples for trametinib should be drawn (1) at the same time as when the post-dose pembrolizumab PK sample is drawn (the end of infusion), and, (2) at 
approximately 4-6 hours post-dose.  
iDL1, iDL2:  Pre-dose plasma will be collected.
PK for trametinib on C2D1:cDL2a, cDL3, iDL-1a , iDL-1b:  Subject should take morning dose at home.  A post-dose sample will be obtained during study visit.  
iDL1, iDL2:  Pre-dose plasma will be collected.
Thereafter, for all regimens, PK plasma samples will be collected at Day 1 of every alternate cycle (i.e., Day 1 of Cycle 3, Day 1 of Cycle 5, etc.) during study visit.  If visit is in the 
morning, subjects will be asked to withhold their morning dose; if visit is in the afternoon, subjects will be asked to take their morning dose as usual. Procedures for collection of samples 
are described in the Procedures Manual.
19  The initial tumor imaging will be performed within 28 days prior to the date of allocation.  Scans performed as part of routine clinical management are acceptable for use as the 
screening scan if they are of diagnostic quality and performed within 28 days prior to the first dose of trial treatment.  CT scans are the required modality for measurable disease unless a 
subject has a clinical condition, e.g., severe contrast allergy.  The same imaging technique has to be used for the subject throughout the study.  The visit window for subsequent imaging is 
±7 days.  If there is progressive disease, radiologic assessment/tumor imaging should be obtained at least four weeks from scan date for confirmation.  CT timing should follow calendar 
days and should not be adjusted for delays in cycle starts.  The process for collection of CT images is described in the Procedures Manual.  Tumor imaging will be performed every 6 
weeks (or whenever clinically indicated) starting at Week 15 while the subject remains on study therapy; after 18 months, tumor imaging will be performed every 12 weeks (or whenever 
clinically indicated) while the subject remains on study therapy.  Per the modified RECIST 1.1 used in this protocol, if imaging shows progressive disease, the imaging assessment should 
be repeated at a minimum of 4 weeks later in order to confirm progressive disease as described in Section 4.2.3.1.  
20  BRAF mutation testing is only required for melanoma subjects; BRAF mutation testing is not required for solid tumor subjects.  BRAF V600 E or K mutation analysis should be 
performed by sites during screening in subjects without documented BRAF status.  This specimen may be collected any time from the initial diagnosis to the study entry and may be an 
archival tissue sample (within 6 months of study entry).  BRAF analysis may be performed at a local laboratory, provided that the methodology is able to detect V600E and/or V600K 
mutations.  A sample from the originally-tested tissue block must be collected and stored at the central laboratory for possible assay at a later date (i.e., in the event that BRAF status must 
be confirmed).  Detailed instructions for tissue collection, processing and shipment are provided in the Procedures Manual.  
21  In order to be eligible for the study, all subjects must provide a tumor tissue specimen for biomarker analysis and blood samples for pharmacodynamic assessment.  The tissue specimen 
may be collected any time from the initial diagnosis to the study entry and may be an archival tissue sample (within 90 days of Study Day 1=first dose(s) of study treatment) if it is not 
feasible to obtain a fresh biopsy not previously irradiated.  Site documentation that the sample has been shipped to the biomarker analysis laboratory is sufficient evidence to meet eligibility 
criterion.  If a tumor biopsy was obtained of a target lesion during eligibility assessment, it is preferred to obtain a new baseline scan.  Biopsy of lesions on study should be limited to non-
target lesions or new lesions if their pathologic etiology is ambiguous.  The tissue sample should have proper size to enable multiple planned biomarker analyses, but not artificially 
decrease the longest diameter of the lesion.  Additionally, a fresh biopsy should be obtained 10-14 days following initiation of pembrolizumab study treatment for Parts 4 and 5 of the study.  
Detailed instructions for blood sample collection, tissue collection, processing and shipment are provided in the Laboratory and Procedures Manual, respectively. Any leftover blood or 
tumor tissue may be stored for future research if the subject signs the optional FBR consent.  
22  Blood for genetics sample will be collected to explore host genetics and to identify genetic predictors which may have a role in therapeutic response to pembrolizumab.
23  The discontinuation visit should be scheduled at the time of permanent discontinuation of all treatments (pembrolizumab and trametinib).  The window for this visit is +10 days.  All 
 
 
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study treatments must be discontinued after 24 months.  Required assessments for this visit are identified in the study flow chart; additional assessments that are not flagged as required may 
be performed if clinically indicated (e.g., coagulation tests, thyroid function tests, etc.).
24  Perform a full physical examination on the first day of each cycle and a directed physical examination on Day 22 of each cycle.  Example:  full physical exam on C3D1, directed 
physical exam on C3D22, full physical exam on C4D1, directed physical exam on C4D22, etc.
25  Day 1 and 22 of Cycle 3:  CBC with Differential, Comprehensive Chemistry Panel, Urinalysis
Day 1 ONLY from C4D1 onwards:  CBC with Differential, Comprehensive Chemistry Panel, Urinalysis
Day 1 ONLY of every cycle (e.g., C3D1, C4D1, C5D1, etc.):  ECOG Performance Status
Day 1 and 22 of every cycle (e.g., C3D1, C3D22, C4D1, C4D22, etc.):  Dispensation of Drug Kit
Day 1 ONLY of every cycle (e.g., C3D1, C4D1, C5D1, etc.) until 18 months, then Day 1 ONLY of every other cycle:  Tumor Imaging
Day 1 ONLY of every alternate cycle, as indicated (e.g., C3D1, C5D1, C7D1, etc.):  ECG, ECHO, Pharmacokinetics of pembrolizumab and/or trametinib and/or dabrafenib, Anti-pembrolizumab Antibodies testing
26  pembrolizumab treated subjects in the Treatment Phase – Additional optional biopsy at disease progression is highly desired when feasible.   Detailed instructions for tissue collection, 
processing and shipment are provided in the Procedures Manual.
27  Dermatological examination will be part of full physical examination on the first day of each cycle.
28  The following dosing regimens reflect the intended dosing of the subject at study initiation.  The original dosing code should be utilized to determine when the subject should be dosed 
during the study.  The dose timing associated with the original dosing code should continue to be used to bring the patient back into the schedule (1) if the patient ultimately dose reduced 
(e.g., due to AE) or (2) following study treatment interruption:
cDL2a = Subject allocated to study on 2 weeks of 1.5 mg QD trametinib, pembrolizumab 200 mg Q3W dosed at week 3 (Day 15) and week 6 (Day 36) with continuous dosing of trametinib 
in Cycle 1.  Cycle 2 and beyond:   pembrolizumab dosed at week 1 (Day 1) and week 4 (Day 22) with continuous dosing of trametinib in the cycle.
cDL3 = Subject allocated to study on 2 weeks of 2 mg QD trametinib, pembrolizumab 200 mg Q3W dosed at week 3 (Day 15) and week 6 (Day 36)  with continuous dosing of trametinib
in Cycle 1.  Cycle 2 and beyond:  MK-347 dosed at week 1 (Day 1) and week 4 (Day 22) with continuous dosing of trametinib in the cycle.
29  The following dosing regimens reflect the intended dosing of the subject at initiation and the original dosing code should be utilized to determine when the patient should be dosed 
during the study The dose timing associated with the original dosing code should continue to be used to bring the patient back into the schedule (1) if the patient ultimately dose reduced 
(e.g., due to AE) or (2) following study treatment interruption:
iDL1 =  Subject allocated to study on 2 weeks of 1.5 mg QD trametinib, pembrolizumab 200 mg Q3W dosed week 3 (Day 15) and week 6 (Day 36) with no dosing of trametinib during 
week 3 (Days 15-21), dosing of trametinib during weeks 4 and 5 (Days 22-35), no dosing of trametinib during week 6 (Days 36-42), and dosing of trametinib during weeks 7 and 8 (Days 
43-56) of Cycle 1.  Cycles 2, 3, and beyond:  pembrolizumab dosed at week 1 (Day 1) and week 4 (Day 22), with no dosing of trametinib during week 1 (Days 1-7), dosing of trametinib 
during weeks 2 and 3 (Days 8-21), no dosing of trametinib during week 4 (Days 22-28), and dosing of trametinib during  weeks 5 and 6 (Days 29-42).
iDL2 = Subject allocated to study on 2 weeks of 2 mg QD trametinib, pembrolizumab 200 mg Q3W dosed week 3 (Day 15) and week 6 (Day 36) with no dosing of trametinib during week 
3 (Days 15-21), dosing of trametinib during weeks 4 and 5 (Days 22-35), no dosing of trametinib during week 6 (Days 36-42), and dosing of trametinib during weeks 7 and 8 (Days 43-56) 
of Cycle 1.  Cycles 2, 3, and beyond:  pembrolizumab dosed at week 1 (Day 1) and week 4 (Day 22), with no dosing of trametinib during week 1 (Days 1-7), dosing of trametinib during 
weeks 2 and 3 (Days 8-21), no dosing of trametinib during week 4 (Days 22-28), and dosing of trametinib during  weeks 5 and 6 (Days 29-42). 
30  The following dosing regimens reflect the intended dosing of the subject at initiation and the original dosing code should be utilized to determine when the patient should be dosed 
during the study The dose timing associated with the original dosing code should continue to be used to bring the patient back into the schedule (1) if the patient ultimately dose reduced 
(e.g., due to AE) or (2) following study treatment interruption:
iDL-1a =  Subject allocated to study on 2 weeks of 1.5 mg QD trametinib, pembrolizumab 200 mg Q3W dosed week 3 (Day 15) and week 6 (Day 36) with no dosing of trametinib during 
weeks 3 and 4 (Days 15-28), dosing of trametinib during weeks 5 and 6 (Days 29-42), and no dosing of trametinib during weeks 7 and 8 (Days 43-56) of Cycle 1.  Cycles 2, 4, and even-
numbered cycles:  pembrolizumab dosed at week 1 (Day 1) and week 4 (Day 22), with dosing of trametinib during weeks 1 and 2 (Days 1-14), no dosing of trametinib during weeks 3 and 4 
(Days 15-28), and dosing of trametinib during weeks 5 and 6 (Days 29-42).  Cycles 3, 5, and subsequent odd-numbered cycles:  pembrolizumab dosed at week 1 (Day 1) and week 4 (Day 
22), with no dosing of trametinib during weeks 1 and 2 (Days 1-14), dosing of trametinib during weeks 3 and 4 (Days 15-28), and no dosing of trametinib during weeks 5 and 6 (Days 29-
42).  
iDL-1b = Subject allocated to study on 2 weeks of 2 mg QD trametinib, pembrolizumab 200 mg Q3W dosed week 3 (Day 15) and week 6 (Day 36) with no dosing of trametinib during 
weeks 3 and 4 (Days 15-28), dosing of trametinib during weeks 5 and 6 (Days 29-42), and no dosing of trametinib during weeks 7 and 8 (Days 43-56) of Cycle 1.  Cycles 2, 4, and even-
numbered cycles:  pembrolizumab dosed at week 1 (Day 1) and week 4 (Day 22), with dosing of trametinib during weeks 1 and 2 (Days 1-14), no dosing of trametinib during weeks 3 and 4 
(Days 15-28), and dosing of trametinib during weeks 5 and 6 (Days 29-42).  Cycles 3, 5, and subsequent odd-numbered cycles:  pembrolizumab dosed at week 1 (Day 1) and week 4 (Day 
22), with no dosing of trametinib during weeks 1 and 2 (Days 1-14), dosing of trametinib during weeks 3 and 4 (Days 15-28), and no dosing of trametinib during weeks 5 and 6 (Days 29-
42).  
31  Updated survival status may be requested by the Sponsor at any time during the course of the study. Upon Sponsor notification, all participants who do not/will not have a scheduled 
study visit or study contact during the Sponsor defined time period will be contacted for their survival status (excluding participants who have a death event previously recorded).
 
 
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Post-Treatment Follow-Up ONLY for Subjects Who Discontinue Pembrolizumab Due to SD, PR or CR and Continue on 
Dabrafenib and/or Trametinib
Trial Period:
Treatment (6-Week Cycle)
End of Treatment
Visit
Post SD, PR or CR Treatment Cycle and beyond
Discontinuation10
Days
1
22
1
22
1,22
Scheduling Window (Days)
±3
±3
±3
±3
±3
Administrative Procedures
Prior and Concomitant Medication Review1
X
X
X
X
X
X
Survival Status17
Clinical Procedures / Assessments
Review Adverse Events2,3,4
X
X
X
X
X
X
Full Physical Examination14
X
X
X11
Directed Physical Examination
X
X
X11
X
Vital Signs and Weight5
X
X
X
X
X
X
12-Lead Electrocardiogram (ECG)
X
X
X12
ECHO
X
X
X12
ECOG Performance Status
X
X
X12
X
Laboratory Procedures / Assessments6
CBC with Differential7
X
X
X
X
X12
X
Comprehensive Chemistry Panel7
X
X
X
X
X12
X
Urinalysis7
X
X
X12
X
PT/INR and aPTT8
As clinically indicated
T3, FT4 and TSH7
X
X
X13
X
Drug Dispensation, Administration, and Associated Analyses
Dispensation of Drug Kit
X
X
X
X
X
Efficacy Measurements
Tumor Imaging9
X
X
X12
X
 
 
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1  Prior Medications - Report all medications taken within 30 days of Visit 1 and all treatments for a prior cancer even if taken greater than 30 days prior to Visit 1.  Concomitant 
Medications - Enter new medications started during the trial through the Safety Follow-Up visit.  
2  Adverse experiences and laboratory safety measurements will be graded per NCI CTCAE version 4.0. All adverse experiences, whether gradable by CTCAE or not, will also be 
evaluated for seriousness.
3  Any adverse experience of unknown etiology associated with trial treatment exposure should be evaluated to determine if it is possibly an Event of Clinical Interest (ECI).
4  Evaluate subjects for symptoms or clinical signs of non-cutaneous, new primary/recurrent malignancies before initiation of treatment, periodically during treatment, or as 
clinically indicated. Following discontinuation of dabrafenib, monitoring for non-cutaneous secondary/recurrent malignancies should continue for up to 6 months or until initiation 
of another anti-neoplastic therapy. Abnormal findings should be managed according to clinical practices.
5  Vital signs to include temperature, pulse, respiratory rate and blood pressure. If a subject's baseline weight does not fluctuate by more than 10%, this weight can be used to 
calculate dose.  Height will be measured at Visit 1 only.
6  Routine laboratory tests (chemistry; hematology) for screening should be performed  within 10 days prior to the first dose of trial treatment.  See Section 7.1.3 for details 
regarding laboratory tests.
7  After Cycle 1, lab samples can be collected up to 48 hours prior to the scheduled time point.  Laboratory results must be known and acceptable prior to dosing.  In countries 
where T3 results are not available, FT3 results may be reported.  See Section 7.1.3 for details regarding laboratory tests.
8  Coagulation factors (PT/INR and aPTT) should be monitored closely throughout the trial for any subject receiving anticoagulant therapy.
9  CT scans are the required modality for measurable disease unless a subject has a clinical condition, e.g., severe contrast allergy.  The same imaging technique has to be used for 
the patient throughout the study.  The visit window for imaging is ± 7 days. If there is progressive disease, radiologic assessment/tumor imaging should be obtained at least four 
weeks from scan date for confirmation.  CT timing should follow calendar days and should not be adjusted for delays in cycle starts.  Response status will be assessed by the 
investigator and/or the central vendor, depending on what part of the study and treatment arm the subject has discontinued.  The process for collection of CT images is described 
in the Procedures Manual.  Tumor imaging will be performed every 6 weeks (or whenever clinically indicated) starting at Week 13 while the subject remains on study therapy; 
after 18 months, tumor imaging will be performed every 12 weeks (or whenever clinically indicated) while the subject remains on study therapy.  Per the modified RECIST 1.1 
used in this protocol, if imaging shows progressive disease, the imaging assessment should be repeated at a minimum of 4 weeks later in order to confirm progressive disease as 
described in Section 4.2.3.1.    
10  The discontinuation visit should be scheduled at the time of permanent discontinuation of all treatments (pembrolizumab, trametinib, and/or dabrafenib).  The window for this 
visit is +10 days.  Required assessments for this visit are identified in the study flow chart; additional assessments that are not flagged as required may be performed if clinically 
indicated (e.g., coagulation tests, thyroid function tests, etc.).
11  Perform a full physical examination on the first day of each cycle and a directed physical examination on Day 22 of each cycle.  Example:  full physical exam on C3D1, 
directed physical exam on C3D22, full physical exam on C4D1, directed physical exam on C4D22, etc. 
12  Day 1 and 22 of Cycle 3:  CBC with Differential, Comprehensive Chemistry Panel
Day 1 ONLY from C3D1 onwards:  Urinalysis
Day 1 ONLY from C4D1 onwards:  CBC with Differential, Comprehensive Chemistry Panel
Day 1 ONLY of every cycle (e.g., C3D1, C4D1, C5D1, etc.):  ECOG Performance Status
Day 1 ONLY of every cycle (e.g., C3D1, C4D1, C5D1, etc.) until 18 months, then Day 1 ONLY of every other cycle:  Tumor Imaging
Day 1 ONLY of every alternate cycle (e.g., C3D1, C5D1, C7D1, etc.):  ECG, ECHO
13  Thyroid function tests will be performed by a central laboratory only if the local laboratory is unable to perform this service.  Following Cycle 4, testing will be performed 
every other cycle.
14  Dermatological examination will be part of full physical examination on the first day of each cycle.
15  Updated survival status may be requested by the Sponsor at any time during the course of the study. Upon Sponsor notification, all participants who do not/will not have a 
scheduled study visit or study contact during the Sponsor defined time period will be contacted for their survival status (excluding participants who have a death event previously 
recorded).
 
 
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Post-Treatment: Follow-Up
Trial Period:
Post-Treatment
Visit
Safety Follow-Up9
Follow-Up10 Visit 
1
Follow-Up10
Visit 2
Follow-Up10
> Visit 3 
Survival Follow-Up1 
> Visit 1
Time from Last Dose of Trial Treatment
30 Days
3 Months
6 Months
> 9 Months
Every 3 Months
Scheduling Window (Days)
± 3
± 7
± 7
± 7
± 30
Administrative Procedures
Review Medications
X
Subsequent Antineoplastic Therapy Status
X
X
X
X
X
Survival Status1
 
X
Clinical Procedures / Assessments
Review Adverse Events2,3
X
X
X
X
Vital Signs and Weight4
X
Directed Physical Examination11
X
X
X
12-Lead Electrocardiogram (ECG)
X
ECOG Performance Status
X
Efficacy Measurements
Tumor Imaging5
X
X
X
X
Laboratory Procedures / Assessments
CBC with Differential6
X
Comprehensive Chemistry Panel6
X
Laboratory Procedures / Assessments
Urinalysis
X
PT/INR and aPTT7
As clinically indicated
T3, FT4 and TSH
X
 
 
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Other Analyses
Patient Reported Outcomes (PRO)
EuroQol EQ-5D8
X
EORTC QLQ-C308
X
1  Once a subject experiences disease progression, starts a new antineoplastic therapy, or continues off study on any combination of treatments received during the 
trial, the subject moves into the Survival Follow-up Phase and should be contacted by telephone every 3 months to assess for survival status and start of new 
antineoplastic therapy, if applicable.  In addition, follow-up will be required at time of study completion if last follow-up was >30 days prior.  Updated survival 
status may be requested by the Sponsor at any time during the course of the study. Upon Sponsor notification, all participants who do not/will not have a scheduled 
study visit or study contact during the Sponsor defined time period will be contacted for their survival status (excluding participants who have a death event 
previously recorded), as per Section 7.1.5.
2  Record all AEs occurring within 30 days after the last dose of trial treatment.  Report all SAEs (related and unrelated to trial treatment), ECIs, and irAEs 
occurring within 90 days of the last dose of trial treatment or until the start of new anti-cancer treatment, whichever comes first.  After this time, report only SAEs 
and ECIs that are considered related to trial treatment.
3  Evaluate subjects for symptoms or clinical signs of non-cutaneous, new primary/recurrent malignancies before initiation of treatment, periodically during 
treatment, or as clinically indicated. Following discontinuation of dabrafenib, monitoring for non-cutaneous secondary/recurrent malignancies should continue for 
up to 6 months or until initiation of another anti-neoplastic therapy. Abnormal findings should be managed according to clinical practices.
4  Vital signs to include temperature, pulse, respiratory rate and blood pressure.
5  The same imaging technique should be used in a subject as was used earlier in the trial.  Subjects who discontinue study treatment due to reasons other than 
disease progression, should continue to be assessed every 3 months by radiologic imaging.  Monitoring should continue until the start of a new antineoplastic 
therapy, documented disease progression, or death, whichever occurs first.
6  See Section 7.1.3 for details regarding laboratory tests.
7  Coagulation factors (PT/INR and aPTT) should  be determined throughout the study when clinically indicated.
8  PROs apply to Part 3 Post-Treatment subjects only:  Patient reported outcomes (PROs) are to be administered by trained site personnel and completed 
electronically by subjects prior to all other study procedures in the following order: EuroQol EQ-5D first, followed by EORTC QLQ C-30.  Subjects that complete 
24 months on trial and opt to continue Dabrafenib and Trametinib will not be required to complete PROs at the 30-Day Safety follow up visit (Flow Chart 6.2).  
Subjects who complete 24 months on trial and move to Follow-Up or Survival Follow-Up will complete ePROs at the 30-Day Safety Follow-Up visit.  
pembrolizumab. PROs do not apply to Part 1, Part 2, Part 4, or Part 5It is most relevant and strongly recommended that ePROs are administered prior to drug 
administration, adverse event evaluation and disease status notification.
9  The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the last dose of trial treatment or before the initiation of a new 
antineoplastic treatment, whichever comes first.  Subjects with an AE of Grade >1 will be further followed until the resolution of the AE to Grade 0-1 or until 
beginning of a new antineoplastic therapy, whichever occurs first.
10  Subjects who discontinue trial treatment for a reason other than disease progression will move into the Follow-up Phase and should be assessed every 3 months 
by radiologic imaging to monitor disease status.  Follow-up Visit 1 should be scheduled 3 months after the last dose of trial treatment.  Follow-up Visit 2 should 
occur 6 months after the last dose of trial treatment.  After Follow-up Visit 3 subjects only need to be assessed every 3 months by radiologic imaging to monitor 
disease status, development of drug related SAEs and ECIs, and initiation of new antineoplastic therapy.  Unless otherwise noted in the flow chart, every effort 
should be made to collect subject information until the start of new antineoplastic therapy, disease progression, or death, whichever occurs first.  
11  Dermatological examination will be part of directed physical examination as indicated.   
 
 
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7.0 TRIAL PROCEDURES
Trial Procedures
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to 
perform these procedures at unscheduled time points if deemed clinically necessary by the 
investigator.
Furthermore, additional evaluations/testing may be deemed necessary by the investigator and 
or the Sponsor for reasons related to subject safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations 
may require that additional informed consent be obtained from the subject.  In these cases, 
such evaluations/testing will be performed in accordance with those regulations.
Administrative Procedures
Informed Consent
The investigator must obtain documented consent from each potential subject or each 
subject’s legally acceptable representative prior to participating in a clinical trial or Future 
Biomedical Research.
7.1.1.1.1
General Informed Consent
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion. 
A copy of the signed and dated consent form should be given to the subject before 
participation in the trial.
The initial informed consent form, any subsequent revised written informed consent form 
and any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The subject or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the trial.  The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the subject’s dated signature or 
by the subject’s legally acceptable representative’s dated signature.
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.  
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements.
 
 
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7.1.1.1.2
Consent and Collection of Specimens for Future Biomedical Research
The investigator or qualified designee will explain the Future Biomedical Research consent 
to the subject, answer all of his/her questions, and obtain written informed consent before 
performing any procedure related to the Future Biomedical Research sub-trial.  A copy of the 
informed consent will be given to the subject.
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.
Subject Identification Card
All subjects will be given a Subject Identification Card identifying them as participants in a 
research trial.  The card will contain trial site contact information (including direct telephone 
numbers) to be utilized in the event of an emergency.  The investigator or qualified designee 
will provide the subject with a Subject Identification Card after the subject provides written 
informed consent.
Medical History
A medical history will be obtained by the investigator or qualified designee. Medical history 
will include all active conditions, and any conditions diagnosed within the prior 10 years that 
are considered to be clinically significant by the Investigator.  In addition, record any prior 
cancer other than melanoma even if diagnosed greater than 10 years prior to Visit 1.  
Melanoma history will be recorded separately and not listed as Medical History.  A particular 
attention should be focused in identifying possibly immune related adverse events and 
managing these AEs effectively early on. Please refer to Section 5.6.1.1.3 for guidelines to 
manage irAEs.
Prior and Concomitant Medications Review
7.1.1.5.1
Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject 
within 28 days before starting the trial treatment. In addition, record all treatments for a prior 
cancer other than melanoma even if taken greater than 28 days prior to starting trial 
treatment.  Prior treatments for melanoma will be recorded separately and not listed as a prior 
medication.
7.1.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial through the 30-day Safety Follow-up Visit.  After the Safety Follow-up Visit 
record all medications related to reportable SAEs and ECIs as defined in Section 7.2.
 
 
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Assignment of Screening Number
All consented subjects will be given a unique screening number that will be used to identify 
the subject for all procedures that occur prior to randomization or allocation.  Each subject 
will be assigned only one screening number.  Screening numbers must not be re-used for 
different subjects.  
Any subject who is screened multiple times will retain the original screening number 
assigned at the initial screening visit.
Specific details on the screening visit requirements (screening/rescreening) are provided in 
Section 7.1.5.1.  
Assignment of Randomization Number
All eligible subjects will be randomly allocated and will receive a randomization number.  
The randomization number identifies the subject for all procedures occurring after 
randomization.  Once a randomization number is assigned to a subject, it can never be re-
assigned to another subject.
A single subject cannot be assigned more than 1 randomization number.
Trial Compliance (Medication/Diet/Activity/Other)
Interruptions from the protocol specified treatment ≥12 weeks require consultation between 
the investigator and the Sponsor and written documentation of the collaborative decision on 
subject management.
In exceptional cases and upon Sponsor consultation and approval, subjects receiving 
trametinib and/or dabrafenib in Part 3 may continue on study after completion of 24 months 
of treatment with pembrolizumab combined with trametinib and dabrafenib or placebo 
combined with trametinib and dabrafenib. These subjects can continue in accordance with 
the flow chart in Section 6.2 until disease progression, unacceptable toxicity, or the study is 
closed by the Sponsor.  At the time of study closure, the subjects would move to local supply 
and continue care under their local treating physician.
After completion of pembrolizumab and/or trametinib at 24 months in Part 4 and 5, subjects 
will be discontinued from the trial.  Subjects will be discontinued from the trial, move to 
follow -up until progression or survival follow-up if they opt to continue on any oncologic 
therapy.  This would include pembrolizumab or trametinib and would be sourced locally as 
per standard of care. 
Administration of trial medication pembrolizumab will be witnessed by the investigator 
and/or trial staff. The instructions for preparing and administering pembrolizumab will be 
provided in the Pharmacy Manual.
 
 
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Clinical Procedures/Assessments
Adverse Event (AE) Monitoring
The investigator or qualified designee will assess each subject to evaluate for potential new 
or worsening AEs as specified in the Trial Flow Chart and more frequently if clinically 
indicated. Adverse experiences will be graded and recorded throughout the study and during
the follow-up period according to NCI CTCAE Version 4.0 (see Section 12.5). Toxicities 
will be characterized in terms including seriousness, causality, toxicity grading, and action 
taken with regard to trial treatment.
An immune related adverse event (irAE) may be defined as an adverse event of unknown 
etiology, associated with drug exposure and is consistent with an immune phenomenon.
Efforts should be made to rule out neoplastic, infectious, metabolic, toxin or other etiologic 
causes prior to labeling an adverse event immune related. Immunological, serological and 
histological (biopsy) data should be used to support the diagnosis of an immune-related 
toxicity.  Following the guidance described in Section 7.2.3.2., certain AEs should also be 
reported to the Sponsor as ECIs.
Physical Exam
7.1.2.2.1
Full Physical Exam
The investigator or qualified designee will perform a complete physical exam during the 
screening period. Clinically significant abnormal findings should be recorded as medical 
history. The time points for full physical exam are described in Section 6 - Trial Flow Chart.  
After the first dose of trial treatment new clinically significant abnormal findings should be 
recorded as AEs.
7.1.2.2.2
Directed Physical Exam
For cycles that do not required a full physical exam per the Trial Flow Chart, the investigator 
or qualified designee will perform a directed physical exam as clinically indicated prior to 
trial treatment administration. New clinically significant abnormal findings should be 
recorded as AEs.
Dermatologic Exam
Dermatological exams should be performed as part of the physical exam.  The time points for 
the dermatological exam are described in Section 6 - Trial Flow Chart.  Exams may be 
performed by the investigator or may be referred to a dermatologist, at the discretion of the 
investigator.   If possible, the same physician should perform each exam for the duration of 
the study (i.e., if the subject is referred to a dermatologist for the screening exam, the 
dermatologist should do all follow up dermatologic assessments) to ensure consistency 
between evaluations.  
 
 
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Vital Signs
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment and during the Follow-up period as specified in 
the Trial Flow Chart. Vital signs include temperature, pulse, respiratory rate, weight and 
blood pressure. Height will be measured at Visit 1 only.
12-Lead Electrocardiogram (ECG)
A standard 12-lead ECG will be performed using local standard procedures once at 
screening. Clinically significant abnormal findings should be recorded as medical history.  
Additional time points for standard 12-lead ECG are described in Section 6 – Trial Flow
Chart.
Echocardiogram (ECHO)
An ECHO will be performed using local standard procedures once at screening. Clinically 
significant abnormal findings should be recorded as medical history. Additional timepoints 
for ECHO are described in Section 6 – Trial Flow Chart. 
Eastern Cooperative Oncology Group (ECOG) Performance Scale
The investigator or qualified designee will assess ECOG status (see Section 12.6) at 
screening, prior to the administration of each dose of trial treatment and during the Follow-up 
period as specified in the Trial Flow Chart.
Tumor Imaging and Assessment of Disease
See Section 4.2.3.1.1 and Section 6.0 – Trial Flow charts and associated footnotes for more 
information on tumor imaging and assessment of disease.
Laboratory Procedures/Assessments
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below.
 
 
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Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
Laboratory tests for hematology, chemistry and urinalysis are specified in Table 36.
Table 36
Laboratory Tests
Hematology
Chemistrya
Urinalysis
Other
Hematocrit
Albumin
Blood
Pregnancy 
test 
–
Urine 
and/or 
Serum 
β-human 
chorionic gonadotropin (β-
hCG)b
Hemoglobin
Alkaline phosphatase
Glucose
PT (INR)
Platelet count
Alanine aminotransferase (ALT)
Protein
aPTT
WBC (total and 
differential)
Aspartate 
aminotransferase 
(AST)
Specific gravity 
Triiodothyronine (T3)c
Red 
blood 
cell 
count
Bicarbonate
Microscopic 
exam, 
if 
abnormal 
results 
are 
noted
Free thyroxine (FT4)
Absolute 
Neutrophil count
Calcium
Thyroid 
stimulating 
hormone (TSH)
Absolute 
lymphocyte count
Chloride
Anti-pembrolizumab
Antibodies
Creatinine
PK
Glucose
Blood for FBR
Lactic 
Acid 
Dehydrogenase 
(LDH)d
Phosphorus
Potassium
Sodium
Total Bilirubin  
Direct Bilirubin, if total bilirubin 
is elevated above the upper limit 
of normal
Total protein
Blood Urea Nitrogen
Creatinine 
or 
calculated 
creatinine clearance (CrCl)
Uric acid
Magnesium
Total cholesterol
Triglycerides
aIn the event of abdominal pain or suspected pancreatitis, amylase and lipase laboratory samples should be 
collected for confirmation of the diagnosis.
bPerform on women of child bearing potential only. If urine pregnancy results cannot be confirmed as negative, 
a serum pregnancy test will be required.
cIn countries where T3 results are not available, free triiodothyronine (FT3) results may be reported.
dLDH required for Part 3 (stratification factor).
Laboratory safety tests for screening should be performed within 10 days prior to the first 
dose of trial treatment. After Cycle 1, pre-dose laboratory procedures can be conducted up to 
48 hours prior to dosing.
 
 
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Results must be reviewed by the Investigator or qualified designee and found to be 
acceptable prior to each dose of trial treatment.
Pharmacokinetic/Pharmacodynamic Evaluations
7.1.3.2.1
Blood Collection for PK Serum MK-3475
Sample collection, storage and shipment instructions for serum samples is provided in the
Procedures Manual.
7.1.3.2.2
Blood Collection for PK Plasma Trametinib
Sample collection, storage and shipment instructions for plasma samples is provided in the
Procedures Manual. 
7.1.3.2.3
Blood Collection for PK Plasma Dabrafenib and Metabolites (Hydroxy-
and Desmethyl-dabrafenib)
Sample collection, storage and shipment instructions for plasma samples is provided in the
Procedures Manual. 
7.1.3.2.4
Anti-MK-3475 Antibodies
Sample collection, storage and shipment instructions for serum samples is provided in the
Procedures Manual.
Future Biomedical Research
The following specimens are to be obtained as part of Future Biomedical Research:

Blood for genomics use

Leftover tumor tissue

Leftover correlative blood samples
Other Procedures
Withdrawal/Discontinuation
Subjects who discontinue/withdraw from treatment prior to completion of the treatment 
regimen should be encouraged to continue to be followed for all remaining study visits.
When a subject discontinues/withdraws from participation in the trial, all applicable activities 
scheduled for the end of trial visit should be performed at the time of discontinuation.  Any 
adverse events which are present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements outlined in Section 7.2 - Assessing and 
Recording Adverse Events.
 
 
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7.1.4.1.1
Withdrawal From Future Biomedical Research
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   Subjects may withdraw consent at any time by 
contacting the principal investigator for the main trial.  If medical records for the main trial 
are still available, the investigator will contact the Sponsor using the designated mailbox 
(clinical.specimen.management@merck.com), and a form will be provided by the Sponsor to 
obtain appropriate information to complete specimen withdrawal.  Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed.  A letter will 
be sent from the Sponsor to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for destruction or already performed prior to the 
request being received by the Sponsor will continue to be used as part of the overall research 
trial data and results.   No new analyses would be generated after the request is received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial records) or 
the specimens have been completely anonymized, there will no longer be a link between the 
subject’s personal information and their specimens.  In this situation, the request for 
specimen destruction cannot be processed.
Blinding/Unblinding
When the investigator or sub-investigator needs to identify the drug used by a subject and the 
dosage administered in case of emergency e.g., the occurrence of serious adverse 
experiences, he/she will contact the emergency unblinding call center by telephone and make 
a request for emergency unblinding.  As requested by the investigator or sub-investigator the 
emergency unblinding call center will provide the information to him/her promptly and 
report unblinding to the sponsor.  The emergency unblinding call-center will make a record 
promptly however, the investigator or sub-investigator must enter the intensity of the adverse 
experiences observed,   their relation to study drug, the reason thereof, etc., in the medical 
chart etc., before unblinding is performed.  Additionally, the investigator must go into the 
IVRS system and perform the unblind in the IVRS system to update drug disposition.  In the 
event that the emergency unblinding call center is not available for a given site in this trial, 
IVRS/IWRS should be used for emergency unblinding in the event that this is required for 
subject safety.
In the event that unblinding has occurred, the circumstances around the unblinding (e.g., date 
and reason) must be documented promptly, and the Sponsor Clinical Monitor notified as 
soon as possible.  Only the principal investigator or delegate and the respective subject’s 
code should be unblinded.  Trial site personnel and Sponsor personnel directly associated 
with the conduct of the trial should not be unblinded.
At the end of the trial, random code/disclosure envelopes or lists and unblinding logs are to 
be returned to the Sponsor or designee.
 
 
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Visit Requirements
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures.
Screening
Approximately 28 days prior to randomization, potential subjects will be evaluated to 
determine that they fulfill the entry requirements as set forth in Section 5.1.  Screening 
procedures may be repeated after consultation with the Sponsor.
Written consent must be obtained prior to performing any protocol specific procedure. 
Results of a test performed prior to the subject signing consent as part of routine clinical 
management are acceptable in lieu of a screening test if performed within the specified time 
frame. Screening procedures are to be completed within 28 days prior to the first dose of the 
trial treatment except for the following: 

Laboratory tests are to be performed within 10 days prior to the first dose of trial 
treatment

For women of reproductive potential, a urine pregnancy test will be performed within 
72 hours prior to first dose of trial treatment. If urine pregnancy results cannot be 
confirmed as negative, a serum pregnancy test will be required. 

Tumor imaging must be performed within 28 days prior to the date of allocation.
Subjects may be rescreened after initially failing to meet inclusion/exclusion criteria. Results 
from assessments performed during the initial screening period are acceptable in lieu of 
repeating a screening test if performed within the specified time frame and the results meet 
the inclusion/exclusion criteria.  
Treatment Period
Visit requirements are outlined in Section 6.0 – Trial Flow Chart. Specific procedure-related 
details are provided above in Section 7.1 – Trial Procedures.
Post-Treatment Follow-up Phase
Visit requirements are outlined in Section 6.0 - Trial Flow Chart. Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures. Second Course Phase
The Part 3 final analysis did not demonstrate a statistically significant increase in PFS in the 
experimental arm compared to the control arm. Subjects in the Part 3 experimental arm 
experienced a higher rate of Grade 3-5 AEs, SAEs, and discontinuations due to AEs 
compared to the control arm. Therefore, there is no further rationale to offer re-challenge 
with triplet therapy and Second Course Phase will not be offered to subjects in KEYNOTE-
022.
 
 
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Survival Status
To ensure current and complete survival data is available at the time of database locks, 
updated survival status may be requested during the course of the study by the Sponsor.  For 
example, updated survival status may be requested prior to but not limited to an siDMC
review, interim and/or final analysis.  Upon Sponsor notification, all subjects who do not/will 
not have a scheduled study visit or study contact during the Sponsor defined time period will 
be contacted for their survival status (excluding subjects who have a previously recorded 
death event in the collection tool).
Treatment After the End of the Study
Upon study completion, subjects are discontinued and may be enrolled in an
extension 
study.
Assessing and Recording Adverse Events
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavourable and unintended sign (including an abnormal laboratory finding, for example), 
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 (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the 
use of the Sponsor’s product, is also an adverse event.
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  
Examples of this may include, but are not limited to, teething, typical crying in infants and 
children and onset of menses or menopause occurring at a physiologically appropriate time.
Sponsor's product includes any pharmaceutical product, biological product, device, 
diagnostic agent or protocol-specified procedure, whether investigational (including placebo 
or active comparator medication) or marketed, manufactured by, licensed by, provided by or 
distributed by the Sponsor for human use.
Adverse events may occur during clinical trials, or as prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal.
Progression of the cancer under study is not considered an adverse event.
All adverse events that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure. 
 
 
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From the time of treatment allocation/randomization through 30 days following cessation of 
treatment, all adverse events must be reported by the investigator. Such events will be 
recorded at each examination on the Adverse Event case report forms/worksheets.  The 
reporting timeframe for adverse events meeting any serious criteria is described in section 
7.2.3.1. The investigator will make every attempt to follow all subjects with non-serious 
adverse events for outcome.
Electronic reporting procedures can be found in the EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
Adverse events will not be collected for subjects during the pre-screening period (for 
determination of archival tissue status) as long as that subject has not undergone any 
protocol-specified procedure or intervention.  If the subject requires a blood draw, fresh 
tumor biopsy etc., the subject is first required to provide consent to the main study and AEs 
will be captured according to guidelines for standard AE reporting.
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor
Dabrafenib
In the event of a dabrafenib overdose, defined as administration of more than 300 mg as a 
single dose or 600 mg per day (the highest dose tested in clinical studies to date), the 
investigator should contact the Clinical Monitor immediately and closely monitor the subject 
for AEs/SAEs and laboratory abnormalities.  There is no specific antidote for an overdose of 
dabrafenib or trametinib. Patients who develop adverse reactions should receive appropriate 
symptomatic treatment. In case of suspected overdose, dabrafenib should be withheld and 
supportive care instituted. Further management should be as clinically indicated or as 
recommended by the national poisons centre, where available. Haemodialysis is not expected 
to enhance the elimination of dabrafenib as it is highly bound to plasma proteins.
Trametinib
In the event of a trametinib overdose, defined as administration of more than 3.0 mg once 
daily (the maximum tolerated dose defined in the MEK111054 Study), the investigator 
should contact the Clinical Monitor immediately and closely monitor the subject for 
AEs/SAEs and laboratory abnormalities.  No specific treatment is recommended.  The 
investigator will use clinical judgment to treat any overdose. Decisions regarding dose 
interruptions or modifications will be made by the investigator in consultation with the 
Clinical Monitor based on the clinical evaluation of the subject.
Note:  In the event of an overdose of either dabrafenib or trametinib, a plasma sample for PK 
analysis may be requested by the Clinical Monitor on a case-by-case basis.  This plasma 
sample should be collected as soon as possible, but within 10 days from the date of the last 
dose of on-study dosing.  Information regarding the quantity of the excess dose as well as the 
duration of the overdosing should be documented in the eCRF.
 
 
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For purposes of this trial, an overdose will be defined as any dose exceeding the prescribed 
dose for pembrolizumab by 20% over the prescribed dose. No specific information is 
available on the treatment of overdose of pembrolizumab. In the event of overdose, 
pembrolizumab should be discontinued and the subject should be observed closely for signs 
of toxicity.  Appropriate supportive treatment should be provided if clinically indicated.
If an adverse event(s) is associated with (“results from”) the overdose of Sponsor's product or 
vaccine, the adverse event(s) is reported as a serious adverse event, even if no other 
seriousness criteria are met.
If a dose of Sponsor's product or vaccine meeting the protocol definition of overdose is taken 
without any associated clinical symptoms or abnormal laboratory results, the overdose is 
reported as a non-serious Event of Clinical Interest (ECI), using the terminology “accidental 
or intentional overdose without adverse effect.”
All reports of overdose with and without an adverse event must be reported by the 
investigator within 24 hours to the Sponsor either by electronic media or paper. Electronic 
reporting procedures can be found in the EDC data entry guidelines. Paper reporting 
procedures can be found in the Investigator Trial File Binder (or equivalent).
Reporting of Pregnancy and Lactation to the Sponsor
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them) that occurs during the trial.
Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure.  
Pregnancies and lactations that occur from the time of treatment allocation/randomization 
through 120 days following cessation of Sponsor’s product, or 30 days following cessation of 
treatment if the subject initiates new anticancer therapy, whichever is earlier, must be 
reported by the investigator.  All reported pregnancies must be followed to the 
completion/termination of the pregnancy. Pregnancy outcomes of spontaneous abortion, 
missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, 
miscarriage and stillbirth must be reported as serious events (Important Medical Events). If 
the pregnancy continues to term, the outcome (health of infant) must also be reported..
Such events must be reported within 24 hours to the Sponsor either by electronic media or 
paper.  Sponsor Contact information can be found in the Investigator Trial File Binder (or 
equivalent).
 
 
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Immediate Reporting of Adverse Events to the Sponsor
Serious Adverse Events
A serious adverse event is any adverse event occurring at any dose or during any use of 
Sponsor's product that:

Results in death;

Is life threatening;

Results in persistent or significant disability/incapacity;

Results in or prolongs an existing inpatient hospitalization;

Is a congenital anomaly/birth defect;

Is an other important medical event 
Note: In addition to the above criteria, adverse events meeting either of the below criteria, 
although not serious per ICH definition, are reportable to the Sponsor in the same 
timeframe as SAEs to meet certain local requirements. Therefore, these events are 
considered serious by the Sponsor for collection purposes.

Is a new cancer (that is not a condition of the study);

Is associated with an overdose.
Refer to Table 37 for additional details regarding each of the above criteria.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any serious adverse event, or follow up to a serious adverse event, 
including death due to any cause other than progression of the cancer under study (reference 
Section 7.2.3.3 for additional details), that occurs to any subject must be reported within 24 
hours to the Sponsor if it causes the subject to be excluded from the trial, or is the result of a 
protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 90 days 
following cessation of treatment, or 30 days following cessation of treatment if the subject 
initiates new anticancer therapy, whichever is earlier, any serious adverse event, or follow up 
to a serious adverse event, including death due to any cause other than progression of the 
cancer under study (reference Section 7.2.3.3 for additional details), whether or not related to 
the Sponsor's product, must be reported within 24 hours to the Sponsor either by electronic 
media or paper. Electronic reporting procedures can be found in the EDC data entry 
guidelines. Paper reporting procedures can be found in the Investigator Trial File Binder (or 
equivalent)
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to the Sponsor's product that is brought to the attention of the 
investigator at any time following consent through the end of the specified safety follow-up 
 
 
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period specified in the paragraph above, or at any time outside of the time period specified in 
the previous paragraph also must be reported immediately to the Sponsor.
All subjects with serious adverse events must be followed up for outcome.
Events of Clinical Interest
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported to the Sponsor.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any subject must be 
reported within 24 hours to the Sponsor if it causes the subject to be excluded from the trial, 
or is the result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 90 days 
following cessation of treatment, or 30 days following cessation of treatment if the subject 
initiates new anticancer therapy, whichever is earlier, any ECI, or follow up to an ECI, 
whether or not related to the Sponsor’s product, must be reported within 24 hours to the 
Sponsor, either by electronic media or paper.  Electronic reporting procedures can be found 
in the EDC data entry guidelines.  Paper reporting procedures can be found in the 
Investigator Trial File Binder (or equivalent)
Events of clinical interest for this trial include:
1. an overdose of Sponsor's product, as defined in Section 7.2.1 - Definition of an Overdose 
for This Protocol and Reporting of Overdose to the Sponsor, that is not associated with
clinical symptoms or abnormal laboratory results. 
2. an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less 
than 2X the upper limit of normal, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.*
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology.  The trial site guidance for 
assessment and follow up of these criteria can be found in the Investigator Trial File 
Binder (or equivalent).
 
 
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3. Specific hepatic events, Grade 2, OR, any grade resulting in dose modification or use of 
systemic steroids to treat the AE:
–
Hepatitis
–
Autoimmune hepatitis
–
Transaminase elevations
Protocol-Specific Exceptions to Serious Adverse Event Reporting
Efficacy endpoints as outlined in this section will not be reported to the Sponsor as described 
in Section 7.2.3. - Immediate Reporting of Adverse Events to the Sponsor.
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study.  
The Sponsor will monitor unblinded aggregated efficacy endpoint events and safety data to 
ensure the safety of the subjects in the trial.  Any suspected endpoint which upon review is 
not progression of the cancer under study will be forwarded to global safety as a SAE within 
24 hours of determination that the event is not progression of the cancer under study.
Evaluating Adverse Events
An investigator who is a qualified physician will evaluate all adverse events with respect to 
the elements outlined in Table 37. The investigator’s assessment of causality is required for 
each adverse event.  Refer to Table 37 for instructions in evaluating adverse events.
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 4.0. Any adverse event 
which changes CTCAE grade over the course of a given episode will have each change of 
grade recorded on the adverse event case report forms/worksheets.
All adverse events regardless of CTCAE grade must also be evaluated for seriousness.
For studies in which multiple agents are administered as part of a combination regimen, the 
investigator may attribute each adverse event causality to the combination regimen or to a 
single agent of the combination.  In general, causality attribution should be assigned to the 
combination regimen (i.e., to all agents in the regimen). However, causality attribution may 
be assigned to a single agent if in the investigator’s opinion, there is sufficient data to support 
full attribution of the adverse experience to the single agent.
 
 
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Table 37
Evaluating Adverse Events
An investigator who is a qualified physician, will evaluate all adverse events as to:
V4.0 CTCAE 
Grading
Grade 1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated.
Grade 2
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL.
Grade 3
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; 
disabling; limiting self-care ADL.
Grade 4
Life threatening consequences; urgent intervention indicated.
Grade 5
Death related to AE
Seriousness
A serious adverse event is any adverse event occurring at any dose or during any use of Sponsor’s product that:
†Results in death; or
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include an 
adverse event that, had it occurred in a more severe form, might have caused death.); or
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation. (Note: Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not a serious adverse event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of a Merck product and is documented in 
the patient’s medical history.); or
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or
Is a new cancer (that is not a condition of the study) (although not serious per ICH definition, is reportable to the Sponsor within 24 hours to meet certain local 
requirements); or
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event for collection purposes. An 
overdose that is not associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 hours.
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes 
listed previously (designated above by a †).
Duration
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units
Action taken 
Did the adverse event cause the Sponsor’s product to be discontinued?
Relationship to 
Sponsor’s 
Product 
Did the Sponsor’s product cause the adverse event? The determination of the likelihood that the Sponsor’s product caused the adverse event will be provided by an 
investigator who is a qualified physician. The investigator’s signed/dated initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed document must be retained for the required regulatory time frame. The 
criteria below are intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the adverse event 
based upon the available information.
The following components are to be used to assess the relationship between the Sponsor’s product and the AE; the greater the correlation with the components 
and their respective elements (in number and/or intensity), the more likely the Sponsor’s product caused the adverse event (AE):
Exposure
Is there evidence that the subject was actually exposed to the Sponsor’s product such as: reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen?
Time Course
Did 
the 
AE 
follow 
in 
a 
reasonable 
temporal 
sequence 
from 
administration 
of 
the 
Sponsor’s 
product? 
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)?
Likely Cause
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental factors
 
 
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Relationship
The following components are to be used to assess the relationship between the test drug and the AE: (continued)
to Sponsor's 
Product
(continued) 
Dechallenge
Was the Sponsor’s product discontinued or dose/exposure/frequency reduced?
If yes, did the AE resolve or improve?
If yes, this is a positive dechallenge. If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite continuation of 
the Sponsor’s product; or (3) the trial is a single-dose drug trial); or (4) Sponsor’s product(s) is/are only used one time.)
Rechallenge
Was the subject re-exposed to the Sponsor’s product in this study?
If yes, did the AE recur or worsen?
If yes, this is a positive rechallenge. If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose drug trial); or 
(3) Sponsor’s product(s) is/are used only one time).
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN 
CAUSED BY THE SPONSOR'S PRODUCT, OR IF REEXPOSURE TO THE SPONSOR'S PRODUCT POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR 
CLINICAL DIRECTOR AS PER DOSE MODIFICATION GUIDELINES IN THE PROTOCOL.
Consistency 
with Trial 
Treatment 
Profile
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the Sponsor’s product or drug class pharmacology 
or toxicology?
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements.
Record one of the following
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a Sponsor’s product relationship).
Yes, there is a reasonable 
possibility of Sponsor's product 
relationship.
There is evidence of exposure to the Sponsor's product.  The temporal sequence of the AE onset relative to the administration of the Sponsor's 
product is reasonable.  The AE is more likely explained by the Sponsor's product than by another cause.
No, there is not a reasonable 
possibility of Sponsor's product 
relationship
Subject did not receive the Sponsor's product OR temporal sequence of the AE onset relative to administration of the Sponsor's product is not 
reasonable OR the AE is more likely explained by another cause than the Sponsor’s product.  (Also entered for a subject with overdose without an 
associated AE.)
 
 
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Sponsor Responsibility for Reporting Adverse Events
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations.
TRIAL GOVERNANCE AND OVERSIGHT
Data Monitoring Committee
To supplement the routine monitoring outlined in this protocol, a separate Standing Internal 
Data Monitoring Committee (siDMC) will monitor the interim data from this trial. The 
siDMC comprises members of Sponsor Senior Management, none of whom are directly 
associated with the conduct of this trial. The siDMC will monitor the trial at an appropriate 
frequency (see Section 8.2.9 - Interim Analyses) for evidence of adverse effects of trial 
treatment and efficacy targets/dose selection/futility, as described in the detailed monitoring 
guidelines. The siDMC will determine whether the trial should continue (or other 
modifications, pre-specified or otherwise, should be made) according to the protocol, 
considering the overall risk and benefit to trial participants. The siDMC will also make 
recommendations to the Sponsor protocol team regarding steps to ensure both subject safety 
and the continued ethical integrity of the trial.
Specific details regarding responsibilities of the siDMC will be described in a separate 
charter that is reviewed and approved by the siDMC.
8.0 STATISTICAL ANALYSIS PLAN
Statistical Analysis Plan Summary
This section contains a brief summary of the statistical analyses for this trial. Full detail is in 
the Statistical Analysis Plan (SAP) (Section 8.2).
Parts 1 and 2:
Pembrolizumab in Combination with Trametinib and 
Dabrafenib
The primary purpose of Part 1 and Part 2 is to investigate the safety and tolerability of 
pembrolizumab in combination with trametinib and dabrafenib in adult subjects with 
advanced melanoma.  Descriptive tables that summarize the number and percentage of 
subjects who experience a DLT (dose limiting toxicity) as well as AE summaries will be 
generated for MK+D+T (as well as for MK+D, if MK+D combination is studied) by dose 
level for the all subjects as treated population. Percentage of subjects treated with the 
confirmed dose of (MK+D+T) (across Parts 1 and 2) that attained Objective Response will 
be estimated.
The final number of subjects enrolled in Part 1 and Part 2 of (MK+D+T) will depend on 
empirical safety (DLT) observations. The sample size of Part 1 will range from 3 (0/3 DLTs 
on Dose Level 1) to 12 subjects (6 subjects on Dose Level 1 followed by de-escalation and 
enrollment of 6 subjects into Dose Level -1); a likely size of 6 subjects is used as an 
 
 
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estimated size of Part 1 for operation purposes.  If the safety of MK+D+T Dose Level 1 is 
acceptable, the sample size of Part 2 will range from 8 (if 6 subjects enrolled in Dose Level 1 
in Part 1 are followed by enrollment of 8 more patients in Dose Level 1 in Part 2) to 24
subjects (if 3 subjects enrolled in Dose Level 1 in Part 1 are followed by enrollment of 10 
more subjects in Dose Level 1 in Part 2 with 5/13 DLTs, followed by de-escalation and 
enrollment of 14 subjects on Dose Level -1); 11 subjects is used as an estimated size of Part 2 
for operational purposes.  
However, the most likely scenario is that after the MAD is identified in dose escalation 
(Part1), the enrollment will continue on that dose in Part 2 until 14 subjects across Parts 1 
and 2 are enrolled on that dose.  Thus, the most likely scenarios will include 14 subjects
enrolled across Parts 1 and 2 combined (used for operational purposes), with the range across 
Parts 1 and 2 being 14 to 27.
Parts 1, 2, 4, and 5:  Pembrolizumab in Combination With Trametinib
The safety and tolerability of (MK+T) (Table 3) in adult subjects with advanced melanoma 
will be investigated in dose escalation (Part 1) and dose confirmation (TPI design of Part 2)
of the study.  
The final number of subjects enrolled in Part 1 and Part 2 of (MK+T) will depend on 
empirical safety (DLT) observations. The sample size of Part 1 will range from 3 (0/3 DLTs 
at Dose Level 1) to 12 subjects (6 subjects at Dose Level 1 followed by de-escalation and 
enrollment of 6 subjects at Dose Level -1); a likely size of 6 subjects is used as an estimated 
size of Part 1 for operation purposes.  If the safety of (MK+T) Dose Level 1 is acceptable, the 
sample size of Part 2 will range from 34 (if 6 subjects enrolled at Dose Level 1 in Part 1 are 
followed by enrollment of 34 more patients at Dose Level 1 in Part 2) to 50 subjects (if 3 
subjects enrolled at Dose Level 1 in Part 1 are followed by enrollment of 10 more subjects at
Dose Level 1 in Part 2 with 5/13 DLTs, followed by de-escalation and enrollment of 40 
subjects at Dose Level -1); 34 subjects is used as an estimated size of Part 2 for operational
purposes.
The safety and tolerability of the concurrent (Table 6) and intermittent (Table 7) dosing 
regimens of (MK+T) in adult subjects with melanoma or solid tumors will be investigated in 
dose escalation (Part 4) and dose confirmation (modified TPI design of Part 5) of the study.  
After 14 subjects are observed for DLTs on the (MK+T) dose of the concurrent regimen 
confirmed in Part 4 of the study and 14 subjects are observed for DLTs on the (MK+T) dose 
of the intermittent regimen confirmed in Part 4 of the study (across the dose escalation and 
confirmation parts combined), the choice of the regimen (concurrent or intermittent) for the 
efficacy expansion will be complete.  
The final numbers of subjects enrolled in Parts 4 and 5 will depend on empirical safety 
(DLT) observations for both regimens. For operational purposes, the sample sizes of Parts 4 
and 5 are estimated as follows. 
 
 
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The minimum size of Part 4 for the concurrent dosing cohort is 6 subjects which can occur if 
the first dose is rejected with 3 subjects and the dose below it is rejected with 3 subjects.  
Assuming 6 subjects per dose in the 3+3 design, the maximum size of Part 4 for the 
concurrent dosing cohort is 24 subjects.  The minimum size of Part 5 TPI (dose confirmation)
is then 8 subjects; the estimated sample size of the Part 5 TPI is increased to 16 subjects to 
allow for dose escalation and de-escalation steps, in the event this becomes necessary. Thus,
for operational purposes, the maximum estimated subject numbers for enrollment in the 
concurrent dosing cohort in Parts 4 and 5 are 24 and 16 , respectively, for a total of 40
subjects across Parts 4 and 5. 
Similarly, the minimum size of Part 4 for the intermittent dosing cohort is 6 subjects, which 
can occur if the first dose is rejected with 3 subjects and the dose below it is rejected with 3 
subjects. Assuming 6 subjects per dose in the 3+3 design, the maximum size of Part 4 for 
intermittent dosing cohort is 18 subjects. 
The minimum size of Part 5 TPI (dose 
confirmation) is then 8 subjects; the estimated sample size of the Part 5 TPI part is increased 
to 16 subjects to allow for dose escalation and de-escalation steps, in the event this becomes 
necessary. Thus, for operational purposes, the maximum estimated subject numbers for 
enrollment in the intermittent dosing cohort in Parts 4 and 5 are 18 and 16, respectively, for
a total of 34 subjects across Parts 4 and 5.
An efficacy evaluation of (MK+T) with respect to progression-free survival (PFS) will also 
be performed by Kaplan-Meier method. 
Part 3:  Pembrolizumab in Combination with Trametinib and Dabrafenib
Final Efficacy Analyses  
The primary analysis population in Part 3, Intent-to-Treat Set (ITT), will include all 
randomized subjects.  Primary endpoint in Part 3 is the Progression-Free Survival (PFS) per 
RECIST 1.1 defined as the time from randomization to the first documented disease 
progression or death due to any cause, whichever occurs first. The treatment groups will be 
compared in PFS by stratified log-rank test.  While the randomization is stratified by ECOG 
PS (0 vs. 1) and LDH (>1.1xULN vs. ≤1.1xULN), due to a very low number of subjects 
enrolled in the stratum ECOG=1 and LDH ≤1.1xULN, the two strata with ECOG=1 
(ECOG=1 and LDH ≤1.1xULN; ECOG=1 and LDH >1.1xULN) will be combined for all 
analyses.  A Cox proportional hazard model stratified using the same strata with Efron's 
method of tie handling will be used to estimate the hazard ratio and its 95% confidence 
interval. The Kaplan-Meier method will be used to estimate the PFS survival curve.
Secondary endpoints include objective response rate (ORR) per RECIST 1.1, response 
duration per RECIST 1.1, and overall survival (time to death).
The analysis strategy for primary and efficacy endpoints are provided in Table 38.
 
 
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Table 38
Analysis Strategy for Primary and Secondary Efficacy Endpoints in Part 3
Endpoint
(Description, 
Time Point)
Approach†
Statistical Method‡
Analysis 
Population
Missing Data 
Approach
Progression-
free-survival
P
Testing:  Stratified Log-rank test
Estimation: Stratified Cox model 
with Efron's tie handling method
Kaplan-Meier method for PFS curve 
estimation in each treatment group
ITT
Censored at last 
assessment
Objective 
response 
rate
S
Stratified Miettinen and Nurminen 
method [100]
ITT
Subjects with 
missing data are 
considered as 
non-responders
Response 
Duration
S
Summary statistics using Kaplan-
Meier method
All 
responders
Non-responders 
are excluded in 
analysis
Overall 
survival
S
Summary statistics using Kaplan-
Meier method
ITT
Censored at last 
date
  † P=Primary , S=Secondary  
8.1.3.1.1
Power of the Final Efficacy Analysis of Part 3
If the true hazard ratio is 0.5, the study will need approximately 74 PFS events to have 80% 
power to reject a null hypothesis of equal PFS distributions in the two groups at one-sided 
0.025 Type I error.  Approximately 120 subjects will be randomized in 1:1 ratio to 
accumulate this number of events with 0.5-year enrollment period and 2-year total study 
duration assuming the median PFS in the (PBO+D+T) group is 10 months (rounded up 
estimate of 9.4 months provided in Flaherty et al. paper [101]) and yearly dropout rate is 5%.  
The observed hazard ratio needs to be approximately 0.62 or lower for the treatment effect to 
be statistically significant.  This ratio translates to approximately 6.2 months increase in 
median duration. 
Safety Analyses of Part 3
The All-Subjects-as-Treated population will be employed for safety analyses. There will be 
no Tier 1 events in this study. Tier 2 and Tier 3 safety endpoints will be evaluated as 
described in Section 8.2.5.4.
Interim Analysis of Part 3
One interim analysis of Part 3 will be conducted to inform potential early Go/No Go decision 
for initiation of Phase III study before the completion of Part 3.  The data from the first 80 
subjects randomized into the study will be used in the interim analysis.  The interim analysis 
 
 
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will be conducted when the first 80 subjects randomized into the study will have completed 
their Week 36 visit and have their central radiology assessment at Week 36 available or have 
discontinued prior to Week 36.
Results of the interim analysis will be reviewed by the siDMC.  The endpoint(s), timing, and 
purpose of the interim analysis are summarized in the Table 39.  The decision rules and other 
statistical details are further described in Section 8.2.9.
Table 39
Summary of Interim Analysis Strategy
Key Endpoints for Interim 
Analysis
Timing of Interim Analysis
Purpose of Interim Analysis
5-category ordinal 
response at Week 36
First 80 randomized subjects
either complete Week 36 
visit or discontinue prior to 
Week 36 visit
Start Phase III prior to 
Part 3 completion
Futility
Subgroup Analyses
Subjects with high PD-L1 expression level are of special interest in this study. The PFS 
hazard estimates (95% CIs) and ORR estimates (95% CI) will be provided for the subgroups
of PD-L1 positive subjects and PD-L1 negative subjects. 
Statistical Analysis Plan
This section outlines the statistical analysis strategy and procedures for the study.  If, after 
the study has begun, changes are made to primary and/or key secondary hypotheses, or the 
statistical methods related to those hypotheses, then the protocol will be amended (consistent 
with ICH Guideline E-9).  Changes to exploratory or other non-confirmatory analyses made 
after the protocol has been finalized, along with an explanation as to when and why they 
occurred, will be listed in the Clinical Study Report (CSR) for the study.  Post hoc 
exploratory analyses will be clearly identified in the CSR.  No separate Statistical Analysis 
Plan (SAP) will be issued for this study.
Responsibility for Analysis/In-House Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the SPONSOR.
Parts 1, 2, 4, and 5 of this trial are conducted as open-label trials, i.e., subjects, investigators, 
and SPONSOR personnel will be aware of subject treatment assignments after each subject is 
enrolled and treatment is assigned.
The database will be locked for analysis of Parts 1 and 2 for (MK+D+T) 6 months after the 
enrollment of the last (MK+D+T) Part 2 subject.  The database will be locked for analysis of 
Parts 1 and 2, 4, and 5 for (MK+T) 6 months after the enrollment of the last (MK+T) Part 5
subject. Part 3 will not be unblinded when these analyses takes place.
 
 
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Part 3 of this study will be conducted as a double-blind study under in-house blinding 
procedures.  The official, final database will not be unblinded until medical/scientific review 
has been performed, protocol violators have been identified, and data have been declared 
final and complete.
Planned interim analysis of Part 3 is described in Section 8.2.9. Blinding to Part 3 treatment 
assignment will be maintained at all investigational sites.  The results of the interim analysis 
will not be shared with the investigators prior to the completion of the study.  Subject-level 
unblinding will be restricted to an internal unblinded statistician and scientific programmer 
performing the interim analysis, who will have no other responsibilities associated with the 
study.Treatment-level results and/or subject-level data of the interim analysis will be 
provided by the unblinded statistician to the standing internal Data Monitoring Committee 
(siDMC) which consists of SPONSOR personnel.  Limited additional SPONSOR personnel 
may be unblinded to the treatment level results of the interim analysis, if required, in order to 
act on the recommendations of the siDMC.  The extent to which individuals are unblinded 
with respect to results of interim analyses will be documented by the unblinded statistician.
The processes by which recommendations and decisions are reached and communicated are 
documented in the siDMC charter for the SPONSOR.  The protocol-specific siDMC charter 
will be referenced in the CSR.  Prior to final study unblinding, individuals who have been 
unblinded at any level will not be involved in any discussions regarding modifications to the 
protocol, statistical methods, identification of protocol violators, or data validation efforts 
after the interim analyses.  Key aspects of the interim analyses are described in Section 8.2.9.
The Sponsor, the investigator, and the subject will be unblinded after database lock for the 
final analysis of Part 3.  At unblinding, the Sponsor will inform each investigator of the trial 
treatment allocated to subjects at their site. Subjects who are receiving treatment with 
pembrolizumab in combination with trametinib and dabrafenib will be allowed to continue 
treatment per protocol after being informed of the results of the final analysis.  These subjects 
will continue to follow the dose modification and toxicity management guidelines as per 
protocol. Combinations other than the therapy they are already receiving will not be allowed 
for these subjects.  
Subjects who are receiving treatment with placebo in combination with trametinib and 
dabrafenib will be allowed to continue trametinib and dabrafenib per protocol (without 
placebo) after being informed of the final analysis results. These subjects will continue to 
follow the dose modification and toxicity management guidelines as per protocol.These 
subjects will not be allowed to cross over to the treatment arm with pembrolizumab in 
combination with trametinib and dabrafenib.
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.0.
 
 
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Analysis Endpoints
Efficacy Endpoints
Efficacy endpoints and their definitions are presented below.
8.2.3.1.1
Primary Endpoint
Progression-free Survival (PFS): is defined as the time from randomization in Part 3 (or the 
start of treatment in other Parts) to progressive disease (PD) or death, whichever occurs 
earlier, based upon RECIST 1.1 by the investigator review. Subjects without documented 
PD/death will be censored at the last disease assessment date. 
8.2.3.1.2
Secondary Endpoints
Objective Response Rate (ORR): is defined as the percentage of subjects who have 
achieved confirmed complete response (CR) or partial response (PR) according to RECIST 
1.1 by the investigator review. Subjects with missing outcome on objective response will be 
considered non-responders. 
Response Duration: is defined as the time interval between the date of the first confirmed
response (CR/PR) (the response prior to confirmation) and the date of first documented 
disease progression based upon RECIST 1.1 by the investigator review. Response duration 
will be only determined for confirmed responses.
Overall survival (OS): is defined as the time from randomization (or the start of treatment 
when there is no randomization) to death due to any cause. Subjects without documented 
death at the time of analysis will be censored at the date last known to be alive. 
5-Category Ordinal Response at Week 36 – an ordinal endpoint that classifies the response 
at Week 36 into one of 5 categories:  CR, VGPR defined as partial response with percent 
reduction from baseline in tumor line length >60%, MPR defined as partial response with 
percent reduction from baseline in tumor line length ≤60%, SD, and PD, where CR, PR, SD 
and PD categories are based upon RECIST 1.1 by central review. This will be the primary 
endpoint of the interim analysis of Part 3.  See details of the definition in the description of 
the 5-Category Ordinal Response at a Timepoint.
8.2.3.1.3
Exploratory Endpoints
Best Overall Response per RECIST 1.1 [Appendix 12.4]: the best response attained during 
the study with 4 categories based upon RECIST 1.1 by the investigator review:  Complete 
Response (CR), Partial Response (PR), Stable Disease (SD), and Progressive Disease (PD).  
Categories of CR and PR need to be confirmed in this endpoint.
5-Category Best Overall Response (BOR-5) – an ordinal endpoint that represents the best 
response attained during the study with 5 categories:  CR (confirmed), Very Good Partial 
Response (VGPR) defined as confirmed partial response with maximum percent reduction 
 
 
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from baseline in tumor line length >60%, Moderate Partial Response (MPR) defined as 
confirmed partial response with maximum percent reduction from baseline in tumor line 
length ≤60%, SD, and PD.  In this endpoint, CR, PR, SD and PD categories are based upon 
RECIST 1.1 by the investigator review and the RECIST 1.1 category of PR is split into two 
categories: VGPR and MPR.
5-Category Ordinal Response at a Timepoint – an ordinal endpoint that classifies the 
response at given timepoint into one of 5 categories:  CR, VGPR defined as partial response 
with percent reduction from baseline in tumor line length >60%, MPR defined as partial 
response with percent reduction from baseline in tumor line length ≤60%, SD, and PD. In 
this endpoint, CR, PR, SD and PD categories are based upon RECIST 1.1 by the investigator 
review. No confirmation will be required for complete or partial responses at a timepoint.  
Subjects who discontinued prior to timepoint will be assigned to one of these categories 
according to their reason for discontinuation.  Subjects who discontinued for the following 
reasons will be included in the PD category: documented disease progression, unacceptable 
adverse event(s), intercurrent illness that prevents further administration of treatment, 
noncompliance with trial treatment or procedure requirements, investigator’s decision to 
withdraw the subject, subject withdraws consent. Subjects who discontinued due to 
pregnancy of the subject or for administrative reasons will be included in the SD category.  
Subjects who attained an investigator-determined confirmed complete response (CR) per 
RECIST 1.1 and stopped the trial treatment will be included in the CR category. The 
categories are assigned scores 1 to 5 for analysis: CR=1, VGPR=2, MPR=3, SD=4, PD=5.
Percentage of Subjects with CR based upon RECIST 1.1 by the investigator review
Percentage of Subjects with PR based upon RECIST 1.1 by the investigator review
Percentage of Subjects with Deep Response (DR) where DR is a response that is either CR 
or VGPR by the investigator review.
Best Target Lesion Response - maximum percent reduction in tumor line length over target 
lesions by the investigator review.
Time to Confirmed Response – defined only for subjects with confirmed response by the 
investigator review. The time interval between the date of randomization and the date of the 
first confirmed response (CR/PR) (the response prior to confirmation).
Percentage of Subjects with Sustained Response at Week 36  (used in the interim 
analysis) - subjects who achieved response (confirmed CR or PR) prior to Week 36 but have 
not yet progressed at Week 36 by central review.  
Tumor growth kinetics endpoints: growth rate constant (GST) and time-to-growth (TTG)
and other as appropriate.
These endpoints will be used in Modeling and Simulations
analysis.
 
 
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EuroQol (EQ-5D) and EORTC (QLQ-C30) endpoints
Additional supportive analyses of PFS, objective response rate, best overall response, and 
duration of response will be conducted using modified RECIST 1.1 criteria, in which a 
confirmation assessment of disease progression must be obtained at least 4 weeks after the 
initial disease assessment indicating progressive disease.
Safety Endpoints
The primary safety endpoint in Parts 1, 2, 4, and 5 of the study is DLT. In Part 3, there will 
be no Tier 1 safety endpoints; Tier 2 and Tier 3 safety endpoints will be evaluated as 
described  in 8.2.5.4. Safety will be monitored by cumulative data reviews throughout the 
trial. The toxicities and grades experienced by subjects who have received study treatment, 
including adverse events (AEs), serious adverse events (SAEs) and events of clinical interest 
(ECIs) will be summarized. Other safety measures evaluated in all parts of the study include 
laboratory safety assessments, ECGs, vital signs, and physical examinations. 
Analysis Populations
Efficacy Analysis Populations
The primary analysis population in Part 3, Intent-to-Treat Analysis Set (ITT), will include all 
randomized subjects.  The ITT will serve as the primary population for the analyses of PFS, 
OS, and ORR in this study.  Analysis of response duration is based on all confirmed
responders.
In Parts 1, 2, 4, and 5 of the study the All-Subjects-as-Treated (ASaT) will be used for 
efficacy analyses. Analysis of response duration will be based on all confirmed responders 
in the ASaT.
Safety Analysis Populations
The ASaT population will be used for the analysis of safety data in this study. In all parts of 
the study, the ASaT population consists of all subjects who received at least one dose of 
study treatment. In Parts 4 and 5, subjects treated during the trametinib run-in period will be 
included in the ASaT population even if they discontinued treatment before receiving 
pembrolizumab.
In case of treatment administration errors, subjects will be analyzed 
according to the treatment they actually received. 
At least one laboratory or vital sign measurement obtained subsequent to at least one dose of 
study treatment is required for inclusion in the analysis of each specific parameter.  To assess 
change from baseline, a baseline measurement is also required.
The DLT analysis will be performed on a DLT-evaluable population. 
In Parts 1 and 2, a DLT evaluable subject is defined as a subject who receives at least 66% of 
all planned treatments during the 6-week DLT observation period (i.e., Cycle 1, initiated with 
 
 
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the first pembrolizumab dose) or a subject who discontinues the DLT observation period due 
to a DLT.  In Parts 4 and 5, a DLT evaluable subject is defined as a subject who receives at 
least 66% of all planned treatments during the 6-week DLT observation period (i.e., 
following the trametinib run-in period in Cycle 1, initiated with the first pembrolizumab
dose) or a subject who discontinues the DLT observation period due to a DLT.  In Parts 4 
and 5, any subject who discontinues trametinib during the trametinib monotherapy run-in 
period is not considered evaluable for DLTs for the (MK+T) combination, even if the subject 
discontinued due to a DLT.
Statistical Methods
Statistical Methods for Efficacy Analyses
Parts 1, 2, 4 and 5 in Subjects Treated with (MK+D+T) or (MK+T)
The best overall response and PFS based on the investigator review per RECIST 1.1 in 
subjects along with baseline characteristics will be listed. Percentage of subjects that attained 
Objective Response will be estimated.
Part 3
The analysis strategy for primary and secondary endpoints in Part 3 is summarized in
Table 40. 
Table 40
Analysis Strategy for Primary and Secondary Efficacy Endpoints in Part 3
Endpoint
(Description, 
Time Point)
Approach†
Statistical Method‡
Analysis 
Population
Missing Data 
Approach
Progression-
free-survival
P
Testing:  Stratified Log-rank test
Estimation: Stratified Cox model 
with Efron's tie handling method
Kaplan-Meier method for PFS curve 
estimation in each treatment group
ITT
Censored at last 
assessment
Objective
response 
rate
S
Stratified Miettinen and Nurminen 
method [100]
ITT
Subjects with 
missing data are 
considered as 
non-responders
Response 
Duration
S
Summary statistics using Kaplan-
Meier method
All 
responders
Non-responders 
are excluded in 
analysis
Overall 
survival
S
Summary statistics using Kaplan-
Meier method
ITT
Censored at last 
date
  † P=Primary , S=Secondary  
 
 
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Primary endpoint in Part 3 is PFS. The treatment groups will be compared in PFS by 
stratified log-rank test. While the randomization is stratified by ECOG PS (0 vs. 1) and LDH 
(>1.1xULN vs. ≤1.1xULN), due to a very low number of subjects enrolled in the stratum 
ECOG=1 and LDH ≤1.1xULN, the two strata with ECOG=1 (ECOG=1 and LDH 
≤1.1xULN; ECOG=1 and LDH >1.1xULN) will be combined for all analyses A Cox 
proportional hazard model with a factor for treatment group stratified using the strata above
with Efron's method of tie handling will be used to estimate the hazard ratio and its 95% 
confidence interval. The Kaplan-Meier method will be used to estimate the PFS survival 
curve, the median PFS and its 95% CI, PFS at 44 weeks (10.1 months) and its 95% CI, and 
PFS at 74 weeks (17 months) and its 95% CI will be estimated. The time points chosen for 
estimation are close to the expected time of median PFS in the (PBO+D+T) treatment group 
(44 weeks) and the respective smallest detectable median in the (MK+D+T) treatment group.  
Both time points are placed 2 weeks after the scheduled visit as lower variability of the 
Kaplan-Meier estimate is expected outside of the clinic visit window.
For PFS, subjects without documented PD/death will be censored at the last disease 
assessment date or, if they started new anti-cancer treatment, at the last disease assessment 
before initiation of the new anticancer treatment (Table 40). Two sensitivity analyses of PFS 
will be performed. The rules for defining the time of progression or censoring in the primary 
and two sensitivity PFS analyses are provided in Table 41.
Table 41
Censoring Rules for Primary and Sensitivity Analyses of PFS
Situation
Primary Analysis
Sensitivity
Analysis 1
Sensitivity
Analysis 2
No PD and no 
death; new
anticancer treatment 
is not initiated
Censored at last 
disease assessment 
Censored at last 
disease assessment 
Censored at last disease 
assessment if still on study 
therapy; progressed at 
treatment discontinuation 
otherwise
No PD and no 
death; new 
anticancer treatment 
is initiated
Censored at last 
disease assessment 
before new 
anticancer treatment
Censored at last 
disease assessment 
before new anticancer 
treatment
Progressed at date of new 
anticancer treatment
PD or death 
documented after ≤ 
1 missed disease 
assessment
Progressed at date of 
documented PD or 
death
Progressed at date of 
documented PD or 
death
Progressed at date of 
documented PD or death
PD or death 
documented after ≥ 
2 missed disease 
assessments
Progressed at date of 
documented PD or 
death
Censored at last 
disease assessment 
prior to the ≥ 2 missed 
disease assessment
Progressed at date of 
documented PD or death
ORR will be estimated as the percentage of responders among subjects in each treatment 
group. 95% CIs for within-group ORRs will be provided using the Clopper-Pearson method
[102]. The treatment comparison between arms will be based on Miettinen and Nurminen's 
method [100] based on difference in proportions stratified using strata from the PFS analysis. 
 
 
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The response duration analysis will include subjects who achieved objective response. The 
responders who have not yet progressed by the last disease assessment will be censored at the 
last disease assessment date. The treatment groups will be compared in response duration by 
log-rank test stratified using strata from the PFS analysis. A Cox proportional hazard model 
with a factor for treatment group stratified using the strata from the PFS analysis with Efron's 
method of tie handling will be used to estimate the hazard ratio and its 95% confidence 
interval. The Kaplan-Meier method will be used to estimate the response duration survival 
curve, the 25-th percentile and the median of response duration and their 95% CIs. 
Time to response analysis will include all subjects who achieved objective response, and 
thus, will contain no censored endpoints. The Kaplan-Meier method will be used to estimate 
the time to response survival curve, the 25th percentile and the median of response duration 
and their 95% CIs.
The treatment groups will be compared in OS by log-rank test stratified using the strata from 
the PFS analysis. A Cox proportional hazard model with a factor for treatment group 
stratified by the covariates above with Efron's method of tie handling will be used to estimate 
the hazard ratio and its 95% confidence interval. The Kaplan-Meier method will be used to 
estimate the OS survival curve, the 25th percentile and the median of OS and their 95% CIs. 
Subjects without documented death at the time of analysis will be censored at the date last 
known to be alive.  
Best Overall Response (BOR) will be summarized by treatment groups, with frequency of 
categories presented. BOR-5 will be analyzed by ANOVA on scores 1 to 5 assigned to the 
response categories: CR=1, VGPR=2, MPR=3, SD=4, PD=5. ANOVA will include factors 
for treatment group, ECOG PS (0 vs. 1) and LDH (>1.1xULN vs. ≤1.1xULN). 
The 
variances in the two treatment groups will be allowed to be unequal. The desired effect of the 
addition of pembrolizumab to the (PBO+D+T) combination is to shift BOR response towards 
lower scores, [lower the treatment group mean score of (MK+D+T) compared to 
(PBO+D+T)]. 
Individual Best Target Lesion Responses (maximum percent reduction in tumor line length
over target lesions) will be plotted for each treatment group separately in a waterfall plot.
Descriptive statistics according to the individual scoring will be provided for EuroQol (EQ-
5D) and EORTC (QLQ-C30) by cycle and at the end of treatment for each treatment arm 
separately; additional modeling might be performed.  
An exploratory analysis that relates PFS to BOR-5 will be conducted for each treatment 
group separately. Subjects will be classified according to their BOR; five PFS Kaplan-Meier 
curves will be plotted for each category of BOR and examined for presence of trend across 
the categories. In addition, potential of the 5-category Ordinal Response at a landmark to 
predict the PFS beyond the landmark will be explored in the following way. Subjects who
had not experienced PD by Week 12 will be classified into 4 categories according to their 5-
category Ordinal Response at Week 12.  Four overlaid Kaplan-Meier curves for PFS beyond 
Week 12 will be plotted and examined for presence of trend across the categories. Similar 
 
 
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exploratory analysis will be performed for 5-category Ordinal Response at later weeks, 
although diminishing size of the data set will lead to higher variability of Kaplan-Meier 
curves.
Pharmacokinetic Analysis
Serum concentrations of pembrolizumab will be summarized by planned visit and time and 
PK data will be compared to the existing population PK model. Graphical, non-
compartmental and potentially exploratory compartmental analyses will be used for the 
analysis of the PK data.
Plasma concentrations of dabrafenib, hydroxy-dabrafenib, desmethyl-dabrafenib, and 
trametinib will be summarized by planned visit and time.  PK parameters such as oral 
clearance (CL/F), volume of distribution (Vc/F) and other measures of exposure (average 
concentration [Cavg], and/or minimum concentration [Cmin]) will be derived using previously 
validated models and summarized.
Biomarker Analysis
In Parts 1, 2, 4, and 5, the key biomarker will be the PD-L1 expression measured using 0-5 
Allred Proportion Scores (APS) for PD-L1 staining in melanoma using the Dako assay. The 
mean change from baseline to Day 10-14 after administration of oral dabrafenib and/or 
trametinib in combination with intravenously administered pembrolizumab in PD-L1 
expression will be estimated and the 95% CI for the change will be provided.  
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, SAEs, laboratory tests, vital signs, ECG measurements and physical examinations.
In Parts 1, 2, 4, and 5, DLTs will be listed. Adverse experiences will be summarized as 
counts and frequencies for each dose level in Parts 1, 2, 4, and 5 of the study. Laboratory 
assessments, vital signs, and other safety endpoints will be summarized as appropriate.
AEs of potentially immunologic etiology (AEs of special interest, AEOSI) will be identified
using a pre-specified list of terms.   
Part 3.  The analysis of safety results in Part 3 will follow a tiered approach (Table 42).  The 
tiers differ with respect to the analyses that will be performed. There are no Tier 1 events in 
this study; safety parameters will be considered Tier 2 or Tier 3.  Tier 2 parameters will be 
assessed via point estimates with 95% confidence intervals provided for between-group 
comparisons; only point estimates by treatment group are provided for Tier 3 safety 
parameters.
Adverse experiences (specific terms as well as system organ class terms) and predefined 
limits of change in laboratory, vital signs, and ECG parameters will be classified as 
belonging to "Tier 2" or "Tier 3," based on the number of events observed.  Membership in 
 
 
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Tier 2 requires that at least 4 subjects in any treatment group exhibit the event; all other 
adverse experiences and predefined limits of change will belong to Tier 3.
The threshold of at least 4 events was chosen because the 95% confidence interval for the
between-group difference in percent incidence will always include zero when treatment 
groups of equal size each have less than 4 events and thus would add little to the 
interpretation of potentially meaningful differences.  Because many 95% confidence intervals 
may be provided without adjustment for multiplicity, the confidence intervals should be 
regarded as a helpful descriptive measure to be used in review, not a formal method for 
assessing the statistical significance of the between-group differences in adverse experiences 
and predefined limits of change.
Continuous measures such as changes from baseline in laboratory, vital signs, and ECG 
parameters that are not pre-specified as Tier-1 endpoints will be considered Tier 3 safety 
parameters.  Summary statistics for baseline, on-treatment, and change from baseline values 
will be provided by treatment group in table format.  
In addition, the broad clinical and laboratory AE categories consisting of the percentage of 
subjects with any AE, a drug related AE, a serious AE, an AE which is both drug-related and 
serious, and who discontinued due to an AE will be considered Tier 2 endpoints.  
AEs of potentially immunologic etiology (AEs of special interest [AEOSI]) will be identified 
using a pre-specified list of terms and summarized.
 
 
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Table 42
Analysis Strategy for Safety Parameters
Safety Tier
Safety Endpoint†
p-Value
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 2
Any AE
X
X
Any Serious AE
X
X
Any Grade 3-5 AE
X
X
Onset and Duration of First Grade 3-5 AE
X
X
Any Drug-Related AE
X
X
Any Serious and Drug-Related AE
X
X
Any Grade3-5 and Drug-Related AE
X
X
Dose Modification due to AE
X
X
Discontinuation due to AE
X
X
Death
X
X
Specific AEs, SOCs, or PDLCs‡ (incidence ≥4 
subjects in at least one of the treatment 
groups)
X
X
Tier 3
Specific AEs, SOCs or PDLCs‡ (incidence <4 
subjects in all of the treatment groups), 
AEOSI
X
Change from Baseline Results (Labs, ECGs, 
Vital Signs)
X
†
Adverse Experience references refer to both Clinical and Laboratory AEs.
‡
Includes only those endpoints not pre-specified as Tier-2 endpoints.
Note: SOC=System Organ Class; PDLC=Pre-Defined Limit of Change; X = results will be provided.
Summaries of Baseline Characteristics, Demographics, and Other Analyses
Demographic variables (e.g., age, gender), baseline characteristics, primary and secondary 
diagnoses, and prior and concomitant therapies will be summarized by descriptive statistics 
or categorical tables. The number and percentage of subjects screened, randomized, the 
primary reasons for screening failure, and the primary reason for discontinuation will be 
displayed.  
Multiplicity
There will be no multiplicity control across the primary and secondary endpoints tests in this 
study or across the interim and final analysis.
Sample Size and Power Calculations
If the true hazard ratio is 0.5, the study will need approximately 74 PFS events to have 80% 
power to reject a null hypothesis of equal PFS distributions in the two groups at one-sided 
0.025 Type I error.  Approximately 120 subjects will be randomized in 1:1 ratio to 
accumulate this number of events with 0.5-year enrollment period and 2-year total study 
duration assuming the median PFS in the (PBO+D+T) group is 10 months (rounded up 
estimate of 9.4 months provided in Flaherty et al. paper [101]) and yearly dropout rate is 5%. 
 
 
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The observed hazard ratio needs to be approximately 0.62 or lower for the treatment effect to 
be statistically significant.  This ratio translates to approximately 6.2 months increase in 
median duration. 
Subgroup Analyses and Effect of Baseline Factors
The hazard ratio estimate and its 95% confidence interval for PFS and the ORR estimate and 
its 95% CI will be provided in the subgroups of subjects who are PD-L1 positive and PD-L1 
negative. In addition, we will explore the treatment effect on the PFS (hazard ratio estimates 
and 95% CI) within each of the following subgroups: Age (≤ 65 vs. > 65 years), Sex (female 
vs. male), Race (white, non-white), ECOG status (0 vs. 1), LDH (>1.1xULN vs. ≤1.1xULN). 
The consistency of the treatment effect will be assessed descriptively via summary statistics 
by category for the classification variables listed above.  The number of subjects in each 
subgroup and the number (percent) of subjects with the PD will be also provided by 
treatment group.  If a subgroup has no subjects with the PD in at least one of the treatment 
groups, the hazard ratio estimate and its 95% CI will not be derived.  
Interim Analyses
Interim analysis of Part 3 will be conducted to inform potential early Go/No Go decision for 
initiation of Phase III study before the completion of Part 3.  The data from the first 80 
subjects randomized into the study will be used in the interim analysis.  The interim analysis 
will be conducted when the first 80 subjects randomized into the study will have completed 
their Week 36 visit and have their central radiology assessment at Week 36 available or have 
discontinued prior to Week 36.
Primary Endpoint for the Interim Analysis  
The primary endpoint for the interim analysis is the ordinal response at Week 36 with the 
following five categories: CR, VGPR, MPR, SD, and PD determined by central review.  
Subjects who discontinued prior to Week 36 will be assigned to one of these categories for 
Week 36 according to their reason for discontinuation (see the endpoint definition).  
Analysis of the Primary Endpoint for the Interim Analysis  
The two treatment groups will be compared in the primary endpoint by Analysis of Variances 
(ANOVA) on scores 1 to 5 assigned to the response categories: CR=1, VGPR=2, MPR=3, 
SD=4, PD=5. ANOVA will include factors for treatment group and the strata from the PFS 
analysis.  The variances in the two treatment groups will be allowed to be unequal. The 
desired effect of the addition of pembrolizumab to the (PBO+D+T) combination is to shift 
the ordinal response towards lower scores [lower the treatment group mean of (MK+D+T) 
compared to (PBO+D+T)].
8.2.9.2.1
Interim Decision Rules 
If analysis of the ordinal response at Week 36 results in a statistically significant comparison 
in favor of the (MK+D+T) combination at one-sided Type I error of 0.025, the decision to 
 
 
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initiate Phase III study without waiting for PFS results will be considered.  If the analysis 
shows that (MK+D+T) is worse than (PBO+D+T) at one-sided 0.05 Type I error, the futility 
will be established and the decision not to initiate a Phase III study may be considered. 
8.2.9.2.2
Power of the Interim Analysis
The true mean of the ordinal endpoint at Week 36 in the high dose dabrafenib and trametinib 
combination treatment group in Flaherty et al. study [101] is projected to be 3.51 (an average 
of Week 32 and Week 40 means in Flaherty et al. study [101]). The following assumptions 
were used to derive the distribution of the ordinal endpoint at Week 36 in (MK+D+T) 
treatment group.  We assumed that the subjects in (MK+D+T) treatment group reach their 
Best Overall Response by Week 36 and retain it at Week 36.  We further assumed that the 
Best Overall Response in subjects in the (MK+D+T) treatment group is the same as the Best 
Overall Response in the high dose dabrafenib and trametinib combination treatment group in 
the Flaherty et al. study [101]. Therefore, the assumed distribution of the ordinal endpoint at 
Week 36 in (MK+D+T) treatment group matches the distribution of the Best Overall 
Response in the high dose dabrafenib and trametinib combination treatment group in the 
Flaherty et al. study [101], with the mean of 2.59. Thus, the true between-treatment 
difference in the mean ordinal response under the alternative hypotheses is 0.92; the standard 
deviation that corresponds to the specified distributions of the ordinal response at Week 36 is 
approximately 1.29.
Under the null hypotheses (the ordinal response in the (MK+D+T)
treatment group at Week 36 is the same as in the (PBO+D+T) treatment group), the true 
difference in means is 0 and the standard deviation is 1.53.
Power for Superiority Decision  
With 40 subjects per treatment group, between-treatment difference of 0.92 and standard 
deviation of 1.29, the interim analysis has approximately 88% power to establish superiority 
of (MK+D+T) in ordinal response at Week 36.  The smallest difference in treatment means 
detectable at one-side 0.025 Type I error is approximately 0.57 (with the mean in the 
(MK+D+T) treatment group lower than the mean in the (PBO+D+T) treatment group).
Observed Difference Required for Futility Decision  
With 40 subjects per treatment group and standard deviation of 1.53, the observed difference 
in the treatment means of the ordinal response should be at least 0.56 (with mean in the 
(MK+D+T) treatment group higher than the mean in the (PBO+D+T) treatment group) to 
reject the null hypothesis of the equal means at one-sided 0.05 Type I error.
Interpretation of the Difference in the Means of the Ordinal Endpoint
The difference of 0.57 in the treatment group means can be achieved if, for example, the 
responses of 57% of subjects in one treatment group are moved one category down on the 
ordinal scale (VGPR to CR, or MPR to VGPR, or SD to MPR, or PD to SD); or the 
responses of 20% of subjects are moved 2 categories down (from MPR to CR, or SD to 
 
 
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VGPR, or PD to MPR) and the responses of another 17% of subjects are moved one category 
down. 
8.2.9.2.3
Secondary and Exploratory Endpoints at the Interim Analysis
Secondary endpoints at the Interim Analysis
1) Percentage of subjects with Deep Response (DR) at Week 36 defined as either CR or 
VGPR at Week 36
2) Percentage of subjects with CR at Week 36
3) Ordinal response at Week 36 with the following five categories: CR, VGPR, MPR, SD, 
and PD determined by the investigator review
Exploratory endpoints at the Interim Analysis
1) Percentage of subjects with PR at Week 36
2) Best Overall Response (analyzed as an ordinal endpoint)
3) Best Percent Reduction in Tumor Line Length by Week 36
4) Percentage of subjects with sustained response at Week 36 -subjects who achieved 
response (confirmed CR or PR) prior to Week 36 but have not yet progressed at Week 36
5) Tumor growth kinetics endpoints: growth rate constant (GST) and time-to-growth (TTG)
Analysis of Secondary and Exploratory Endpoints
Binary secondary and exploratory endpoints will be compared between the two treatment 
groups by Fisher’s exact test. All analyses will be performed at two-sided Type I error 0.05; 
there will be no control of Type I error across the primary and secondary hypotheses.
Summaries of the ordinal response (based on investigator review) distribution by week, 
including frequencies of categories and the mean response, will be provided.  
A sensitivity analysis of the ordinal response at Week 36 based on the investigator review
will be performed using the analysis described for the ordinal response at Week 36 based on 
central review.
Power of the Analyses of Secondary Endpoints at the Interim Analysis  
If the true percentage of subjects with CR at Week 36 in (PBO+D+T) group is 10% 
(approximate expected percentage) and the true percentage of subjects with CR at Week 36 
in (MK+D+T) group is 35%, the power for comparison of the percentages of subjects with 
CR at Week 36 is 71%.  If the true percentage of subjects with DR at Week 36 in 
(PBO+D+T) group is 37.5% (approximate expected percentage) and the true percentage of 
 
 
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subjects with CR at Week 36 in (MK+D+T) group is 70%, the power for comparison of the 
percentages of subjects with CR at Week 36 is 79%. 
If there are 4 subjects out of 40 (10%) with CR at Week 36 in the (PBO+D+T) treatment 
group, the (MK+D+T) treatment group should have at least 12 subjects with CR (36 %) at 
Week 36 for the comparison to be statistically significant.  If there are 15 subjects with DR 
(37.5%) at Week 36 in the (PBO+D+T) treatment group, the (MK+D+T) treatment group 
should have at least 24 subjects with DR at Week 36 (60%) for the comparison to be 
statistically significant.
Compliance (Medication Adherence)
Drug accountability data for trial treatment will be collected during the study.  Any deviation 
from protocol-directed administration will be reported.
Extent of Exposure
For a pembrolizumab regimen, a subject’s extent of exposure to pembrolizumab (or matching 
IV placebo) is defined as the total number of doses of pembrolizumab (or matching IV 
placebo) the subject received. A subject’s extent of exposure to dabrafenib or trametinib will 
be described through the cumulative dose of each drug.
Summary statistics will be provided to characterize Extent of Exposure, Time on Study 
Treatment (in months; calculated as the total number of days from the first post-
randomization dose date to the date of the last dose of study medication multiplied by 
12/365.24), and, for dabrafenib and trametinib, the Average Daily Dose. The summary 
statistics will be provided for the APaT population in Part 3, for each treatment group 
separately.
9.0 LABELING, PACKAGING,
STORAGE AND RETURN OF CLINICAL 
SUPPLIES
Investigational Product
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations.
Clinical Supplies will be provided by the Sponsor as summarized in Table 43.
 
 
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Table 43
Product Descriptions
Product Name & Potency
Dosage Form
Pembrolizumab 100 mg / 4 mL
solution for IV infusion
Trametinib 2 mg 
tablets
Trametinib 0.5 mg
tablets
Dabrafenib 75 mg
capsules
Dabrafenib 50 mg
capsules
Packaging and Labeling Information
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
Open label vials of pembrolizumab and open label bottles of trametinib and dabrafenib will 
be provided. No kitting is required.
Clinical Supplies Disclosure
Parts 1, 2, 4, and 5 of the trial is open-label; therefore, the subject, the trial site personnel, the 
Sponsor and/or designee are not blinded. Treatment identity (name, strength or potency) is 
included in the label text; random code/disclosure envelopes or lists are not provided.
Part 3 of the trial is blinded but provided open label; therefore, an unblinded pharmacist or 
qualified trial site personnel will be used to blind supplies. Treatment identity (name, 
strength or potency) is included in the label text; random code/disclosure envelopes or lists 
are provided.
At unblinding, trial personnel will dispense unblinded supplies. Additional details are 
included in the pharmacy and procedures manuals.
The emergency unblinding call center will use the randomization schedule for the trial to 
unblind subjects and to unmask treatment for Part 3 of this trial. In the event that the 
emergency unblinding call center is not available for a given site in this trial, the central 
electronic randomization system (IVRS/IWRS) should be used in order to unblind subjects 
and to unmask treatment/vaccine identity. The Sponsor will provide random code/disclosure 
envelopes or lists to the emergency unblinding call center.
Treatment identification information is to be unmasked ONLY if necessary for the welfare of 
the subject.  Every effort should be made not to unblind. 
In the event that unblinding has occurred, the circumstances around the unblinding (e.g., date 
and reason) must be documented promptly, and the Sponsor Clinical Monitor notified as 
soon as possible.  Only the principal investigator or delegate and the respective subject’s 
code should be unblinded.  Trial site personnel and Sponsor personnel directly associated 
with the conduct of the trial should not be unblinded.
 
 
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Storage and Handling Requirements
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.  
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site.
Clinical supplies may not be used for any purpose other than that stated in the protocol.
Returns and Reconciliation
The investigator is responsible for keeping accurate records of the clinical supplies received 
from the Sponsor or designee, the amount dispensed to and returned by the subjects and the 
amount remaining at the conclusion of the trial. 
For all trial sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return.
Standard Policies
Trial site personnel will have access to a central electronic randomization system 
(IVRS/IWRS system) to allocate subjects, to assign treatment to subjects and to manage the 
distribution of clinical supplies. Each person accessing the IVRS system must be assigned an 
individual unique PIN.  They must use only their assigned PIN to access the system, and they 
must not share their assigned PIN with anyone.
10.0 ADMINISTRATIVE AND REGULATORY DETAILS
Confidentiality
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the institutional review board, ethics review committee (IRB/ERC) or similar 
or expert committee; affiliated institution and employees, only under an appropriate 
understanding of confidentiality with such board or committee, affiliated institution and 
employees.  Data generated by this trial will be considered confidential by the investigator, 
except to the extent that it is included in a publication as provided in the Publications section 
of this protocol.
Confidentiality of Subject Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/ERC, or regulatory authority representatives may consult and/or copy trial documents in 
order to verify worksheet/case report form data.  By signing the consent form, the subject 
agrees to this process.  If trial documents will be photocopied during the process of verifying 
 
 
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worksheet/case report form information, the subject will be identified by unique code only; 
full names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all subject data used and disclosed in 
connection with this trial in accordance with all applicable privacy laws, rules and 
regulations.
Confidentiality of Investigator Information
By signing this protocol, the investigator recognizes that certain personal identifying 
information with respect to the investigator, and all subinvestigators and trial site personnel, 
may be used and disclosed for trial management purposes, as part of a regulatory 
submissions, and as required by law.  This information may include:
1. name, address, telephone number and e-mail address;
2. hospital or clinic address and telephone number;
3. curriculum vitae or other summary of qualifications and credentials; and
4. other professional documentation.
Consistent with the purposes described above, this information may be transmitted to the 
Sponsor, and subsidiaries, affiliates and agents of the Sponsor, in your country and other 
countries, including countries that do not have laws protecting such information.  
Additionally, the investigator’s name and business contact information may be included 
when reporting certain serious adverse events to regulatory authorities or to other 
investigators.  By signing this protocol, the investigator expressly consents to these uses and 
disclosures.
If this is a multicenter trial, in order to facilitate contact between investigators, the Sponsor 
may share an investigator’s name and contact information with other participating 
investigators upon request.
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC member that 
reviews and approves this trial.  The Sponsor is also required to document that each IRB/IEC 
meets regulatory and ICH GCP requirements by requesting and maintaining records of the 
names and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
Compliance with Financial Disclosure Requirements
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54).  It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
 
 
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Financial Disclosure information is required.  It is the investigator's/subinvestigator's 
responsibility to comply with any such request.  
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements.  
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor or through a secure password-protected electronic portal provided by the 
Sponsor.  The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes.  This may involve the 
transmission of information to countries that do not have laws protecting personal data.
Compliance with Law, Audit and Debarment
By signing this protocol, the investigator agrees to conduct the trial in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of Good 
Clinical Practice (e.g., International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice: 
Consolidated Guideline and other generally accepted standards of good clinical practice); and 
all applicable federal, state and local laws, rules and regulations relating to the conduct of the 
clinical trial.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by Merck, is provided in Section 12.1 -
Merck Code of Conduct for Clinical Trials.
The investigator also agrees to allow monitoring, audits, IRB/ERC review and regulatory 
authority inspection of trial-related documents and procedures and provide for direct access 
to all trial-related source data and documents.
The investigator agrees not to seek reimbursement from subjects, their insurance providers or 
from government programs for procedures included as part of the trial reimbursed to the 
investigator by the Sponsor.
The investigator shall prepare and maintain complete and accurate trial documentation in 
compliance with Good Clinical Practice standards and applicable federal, state and local 
laws, rules and regulations; and, for each subject participating in the trial, provide all data, 
and, upon completion or termination of the clinical trial, submit any other reports to the 
Sponsor as required by this protocol or as otherwise required pursuant to any agreement with 
the Sponsor.
Trial documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the trial site upon request for inspection, 
copying, review and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities.  The investigator agrees to promptly take any reasonable steps that are 
 
 
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requested by the Sponsor as a result of an audit to cure deficiencies in the trial documentation 
and worksheets/case report forms.
The investigator must maintain copies of all documentation and records relating to the 
conduct of the trial in compliance with all applicable legal and regulatory requirements.  This 
documentation includes, but is not limited to, the protocol, worksheets/case report forms, 
advertising for subject participation, adverse event reports, subject source data, 
correspondence with regulatory authorities and IRBs/ERCs, consent forms, investigator’s 
curricula vitae, monitor visit logs, laboratory reference ranges, laboratory certification or 
quality control procedures and laboratory director curriculum vitae.  By signing this protocol, 
the investigator agrees that documentation shall be retained until at least 2 years after the last 
approval of a marketing application in an ICH region or until there are no pending or 
contemplated marketing applications in an ICH region or until at least 2 years have elapsed 
since the formal discontinuation of clinical development of the investigational product.  
Because the clinical development and marketing application process is variable, it is 
anticipated that the retention period can be up to 15 years or longer after protocol database 
lock. The Sponsor will determine the minimum retention period and notify the investigator 
when documents may be destroyed.  The sponsor also recognizes that documents may need 
to be retained for a longer period if required by local regulatory requirements. All trial 
documents shall be made available if required by relevant regulatory authorities. The 
investigator must consult with and obtain written approval by the Sponsor prior to discarding 
trial and/or subject files.  
ICH Good Clinical Practice guidelines recommend that the investigator inform the subject’s 
primary physician about the subject’s participation in the trial if the subject has a primary 
physician and if the subject agrees to the primary physician being informed.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this trial.
Persons debarred from conducting or working on clinical trials by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s trials.  The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the trial is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will 
promptly notify that trial site’s IRB/IEC.
According to European legislation, a Sponsor must designate an overall coordinating 
investigator for a multi-center trial (including multinational).  When more than one trial site 
is open in an EU country, Merck, as the Sponsor, will designate, per country, a national 
principal coordinator (Protocol CI), responsible for coordinating the work of the principal 
investigators at the different trial sites in that Member State, according to national 
regulations.  For a single-center trial, the Protocol CI is the principal investigator.  In 
addition, the Sponsor must designate a principal or coordinating investigator to review the 
 
 
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trial report that summarizes the trial results and confirm that, to the best of his/her 
knowledge, the report accurately describes the conduct and results of the trial [Clinical Study 
Report (CSR) CI].  The Sponsor may consider one or more factors in the selection of the 
individual to serve as the Protocol CI and or CSR CI (e.g., availability of the CI during the 
anticipated review process, thorough understanding of clinical trial methods, appropriate 
enrollment of subject cohort, timely achievement of trial milestones).  The Protocol CI must 
be a participating trial investigator.
Compliance with Trial Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Amendments Act (FDAAA) of 2007 
and the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, the Sponsor 
of the trial is solely responsible for determining whether the trial and its results are subject to 
the 
requirements 
for 
submission 
to 
http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries.  Merck, as Sponsor of this trial, will 
review this protocol and submit the information necessary to fulfill these requirements. 
Merck entries are not limited to FDAAA or the EMA clinical trial directive mandated trials.  
Information posted will allow subjects to identify potentially appropriate trials for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate trial locations and trial site contact information.  
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this trial or its results to those 
registries.
Quality Management System
By signing this protocol, the Sponsor agrees to be responsible for implementing and 
maintaining a quality management system with written development procedures and 
functional area standard operating procedures (SOPs) to ensure that trials are conducted and 
data are generated, documented, and reported in compliance with the protocol, accepted 
standards of Good Clinical Practice, and all applicable federal, state, and local laws, rules and 
regulations relating to the conduct of the clinical trial.
Data Management
The investigator or qualified designee is responsible for recording and verifying the accuracy 
of subject data.  By signing this protocol, the investigator acknowledges that his/her 
electronic signature is the legally binding equivalent of a written signature.  By entering 
his/her electronic signature, the investigator confirms that all recorded data have been 
verified as accurate.
Detailed information regarding Data Management procedures for this protocol will be 
provided by the Sponsor.
 
 
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Publications
This trial is intended for publication, even if terminated prematurely. Publication may include 
any or all of the following: posting of a synopsis online, abstract and/or presentation at a 
scientific conference, or publication of a full manuscript.  The Sponsor will work with the 
authors to submit a manuscript describing trial results within 12 months after the last data 
become available, which may take up to several months after the last subject visit in some 
cases such as vaccine trials.  However, manuscript submission timelines may be extended on 
OTC trials.  For trials intended for pediatric-related regulatory filings, the investigator agrees 
to delay publication of the trial results until the Sponsor notifies the investigator that all 
relevant regulatory authority decisions on the trial drug have been made with regard to 
pediatric-related regulatory filings. Merck will post a synopsis of trial results for approved 
products on www.clinicaltrials.gov by 12 months after the last subject's last visit for the 
primary outcome, 12 months after the decision to discontinue development, or product 
marketing (dispensed, administered, delivered or promoted), whichever is later.
These timelines may be extended for products that are not yet marketed, if additional time is 
needed for analysis, to protect intellectual property, or to comply with confidentiality 
agreements with other parties.  Authors of the primary results manuscript will be provided 
the complete results from the Clinical Study Report, subject to the confidentiality agreement. 
When a manuscript is submitted to a biomedical journal, the Sponsor's policy is to also 
include the protocol and statistical analysis plan to facilitate the peer and editorial review of 
the manuscript.  If the manuscript is subsequently accepted for publication, the Sponsor will 
allow the journal, if it so desires, to post on its website the key sections of the protocol that 
are relevant to evaluating the trial, specifically those sections describing the trial objectives 
and hypotheses, the subject inclusion and exclusion criteria, the trial design and procedures, 
the efficacy and safety measures, the statistical analysis plan, and any amendments relating to 
those sections.  The Sponsor reserves the right to redact proprietary information.
For multicenter trials, subsequent to the multicenter publication (or after public disclosure of 
the results online at www.clinicaltrials.gov if a multicenter manuscript is not planned), an 
investigator and his/her colleagues may publish their data independently.  In most cases, 
publication of individual trial site data does not add value to complete multicenter results, 
due to statistical concerns.  In rare cases, publication of single trial site data prior to the main 
paper may be of value.  Limitations of single trial site observations in a multicenter trial 
should always be described in such a manuscript.
Authorship credit should be based on 1) substantial contributions to conception and design, 
or acquisition of data, or analysis and interpretation of data; 2) drafting the article or revising 
it critically for important intellectual content; and 3) final approval of the version to be 
published. Authors must meet conditions 1, 2 and 3.  Significant contributions to trial 
execution may also be taken into account to determine authorship, provided that 
contributions have also been made to all three of the preceding authorship criteria.  Although 
publication planning may begin before conducting the trial, final decisions on authorship and 
the order of authors’ names will be made based on participation and actual contributions to 
 
 
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the trial and writing, as discussed above. The first author is responsible for defending the 
integrity of the data, method(s) of data analysis and the scientific content of the manuscript.
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.
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11. Fourcade J, Kudela P, Sun Z, Shen H, Land SR, Lenzner D, et al. PD-1 is a regulator 
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19. Patnaik A, Kang SP, Tolcher AW, Rasco DW, Papadopoulos KP, Beeram M, et al. 
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20. Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. 
Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J 
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21. Chapman PB, Hauschild A, Robert C, Hannen JB, Ascierto P, Larkin J, et al. 
Improved survival with vemurafenib in melanoma with BRAF V600E mutation. New 
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22. Robert C, Thomas L, Bondarenko I, O'Day S, Weber J, Garbe C, et al. Ipilimumab 
plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 2011;
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23. Bellati F, Visconti V, Napoletano C, Antonilli M, Frati L, Benedetti Panici P, et al. 
Immunology of gynecologic neoplasms: analysis of the prognostic significance of the 
immune status. Curr Cancer Drug Targets 2009; 9(4):541-65.  
24. Ruffell B, DeNardo DG, Affara NI, Coussens LM. Lymphocytes in cancer 
development: polarization towards pro-tumor immunity. Cytokine Growth Factor Rev 
2010; 21:3-10.  
25. Shirabe K, Motomura T, Muto J, Toshima T, Matono R, Mano Y, et al. Tumor-
infiltrating lymphocytes and hepatocellular carcinoma: pathology and clinical 
management. Int J Clin Oncol 2010; 15:552-8.  
26. Al-Shibli K, Al-Saad S, Andersen S, Donnem T, Bremnes RM, Busund L-T. The 
prognostic value of intraepithelial and stromal CD3-, CD117- and CD138-positive 
cells in non-small cell lung carcinoma. APMIS 2010; 118:371-82.  
27. Clark CE, Beatty GL, Vonderheide RH. Immunosurveillance of pancreatic 
adenocarcinoma: insights from genetically engineered mouse models of cancer. 
Cancer Lett 2009; 279:1-7.  
28. Diederichsen ACP, Hjelmborg JvB, Christensen PB, Zeuthen J, Fenger C. Prognostic 
value of the CD4+/CD8+ ratio of tumour infiltrating lymphocytes in colorectal cancer 
and HLA-DR expression on tumour cells. Cancer Immunol Immunother 2003;
52:423-8.  
29. Gao Q, Qiu S-J, Fan J, Zhou J, Wang X-Y, Xiao Y-S, et al. Intratumoral balance of 
regulatory and cytotoxic T cells is associated with prognosis of hepatocellular 
carcinoma after resection. J Clin Oncol 2007; 25(18):2586-93.  
30. Hillen F, Baeten CIM, van de Winkel A, Creytens D, van der Schaft DWJ, 
Winnepenninckx V, et al. Leukocyte infiltration and tumor cell plasticity are 
parameters of aggressiveness in primary cutaneous melanoma. Cancer Immunol 
Immunother 2008; 57:97-106.  
31. Laghi L, Bianchi P, Miranda E, Balladore E, Pacetti V, Grizzi F, et al. CD3+ cells at 
the invasive margin of deeply invading (pT3-T4) colorectal cancer and risk of post-
surgical metastatsis: a longitudinal study. Lancet Oncol 2009; 10:877-84.  
32. Li JF, Chu YW, Wang GM, Zhu TY, Rong RM, Hou J, et al. The prognostic value of 
peritumoral regulatory T cells and its correlation with intratumoral cyclooxygenase-2 
expression in clear cell renal cell carcinoma. BJU Intern 2008; 103:399-405.  
33. Nemolato S, Fanni D, Naccarato AG, Ravarino A, Bevilacqua G, Faa G. 
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carcinoma as essential immune response. J Surg Oncol 2003; 84:224-8.  
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cancer patients. Human Immunol 2008; 69:241-9.  
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infiltrating lymphocytes and a dominant nodule within primary melanoma are 
prognostic factors for relapse-free survival of patients with thick (T4) primary 
melanoma: pathologic analysis of the E1690 and E1694 intergroup trials. Am J Clin 
Pathol 2010; 133:646-53.  
38. Sasaki A, Tanaka F, Mimori K, Inoue H, Kai S, Shibata K, et al. Prognostic value of 
tumor-infiltrating FOXP3+ regulatory T cells in patients with hepatocellular 
carcinoma. EJSO 2008; 34:173-9.  
39. Shen Z, Zhou S, Wang Y, Li R, Zhong C, Liang C, et al. Higher intratumoral 
infiltrated Foxp3+ Treg numbers and Foxp3+/CD8+ ratio are associated with adverse 
prognosis in resectable gastric cancer. J Cancer Res Clin Oncol 2010; 136:1585-95.  
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or Hyde. Cancer Metastasis Rev 2007; 26:373-400.  
41. Usubütün A, Ayhan A, Uygur MC, zen H, klu C, acan S. Prognostic factors in renal 
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42. Al-Shibli KI, Donnem T, Al-Saad S, Persson M, Bremnes RM, Busund L-T. 
Prognostic effect of epithelial and stromal lymphocyte infiltration in non-small cell 
lung cancer. Clin Cancer Res 2008; 14(16):5220-7.  
43. Deschoolmeester V, Baay M, Van Marck E, Weyler J, Vermeulen p, Lardon F, et al. 
Tumor infiltrating lymphocytes: an intriguing player in the survival of colorectal 
cancer patients. BMC Immunol 2010; 11:19.  
44. Diez M, Pollán M, Enriquez JM, Dominguez P, Santana A, Tobaruela E, et al. 
Histopathologic prognostic score in colorectal adenocarcinomas. Anticancer Res 
1998; 18:689-94.  
45. Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pagès C, et 
al. Type, density, and location of immune cells within human colorectal tumors 
predict clinical outcome. Science 2006; 313:1960-4.  
 
 
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46. Hiraoka N. Tumor-infiltrating lymphocytes and hepatocellular carcinoma: molecular 
biology. Int J Clin Oncol 2010; 15:544-51.  
47. Hodi FS, Dranoff G. The biologic importance of tumor-infiltrating lymphocytes. J 
Cutan Pathol 2010; 37(Suppl 1):48-53.  
48. Kloor M. Lymphocyte infiltration and prognosis in colorectal cancer. Lancet 2009;
10(840):841.  
49. Lee HE, Chae SW, Lee YJ, Kim MA, Lee HS, Lee BL, et al. Prognostic implications 
of type and density of tumour-infiltrating lymphocytes in gastric cancer. Br J Cancer 
2008; 99(10):1704-11.  
50. Leffers N, Gooden MJM, de Jong RA, Hoogeboom B-N, ten Hoor KA, Hollema H, et 
al. Prognostic significance of tumor-infiltrating T-lymphocytes in primary and 
metastatic lesions of advanced stage ovarian cancer. Cancer Immunol Immunother 
2009; 58:449-59.  
51. Nishimura H, Honjo T, Minato N. Facilitation of β selection and modification of 
positive selection in the thymus of PD-1-deficient mice. J Exp Med 2000;191(5):891-
7.  
52. Oble DA, Loewe R, Yu P, Mihm Jr. MC. Focus on TILs: prognostic significance of 
tumor infiltrating lymphocytes in human melanoma. Cancer Immunity 2009; 9:3.  
53. Pölcher M, Braun M, Friedrichs N, Rudlowski C, Bercht E, Fimmers R, et al. Foxp3+
cell infiltration and granzyme B+/Foxp3+ cell ratio are associated with outcome in 
neoadjuvant chemotherapy-treated ovarian carcinoma. Cancer Immunol Immunother 
2010; 59:909-19.  
54. Suzuki H, Chikazawa N, Tasaka T, Wada J, Yamasaki A, Kitaura Y, et al. 
Intratumoral CD8+ T/FOXP3+ cell ratio is a predictive marker for survival in patients 
with colorectal cancer. Cancer Immunol Immunother 2010; 59:653-61.  
55. Chew V, Tow C, Teo M, Wong HL, Chan J, Gehring A, et al. Inflammatory tumor 
microenvironment is associated with superior survival in hepatocellular carcinoma 
patients. J Hepatol 2010; 52:370-9.  
56. Liotta F, Gacci M, Frosali F, Querci V, Vittori G, Lapini A, et al. Frequency of 
regulatory T cells in peripheral blood and in tumour-infiltrating lymphocytes 
correlates with poor prognosis in renal cell carcinoma. BJU Intern 2010; 107:1500-6.  
57. Ropponen KM, Eskelinen MJ, Lipponen PK, Alhava E, Kosma V-M. Prognostic 
value of tumour-infiltrating lymphocytes (TILs) in colorectal cancer. J Pathol 1997;
182:318-24.  
 
 
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58. Dudley ME, Wunderlich JR, Yang JC, Sherry RM, Topalian SL, Restifo NP, et al. 
Adoptive cell transfer therapy following non-myeloablative but lymphodepleting 
chemotherapy for the treatment of patients with refractory metastatic melanoma. J 
Clin Oncol 2005; 23(10):2346-57.  
59. Hunder NN, Wallen H, Cao J, Hendricks DW, Reilly JZ, Rodmyre R, et al. Treatment 
of metastatic melanoma with autologous CD4+ T cells against NY-ESO-1. N Engl J 
Med 2008; 358(25):2698-703.  
60. Okazaki T, Maeda A, Nishimura H, Kurosaki T, Honjo T. PD-1 immunoreceptor 
inhibits B cell receptor-mediated signaling by recruiting src homology 2-domain-
containing tyrosine phosphatase 2 to phosphotyrosine. PNAS 2001; 98(24):13866-71.  
61. Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Annu Rev 
Immunol 2005; 23:515-48.  
62. Hamid O, Robert C, Daud A, Hodi FS, et al.  Safety and Tumor Responses with 
Lambroluzimab (Anti-PD-1) in Melanoma.  N Engl J Med 2013; 369(2): 134-44.
63. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, et al. Mutations of the BRAF 
gene in human cancer. Nature. 2002; 417:949-954.
64. Allen LF, Sebolt-Leopold J, Meyer MB. CI-140 (PD184352), a targeted signal 
transduction inhibitor of MEK (MAPKK). Semin Oncol, 2003; 30 (suppl 16):105-66.
65. Wellbrock C, Karasaides M, Marais R. The RAF proteins take center stage. Nature 
Reviews Mol Cell Biol. 2004; 5:875-885.
66. Gorden A, Osman I, Gai W, et al. Analysis of BRAF and N-RAS mutations in 
metastatic melanoma tissues. Cancer Res., 2003; 63:3955-3957.
67. Houben R, Becker JC, Kappel A, et al. Constitutive activation of the Ras-Raf 
signalling pathway in metastatic melanoma is associated with poor prognosis. J 
Carcinog, 2004; 3:6.
68. Kirschner M, Helmke B, Starz H, et al. Preponderance of the oncogenic V599E and 
V599K mutations in the B-raf kinase domain is enhanced in melanoma lymph node 
metastases.
69. Kumar R, Angelini S, Czene K, et al. BRAF mutations in metastatic melanoma: a 
possible association with clinical outcome. Clin Cancer Res., 2003; 9:3362-3368.
70. Libra M, Malaponte G, Navolanic PM, et al. Analysis of BRAF mutation in primary 
and metastatic melanoma. Cell Cycle, 2005; 4:1382-1384.
 
 
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71. Omholt K, Platz A, Kanter L, et al. NRAS and BRAF mutations arise early during 
melanoma pathogenesis and are preserved throughout tumor progression. Clin Cancer 
Res., 2003; 9:6483-6488.
72. Nissan MH, Solit DB.
The “SWOT” of BRAF inhibition in melanoma: RAF 
inhibitors, MEK inhibitors, or both? Curr Oncol Rep, 2011; 13:479-87.
73. Chapman P, Hauschild A, Robert C, et al. Improved survival with vemurafenib in 
melanoma with BRAF V600E mutation. N Eng J Med, 2011a; 364:2507-2516.
74. Alcala AM, Flaherty, KT. BRAF inhibitors for the treatment of metastatic melanoma: 
clinical trials and mechanisms of resistance. Clin Cancer Res. 2012; 18(1):33-39.
75. Su F, Viros A, Milagre C, et al. RAS-mutaions in cutaneous squamous-cell 
carcinomas in patients treated with BRAF inhibitors. N Engl J Med; 2012; 366:207-
215.
76. Gilmartin AG, Bleam MR. Groy R, et al. GSK1120212 (JTP-74057) is an inhibitor of 
MEK activity and activation with favourable pharmacokinetic properties for sustained 
in vivo pathway inhibition. Clin Cancer Res, 2011; 17:989-1000.
77. Flaherty KT, Robert C, Hersey P, et al. Improved survival with MEK inhibition in 
BRAF-Mutated Melanoma. N Engl J Med. 2012; 367(2):107-114.
78. Bollag G, Hirth P, Tsai J, et al. Clinical efficacy of a RAF inhibitor needs broad target 
blockade in BRAF-mutant melanoma. Nature 2010;467:596-9
79. Flaherty KT, Puzanov I, Kim KB, et al. Inhibition of mutated, activated BRAF in 
metastatic melanoma. N Engl J Med 2010; 363:809-19.
80. Sosman JA, Kim KB, Schuchter L, et al. Survival in BRAF V600–mutant advanced 
melanoma treated with vemurafenib. N Engl J Med 2012;366:707-14.
81. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in 
melanoma with BRAF V600E mutation. N Engl J Med 2011;364:2507-16.
82. Falchook GS, Long GV, Kurzrock R, et al. Dabrafenib in patients with melanoma, 
untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial. 
Lancet 2012;379:1893-901.
83. Hauschild A, Grob JJ, Demidov LV, et al. Dabrafenib in BRAF-mutated metastatic 
melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet 
2012;380:358-65.
84. Falchook GS, Lewis KD, Infante JR, et al. Activity of the oral MEK inhibitor 
trametinib in patients with advanced melanoma: a phase 1 dose-escalation trial. 
Lancet Oncol 2012;13:782-9.
 
 
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85. Flaherty KT, Infante JR, Daud A, et al. Combined BRAF and MEK Inhibition in 
Melanoma with BRAF V600 Mutations. N Engl J Med. 2012 November ; 367(18): 
1694–1703.
86. Paraiso KH, Fedorenko IV, Cantini LP, et al. Recovery of phospho-ERK activity 
allows melanoma cells to escape from BRAF inhibitor therapy. Br J Cancer 2010; 
102:1724-30.
87. Sturm OE, Orton R, Grindlay J, et al. The mammalian MAPK/ERK pathway exhibits 
properties of a negative feedback amplifier. Sci Signal 2010;3:ra90. 
88. Su F, Viros A, Milagre C, et al. RAS mutations in cutaneous squamous-cell 
carcinomas in patients treated with BRAF inhibitors. N Engl J Med 2012;366:207-15.
89. Frederick DT, Piris A, Cogdill AP, et al. BRAF Inhibition is Associated with 
Enhanced Melanoma Antigen Expression and a More Favorable Tumor 
Microenvironment in Patients with Metastatic Melanoma.  Clin Cancer Res, 2013 
Mar 1;19(5):1225-31.
90. Bazett HC.  An analysis of the time-relations of electrocardiograms.  Heart 1920; 7: 
353-370.
91. The Criteria Committee of the New York Heart Association.  Nomenclature and 
criteria for diagnosis of diseases of the heart and great vessels.  9th ed.  Boston, Mass: 
Little, Brown, & Co; 1994:253 256.
92. Ji Y, Li Y, and Bekele BN. Dose-finding in phase I clinical trials based on toxicity 
probability intervals. Clin Trials 2007 4: 235. DOI: 10.1177/1740774507079442.
93. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nature 
Reviews Cancer 2012; 12:252-264
94. Weber JS Practical Management of Immune-related Adverse Events from Immune 
Checkpoint Protein Antibodies for the Oncologist. American Society of Clinical 
Oncology 2012a; 1092-9118/10/1-10.
95. Weber JS, Kahler KC, and Hauschild A. Management of Immune-related Adverse 
Events and Kinetics of Response With Ipilimumab. J Clin Oncol 30. 2012b. 
http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2012.41.6750.
96. Balagula Y, Huston KB, Busam KJ, et al. Dermatologic side effects associated with 
the MEK 1/2 inhibitor selumetinib (AZD6244, ARRY-142886). Invest New Drugs 
2010; 29:  1114-1121
97. Lacouture ME, Anadkat MJ, Bensadoun RJ, et al, Clinical practice guidelines for the 
prevention and treatment of EGFR inhibitor-associated dermatologic toxicities. 
Support Care Cancer 2011; 19:1079-1095.
 
 
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98. Lacouture ME, Shenhong W, Robert C, et al. Evolving strategies for the management 
of hand-foot skin reaction associated with the multitargeted kinase inhibitors 
sorafenib and sunitinib.  The Oncologist 2008; 13: 1001-1011. 
99. McLellan B, Kerr H. Cutaneous toxicities of the multikinase inhibitors sorafenib and 
sunitinib. Dermatologic Therapy 2011; 24: 396-400.
100.Miettinen OS, Nurminen M. Comparative analysis of two rates. Statistics in 
Medicine 1985;4:213-226.
101.Flaherty KT, Infante J, Daud A, et al.  Combined BRAF and MEK Inhibition in 
Melanoma with BRAF V600 Mutations.  N Engl J Med 2012:367: 1694-703.
102.Clopper, C.; Pearson, E. S. (1934). "The Use of Confidence or Fiducial Limits 
Illustrated in the Case of the Binomial.”  Biometrika 26: 404–413.
103.Liu L, Mayes PA, Eastman S, Shi H, Yadavilli S, Zhang T, et al. The BRAF and 
MEK Inhibitors Dabrafenib and Trametinib: Effects on Immune Function and in 
Combination with Immunomodulatory Antibodies Targeting PD-1, PD-L1, and 
CTLA-4. Clin Cancer Res. 2015 Apr 1;21 (7):1639–51.
104.Yang S, Wang SJ, Ji Y. An Integrated Dose-Finding Tool for Phase I Trials in 
Oncology. Contemporary Clinical Trials 45 (2015) 426–434.
 
 
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12.0 APPENDICES
Merck Code of Conduct for Clinical Trials
Merck*
Code of Conduct for Clinical Trials
I.
Introduction
A. Purpose
Merck, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing and reporting these trials in 
compliance with the highest ethical and scientific standards. Protection of subject safety is the overriding concern in 
the design of clinical trials. In all cases, Merck clinical trials will be conducted in compliance with local and/or 
national regulations and in accordance with the ethical principles that have their origin in the Declaration of Helsinki. 
B. Scope
Such standards shall be endorsed for all clinical interventional investigations sponsored by Merck irrespective of the 
party (parties) employed for their execution (e.g., contract research organizations, collaborative research efforts). This 
Code is not intended to apply to trials which are observational in nature, or which are retrospective. Further, this Code 
does not apply to investigator-initiated trials which are not under the control of Merck.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of Merck or comparator products.  Alternatively, Merck may 
conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to determine 
subject preferences, etc.  
The design (i.e., subject population, duration, statistical power) must be adequate to address the specific purpose 
of the trial.  Research subjects must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
Merck selects investigative sites based on medical expertise, access to appropriate subjects, adequacy of facilities 
and staff, previous performance in Merck trials, as well as budgetary considerations.  Prior to trial initiation, sites 
are evaluated by Merck personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Trial sites are monitored to assess compliance with the trial protocol and general principles of Good Clinical 
Practice.  Merck reviews clinical data for accuracy, completeness and consistency. Data are verified versus source 
documentation according to standard operating procedures.  Per Merck policies and procedures, if fraud, 
misconduct or serious GCP-non-Compliance are suspected, the issues are promptly investigated. When necessary, 
the clinical site will be closed, the responsible regulatory authorities and ethics review committees notified and 
data disclosed accordingly. 
B. Publication and Authorship
To the extent scientifically appropriate, Merck seeks to publish the results of trials it conducts.  Some early phase or 
pilot trials are intended to be hypothesis-generating rather than hypothesis testing.  In such cases, publication of 
results may not be appropriate since the trial may be underpowered and the analyses complicated by statistical issues 
of multiplicity.
Merck’s policy on authorship is consistent with the requirements outlined in the ICH-Good Clinical Practice 
guidelines. In summary, authorship should reflect significant contribution to the design and conduct of the trial, 
performance or interpretation of the analysis, and/or writing of the manuscript.  All named authors must be able to 
defend the trial results and conclusions.  Merck funding of a trial will be acknowledged in publications. 
 
 
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III. Subject Protection
A. IRB/ERC review
All clinical trials will be reviewed and approved by an independent IRB/ERC before being initiated at each site.  
Significant changes or revisions to the protocol will be approved by the IRB/ERC prior to implementation, except that 
changes required urgently to protect subject safety and well-being may be enacted in anticipation of IRB/ERC 
approval. For each site, the IRB/ERC and Merck will approve the subject informed consent form. 
B. Safety
The guiding principle in decision-making in clinical trials is that subject welfare is of primary importance.  Potential 
subjects will be informed of the risks and benefits of, as well as alternatives to, trial participation. At a minimum, trial
designs will take into account the local standard of care.  Subjects are never denied access to appropriate medical care 
based on participation in a Merck clinical trial. 
All participation in Merck clinical trials is voluntary.  Subjects are enrolled only after providing informed consent for 
participation.  Subjects may withdraw from a Merck trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
Merck is committed to safeguarding subject confidentiality, to the greatest extent possible. Unless required by law, 
only the investigator, sponsor (or representative) and/or regulatory authorities will have access to confidential medical 
records that might identify the research subject by name.  
D. Genomic Research
Genomic Research will only be conducted in accordance with informed consent and/or as specifically authorized by 
an Ethics Committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive.  It is Merck’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of Merck trials.   Merck does not pay incentives to 
enroll subjects in its trials.  However, when enrollment is particularly challenging, additional payments may be made 
to compensate for the time spent in extra recruiting efforts.
Merck does not pay for subject referrals.  However, Merck may compensate referring physicians for time spent on 
chart review to identify potentially eligible subjects.
B. Clinical Research Funding 
Informed consent forms will disclose that the trial is sponsored by Merck, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial.  However, the local IRB/ERC may wish to alter 
the wording of the disclosure statement to be consistent with financial practices at that institution.  As noted above, 
publications resulting from Merck trials will indicate Merck as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices including, in the U.S., those established by the American Medical 
Association (AMA). 
V. Investigator Commitment
Investigators will be expected to review Merck’s Code of Conduct as an appendix to the trial protocol, and in signing 
the protocol, agree to support these ethical and scientific standards.
* In this document, "Merck" refers to Merck Sharp & Dohme Corp. and Schering Corporation, each of which is a 
subsidiary of Merck & Co., Inc.  Merck is known as MSD outside of the United States and Canada.  As warranted by 
context, Merck also includes affiliates and subsidiaries of Merck & Co., Inc."
 
 
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Collection and Management of Specimens for Future Biomedical Research
1. Definitions
a.
Biomarker:  A biological molecule found in blood, other body fluids, or tissues that is a 
sign of a normal or abnormal process or of a condition or disease.  A biomarker may be 
used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics:  The investigation of variations of DNA and RNA characteristics as 
related to drug/vaccine response.2
c.
Pharmacogenetics:  A subset of pharmacogenomics, pharmacogenetics is the influence of 
variations in DNA sequence on drug/vaccine response.2
d. DNA:  Deoxyribonucleic acid.
e.
RNA:  Ribonucleic acid.
2. Scope of Future Biomedical Research
The DNA, tumor and blood specimen(s) collected in the current trial will be used to study 
various causes for how subjects may respond to a drug/vaccine.  The DNA, tumor
specimen(s) will be stored to provide a resource for future trials conducted by Merck 
focused on the study of biomarkers responsible for how a drug/vaccine enters and is 
removed by the body, how a drug/vaccine works, other pathways a drug/vaccine may 
interact with, or other aspects of disease.  The specimen(s) may be used for future assay 
development and/or drug/vaccine development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need.  All specimens will be used by Merck or designees and research 
will be monitored and reviewed by a committee of our scientists and clinicians.
3. Summary of Procedures for Future Biomedical Research
a.
Subjects for Enrollment
All subjects enrolled in the clinical trial will be considered for enrollment in the 
Future Biomedical Research sub-trial.
b. Informed Consent
Informed consent for specimens (i.e., DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all subjects or legal guardians, at a trial 
visit by the investigator or his or her designate.  Informed consent for Future 
Biomedical Research should be presented to the subjects on Visit 1.  If delayed, 
present consent at next possible Subject Visit. Informed consent must be obtained 
prior to collection of all Future Biomedical Research specimens.  Consent forms 
signed by the subject will be kept at the clinical trial site under secure storage for 
regulatory reasons.  Information contained on the consent form alone cannot be traced 
 
 
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to any specimens, test results, or medical information once the specimens have been 
rendered de-identified.
Subjects are not required to participate in the Future Biomedical Research sub-trial in 
order to participate in the main trial. Subjects who decline to sign the Future 
Biomedical Research informed consent will not have the specimen collected nor will 
they be discontinued from the main trial.
A template of each trial site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.  Each consent will be assessed for 
appropriate specimen permissions.  
Each informed consent approved by an ethics committee is assigned a unique tracking 
number.  The tracking number on this document will be used to assign specimen 
permissions for each specimen into the Entrusted Keyholder’s Specimen Database.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of both consent and acquisition of Future Biomedical Research 
specimens will be captured in the electronic Case Report Forms (eCRFs).  
Reconciliation of both forms will be performed to assure that only appropriately-
consented specimens are used for this sub-trial's research purposes. Any specimens 
for which such an informed consent cannot be verified will be destroyed.
d. Future Biomedical Research Specimen Collections
Blood specimens for DNA or RNA isolation will usually be obtained at a time when 
the subject is having blood drawn for other trial purposes. Specimens like tissue and 
bone marrow will usually be obtained at a time when the subject is having such a 
procedure for clinical purposes.
Specimens will be collected and sent to the laboratory designated for the trial where 
they will be processed (e.g., DNA or RNA extraction, etc) following the Merck 
approved policies and procedures for specimen handling and preparation.
If specimens are collected for a specific genotype or expression analysis as an objective 
to the main trial, this analysis is detailed in the main body of this protocol (Section 8.0 –
Statistical Analysis Plan).  These specimens will be processed, analyzed, and the 
remainder of the specimen will be destroyed.  The results of these analyses will be 
reported along with the other trial results.  A separate specimen will be obtained from 
properly-consented subjects in this protocol for storage in the biorepository for Future 
Biomedical Research.
4. Confidential Subject Information for Future Biomedical Research 
In order to optimize the research that can be conducted with Future Biomedical Research 
specimens, it is critical to link subject' clinical information with future test results. In fact 
little or no research can be conducted without connecting the clinical trial data to the 
specimen. The clinical data allow specific analyses to be conducted. Knowing subject 
characteristics like gender, age, medical history and treatment outcomes are critical to 
understanding clinical context of analytical results.
 
 
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To maintain privacy of information collected from specimens obtained for Future 
Biomedical Research, Merck has developed secure policies and procedures.  All 
specimens will be de-identified as described below. 
At the clinical trial site, unique codes will be placed on the Future Biomedical Research 
specimens for transfer to the storage facility.  This first code is a random number which 
does not contain any personally identifying information embedded within it. The link (or 
key) between subject identifiers and this first unique code will be held at the trial site.  No 
personal identifiers will appear on the specimen tube.  
This first code will be replaced with a second code at a Merck designated storage/lab 
facility.  The second code is linked to the first code via a second key. The specimen is 
now double coded.  Specimens with the second code are sometimes referred to as de-
identified specimens. The use of the second code provides additional confidentiality and 
privacy protection for subjects over the use of a single code.  Access to both keys would 
be needed to link any data or specimens back to the subject's identification.
The second code is stored separately from the first code and all associated personal 
specimen identifiers.  A secure link, the second key, will be utilized to match the second 
code to the first code to allow clinical information collected during the course of the trial 
to be associated with the specimen.  This second key will be transferred under secure 
procedures by the Merck designated facility to an Entrusted Keyholder at Merck.  The 
second code will be logged into the primary biorepository database at Merck and, in this 
database, this identifier will not have identifying demographic data or identifying clinical 
information (i.e., race, sex, age, diagnosis, lab values) associated with it. The specimen 
will be stored in a designated biorepository site with secure policies and procedures for 
specimen storage and usage.
The second key can be utilized to reconstruct the link between the results of future 
biomedical research and the clinical information, at the time of analysis.  This linkage 
would not be possible for the scientist conducting the analysis, but can only be done by 
the Merck Entrusted Keyholder under strict security policies and procedures.  The Merck 
Entrusted Keyholder will link the information and then issue a de-identified data set for 
analysis.  The only other circumstance by which future biomedical research data would 
be directly linked to the full clinical data set would be those situations mandated by 
regulatory authorities (e.g., EMEA, FDA), whereby this information would be directly 
transferred to the regulatory authority.
5. Biorepository Specimen Usage
Specimens obtained for the Merck Biorepository will be used for analyses using good 
scientific practices.  However, exploratory analyses will not be conducted under the 
highly validated conditions usually associated with regulatory approval of diagnostics.  
The scope of research performed on these specimens is limited to the investigation of the 
variability in biomarkers that may correlate with a clinical phenotype in subjects.
Analyses utilizing the Future Biomedical Research specimens may be performed by 
Merck, or an additional third party (e.g., a university investigator) designated by Merck.  
The investigator conducting the analysis will be provided with double coded specimens.  
 
 
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Re-association of analysis results with corresponding clinical data will only be conducted 
by the Merck Entrusted Keyholder.  Any contracted third party analyses will conform to 
the specific scope of analysis outlined in this sub-trial.  Future Biomedical Research 
specimens remaining with the third party after the specific analysis is performed will be 
returned to the sponsor or destroyed and documentation of destruction will be reported to 
Merck.
6. Withdrawal From Future Biomedical Research 
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   Subjects may withdraw consent at any time by 
writing to the principal investigator for the main trial.  If medical records for the main 
trial are still available, the investigator will contact Merck using the designated mailbox 
(clinical.specimen.management@merck.com) and a form will be provided by Merck to 
obtain appropriate information to complete specimen withdrawal.  Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed. A letter 
will be sent from Merck to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for destruction or already performed prior to 
the request being received by the Sponsor will continue to be used as part of the overall 
research trial data and results. No new analyses would be generated after the request is 
received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the subject’s personal information and their specimens. In this situation, the 
request for specimen destruction can not be processed. 
7. Retention of Specimens 
Future Biomedical Research specimens will be stored in the biorepository for potential
analysis for up to 20 years from acquisition.  Specimens may be stored for longer if a 
regulatory or governmental authority has active questions that are being answered.  In 
this special circumstance, specimens will be stored until these questions have been 
adequately addressed.
Specimens from the trial site will be shipped to a central laboratory and then shipped to 
the Merck designated biorepository.  The specimens will be stored under strict 
supervision in a limited access facility which operates to assure the integrity of the 
specimens.  Specimens will be destroyed according to Merck policies and procedures and 
this destruction will be documented in the biorepository database.
8. Data Security
Separate databases for specimen information and for results from the Future Biomedical 
Research sub-trial will be maintained by Merck.  This is done to separate the future 
exploratory test results (which include genetic data) from the clinical trial database 
thereby maintaining a separation of subject number and these results.  The separate 
databases are accessible only to the authorized Sponsor and the designated trial 
 
 
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administrator research personnel and/or collaborators.  Database user authentication is 
highly secure, and is accomplished using network security policies and practices based in 
international standards (e.g., ISO17799) to protect against unauthorized access.  The 
Merck Entrusted Keyholder maintains control over access to all specimen data.  These 
data are collected for future biomedical research purposes only as specified in this sub-
trial will not be used for any other purpose.
9. Reporting of Future Biomedical Research Data to Subjects
There is no definitive requirement in either authoritative ethical guidelines or in relevant 
laws/regulations globally that research results have to be, in all circumstances, returned to 
the trial participant.  Some guidelines advocate a proactive return of data in certain 
instances.  No information obtained from exploratory laboratory studies will be reported 
to the subject or family, and this information will not be entered into the clinical database 
maintained by Merck on subjects.  Principle reasons not to inform or return results to the 
subject include: lack of relevance to subject health, limitations of predictive capability, 
concerns of misinterpretation and absence of good clinical practice standards in 
exploratory research typically used for diagnostic testing.
If any exploratory results are definitively associated with clinical significance for subjects 
while the clinical trial is still ongoing, investigators will be contacted with information as 
to how to offer clinical diagnostic  testing (paid for by Merck) to subjects enrolled and 
will be advised that counseling should be made available for all who choose to participate 
in this diagnostic testing. 
If any exploratory results are definitively associated with clinical significance after 
completion of a clinical trial, Merck will publish the results without revealing specific 
subject information, inform all trial sites who participated in the Merck clinical trial and 
post anonymized results on our website or other accredited website(s) that allow for 
public access (e.g., disease societies who have primary interest in the results) in order that 
physicians and patients may pursue clinical diagnostic testing if they wish to do so.
10. Gender, Ethnicity and Minorities
Although many diagnoses differ in terms of frequency by ethnic population and gender, 
every effort will be made to recruit all subjects diagnosed and treated on Merck clinical 
trials for future biomedical research.  When trials with specimens are conducted and 
subjects identified to serve as controls, every effort will be made to group specimens 
from subjects and controls to represent the ethnic and gender population representative of 
the disease under current investigation.
11. Risks Versus Benefits of Future Biomedical Research 
For future biomedical research, risks to the subject have been minimized. Risks include 
those associated with venipuncture to obtain the whole blood specimen.  This specimen 
will be obtained at the time of routine blood specimens drawn in the main trial. 
Merck has developed strict security, policies and procedures to address subject data 
privacy concerns.  Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality.  In this highly unlikely situation there is risk that the 
information, like all medical information, may be misused.
 
 
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It is necessary for subject-related data (i.e., ethnicity, diagnosis, drug therapy and dosage, 
age, toxicities, etc.) to be re-associated to double coded specimens at the time of data 
analysis.  These subject data will be kept in a separate, secure Merck database, and all 
specimens will be stripped of subject identifiers.  No information concerning results 
obtained from future biomedical research will be entered into clinical records, nor will it 
be released to outside persons or agencies, in any way that could be tied to an individual 
subject.
12. Self-Reported Ethnicity
Subjects who participate in future biomedical research will be asked to provide self-
reported ethnicity.  Subjects who do not wish to provide this data may still participate in 
future biomedical research.
13. Questions
Any questions related to the future biomedical research should be e-mailed directly to 
clinical.specimen.management@merck.com.
14. References
1. National Cancer Institute: http://www.cancer.gov/dictionary/?searchTxt=biomarker
2. International Conference on Harmonization [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample 
Coding Categories. Available from 
http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/definitions-
for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-genomic-data-and-
sample-cod.html
 
 
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Pharmacogenetics Informational Brochure for IRBs/IECs & Investigational Site StaffUnderstanding the Intent, Scope 
and Public Health Benefits of Exploratory Biomarker Research: A Guide for IRBs/IECs and Investigational Site Staff
 
 
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Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
RECIST version 1.1* will be used in this study for assessment of tumor response. While 
either CT or MRI may be used utilized, as per RECIST 1.1, CT is the preferred imaging 
technique in this study.
* As published in the European Journal of Cancer: E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. 
Sargent, R. Ford, J. Dancey, S. Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. 
Kaplan, D. Lacombe, J. Verweij. New response evaluation criteria in solid tumours: Revised RECIST guideline 
(version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47.
 
 
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Common Terminology Criteria for Adverse Events (CTCAE) v4.0
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting. 
(https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm)
 
 
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ECOG Performance Status
GRADE ECOG PERFORMANCE STATUS
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature, e.g., light house work, office work
2
Ambulatory and capable of all selfcare but unable to carry out any work activities; up 
and about more than 50% of waking hours
3
Capable of only limited selfcare; confined to bed or chair more than 50% of waking 
hours
4
Completely disabled; cannot carry on any selfcare; totally confined to bed or chair
5
Dead
*Oken M, Creech R, Tormey D, et al. Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol. 1982;5:649-655
http://ecog-acrin.org/resources/ecog-performance-status
 
 
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CCG Formula
ClCr (mL/min) =                    Qx(140-age[yr]) x  idealbodyweight[kg]*
      72 x serum creatinine [mg/dL]
Q = 0.85 for females
Q = 1.0 for males
-- OR--
ClCr (mL/min) =  
K x (140-age[yr])xidealbodyweight[kg]*
Serum creatinine [umol/L]
K = 1.0 for females
K = 1.23 for males
*Calculation of Ideal Body Weight Using the Devine Formula
Ideal body weight:
Males =  50.0 kg + (2.3 kg x each inch over 5 feet) or 50.0 kg + (0.906 kg x each cm over
152.4 cm)
Females = 45.5 kg + (2.3 kg x each inch over 5 feet) or 45.5 kg + (0.906 kg x each cm over
152.4 cm)
Example:        Male, actual body weight = 90.0 kg, height = 68 inches
Ideal body weight = 50.0 + (2.3) (68-60) = 68.4 kg.
This subject’s actual body weight is >30% over ideal body weight. Therefore, in this 
case, the subject’s ideal body weight of 68.4 kg should be used in calculating estimated
CrCl.
Reference
Devine, BJ.  Case Number 25 Gentamicin Therapy: Clinical Pharmacology Case Studies. 
Drug Intelligence and Clinical Pharmacy. 1974; 8:650-655
 
 
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NYHA Functional Classification System
The NYHA Functional Classification: Class I, II, II or IV Heart Failure provides a simple 
way of classifying the extent of heart failure.  It places subjects in one of 4 categories based 
on the level of limitation experienced during physical activity:
Class
Symptoms
Class I (Mild)
No limitation of physical activity. Ordinary physical activity does not cause 
undue fatigue, palpitation or dyspnea (shortness of breath).
Class II (Mild)
Slight limitation of physical activity. Comfortable at rest, but ordinary 
physical activity results in fatigue, palpitation or dyspnea.
Class III (Moderate)
Marked limitation of physical activity. Comfortable at rest, but less than 
ordinary physical activity results in fatigue, palpitation or dyspnea.
Class IV (Severe)
Unable to carry out any physical activity without discomfort. Symptoms of 
cardiac insufficiency at rest. If any physical activity is undertaken, 
discomfort is increased.
The Criteria Committee of the New York Heart Association (NYHA). Nomenclature and Criteria for Diagnosis 
of Diseases of the Heart and Great Vessels. 9th Ed. Boston, Mass: Little, Brown & Co.; 1994:253-256.
 
 
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Sample Patient Daily Dosing Diary 
 
 
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List of Abbreviations
Abbreviation/Acronym
Definition
ADCC
Antibody-Dependent Cell-Mediated Cytotoxicity
AE
Adverse Event
AEOSI
Adverse Event of Special Interest
ALT
Alanine Aminotransferase
aPTT
activated Partial Thromboplastin Time
AST
Aspartate Aminotransferase 
AUC
Area Under the Curve
b-HCG
Beta- Human Chorionic Gonadotropin 
BID
Twice Daily
BOR
Best Overall Response
BP
Blood Pressure
CBC
Complete Blood Count
CDC
Complement-Dependent Cytotoxicity
Cmax
Observed Maximum Concentration
CPK
Creatine Phosphokinase
CR
Complete Response
CSR
Clinical Study Report
CT
Computerized Tomography
CTCAE
Common Terminology Criteria for Adverse Events
Ctrough
Observed Trough Concentration
cuSCC
Cutaneous Squamous Cell Carcinoma
CYP
Cytochrome P450 
DBP
Diastolic Blood Pressure
DILI
Drug-Induced Liver Injury
DL1
Dose Level 1
DLT
Dose Limiting Toxicity
DMSO
Dimethyl Sulfoxide
DNA
Deoxyribonucleic Acid
EC50
Half-Maximal Effective Concentration
ECG
Electrocardiogram
ECHO
Echocardiogram
ECI
Event of Clinical Interest
ECOG
Eastern Cooperative Oncology Group 
FT4
Free Thyroxine 
GCP
Good Clinical Practice
 
 
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Abbreviation/Acronym
Definition
GLP
Good Laboratory Practice
HFSR
Hand-Foot Skin Reaction 
HIV
Human Immunodeficiency Virus 
IB
Investigator’s Brochure 
IC50
Half-Maximal Inhibitory Concentration
IFNγ
Interferon gamma
IgG
Immunoglobulin G
IgM
Immunoglobulin M
IL-2
Interleukin-2
irAE
immune-related Adverse Event
IRBs/ERCs
Institutional Review Boards/Ethics Committees
irECIs
immune-related Events of Clinical Interest 
IUS
Intrauterine Hormone-releasing System
IUD
Intrauterine Device
IV
Intravenous
LDH
Lactate Dehydrogenase 
LFT
Liver Function Test
LLN
Lower Limit of Normal
LVEF
Left Ventricular Ejection Fraction
mAb
Monoclonal Antibody
MAD
Maximum Administered Dose
MAPK
Mitogen-Activated Protein Kinase 
MEL
Melanoma 
MK+D
Pembrolizumab + Dabrafenib 
MK+D+T
Pembrolizumab + Dabrafenib + Trametinib 
MK+T
Pembrolizumab + Trametinib
mmHg
millimeters mercury
MPR
Moderate Partial Response
MRI
Magnetic Resonance Imaging
msec
milliseconds
MTD
Maximum Tolerated Dose
mTPI
modified Toxicity Probability Interval
NOAEL
No-Observed-Adverse-Effect Level
NOEL
No-Observed-Effect Level
ORR
Overall Response Rate 
OS
Overall Survival
PD
Progressive Disease
 
 
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Abbreviation/Acronym
Definition
PFS
Progression Free Survival 
PGt
Pharmacogenetic
PGx
Pharmacogenomics
PK
Pharmacokinetics
PK/PD
Pharmacokinetic/Pharmacodynamic
PBO+D+T
Placebo (saline IV) + Dabrafenib + Trametinib
PO
By mouth
PROs
Patient Reported Outcomes
PT/INR
Prothrombin Time/International Normalized Ratio
QD
Once daily
QTc
corrected QT Interval
QTcB 
QT interval on electrocardiogram corrected using the 
Bazett’s formula
RECIST
Response Evaluation Criteria in Solid Tumors 
RVO
Retinal Vein Occlusion 
SAEs
Serious Adverse Events 
SAP
Statistical Analysis Plan
SBP
Systolic Blood Pressure
SCARs
Severe Cutaneous Adverse Reactions
SD
Stable Disease
siDMC
standing internal Data Monitoring Committee
t1/2
Half life
T3
Triiodothyronine
TBD
To Be Determined
TILs
Tumor-Infiltrating Lymphocytes 
TKIs
Tyrosine Kinase Inhibitors 
Tmax
Time to reach Cmax
TNFα
Tumor Necrosis Factor alpha
TPI
Toxicity Probability Interval
TSH
Thyroid Stimulating Hormone
TT
Tetanus Toxoid
TTG
Time to Growth
ULN
Upper Limit of Normal
VGPR
Very Good Partial Response
 
 
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Past Medical History Related to Dermatologic Event
Past Medical History: 
Any preexisting conditions not previously reported (e.g., drug allergy) should be entered into 
the Medical History eCRF. 
1. Does the subject have any allergies? □ Yes □ No 
If yes, please obtain the following information: 
a. Any allergy to drugs (including topical or ophthalmic drugs)? □ Yes □ No 
List the drug name(s) and describe the type of allergic response (e.g. rash, anaphylaxis, 
etc): ______________________________________________ 
_____________________________________________________________ 
b. Any allergy to external agents, such as laundry detergents, soaps, poison ivy, nickel, 
etc.? □ Yes □ No 
Describe the agent and type of allergic response: _____________________ 
_____________________________________________________________ 
c. Any allergy to food? □ Yes □ No 
Describe the food and type of allergic response: _____________________ 
____________________________________________________________ 
d. Any allergy to animals, insects? □ Yes □ No 
Describe the allergen and type of allergic response: ___________________ 
____________________________________________________________ 
e. Any other allergy? □ Yes □ No 
Describe the allergen and type of allergic response: _________________ 
___________________________________________________________ 
2. Does the subject have any other history of skin reactions, skin eruptions, or rashes? □ Yes □ No 
If so what kind? ______________________________________________ 
 
 
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3. Has the subject ever been treated for a skin condition? □ Yes □ No 
If so what kind? ______________________________________________ 
4. Is the current finding similar to a past experience? □ Yes □ No 
 
 
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Presentation of the Dermatologic Event
Presentation of the event: 
Collect information on clinical presentation and potential contributing factors. Key information 
should be summarized and entered on the Adverse Experience eCRF. Any treatments administered 
should be entered on the Concomitant Medication eCRF. 
1. What is the onset time of the skin reaction, skin eruption, or rash relative to dose of study drug? 
___________________________________________ 
2. Has the subject contacted any known allergens? □ Yes □ No 
If so what kind? ______________________________________________ 
3. Has the subject contacted new, special, or unusual substances (e.g., new laundry detergents, soap, 
personal care product, poison ivy, etc.)? □ Yes □ No 
If so what kind? _________________________________________________ 
4. Has the subject taken any other medication (over the counter, prescription, vitamins, and 
supplement)?           □ Yes □ No 
If so what kind? _________________________________________________ 
5. Has the subject consumed unaccustomed, special or unusual foods? □ Yes □ No 
If so what kind? _________________________________________________ 
6. Does the subject have or had in the last few days any illness? □ Yes □ No 
If so what kind? __________________________________________________ 
7. Has the subject come into contact with any family or house members who are ill? □ Yes □ No 
If so who and what? _____________________________________________ 
8. Has the subject recently been near children who have a skin reaction, skin eruption, or rash (e.g. 
Molluscum Contagiosum)? □ Yes □ No 
9. Has the subject had recent sun exposure? □ Yes □ No 
 
 
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10. For the current rash, have there been any systemic clinical signs? □ Yes □ No 
If so what kind? ________________________________________________ 
i. Anaphylaxis? □ Yes □ No 
ii. Signs of hypotension? □ Yes □ No 
iii. Signs of dyspnea? □ Yes □ No 
iv. Fever, night sweats, chills? □ Yes □ No 
11. For the current rash, has the subject needed subcutaneous epinephrine or other systemic 
catecholamine therapy? □ Yes □ No 
If so what kind? ________________________________________________ 
12. For the current rash, has the subject used any other medication, such as inhaled bronchodilators, 
antihistaminic medication, topical corticosteroid, and/or systemic corticosteroid? □ Yes □ No 
List medication(s) and dose(s): _________________________________________ 
___________________________________________________________________
13. Is the rash pruritic (itchy)? □ Yes □ No 
 
 
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Focused Skin Examination
Focused Skin Examination: 
Key information should be summarized and entered on the Adverse Experience eCRF. 
Primary Skin Lesions Description 
Color: _______________________________________________________ 
General description: 
______________________________________________________________ 
______________________________________________________________ 
Describe the distribution of skin reaction, skin eruption, or rash on the body:
______________________________________________________________ 
______________________________________________________________ 
Is skin reaction, skin eruption, or rash resolving or continuing to spread? 
______________________________________________________________ 
Any associated signs on physical examination? ________________________
 
 
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Contraceptive Guidance
Definitions
Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below):
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
•
Premenarchal
•
Premenopausal female with 1 of the following:
-
Documented hysterectomy
-
Documented bilateral salpingectomy
-
Documented bilateral oophorectomy
This applies to women who have undergone sterilization (have had surgical bilateral 
oophorectomy with or without hysterectomy), total hysterectomy, or tubal ligation at 
least 6 weeks before taking study treatment. In case of oophorectomy alone, this applies 
only when the reproductive status of the woman has been confirmed by follow up 
hormone level assessment. For individuals with permanent infertility due to an alternate 
medical cause other than the above (eg, Mullerian agenesis, androgen insensitivity), 
investigator discretion should be applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
•
Postmenopausal female
-
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
◦
A high follicle stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormone replacement therapy (HRT). However, in the absence 
of 12 months of amenorrhea, confirmation with two FSH measurements in the 
postmenopausal range is required.
-
Females on HRT and whose menopausal status is in doubt will be required to use one 
of the nonhormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
 
 
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Contraception Requirements
Female Participants
Contraceptives allowed during the study includea:
Highly Effective Contraceptive Methods That Have Low User Dependencyb
Failure rate of <1% per year when used consistently and correctly.
•
Intrauterine hormone-releasing system (IUS)
•
Intrauterine device (IUD)
•
Bilateral tubal occlusion
•
Azoospermic partner (vasectomized or secondary to medical cause)
This is a highly effective contraception method provided that the partner is the sole male sexual 
partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional highly 
effective method of contraception should be used. A spermatogenesis cycle is approximately 90 days.
Note: Documentation of azoospermia can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
Highly Effective Contraceptive Methods That Are User Dependentb
Failure rate of <1% per year when used consistently and correctly.
Sexual Abstinence
•
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study intervention. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the 
preferred and usual lifestyle of the participant.
a  Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for participants of clinical studies.
b  Typical use failure rates are higher than perfect-use failure rates (ie, when used consistently and correctly).
Note: The following are not acceptable methods of contraception:
-
Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhea method (LAM).
-
Male condom with cap, diaphragm, or sponge with spermicide.
-
Male and female condom should not be used together (due to risk of failure with friction).
-     Hormonal-based methods (eg, oral contraceptives) are not considered as highly effective methods of 
contraception due to potential drug-drug interactions with dabrafenib and/or trametinib
Male contraception and infertility risks:
Dabrafenib and Trametinib may cause infertility in males, which may be irreversible. Male subjects including 
those who have had a vasectomy 6 months prior to screening must agree to use a condom during intercourse 
while taking the drug and not to father a child during the study and for the period of 120 days following 
stopping of study treatment. In addition, it is advised that their female partner uses a highly effective form of 
birth control method (contraception) if she is sexually active and may become pregnant. If a male participant
fathers a child while in this study, they are asked to report the pregnancy to the study doctor.   Consent from 
their partner will be needed to allow your study doctor to medically follow this pregnancy until delivery to 
monitor the mother`s and child`s safety.
 
 
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13.0 SIGNATURES
Sponsor's Representative
TYPED NAME                                 SIGNATURE                                   DATE
_________________________      ____________________________     __________
Investigator
I agree to conduct this clinical trial in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol (including other manuals and documents 
referenced from this protocol).  I agree to conduct the trial in accordance with generally 
accepted standards of Good Clinical Practice.  I also agree to report all information or data in 
accordance with the protocol and, in particular, I agree to report any serious adverse events 
as defined in Section 7.2 – Assessing and Recording Adverse Events.  I also agree to handle 
all clinical supplies provided by the Sponsor and collect and handle all clinical specimens in 
accordance with the protocol.  I understand that information that identifies me will be used 
and disclosed as described in the protocol, and that such information may be transferred to 
countries that do not have laws protecting such information.  Since the information in this 
protocol and the referenced Investigator’s Brochure is confidential, I understand that its 
disclosure to any third parties, other than those involved in approval, supervision, or conduct 
of the trial is prohibited.  I will ensure that the necessary precautions are taken to protect such 
information from loss, inadvertent disclosure or access by third parties.
TYPED NAME                                 SIGNATURE                                   DATE
_________________________      ____________________________     __________
 
 
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