Clinical trial NCT03374254
Conditions: Metastatic Colorectal Cancer
Keywords: CRC, MSS, non-MSI-H, PD-1, anti-PD-1, anti PD-1, MEK, MEK inhibitor
Sponsor: Merck Sharp & Dohme LLC
Start date: 2018-02-16; Completion date: 2023-07-18
Enrollment: 116 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine safety and tolerability and to establish a preliminary recommended Phase 2 dose (RP2D) for the following combinations: pembrolizumab plus binimetinib (Cohort A), pembrolizumab plus mFOLFOX7 (oxaliplatin 85 mg/m\^2; leucovorin \[calcium folinate\] 400 mg/m\^2; fluorouracil \[5-FU\] 2400 mg/m\^2) (Cohort B), pembrolizumab plus mFOLFOX7 and binimetinib (Cohort C), pembrolizumab plus FOLFIRI (irinotecan 180 mg/m\^2; leucovorin \[calcium folinate\]400 mg/m\^2; 5-FU 2400 mg/m\^2 over 46-48 hours) (Cohort D), and pembrolizumab plus FOLFIRI and binimetinib (Cohort E).

Detailed description:

Arms: arm 1: Participants in Cohort A will receive pembrolizumab (200 mg) intravenous (IV) every 3 weeks (Q3W) plus binimetinib orally at of 30 mg twice a day (BID) until disease progression or discontinuation. arm 2: Participants in Cohort A will receive pembrolizumab (200 mg) IV Q3W plus binimetinib orally at 45 mg BID (Dose Level 2 \[DL2\]) until disease progression or discontinuation. arm 3: Participants in Cohort B will receive pembrolizumab (200 mg) IV Q3W plus mFOLFOX7 (oxaliplatin 85 mg/m\^2; leucovorin \[calcium folinate\] 400 mg/m\^2; fluorouracil \[5-FU\] 2400 mg/m\^2 over 46-48 hours) IV Q2W until disease progression or discontinuation. arm 4: During Part 2, participants in Cohort B will receive pembrolizumab (200 mg) IV Q3W plus mFOLFOX7 (oxaliplatin 85mg/m\^2; leucovorin \[calcium folinate\] 400 mg/m\^2; fluorouracil \[5-FU\] 2400 mg/m\^2 over 46-48 hours) IV Q2W until disease progression or discontinuation. arm 5: Participants in Cohort C will receive pembrolizumab 200 mg IV Q3W plus mFOLFOX7 (oxaliplatin 85mg/m\^2; leucovorin \[calcium folinate\] 400 mg/m\^2; fluorouracil \[5-FU\] 2400 mg/m\^2 over 46-48 hours) IV Q2W in combination with binimetinib orally at a starting dose of 30 mg BID until disease progression or discontinuation. arm 6: Participants in Cohort D will receive a standard dose (DL1) of pembrolizumab 200 mg IV Q3W plus FOLFIRI (irinotecan 180 mg/m\^2; leucovorin \[calcium folinate\] 400 mg/m\^2; 5-FU 2400 mg/m\^2 over 46-48 hours) IV Q2W until disease progression or discontinuation. arm 7: During Part 2, participants in Cohort D will receive pembrolizumab 200 mg IV Q3W plus FOLFIRI (irinotecan 180 mg/m\^2; leucovorin \[calcium folinate\] 400 mg/m\^2; 5-FU 2400 mg/m\^2 over 46-48 hours) until disease progression or discontinuation. arm 8: Participants in Cohort E will receive pembrolizumab 200 mg IV Q3W plus FOLFIRI (irinotecan 180 mg/m\^2; leucovorin \[calcium folinate\] 400 mg/m\^2; 5-FU 2400 mg/m\^2 over 46-48 hours) Q2W in combination with binimetinib orally at a starting dose of 30 mg BID until disease progression or discontinuation. arm 9: During Part 2, participants in Cohort E received pembrolizumab 200 mg IV Q3W plus FOLFIRI (irinotecan 180 mg/m\^2; leucovorin \[calcium folinate\] 400 mg/m\^2; 5-FU 2400 mg/m\^2 over 46-48 hours) Q2W plus binimetinib orally at the starting dose of 45 mg BID until disease progression or discontinuation. Cohort A During Part 2, participants in Cohort E received pembrolizumab 200 mg IV Q3W plus FOLFIRI (irinotecan 180 mg/m\^2; leucovorin \[calcium folinate\] 400 mg/m\^2; 5-FU 2400 mg/m\^2 over 46-48 hours) Q2W plus binimetinib orally at the starting dose of 45 mg BID until disease progression or discontinuation.
Interventions: intervention 1: Pembrolizumab intervention 2: Binimetinib intervention 3: Oxaliplatin intervention 4: Leucovorin intervention 5: 5-Fluorouracil [5-FU] intervention 6: Irinotecan
Intervention descriptions: intervention 1: 200 mg Pembrolizumab solution for IV infusion Q3W intervention 2: tablet orally BID at 30 or 45 mg depending upon DLT profile intervention 3: 85 mg/m\^2 as IV infusion. Administered Q2W as part of mFOLFOX7 cocktail. Dose may be de-escalated to 70 mg/m\^2 if the standard dose of mFOLFOX7 is deemed too toxic per mTPI, based upon occurrence of DLTs. intervention 4: 400 mg/m\^2 as IV infusion. Administered Q2W as part of mFOLFOX7 or FOLFIRI cocktail, depending upon allocation. intervention 5: 2400 mg/m\^2 over 46-48 hours as IV infusion. Administered Q2W as part of mFOLFOX7 or FOLFIRI cocktail, depending upon allocation. Dose may be de-escalated to 2000 mg/m\^2 if the standard dose of mFOLFOX7 or FOLFIRI is deemed too toxic per mTPI, based upon occurrence of DLTs. intervention 6: 180 mg/m\^2 as IV infusion. Administered Q2W as part of FOLFIRI cocktail. Dose may be de-escalated to 150 mg/m\^2 if the standard dose of FOLFIRI is deemed too toxic per mTPI, based upon occurrence of DLTs.

Protocol documents:
Prot_SAP_000.pdf: 
Official Protocol Title:
NCT number:
Document Date:
A Phase 1b Multi-cohort Study of the Combination of 
Pembrolizumab (MK-3475) plus Binimetinib alone or the 
Combination of Pembrolizumab plus Chemotherapy 
with or without Binimetinib in Participants with 
Metastatic Colorectal Cancer (KEYNOTE-651)
NCT03374254
08-Jun-2022


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Title Page
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME LLC, RAHWAY, NJ, USA (MSD).
Protocol Title:
A Phase 1b Multi-cohort Study of the Combination of Pembrolizumab 
(MK-3475) plus Binimetinib alone or the Combination of Pembrolizumab plus 
Chemotherapy with or without Binimetinib in Participants with Metastatic Colorectal Cancer 
(KEYNOTE-651)
Protocol Number: 651-04
Compound Number: MK-3475
Sponsor Name and Legal Registered Address: 
Merck Sharp & Dohme LLC
(hereafter referred to as the Sponsor or MSD)
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Regulatory Agency Identifying Number(s):
IND NUMBER:   123482
EudraCT NUMBER: 2017-000356-26
Approval Date:  08 June 2022
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Sponsor Signatory
Typed 
Name:
Title:
Date
Protocol-specific Sponsor Contact information can be found in the Investigator Trial 
File Binder (or equivalent). 
Investigator Signatory
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.
Typed 
Name:
Title:
Date
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 04
08-JUN-2022
Merck Sharp & Dohme Corp. underwent an entity name and address change to Merck 
Sharp & Dohme LLC, Rahway, NJ, USA. This conversion resulted only in an entity 
name change and update to the address.
Amendment 3
19-MAY-2021
To update the dose modification and toxicity management guidelines for irAEs.
Amendment 2
07-MAY-2020
Clarify that DPD testing is not required at Screening but will be based on “known” 
medical history.
Amendment 1
16-NOV-2017
Provide rationale for the use of chemotherapy (FOLFOX) in combination with 
pembrolizumab and to provide an assessment of the risk of overlapping toxicities with 
chemotherapy combinations
Original Protocol
25-JUL-2017
N/A
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment 04
Overall Rationale for the Amendment:
Sponsor underwent an entity name change and update to the address.
Summary of Changes Table:
Section # and Name
Description of Change
Brief Rationale
Title Page
Section 12.4 Code of 
Conduct for Clinical Trials
Throughout
Sponsor entity name and 
address change.
Merck Sharp & Dohme Corp. underwent an entity name and address 
change to Merck Sharp & Dohme LLC, Rahway, NJ, USA. This 
conversion resulted only in an entity name change and update to the 
address.
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Table of Contents
DOCUMENT HISTORY ....................................................................................................... 3
PROTOCOL AMENDMENT SUMMARY OF CHANGES.............................................. 4
1.
Synopsis...................................................................................................................... 15
2.
Schedule of Activities (SoA)..................................................................................... 20
Pembrolizumab in Combination with Binimetinib (Cohort A)........................ 20
Pembrolizumab in Combination with mFOLFOX7 (Cohort B) ...................... 24
Pembrolizumab in Combination with mFOLFOX7 and Binimetinib 
(Cohort C).............................................................................................................. 28
Pembrolizumab in Combination with FOLFIRI (Cohort D) ........................... 33
Pembrolizumab in Combination with FOLFIRI and Binimetinib (Cohort 
E) ............................................................................................................................ 38
3.
Introduction............................................................................................................... 44
Study Rationale..................................................................................................... 44
Rationale for the Trial and Selected Participant Population............................... 44
Rationale for Cohort A: Pembrolizumab in Combination with Binimetinib in 
Previously-treated non-MSI-H/pMMR mCRC Population ................................ 45
Rationale for Cohorts B and C: Combination of Pembrolizumab plus 
mFOLFOX7 With and Without Binimetinib in Previously Untreated 
Metastatic non MSI-H/pMMR mCRC Population ............................................. 46
Rationale for Cohorts D and E: Combination of Pembrolizumab plus 
FOLFIRI With and Without Binimetinib in Previously-treated non MSI-
H/pMMR mCRC Population .............................................................................. 48
Background ........................................................................................................... 49
Pharmaceutical and Therapeutic Background .................................................... 49
Pembrolizumab Background........................................................................ 49
Pembrolizumab Pre-clinical Studies..................................................... 50
Pembrolizumab Clinical Trials ............................................................. 50
Pembrolizumab Ongoing Clinical Trials .............................................. 50
Binimetinib Background.............................................................................. 51
Binimetinib Pre-clinical Studies........................................................... 51
Binimetinib Clinical Studies................................................................. 51
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FOLFOX as First Line Therapy................................................................... 52
FOLFIRI as Second Line Therapy............................................................... 52
Benefit/Risk Assessment....................................................................................... 53
Potential Overlapping Toxicities ........................................................................ 53
Pneumonitis.................................................................................................. 54
Liver Test Abnormalities ............................................................................. 54
Diarrhea........................................................................................................ 55
Other Risks.......................................................................................................... 55
4.
Objectives/Hypotheses and Endpoints.................................................................... 55
5.
Study Design.............................................................................................................. 57
Overall Design....................................................................................................... 57
Study Design....................................................................................................... 58
Part 1 (Dose Finding)................................................................................... 58
Cohort A: Pembrolizumab plus Binimetinib (Participants Previously 
Treated with Fluoropyrimidine, Irinotecan, and Oxaliplatin)...................... 60
Cohort B: Pembrolizumab plus mFOLFOX7 (Previously Untreated 
Participants) ................................................................................................. 60
Cohort C: Pembrolizumab plus mFOLFOX7 plus Binimetinib 
(Previously Untreated Participants)............................................................. 61
Cohort D: Pembrolizumab plus FOLFIRI (Participants Previously 
Treated With One Line of Fluoropyrimidine plus Oxaliplatin-Based 
Therapy)....................................................................................................... 62
Cohort E: Pembrolizumab plus FOLFIRI plus Binimetinib (Participants 
Previously Treated With One Line of Fluoropyrimidine plus Oxiplatin-
Based Therapy)............................................................................................ 63
Part 2 (Dose Confirmation).......................................................................... 64
Part 1 and Part 2........................................................................................... 64
Tolerability Evaluation Rules and Dose Finding................................................ 65
Definition of Dose Limiting Toxicity................................................................. 67
Replacement of Participants in DLT Period ....................................................... 69
Study Diagram .................................................................................................... 70
Number of Participants........................................................................................ 70
Beginning and End of Study Definition.............................................................. 70
Clinical Criteria for Early Trial Termination...................................................... 70
Scientific Rationale for Study Design.................................................................. 71
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Rationale for Endpoints ...................................................................................... 71
Efficacy Endpoints....................................................................................... 71
Safety Endpoints.......................................................................................... 71
Pharmacokinetic Endpoints ......................................................................... 72
Pharmacodynamic Endpoints....................................................................... 72
Planned Exploratory Biomarker Research................................................... 72
Planned Genetic Analysis ..................................................................... 73
Microsatellite Instability Testing................................................................. 74
Future Biomedical Research........................................................................ 74
Rationale for The Use of Comparator/Placebo................................................... 75
Justification for Dose............................................................................................ 75
Starting Dose for This Trial ................................................................................ 75
Justification for Treatment Regimen ........................................................... 75
Rationale for Fixed Dose Pembrolizumab............................................ 75
Binimetinib Starting Dose .................................................................... 76
mFOLFOX7 Starting Dose................................................................... 76
FOLFIRI Starting Dose ........................................................................ 77
Maximum Dose/Exposure for This Trial............................................................ 77
6.
Study Population....................................................................................................... 77
Inclusion Criteria.................................................................................................. 77
Exclusion Criteria................................................................................................. 79
Lifestyle Restrictions ............................................................................................ 82
Meals and Dietary Restrictions........................................................................... 82
Caffeine, Alcohol, and Tobacco ......................................................................... 82
Activity ............................................................................................................... 82
Screen Failures...................................................................................................... 82
Participant Replacement Strategy ...................................................................... 82
7.
Treatments................................................................................................................. 83
Treatments Administered .................................................................................... 83
Dose Modification (Escalation/Titration/Other)................................................ 84
Guideline for Dose Modification........................................................................ 84
Dose Modification Due to Adverse Events ................................................. 84
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Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue)................................................................................................. 85
Binimetinib .................................................................................................. 89
mFOLFOX7................................................................................................. 94
FOLFIRI ...................................................................................................... 94
Method of Treatment Assignment....................................................................... 94
Stratification........................................................................................................ 95
Blinding.................................................................................................................. 95
Preparation/Handling/Storage/Accountability .................................................. 95
Dose Preparation................................................................................................. 95
Pembrolizumab ............................................................................................ 95
Binimetinib .................................................................................................. 95
Standard of Care Chemotherapies (mFOLFOX7 and FOLFIRI) ................ 95
Handling, Storage and Accountability................................................................ 95
Treatment Compliance......................................................................................... 96
Concomitant Therapy........................................................................................... 96
Rescue Medications & Supportive Care............................................................. 98
Supportive Care Guidelines for Pembrolizumab ......................................... 98
Supportive Care Guidelines for Binimetinib ............................................. 100
Supportive Care Guidelines for mFOLFOX7............................................ 103
Supportive Care Guidelines for FOLFIRI ................................................. 103
Treatment After the End of the Study.............................................................. 104
Clinical Supplies Disclosure............................................................................... 104
8.
Discontinuation/Withdrawal Criteria................................................................... 104
Discontinuation of Study Treatment................................................................. 104
Withdrawal from the Study............................................................................... 105
Lost to Follow Up................................................................................................ 105
9.
Study Assessments and Procedures....................................................................... 106
Administrative and General Procedures .......................................................... 106
Informed Consent.............................................................................................. 106
General Informed Consent......................................................................... 106
Consent and Collection of Specimens for Future Biomedical Research ... 107
Inclusion/Exclusion Criteria ............................................................................. 107
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Participant Identification Card.......................................................................... 107
Medical History ................................................................................................ 107
Prior and Concomitant Medications Review .................................................... 108
Prior Medications....................................................................................... 108
Disease Status and Prior Cancer Treatment History.................................. 108
Concomitant Medications.......................................................................... 108
Assignment of Screening Number.................................................................... 108
Assignment of Treatment/Randomization Number.......................................... 108
Treatment Administration................................................................................. 108
Timing of Dose Administration................................................................. 109
Pembrolizumab Administration.......................................................... 109
Standard of Care ................................................................................. 109
Binimetinib ......................................................................................... 110
Withdrawal/Discontinuation............................................................................. 110
Withdrawal From Future Biomedical Research ........................................ 110
Participant Blinding/Unblinding....................................................................... 110
Domiciling ........................................................................................................ 110
Calibration of Critical Equipment..................................................................... 110
Efficacy Assessments .......................................................................................... 111
Tumor Imaging and Assessment of Disease..................................................... 111
Initial Tumor Imaging................................................................................ 111
Tumor Imaging During the Study.............................................................. 111
End of Treatment and Follow-up Tumor Imaging..................................... 112
RECIST 1.1 Assessment of Disease.......................................................... 112
iRECIST Assessment of Disease............................................................... 112
Adverse Events, Serious Adverse Events and Other Reportable Safety 
Events................................................................................................................... 115
Time Period and Frequency for Collecting AE, SAE and Other Reportable 
Safety Event Information.................................................................................. 115
Method of Detecting AE, SAE and Other Reportable Safety Events............... 118
Follow-up of AE, SAE and Other Reportable Safety Event Information......... 118
Regulatory Reporting Requirements for SAE .................................................. 118
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying 
as AEs or SAEs................................................................................................. 118
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Pregnancy and Exposure During Breastfeeding ............................................... 118
Events of Clinical Interest (ECI)....................................................................... 119
Monitoring Overlapping Toxicities .................................................................. 120
Treatment of Overdose....................................................................................... 120
Safety.................................................................................................................... 120
Physical Examinations...................................................................................... 120
Full Physical Examination......................................................................... 120
Directed Physical Examination.................................................................. 121
Full Ophthalmic Examination.................................................................... 121
Additional Testing ..................................................................................... 121
Vital Signs......................................................................................................... 121
Electrocardiograms ........................................................................................... 121
Echocardiogram/Multigated Acquisition Scan................................................. 122
Eastern Cooperative Oncology Group (ECOG) Performance Status ............... 122
Clinical Safety Laboratory Assessments........................................................... 122
Local Laboratory Assessments .................................................................. 123
Pharmacokinetics................................................................................................ 124
Blood Collection for Binimetinib ..................................................................... 124
Blood Collection for Irinotecan and an Active Metabolite of Irinotecan 
(SN-38) ............................................................................................................. 124
Pharmacodynamics............................................................................................. 125
Future Biomedical Research Sample Collection.............................................. 125
Biomarkers .......................................................................................................... 125
Tumor Tissue Collection................................................................................... 125
Planned Genetic Analysis Sample Collection................................................... 126
Visit Requirements ............................................................................................. 126
Screening........................................................................................................... 126
Treatment Period............................................................................................... 126
Discontinued Participants Continuing to be Monitored in the Study ............... 127
Post-Study.................................................................................................. 127
Safety Follow-up Visits ............................................................................. 127
Imaging Follow-up Visits .......................................................................... 127
Follow-up Visits......................................................................................... 127
Survival Follow-up Contacts ..................................................................... 128
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Survival Status .................................................................................................. 128
10.
Statistical Analysis Plan ......................................................................................... 128
Statistical Analysis Plan Summary ................................................................... 128
Responsibility for Analyses/In-House Blinding ............................................... 129
Hypotheses/Estimation....................................................................................... 129
Analysis Endpoints ............................................................................................. 129
Efficacy Endpoints............................................................................................ 129
Safety Endpoints ............................................................................................... 130
Analysis Populations........................................................................................... 130
Safety Analysis Population............................................................................... 130
Efficacy Analysis Population............................................................................ 130
Statistical Methods.............................................................................................. 130
Statistical Methods for Efficacy Analysis......................................................... 130
Statistical Methods for Safety Analysis............................................................ 130
Interim Analyses ................................................................................................. 131
Multiplicity .......................................................................................................... 131
Sample Size and Power Calculations ................................................................ 131
Subgroup Analyses ............................................................................................. 132
Compliance (Medication Adherence)................................................................ 132
Extent of Exposure.............................................................................................. 132
11.
References................................................................................................................ 133
12.
Appendices............................................................................................................... 147
Appendix 1: Abbreviations and Trademarks .................................................. 147
Appendix 2: ECOG Performance Status.......................................................... 151
Appendix 3: Clinical Laboratory Tests ............................................................ 152
Appendix 4: Study Governance Considerations.............................................. 154
Code of Conduct for Clinical Trials.............................................................................. 154
Financial Disclosure...................................................................................................... 157
Data Protection.............................................................................................................. 157
Confidentiality of Data ................................................................................................. 157
Confidentiality of Participant Records.......................................................................... 157
Confidentiality of IRB/IEC Information....................................................................... 158
Publication Policy ......................................................................................................... 158
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Compliance with Trial Registration and Results Posting Requirements...................... 158
Compliance with Law, Audit and Debarment .............................................................. 158
Data Quality Assurance ................................................................................................ 159
Source Documents ........................................................................................................ 160
Study and Site Closure.................................................................................................. 160
Appendix 5: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................. 161
Definition of AE ........................................................................................................... 161
Definition of SAE ......................................................................................................... 162
Additional Events reported in the same manner as SAE .............................................. 163
Recording AE and SAE ................................................................................................ 163
Reporting of AE, SAE, and Other Reportable Safety Events to the Sponsor............... 167
Appendix 6: Contraceptive Guidance and Pregnancy Testing ...................... 168
Contraception Requirements......................................................................................... 168
Pregnancy Testing......................................................................................................... 170
Appendix 7: Collection and Management of Specimens for Future 
Biomedical Research........................................................................................... 171
Appendix 8: Response Evaluation Criteria in Solid Tumors (RECIST) 
Version 1.1 Criteria for Evaluating Response in Solid Tumors..................... 175
Appendix 9: Description of the iRECIST Process for Assessment of 
Disease Progression............................................................................................. 176
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LIST OF TABLES
   
Table 1
Potential Overlapping Toxicities for Each Cohort ................................................. 53
Table 2
Dose Finding Rules Based on the mTPI Design..................................................... 59
Table 3
Dose Levels in Cohorts A, B, C, D, and E (Parts 1 [Dose Finding] and 2 [Dose 
Confirmation])........................................................................................................ 66
Table 4
Inclusion Criteria Laboratory Parameters............................................................... 78
Table 5
Study Treatment(s) ................................................................................................. 83
Table 6
Dose Modification and Toxicity Management Guidelines for Immune-related 
Adverse 
Events 
Associated 
with 
Pembrolizumab 
Monotherapy, 
Coformulations or IO Combinations...................................................................... 86
Table 7
Dose Modification Guideline for Binimetinib........................................................ 90
Table 8
Pembrolizumab Infusion Reaction Dose Modification and Treatment 
Guidelines............................................................................................................... 99
Table 9
Imaging and Treatment after First Radiologic Evidence of Progressive Disease 114
Table 10 Reporting Time Periods and Timeframes for Adverse Events and Other 
Reportable Safety Events ..................................................................................... 117
Table 11 Laboratory Tests ................................................................................................... 123
Table 12 Estimate and 95% Confidence Interval of Objective Response Rate in Each 
Cohort................................................................................................................... 132
Table 13 Protocol-Required Safety Laboratory Assessments ............................................. 152
Table 14 Contraceptive Methods......................................................................................... 169
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LIST OF FIGURES
Figure 1 Study Diagram (Cohort A) ..................................................................................... 60
Figure 2 Study Diagram (Cohort B)...................................................................................... 61
Figure 3 Study Diagram (Cohort C)...................................................................................... 62
Figure 4 Study Diagram (Cohort D) ..................................................................................... 63
Figure 5 Study Diagram (Cohort E)...................................................................................... 64
Figure 6 Study Diagram ........................................................................................................ 70
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1. Synopsis
Protocol Title:  
A Phase 1b Multi-cohort Study of the Combination of Pembrolizumab (MK-3475) plus 
Binimetinib alone or the Combination of Pembrolizumab plus Chemotherapy with or 
without Binimetinib in Participants with Metastatic Colorectal Cancer (KEYNOTE-651)
Short Title: 
Ph1b study of MK-3475 with chemotherapy and/or binimetinib in participants with mCRC
Objectives/Hypotheses and Endpoints:
The objectives and endpoints apply to all participants enrolled in the trial.  There is no 
intent to compare Cohorts B and C or Cohorts D and E. Each cohort will have independent 
objectives and will be analyzed separately. 
Objective/Hypothesis
Endpoint
Primary
Objectives: 

To 
determine 
the 
safety 
and 
tolerability 
and 
to 
establish 
a 
preliminary recommended Phase 2 
dose (RP2D) for the following 
cohorts:
o
Cohort A (pembrolizumab in 
combination with binimetinib in 
metastatic 
colorectal 
cancer 
(mCRC) participants previously 
treated with fluoropyrimidine, 
irinotecan, and oxaliplatin).

Determined by incidence of dose limiting 
toxicities (DLTs)
o
Cohort B (pembrolizumab in 
combination with mFOLFOX7 in 
previously 
untreated 
mCRC 
participants).
o
Cohort C (pembrolizumab in 
combination with mFOLFOX7
and binimetinib in previously 
untreated mCRC participants).
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o
Cohort D (pembrolizumab in 
combination with FOLFIRI in 
mCRC participants
previously 
treated with one line of a 
fluoropyrimidine 
plus 
oxaliplatin-based regimen).
o
Cohort E (pembrolizumab in 
combination with FOLFIRI and 
binimetinib in mCRC participants
previously treated with one line 
of
fluoropyrimidine 
plus 
oxaliplatin-based regimen).
Secondary 
Objective:

To 
evaluate 
the 
objective 
response rate (ORR) based on 
Response Evaluation Criteria in 
Solid Tumors (RECIST) Version 
1.1
as 
assessed 
by 
the 
investigator for each cohort.    
Endpoint:

Objective response rate (ORR): defined 
as the proportion of participants in the 
analysis 
population 
who 
experience 
complete response 
(CR) 
or 
partial 
response (PR) as assessed by the 
investigator based on RECIST Version 
1.1.
Overall Design:
Trial Phase
Phase 1b
Clinical Indication
The treatment of participants with metastatic colorectal 
cancer (mCRC)
Population
Participants with mCRC with the non-microsatellite 
instability high/proficient mismatch repair (non-MSI-
H/pMMR) phenotype
Trial Type
Interventional
Type of Design
Open label, multicenter, international, cohort-based, dose 
finding and dose confirmation Phase 1b
Type of Control
No treatment control
Trial Blinding
Unblinded Open-label
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Estimated Duration 
of Trial
The Sponsor estimates that the trial will require 
approximately 48 months from the time the first participant 
signs the informed consent until the last participant’s last 
study-related phone call or visit.
Number of Participants:
A maximum of approximately 220 participants will be enrolled (Parts 1 and 2).  A target 
sample size of 159 participants will be used for trial planning purposes.
Treatment Groups and Duration:
Treatment Groups
This trial includes 2 parts: Part 1 will be a dose finding
phase using the modified toxicity probability interval 
(mTPI) design and Part 2 will be a dose confirmation phase 
to further examine safety and exploratory efficacy.  There 
are a total of 5 cohorts.  Each of the 5 cohorts will 
participate in Part 1 and Part 2. The study will evaluate 
safety, tolerability, and efficacy in the following 5 cohorts:
Cohort A: 
Part 1: Dose Finding
Standard 
dose 
(DL1): 
Pembrolizumab 
200 
mg 
intravenous (IV) every 3 weeks (Q3W) + binimetinib 
(oral) 30 mg twice daily (BID)
Escalation dose (DL2): Pembrolizumab 200 mg IV Q3W 
+ binimetinib 45 mg (oral) BID
Part 2: Dose Confirmation
Pembrolizumab 200 mg IV Q3W + binimetinib (oral) 
(preliminary RP2D) BID
Cohort B:
Part 1: Dose Finding
DL1: Pembrolizumab 200 mg IV Q3W + mFOLFOX7 
(oxaliplatin [85 mg/m2]; leucovorin [calcium folinate]
[400 mg/m2]; fluorouracil [5-FU] 2400 mg/m2 over 46 to 
48 hours) IV every 2 weeks (Q2W). 
De-escalation dose (DL-1):  Pembrolizumab 200 mg IV
Q3W + mFOLFOX7 (oxaliplatin [70 mg/m2]; leucovorin 
[calcium folinate] [400 mg/m2]; 5-FU [2000 mg/m2 over 
46 to 48 hours]) IV Q2W
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Product:  MK-3475 
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Protocol/Amendment No.: 651-04
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Confidential
Part 2: Dose Confirmation
Pembrolizumab 200 mg Q3W + mFOLFOX7 (preliminary 
RP2D) IV Q2W
Cohort C:
Part 1: Dose Finding
DL1: Pembrolizumab 200 mg IV Q3W + mFOLFOX7
(preliminary RP2D determined in Cohort B) IV Q2W + 
binimetinib 30 mg (oral) BID 
DL2: Pembrolizumab 200 mg IV Q3W + mFOLFOX7 
(preliminary RP2D determined in Cohort B) IV Q2W + 
binimetinib 45 mg (oral) BID
Part 2: Dose Confirmation
Pembrolizumab 200 mg IV Q3W + mFOLFOX7 
(preliminary RP2D determined in Cohort B) IV Q2W + 
binimetinib (preliminary RP2D) (oral) BID
Cohort D:
Part 1: Dose Finding
DL1:  Pembrolizumab 200 mg IV Q3W + FOLFIRI 
(irinotecan [180 mg/m2]; leucovorin [calcium folinate]
[400 mg/m2]; 5-FU [2400 mg/m2 over 46 to 48 hours]) 
IV Q2W  
DL-1: Pembrolizumab 200 mg IV Q3W + FOLFIRI dose 
may be de-escalated (irinotecan [150 mg/m2]; leucovorin 
(calcium folinate) [400 mg/m2]; 5-FU 2000 mg/m2 over 
46 to 48 hours]) IV Q2W
Part 2: Dose Confirmation
Pembrolizumab 200 mg IV Q3W
+ FOLFIRI 
(preliminary RP2D) IV Q2W
Cohort E: 
Part 1: Dose Finding
DL1: Pembrolizumab 200 mg IV Q3W + FOLFIRI 
(preliminary RP2D determined in Cohort D) IV Q2W + 
binimetinib 30 mg (oral) BID 
DL2: Pembrolizumab 200 mg IV Q3W + FOLFIRI 
(preliminary RP2D determined in Cohort D) IV Q2W + 
binimetinib 45 mg (oral) BID 
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Product:  MK-3475 
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Protocol/Amendment No.: 651-04
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Confidential
Part 2: Dose Confirmation
Pembrolizumab 
200 
mg 
IV 
Q3W
+ 
FOLFIRI 
(preliminary RP2D determined in Cohort D) IV Q2W + 
binimetinib (preliminary RP2D) (oral) BID
Duration of 
Participation
Each participant will participate in the trial from the time 
the participant signs the informed consent form (ICF) 
through the final protocol-specified contact.
After a screening phase of 28 days, each participant will be 
assigned to receive study treatment until disease 
progression is radiographically documented and confirmed 
by the site per modified Response Evaluation Criteria in 
Solid Tumors 1.1, unacceptable adverse event(s) (AEs), 
intercurrent illness that prevents further administration of 
treatment, 
investigator’s 
decision 
to 
withdraw 
the 
participant, noncompliance with study treatment or 
procedure requirements or administrative reasons requiring 
cessation of treatment, or until the participant has received 
35 administrations of pembrolizumab (approximately 2 
years) and binimetinib treatment. Treatment with standard 
of care (SOC) chemotherapy (mFOLFOX7 or FOLFIRI) 
will continue per Investigator’s decision.
Once the participant has achieved the study objective or 
study has ended, the participant is discontinued from this 
study and may be enrolled in an extension study to 
continue protocol-defined assessments and treatment.
A list of abbreviations used in this document can be found in Appendix 1.  Study governance 
considerations are outlined in Appendix 4.
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Product:  MK-3475 
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Protocol/Amendment No.: 651-04
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2. Schedule of Activities (SoA)
Pembrolizumab in Combination with Binimetinib (Cohort A)
Trial Period:
Screening Phase
Treatment Cycles 
(3-Week Cycles)
End of 
Treatment
Post-treatment
Notes
Treatment Cycle/Title:
Screening (Visit 1)
1
2
3
4
5
6
7
8 and 
beyond
Discon
Safety 
Follow-
up
Follow-
Up Visits
Survival 
Follow-up
At time of 
discon
30 days 
post-
discon
Q9W
post-
discon
Q12W
Scheduling Window (Days):
-42 to -29
-28 to -1
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±14
Administrative Procedures
Informed Consent
X
Informed Consent
for optional 
post-treatment tumor biopsy 
X
Informed 
Consent 
for 
FBR
(optional)
X
Participant Identification Card
X
Inclusion/Exclusion Criteria
X
Demographics 
and 
Medical 
History
X
Cancer disease status and Prior 
Treatment history
X
Prior and Concomitant Medication 
Review
X
X
X
X
X
X
X
X
X
X
X
Pembrolizumab Administration
X
X
X
X
X
X
X
X
Binimetinib Administration
<==============X==============
To be administered BID.
Efficacy Assessments
Tumor Imaging
X
<==============X==============
X
X
Tumor imaging at screening must 
be performed within 28 days 
prior to the date of Cycle 1 
Day 1. On-study imaging will be 
performed every 9 weeks 
(63 days ± 7 days) calculated 
from the date of allocation. See 
section 9.2.
08JTB4


Product:  MK-3475 
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Protocol/Amendment No.: 651-04
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Confidential
Pembrolizumab in Combination with Binimetinib (Cohort A)
Trial Period:
Screening 
Phase
Treatment Cycles 
(3-Week Cycles)
End of 
Treatment
Post-treatment
Notes
Treatment 
Cycle/Title:
Screening 
(Visit 1)
1
2
3
4
5
6
7
8 and beyond
Discon
Safety Follow-
up
Follow-Up 
Visits
Survival Follow-
up
At time of 
discon
30 days post-
discon
Q9W
post-discon
Q12W
Scheduling Window 
(Days):
-42 to 
-29
-28 to 
-1
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±14
Clinical 
Procedures/
Assessments
Review Adverse 
Events
X
<=====================X========================
X
X
Full Physical 
Examination
X
X
Full Ophthalmic 
Examination 
(Q8W)
X
X
<==============X==============
X
To be performed at screening, 
Cycle 2 Day 1 and then every 
8 weeks (±7 days) from Cycle 
2 Day 1 and EOT. An 
ophthalmic examination at the 
30-day follow up is only 
required 
if 
there 
was 
a 
clinically 
significant 
abnormality noted at EOT (± 7 
days)
Directed 
Physical 
Examination
X
X
X
X
X
X
X
X
Height, Weight, and 
Vital Signs
X
X
X
X
X
X
X
X
X
X
Height will be measured at 
Visit 1 only.  
12-Lead 
Electrocardiogram
X
X
X
X
X
X
X
X
X
X
ECG will be performed in 
triplicate 
to 
confirm 
QTc 
interval at screening. ECG will 
be performed predose starting 
at Cycle 2.
Echocardiogram/
MUGA scan 
(Q12W)
X
X
X
X
X
ECHO/MUGA scans are to be 
performed at Screening and 
pre-dose on Cycle 2 Day 1 and 
Cycle 5 Day 1, then every 
12 weeks and EOT.  
ECOG Performance 
Status
X
X
X
X
X
X
X
X
X
X
ECOG Performance Status at 
Screening 
to 
be 
assessed 
within 7 days prior to the first 
dose of trial treatment.  
08JTB4


Product:  MK-3475 
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Protocol/Amendment No.: 651-04
MK-3475-651-04 Final Protocol
08-Jun-2022
Confidential
Pembrolizumab in Combination with Binimetinib (Cohort A)
Trial Period:
Screening 
Phase
Treatment Cycles 
(3-Week Cycles)
End of 
Treatment
Post-treatment
Notes
Treatment 
Cycle/Title:
Screening 
(Visit 1)
1
2
3
4
5
6
7
8 and 
beyond
Discon
Safety 
Follow-up
Follow-Up 
Visits
Survival 
Follow-
up
At time 
of discon
30 days 
post-discon
Q9W
post-discon
Q12W
Scheduling 
Window 
(Days):
-42 to 
-29
-28 to 
-1
±3
±3
±3
±
3
±3
±3
±3
±3
±3
±7
±14
Post-study Anticancer 
Therapy Status
X
X
Survival Status
<=============================X=============================
X
After investigator determined PD or start of new 
anticancer treatment. In addition, upon Sponsor request, 
participants may be contacted for survival status at any 
time during the course of the study.
LOCAL Laboratory 
Assessments
MSI/MMR Status 
X
If tumor testing is obtained by both PCR and IHC, the 
tumor result should be neither MSI-H by PCR nor 
dMMR by IHC to identify the non-MSI-H participants.
Pregnancy 
Test 
–
Urine or Serum β-
hCG, if applicable
X 
X
Pregnancy tests may be performed if clinically 
warranted, or as defined by local regulations.
PT/INR and aPTT
X 
CBC 
with 
Differentiala
X 
X
X
X
X
X
X
X
X
X
X
Chemistry Panela
X 
X
X
X
X
X
X
X
X
X
X
Urinalysisa
X 
X
X
X
X
X
X
To be performed at screening, and every other cycle 
starting at Cycle 2.
T3 or FT3, FT4, TSH 
X 
X
X
X
X
X
X
To be performed at screening, and every other cycle 
starting at Cycle 2.
Serum Tumor Marker 
<================X============
X
X
Serum tumor marker (CEA) to be collected Q3W starting 
at Cycle 1.
CENTRAL Laboratory
Assessments
Binimetinib 
Pharmacokinetics
X
PK samples will be collected at time 0 (pre-dose), 0.5, 1, 1.5, 2, 
4, 6 hrs (all ±10 min) on Day 15, pre-dose (24 ± 2 hrs from the 
first binimetinib PK collection) on Day 16 and pre-dose (48 ± 
2 hrs from the first binimetinib PK collection) on Day 17 in 
Cycle 1. The exact time of sample collection and time of 
administration of binimetinib will be recorded.  
Blood for Genetic 
Analysis  
X
To be collected pre-dose. 
08JTB4


Product:  MK-3475 
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Protocol/Amendment No.: 651-04
MK-3475-651-04 Final Protocol
08-Jun-2022
Confidential
Pembrolizumab in Combination with Binimetinib (Cohort A)
Trial Period:
Screening 
Phase
Treatment Cycles 
(3-Week Cycles)
End of 
Treatment
Post-treatment
Notes
Treatment Cycle/Title:
Screening 
(Visit 1)
1
2
3
4
5
6
7
8 and 
beyond
Discon
Safety 
Follow-up
Follow-Up 
Visits
Survival Follow-up
At time of 
discon
30 days post-
discon
Q9W
post-discon
Q12W
Scheduling Window 
(Days):
-42 to 
-29
-28 
to -1
±3
±3
±3
±3
±3
±3
±3
±3
±3
±7
±14
Blood for RNA 
Analyses
X
X
X
X
Samples should be obtained pre-
dose of Cycle 1, Cycle 2, and 
Cycle 5 and at the Treatment 
Discontinuation visit.
Blood for Plasma 
Biomarker Analyses
X
X
X
X
Samples should be obtained pre-
dose of Cycle 1, Cycle 2, and 
Cycle 5 and at the Treatment 
Discontinuation visit.
Blood for Serum 
Biomarker Analyses
X
X
X
X
Samples should be obtained pre-
dose of Cycle 1, Cycle 2, and 
Cycle 5 and at the Treatment 
Discontinuation visit.  
Tumor Tissue 
Collection
Archival or Newly 
Obtained Tumor 
Tissue collection
X
On-Study Tumor 
Biopsy (Optional)
X
Abbreviations:  aPTT/PTT= activate;  β-hCG=human chorionic gonadotropin; BID=twice daily; CBC=complete blood count; CEA= carcinoembryonic antigen; Discon=discontinuation; dMMR= 
deficient mismatch repair; ECG=electrocardiogram; ECHO=echocardiogram; ECOG=Eastern Cooperative Oncology Group; EOT=end of trial; FBR=future biomedical research; FT3=free 
triiodothyronine; FT4=free thyroxine; IHC= immunohistochemistry; IV=intravenous; MSI/MMR= microsatellite instability/mismatch repair; MUGA= multigated acquisition; PCR= polymerase chain 
reaction; PK= pharmacokinetic; PT/INR = prothrombin time/International Normalized Ratio; prothrombin time/partial thromboplastin time; Q8W=every 8 weeks; Q9W=every 9 weeks; Q12W= every 
12 weeks; QTc =Q-T interval; RNA=ribonucleic acid; TSH=thyroid stimulating hormone.
a.
All screening laboratory tests should be performed within 10 days prior to the first dose of trial treatment.
08JTB4


Product:  MK-3475 
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Protocol/Amendment No.: 651-04
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08-Jun-2022
Confidential
Pembrolizumab in Combination with mFOLFOX7 (Cohort B)
Trial Period:
Screening 
Phase
Treatment Phase (3-Week Cycles)
End of Treatment
End of 
Treatment
Post- Treatment
Notes
Treatment Cycle/Title
Screening 
(Visit 1)
1
2
3
4
5 to 35
Discon
Discon
Safety 
Follow 
Up
Follow-
up 
Visits
Survival 
Follow 
up
Treatment Days:
1
8
15
1
8
15
1
8
15
1
8
15
1
8
15
At time 
of 
Treatment
discon
30 days
Post last 
dose
Q9W 
Post-
discon
Q12W
Scheduling Window 
(Days):
-42 
to 
-29
-28 
to 
-1
±
3
±
3
±
3
±
3
±
3
±
3
±
3
±
3
±
3
±
3
±3
±3
±3
±3
±3
±7
±7
±14
Administrative 
Procedures
Informed Consent
X
Informed Consent for 
optional post-treatment 
tumor biopsy
X
Informed Consent for 
FBR (optional)
X
Participant 
Identification Card
X
Inclusion/Exclusion 
Criteria
X
Demographics and 
Medical History
X
Cancer disease status 
and Prior Treatment 
History
X
Prior and Concomitant 
Medication Review
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medication should be 
reviewed at every visit.
Pembrolizumab 
Administration
X
X
X
X
X
mFOLFOX7 
Administration
X
X
X
X
X
X
X
X
X
Efficacy Assessments
Tumor Imaging 
X
<==================X======================
X
X
Tumor imaging at screening must be 
performed within 28 days prior to the 
date of Cycle 1 Day 1. The first 
on-study imaging time point will be 
performed at 9 weeks 
(63 days ± 7 days) calculated from 
the date of allocation. See Section 
9.2.
08JTB4


Product:  MK-3475 
25
Protocol/Amendment No.: 651-04
MK-3475-651-04 Final Protocol
08-Jun-2022
Confidential
Pembrolizumab in Combination with mFOLFOX7 (Cohort B)
Trial Period:
Screening 
Phase
Treatment Phase (3-Week Cycles)
End of Treatment
End of 
Treatment
Post- Treatment
Notes
Treatment Cycle/Title
Screening 
(Visit 1)
1
2
3
4
5 to 35
Discon
Discon
Safety 
Follow 
Up
Follow-up 
Visits
Survival 
Follow up
Treatment Days:
1
8
15
1
8
15
1
8
15
1
8
15
1
8
15
At time of 
Treatment 
discon
30 days
Post last 
dose
Q9W Post-
discon
Q12W
Scheduling Window 
(Days):
-42 
to 
-29
-28 
to 
-1
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±14
Clinical 
Procedures/Assessments
Review adverse events
X
<===========X=============
X
X
X
Full Physical Exam
X
X
Directed Physical Exam
X
X
X
X
X
X
X
X
X
X
Height, Weight, and Vital 
Signs
X
X
X
X
X
X
X
X
X
X
X
X
Height will be measured at 
Visit 1 only.  
12-Lead 
Electrocardiogram
X
To
be performed one time 
during   screening using local 
standard procedures. Additional 
time points may be performed 
as clinically necessary.
ECOG PS
X
X
X
X
X
X
X
ECOG PS at screening to be 
assessed within 7 days prior to 
the first dose of trial treatment.  
Post-Study Anticancer 
Therapy Status
X
X
Survival Status
<=============================X================================
X
After investigator determined 
PD or start of new anticancer 
treatment. In addition, upon 
Sponsor request, participants 
may be contacted for survival 
status at any time during the 
course of the study.
Local Laboratory 
Assessments
MSI/MMR Status
X
If tumor testing is obtained by 
both PCR and IHC, the tumor 
result should be neither MSI-H 
by PCR nor dMMR by IHC to 
identify the non-MSI-H 
participants.
08JTB4


Product:  MK-3475 
26
Protocol/Amendment No.: 651-04
MK-3475-651-04 Final Protocol
08-Jun-2022
Confidential
Pembrolizumab in Combination with mFOLFOX7 (Cohort B)
Trial Period:
Screening 
Phase
Treatment Phase (3-Week Cycles)
End of Treatment
End of 
Treatment
Post- Treatment
Notes
Treatment 
Cycle/Title
Screening 
(Visit 1)
1
2
3
4
5 to 35
Discon
Discon
Safety 
Follow 
Up
Follow-
up 
Visits
Survival 
Follow 
up
Treatment Days:
1
8
15
1
8
15
1
8
15
1
8
15
1
8
15
At time of 
Treatment 
discon
30 days
Post last 
dose
Q9W 
Post-
discon
Q12W
Scheduling 
Window (Days):
-42 
to 
-29
-28 
to -1
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±14
Pregnancy Test-
Urine or Serum β-
HCG
X
X
Pregnancy tests may be performed if 
clinically warranted, or as defined by 
local regulations
PT/INR and aPTT
X
CBC with 
Differentiala
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry Panela
X
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysisa
X
X
X
X
X
X
To be performed at Screening, and every 
other cycle starting at Cycle 2.
T3 or FT3, FT4, 
and TSH
X
X
X
X
X
X
To be performed at screening, and every 
other cycle starting at Cycle 2.
Serum 
Tumor 
Marker
<==============X==============>
X
X
Serum tumor marker (CEA) to be 
collected Q3W.
Laboratory 
Procedures: 
Performed by 
Central 
Laboratory
Blood for Genetic 
Analyses
X
To be collected pre-dose.
Blood for RNA 
Analyses
X
X
X
X
Blood sample for RNA analysis should 
be obtained pre-dose of Cycle 1 Day 1, 
Cycle 2 Day 1, and Cycle 5 Day 1 and at 
the Treatment Discontinuation visit.
Blood for Plasma 
Biomarker 
Analyses
X
X
X
X
Blood sample for plasma should be 
obtained pre-dose of Cycle 1 Day 1, 
Cycle 2 Day 1, and Cycle 5 Day 1 and at 
the Treatment Discontinuation visit.
Blood for Serum 
Biomarker 
Analyses
X
X
X
X
Blood sample for serum should be 
obtained pre-dose of Cycle 1 Day 1, 
Cycle 2 Day 1, and Cycle 5 Day 1 and at 
the Treatment Discontinuation visit.
08JTB4


Product:  MK-3475 
27
Protocol/Amendment No.: 651-04
MK-3475-651-04 Final Protocol
08-Jun-2022
Confidential
Pembrolizumab in Combination with mFOLFOX7 (Cohort B)
Trial Period:
Screening 
Phase
Treatment Phase (3-Week Cycles)
End of Treatment
End of 
Treatment
Post-Treatment
Notes
Treatment 
Cycle/Title
Screening 
(Visit 1)
1
2
3
4
5 to 35
Discon
Discon
Safety 
Follow Up
Follow-
up Visits
Survival 
Follow up
Treatment Days:
1
8
15
1
8
15
1
8
15
1
8
15
1
8
15
At time of 
Treatment 
discon
30 days
Post last 
dose
Q9W 
Post-
discon
Q12W
Scheduling 
Window 
(Days):
-42 
to 
-29
-28 
to 
-1
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±14
Tumor Tissue 
Collection
Archival and/or Newly 
Obtained Tissue 
Collection
X
Post-treatment Tumor 
Biopsy (Optional)
X
Abbreviations: aPTT/PTT= activated prothrombin time/partial thromboplastin time; β-hCG=human chorionic gonadotropin;  CBC=complete blood count; Discon=discontinuation; 
CEA= carcinoembryonic antigen; dMMR= deficient mismatch repair; ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; FBR=future biomedical research; 
FT3=free triiodothyronine; FT4=free thyroxine; IHC= immunohistochemistry; IV=intravenous; mFOLFOX7= (oxaliplatin [85 mg/m2]; leucovorin [calcium folinate] [400 
mg/m2]; 5-FU 2400 mg/m2); MSI/MMR= microsatellite instability/mismatch repair MUGA= multigated acquisition; PCR= polymerase chain reaction; PS=performance score; 
PT/INR = prothrombin time/International Normalized Ratio;; Q9W=every 9 weeks; Q12W= every 12 weeks;  RNA=ribonucleic acid; TSH=thyroid stimulating hormone.
a.
All screening laboratory tests should be performed within 10 days prior to the first dose of trial treatment.
08JTB4


Product:  MK-3475 
28
Protocol/Amendment No.: 651-04
MK-3475-651-04 Final Protocol
08-Jun-2022
Confidential
Pembrolizumab in Combination with mFOLFOX7 and Binimetinib (Cohort C)
Trial Period:
Screening 
Phase
Treatment Phase (3-Week Cycles)
End of Treatment
End of 
Treatment
Post- Treatment
Notes
Treatment Cycle/Title
Screening 
(Visit 1)
1
2
3
4
5 to 35
Discon
Discon
Safety 
Follow 
Up
Follow-
up 
Visits
Survival 
Follow 
up
Treatment Days:
1
8
15
1
8
15
1
8
15
1
8
15
1
8
15
At time of 
Treatment 
discon
30 days
Post last 
dose
Q9W 
Post-
discon
Q12W
Scheduling Window 
(Days):
-42 
to 
-29
-28 
to 
-1
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±14
Administrative 
Procedures
Informed Consent
X
Informed Consent for 
optional post-treatment 
tumor biopsy
X
Informed Consent for 
FBR (optional)
X
Participant Identification 
Card
X
Inclusion/Exclusion 
Criteria
X
Demographics and 
Medical History
X
Cancer disease status 
and Prior Treatment 
History
X
Prior and Concomitant 
Medication Review
X
X
X
X
X
X
X
X
X
X
X
X
X
Pembrolizumab 
Administration
X
X
X
X
X
Binimetinib 
Administration
<==================X======================
To be administered BID.
mFOLFOX7 
Administration
X
X
X
X
X
X
X
X
X
Efficacy Assessments
Tumor Imaging 
X
<==================X======================
X
X
Tumor imaging at screening must be 
performed within 28 days prior to the date 
of Cycle 1 Day 1. The first on-study 
imaging time point will be performed at 
9 weeks (63 days ± 7 days) calculated 
from the date of allocation. See Section 
9.2.
08JTB4


Product:  MK-3475 
29
Protocol/Amendment No.: 651-04
MK-3475-651-04 Final Protocol
08-Jun-2022
Confidential
Pembrolizumab in Combination with mFOLFOX7 and Binimetinib (Cohort C)
Trial Period:
Screening 
Phase
Treatment Phase (3-Week Cycles)
End of Treatment
End of 
Treatment
Post- Treatment
Notes
Treatment Cycle/Title
Screening 
(Visit 1)
1
2
3
4
5 to 35
Discon
Discon
Safety 
Follow 
Up
Follow-
up 
Visits
Survival 
Follow 
up
Treatment Days:
1
8
15
1
8
15
1
8
15
1
8
15
1
8
15
At time of 
Treatment 
discon
30 
days
Post last 
dose
Q9W 
Post-
discon
Q12W
Scheduling Window 
(Days):
-42 
to 
-29
-28 
to 
-1
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±14
Clinical 
Procedures/Assessments
Review adverse events
X
<===========X=============
X
X
X
Full 
Physical 
Examination
X
X
Full Ophthalmic 
Examination (Q8W)
X
X
<===========X=============
X
To be performed at screening, Cycle 2 
Day 1 and then every 8 weeks (±7 
days) from Cycle 2 Day 1 and EOT. 
An ophthalmic examination at the 30-
day follow up is only required if there 
was a clinically significant 
abnormality noted at EOT (± 7 days)
Directed Physical 
Examination
X
X
X
X
X
X
X
X
X
X
Height, Weight, and Vital 
Signs
X
X
X
X
X
X
X
X
X
X
X
X
Height will be measured at Visit 1 
only.  
12-Lead 
Electrocardiogram
X
X
X
X
X
X
X
ECG will be performed in triplicate to 
confirm QTc interval at screening.
ECG will be performed predose 
starting at Cycle 2 Day 1.
Echocardiogram/MUGA 
scan (Q12W)
X
X
<======X===
X
ECHO/MUGA scans are to be 
performed at Screening, and pre-dose
on Cycle 2 Day 1 and Cycle 5 Day 1, 
then every 12 weeks and EOT.  
ECOG 
Performance 
Status
X
X
X
X
X
X
X
ECOG 
Performance 
Status 
at 
screening to be assessed within 7 days 
prior to the first dose of trial 
treatment.  
Post-Study Anticancer 
Therapy Status
X
X
08JTB4


Product:  MK-3475 
30
Protocol/Amendment No.: 651-04
MK-3475-651-04 Final Protocol
08-Jun-2022
Confidential
Pembrolizumab in Combination with mFOLFOX7 and Binimetinib (Cohort C)
Trial Period:
Screening 
Phase
Treatment Phase (3-Week Cycles)
End of Treatment
End of 
Treatment
Post- Treatment
Notes
Treatment 
Cycle/Title
Screening 
(Visit 1)
1
2
3
4
5 to 35
Discon
Discon
Safety 
Follow 
Up
Follow-
up Visits
Survival 
Follow up
Treatment 
Days:
1
8
15
1
8
15
1
8
15
1
8
15
1
8
15
At time of 
Treatment 
discon
30 days
Post last 
dose
Q9W 
Post-
discon
Q12W
Scheduling 
Window (Days):
-42 
to 
-29
-28 
to 
-1
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±14
Survival Status
<=============================X================================
X
After investigator determined PD or 
start of new anticancer treatment. In 
addition, 
upon 
Sponsor 
request, 
participants may be contacted for 
survival status at any time during the 
course of the study.
Local 
Laboratory 
Assessments
MSI/MMR 
Status
X
If tumor testing is obtained by both 
PCR and IHC, the tumor result should 
be neither MSI-H by PCR nor dMMR 
by IHC to identify the non-MSI-H 
participants.
Pregnancy Test-
Urine or Serum 
β-HCG
X
X
Pregnancy tests may be performed if 
clinically warranted, or as defined by 
local regulations.
PT/INR 
and 
aPTT
X
CBC 
with 
Differentiala
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry Panela
X
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysisa
X
X
X
X
X
X
To be performed at screening, and 
every other cycle starting at Cycle 2
Day 1.
T3 or FT3, FT4, 
and TSH
X
X
X
X
X
X
To be performed at Screening, and 
every other cycle starting at Cycle 2
Day 1.
Serum 
Tumor 
Marker
<==============X==============>
X
X
Serum tumor marker (CEA) to be 
collected Q3W.
08JTB4


Product:  MK-3475 
31
Protocol/Amendment No.: 651-04
MK-3475-651-04 Final Protocol
08-Jun-2022
Confidential
Pembrolizumab in Combination with mFOLFOX7 and Binimetinib (Cohort C)
Trial Period:
Screening 
Phase
Treatment Phase (3-Week Cycles)
End of Treatment
Post- Treatment
Notes
Treatment 
Cycle/Title
Screening 
(Visit 1)
1
2
3
4
5 to 35
Discon
Discon
Safety 
Follow 
Up
Follow-up 
Visits
Survival 
Follow 
up
Treatment 
Days:
1
8
15
1
8
15
1
8
15
1
8
15
1
8
15
At time of 
Treatment 
discon
30 days
Post last 
dose
Q9W Post-
discon
Q12W
Scheduling 
Window (Days)
-42 
to 
-29
-28 to 
-1
Laboratory 
Procedures 
Performed by 
Central 
Laboratory
Blood for 
Genetic 
Analyses
X
Collect pre-dose.
Blood for RNA 
Analyses
X
X
X
X
Blood sample for RNA analysis 
should be obtained pre-dose of 
Cycle 1 Day 1, Cycle 2 Day 1, and 
Cycle 5 Day 1 and at the 
Treatment Discontinuation visit
Blood for 
Plasma 
Biomarker 
Analyses
X
X
X
X
Blood sample for plasma should be 
obtained pre-dose of Cycle 1 Day 
1, Cycle 2 Day 1, and Cycle 5 Day 
1 and at the Treatment 
Discontinuation visit.
Blood for Serum 
Biomarker 
Analyses
X
X
X
X
Blood sample for serum should be 
obtained pre-dose of Cycle 1 Day 
1, Cycle 2 Day 1, and Cycle 5 Day 
1 and at the Treatment 
Discontinuation visit.
Tumor Tissue 
Collection
Archival and/or 
Newly Obtained 
Tissue 
Collection
X
Post-treatment 
Tumor Biopsy 
(Optional)
X
08JTB4


Product:  MK-3475 
32
Protocol/Amendment No.: 651-04
MK-3475-651-04 Final Protocol
08-Jun-2022
Confidential
Pembrolizumab in Combination with mFOLFOX7 and Binimetinib (Cohort C)
Abbreviations:  aPTT/PTT= activated prothrombin time/partial thromboplastin time; β-hCG=human chorionic gonadotropin;  CBC=complete blood count; CEA= carcinoembryonic antigen; 
Discon=discontinuation; dMMR= deficient mismatch repair; ECG=electrocardiogram; ECHO=echocardiogram; ECOG=Eastern Cooperative Oncology Group; EOT= end of trial; FBR=future 
biomedical research; FT3=free triiodothyronine; FT4=free thyroxine; IHC= immunohistochemistry; IV=intravenous; mFOLFOX7= (oxaliplatin [85 mg/m2]; leucovorin [calcium folinate] [400 mg/m2]; 
5-FU 2400 mg/m2); MSI/MMR= microsatellite instability/mismatch repair MUGA= multigated acquisition; PCR= polymerase chain reaction; PT/INR = prothrombin time/International Normalized 
Ratio; Q8W=every 8 weeks; Q9W=every 9 weeks; Q12W= every 12 weeks; QTc =Q-T interval; RNA=ribonucleic acid; TSH=thyroid stimulating hormone.
a.
All screening laboratory tests should be performed within 10 days prior to the first dose of trial treatment.
08JTB4


Product:  MK-3475 
33
Protocol/Amendment No.: 651-04
MK-3475-651-04 Final Protocol
08-Jun-2022
Confidential
Pembrolizumab in Combination with FOLFIRI (Cohort D)
Trial Period:
Screening 
Phase
Treatment Phase (3-Week Cycles)
End of Treatment
Post- Treatment
Notes
Treatment Cycle/Title
Screening 
(Visit 1)
1
2
3
4
5 to 35
Discon
Discon
Safety 
Follow 
Up
Follow-
up 
Visits
Survival 
Follow 
up
Treatment Days:
1
8
15
1
8
15
1
8
15
1
8
15
1
8
15
At time 
of 
Treatmen
t discon
30 days
Post last 
dose
Q9W 
Post-
discon
Q12W
Scheduling Window 
(Days):
-42 
to 
-29
-28
to 
-1
±
3
±
3
±
3
±
3
±
3
±
3
±
3
±
3
±
3
±
3
±3
±3
±3
±3
±3
±7
±7
±14
Administrative 
Procedures
Informed Consent
X
Informed Consent for 
optional post-treatment 
tumor biopsy
X
Informed Consent for 
FBR (optional)
X
Participant 
Identification Card
X
Inclusion/Exclusion 
Criteria
X
Demographics and 
Medical History
X
Cancer disease status 
and Prior Treatment 
History
X
Prior and Concomitant 
Medication Review
X
X
X
X
X
X
X
X
X
X
X
X
X
Pembrolizumab 
Administration
X
X
X
X
X
FOLFIRI
Administration
X
X
X
X
X
X
X
X
X
Efficacy Assessments
Tumor Imaging 
X
<==================X======================
X
X
Tumor imaging at screening must be 
performed within 28 days prior to 
the date of Cycle 1 Day 1. The first 
on-study imaging time point will be 
performed at 9 weeks 
(63 days ± 7 days) calculated from 
the date of allocation. See Section 
9.2.
08JTB4


Product:  MK-3475 
34
Protocol/Amendment No.: 651-04
MK-3475-651-04 Final Protocol
08-Jun-2022
Confidential
Pembrolizumab in Combination with FOLFIRI (Cohort D)
Trial Period:
Screening 
Phase
Treatment Phase (3-Week Cycles)
End of Treatment
Post- Treatment
Notes
Treatment Cycle/Title
Screening 
(Visit 1)
1
2
3
4
5 to 35
Discon
Discon
Safety 
Follow Up
Follow-
up 
Visits
Survival 
Follow 
up
Treatment Days:
1
8
15
1
8
15
1
8
15
1
8
15
1
8
15
At time of 
Treatment 
discon
30 days
Post last 
dose
Q9W 
Post-
discon
Q12W
Scheduling Window 
(Days):
-42 
to 
-29
-28 
to 
-1
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±14
Clinical 
Procedures/Assessments
Review adverse events
X
<===========X=============
X
X
X
Full 
Physical 
Examination
X
X
Directed Physical 
Examination
X
X
X
X
X
X
X
X
X
X
Height, Weight, and Vital 
Signs
X
X
X
X
X
X
X
X
X
X
X
X
Height will be measured at Visit 1 
only.  
12-Lead 
Electrocardiogram
X
ECG will be performed one time 
during   screening using local 
standard procedures. Additional time 
points may be performed as clinically 
necessary.
ECOG 
Performance 
Status
X
X
X
X
X
X
X
ECOG 
Performance 
Status 
at 
screening to be assessed within 7 
days prior to the first dose of trial 
treatment.  
Post-Study Anticancer 
Therapy Status
X
X
Survival Status
<=============================X================================>
X
After investigator determined PD or 
start of new anticancer treatment. In 
addition, upon 
Sponsor 
request, 
participants may be contacted for 
survival status at any time during the 
course of the study.
Local Laboratory 
Assessments
MSI/MMR Status
X
If tumor testing is obtained by both 
PCR and IHC, the tumor result 
should be neither MSI-H by PCR nor 
dMMR by IHC to identify the non-
MSI-H participants.
08JTB4


Product:  MK-3475 
35
Protocol/Amendment No.: 651-04
MK-3475-651-04 Final Protocol
08-Jun-2022
Confidential
Trial Period:
Screening 
Phase
Treatment Phase (3-Week Cycles)
End of Treatment
Post- Treatment
Notes
Treatment Cycle/Title
Screening 
(Visit 1)
1
2
3
4
5 to 35
Discon
Discon
Safety 
Follow Up
Follow-
up 
Visits
Survival 
Follow 
up
Treatment Days:
1
8
15
1
8
15
1
8
15
1
8
15
1
8
15
At time of 
Treatment 
discon
30 days
Post last 
dose
Q9W 
Post-
discon
Q12W
Scheduling Window 
(Days):
-42 
to 
-29
-28 
to 
-1
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±14
Pregnancy Test-Urine or 
Serum β-HCG
X
X
Pregnancy tests may be performed if 
clinically warranted, or as defined by 
local regulations.
PT/INR and aPTT
X
CBC with Differentiala
X
X
X
X
X
X
X
X
X
X
X
X
X
08JTB4


Product:  MK-3475 
36
Protocol/Amendment No.: 651-04
MK-3475-651-04 Final Protocol
08-Jun-2022
Confidential
Pembrolizumab in Combination with FOLFIRI (Cohort D)
Trial Period:
Screening 
Phase
Treatment Phase (3-Week Cycles)
End of Treatment
Post- Treatment
Notes
Treatment 
Cycle/Title
Screening 
(Visit 1)
1
2
3
4
5 to 35
Discon
Discon
Safety 
Follow 
Up
Follow-
up 
Visits
Survival 
Follow 
up
Treatment Days:
1
8
15
1
8
15
1
8
15
1
8
15
1
8
15
At time of 
Treatment 
discon
30 days
Post 
last 
dose
Q9W 
Post-
discon
Q12W
Scheduling Window 
(Days):
-42 
to 
-29
-28 
to 
-1
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±14
Chemistry Panela
X
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysisa
X
X
X
X
X
X
To be performed at screening, and every 
other cycle starting at Cycle 2 Day 1.
T3 or FT3, FT4, and 
TSH
X
X
X
X
X
X
To be performed at screening, and every 
other cycle starting at Cycle 2 Day 1.
Serum Tumor Marker
<==============X==============>
X
X
Serum tumor marker (CEA) to be 
collected Q3W.
Laboratory 
Procedures: 
Performed by 
Central Laboratory
Irinotecan and SN-38 
Pharmacokinetics
X
Serial plasma samples for irinotecan and 
its active metabolite (SN-38) will be 
collected before (pre-infusion), the end of 
infusion, 1, 1.5, 2, 4, 6 (all ±10 min), 24
± 2 hrs and 48 ± 2 hrs after the initiation 
of infusion in Cohort D. If irinotecan 
infusion time is between 45 minutes and 
1 hour, then 1-hour sample is not needed, 
but all other time points apply. Irinotecan 
and SN-38 will be measured in the same 
sample.
Blood 
for 
Genetic 
Analyses
X
To be collected pre-dose.
Blood 
for 
RNA 
Analyses
X
X
X
X
Blood sample for RNA analysis should 
be obtained pre-dose of Cycle 1 Day 1, 
Cycle 2 Day 1, and Cycle 5 Day 1 and at 
the Treatment Discontinuation visit.
Blood for Plasma 
Biomarker Analyses
X
X
X
X
Blood sample for plasma should be 
obtained pre-dose of Cycle 1 Day 1, 
Cycle 2 Day 1, and Cycle 5 Day 1 and at 
the Treatment Discontinuation visit.
08JTB4


Product:  MK-3475 
37
Protocol/Amendment No.: 651-04
MK-3475-651-04 Final Protocol
08-Jun-2022
Confidential
Pembrolizumab in Combination with FOLFIRI (Cohort D)
Trial Period:
Screening 
Phase
Treatment Phase (3-Week Cycles)
End of Treatment
Post- Treatment
Notes
Treatment 
Cycle/Title
Screening 
(Visit 1)
1
2
3
4
5 to 35
Discon
Discon
Safety 
Follow 
Up
Follow-
up Visits
Survival 
Follow 
up
Treatment Days:
1
8
15
1
8
15
1
8
15
1
8
15
1
8
15
At time of 
Treatment 
discon
30 days
Post last 
dose
Q9W 
Post-
discon
Q12W
Scheduling 
Window (Days):
-42 
to 
-29
-28 
to 
-1
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±14
Blood for Serum 
Biomarker 
Analyses
X
X
X
X
Blood sample for serum should be 
obtained pre-dose of Cycle 1 Day 1, 
Cycle 2 Day 1, and Cycle 5 Day 1 and at 
the Treatment Discontinuation visit.
Tumor Tissue 
Collection
Archival and/or 
Newly Obtained 
Tissue Collection
X
Post-treatment 
Tumor Biopsy 
(Optional)
X
Abbreviations:  β-hCG=human chorionic gonadotropin;  CBC=complete blood count; CEA= carcinoembryonic antigen; Discon=discontinuation; dMMR= deficient mismatch 
repair; ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; FBR=future biomedical research; FOLFIRI=(irinotecan [180 mg/m2]; leucovorin [calcium 
folinate] [400 mg/m2]; 5-FU 2400 mg/m2); FT3=free triiodothyronine; FT4=free thyroxine; IV=intravenous; IHC= immunohistochemistry; MSI/MMR= microsatellite 
instability/mismatch repair; MUGA= multigated acquisition; PCR= polymerase chain reaction; PT/INR = prothrombin time/International Normalized Ratio; aPTT/PTT= activated 
prothrombin time/partial thromboplastin time; Q9W=every 9 weeks; Q12W= every 12 weeks;  RNA=ribonucleic acid; TSH=thyroid stimulating hormone.
a.
All screening laboratory tests should be performed within 10 days prior to the first dose of trial treatment.
08JTB4


Product:  MK-3475 
38
Protocol/Amendment No.: 651-04
MK-3475-651-04 Final Protocol
08-Jun-2022
Confidential
Pembrolizumab in Combination with FOLFIRI and Binimetinib (Cohort E)
Trial Period:
Screening 
Phase
Treatment Phase (3-Week Cycles)
End of Treatment
Post- Treatment
Notes
Treatment Cycle/Title
Screening 
(Visit 1)
1
2
3
4
5 to 35
Discon
Discon
Safety 
Follow 
Up
Follow-
up 
Visits
Survival 
Follow 
up
Treatment Days:
1
8
15
1
8
15
1
8
15
1
8
15
1
8
15
At time of 
Treatment 
discon
30 days
Post last 
dose
Q9W 
Post-
discon
Q12W
Scheduling Window 
(Days):
-42 
to 
-29
-28 
to 
-1
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±14
Administrative 
Procedures
Informed Consent
X
Informed Consent for 
optional post-treatment 
tumor biopsy
X
Informed Consent for 
FBR (optional)
X
Participant 
Identification Card
X
Inclusion/Exclusion 
Criteria
X
Demographics and 
Medical History
X
Cancer disease status 
and Prior Treatment 
History
X
Prior and Concomitant 
Medication Review
X
X
X
X
X
X
X
X
X
X
X
X
X
Pembrolizumab 
Administration
X
X
X
X
X
Binimetinib 
Administration
<==================X======================
To be administered BID.
FOLFIRI 
Administration
X
X
X
X
X
X
X
X
X
Efficacy Assessments
Tumor Imaging 
X
<==================X======================
X
X
Tumor imaging at screening must be 
performed within 28 days prior to the date 
of Cycle 1 Day 1. The first on-study 
imaging time point will be performed at 
9 weeks (63 days ± 7 days) calculated 
from the date of allocation. See Section 
9.2.
08JTB4


Product:  MK-3475 
39
Protocol/Amendment No.: 651-04
MK-3475-651-04 Final Protocol
08-Jun-2022
Confidential
Pembrolizumab in Combination with FOLFIRI and Binimetinib (Cohort E)
Trial Period:
Screening 
Phase
Treatment Phase (3-Week Cycles)
End of Treatment
End of 
Treatment
Post- Treatment
Notes
Treatment Cycle/Title
Screening 
(Visit 1)
1
2
3
4
5 to 35
Discon
Discon
Safety 
Follow 
Up
Follow-
up 
Visits
Survival 
Follow 
up
Treatment Days:
1
8
15
1
8
15
1
8
15
1
8
15
1
8
15
At time of 
Treatment 
discon
30 
days
Post 
last 
dose
Q9W 
Post-
discon
Q12W
Scheduling Window 
(Days):
-42 
to 
-29
-28 
to 
-1
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±14
Clinical 
Procedures/Assessments
Review adverse events
X
<===========X=============
X
X
X
Full Physical Examination
X
X
Full Ophthalmic 
Examination (Q8W)
X
X
<===========X=============
X
To be performed at screening, 
Cycle 2 Day 1 and then every 8 
weeks (±7 days) from Cycle 2 Day 
1 and EOT. An ophthalmic 
examination at the 30-day follow 
up is only required if there was a 
clinically significant abnormality 
noted at EOT (±7 days)
Directed Physical 
Examination
X
X
X
X
X
X
X
X
X
X
Height, Weight, and Vital 
Signs
X
X
X
X
X
X
X
X
X
X
X
X
Height will be measured at Visit 1 
only.  
12-Lead Electrocardiogram
X
X
X
X
X
X
X
ECG 
will 
be 
performed 
in 
triplicate to confirm QTc interval
at 
screening.
ECG 
will 
be 
performed predose starting at 
Cycle 2 Day 1.
Echocardiogram/MUGA 
scan (Q12W)
X
X
<======X===
X
ECHO/MUGA scans are to be 
performed at Screening, and pre-
dose on Cycle 2 Day 1 and Cycle 
5 Day 1, then every 12 weeks and 
EOT.  
ECOG Performance Status
X
X
X
X
X
X
X
ECOG Performance Status at 
Screening to be assessed within 7 
days prior to the first dose of trial 
treatment.  
Post-Study Anticancer 
Therapy Status
X
X
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Pembrolizumab in Combination with FOLFIRI and Binimetinib (Cohort E)
Trial Period:
Screening 
Phase
Treatment Phase (3-Week Cycles)
End of Treatment
Post- Treatment
Notes
Treatment 
Cycle/Title
Screening (Visit 
1)
1
2
3
4
5 to 35
Discon
Discon
Safety 
Follow 
Up
Follow-
up Visits
Survival 
Follow 
up
Treatment Days:
1
8
15
1
8
15
1
8
15
1
8
15
1
8
15
At time of 
Treatment 
discon
30 days
Post last 
dose
Q9W 
Post-
discon
Q12W
Scheduling 
Window (Days):
-42 
to 
-29
-28 to -1
±
3
±
3
±
3
±
3
±
3
±
3
±
3
±
3
±
3
±
3
±
3
±
3
±
3
±
3
±
3
±
7
±
7
±
14
Survival Status
=============================X================================X
After investigator determined PD or 
start of new anticancer treatment. In 
addition, upon Sponsor request, 
participants may be contacted for 
survival status at any time during the 
course of the study.
Local Laboratory 
Assessments
MSI/MMR Status
X
If tumor testing is obtained by both 
PCR and IHC, the tumor result should 
be neither MSI-H by PCR nor dMMR 
by IHC to identify the non-MSI-H 
participants.
Pregnancy 
Test-
Urine or Serum β-
HCG
X
X
Pregnancy tests may be performed if 
clinically warranted, or as defined by 
local regulations.
PT/INR and aPTT
X
CBC 
with 
Differentiala
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry Panela
X
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysisa
X
X
X
X
X
X
To be performed at screening, and 
every other cycle starting at Cycle 2
Day 1.
T3 or FT3, FT4, 
and TSH
X
X
X
X
X
X
To be performed at Screening, and 
every other cycle starting at Cycle 2
Day 1.
Serum 
Tumor 
Marker
<==============X==============>
X
X
Serum tumor marker (CEA) to be 
collected Q3W.
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Pembrolizumab in Combination with FOLFIRI and Binimetinib (Cohort E)
Trial Period:
Screening 
Phase
Treatment Phase (3-Week Cycles)
End of Treatment
Post- Treatment
Notes
Treatment 
Cycle/Title
Screening 
(Visit 1)
1
2
3
4
5 to 35
Discon
Discon
Safety 
Follow 
Up
Follow-
up 
Visits
Survival 
Follow 
up
Treatment 
Days:
1
8
15
1
8
15
1
8
15
1
8
15
1
8
15
At time of 
Treatment 
discon
30 
days
Post 
last 
dose
Q9W 
Post-
discon
Q12W
Scheduling 
Window (Days):
-42 
to 
-29
-28 
to 
-1
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±14
Laboratory 
Procedures: 
Performed by 
Central 
Laboratory
Binimetinib 
Pharmacokinetics
X
PK samples will be collected at time 0 (pre-dose), 
0.5, 1, 1.5, 2, 4, 6 hrs (all ±10 min) on Day 15, pre-
dose (24 ± 2 hrs from the first binimetinib PK 
collection) on Day 16 and pre-dose (48 ± 2 hrs 
from the first binimetinib PK collection) on Day 
17 at Cycle 1. The exact time of sample collection 
and time of administration of binimetinib will be 
recorded.  Only 1 sample is collected at each time 
point to measure concentrations of binimetinib, 
irinotecan and SN-38.
Irinotecan and 
SN-38 
Pharmacokinetics
X
Serial plasma samples for irinotecan and its 
active metabolite (SN-38) will be collected 
before (pre-infusion), the end of infusion, 1, 
1.5, 2, 4, 6 (all ±10 min), 24 ± 2 hrs and 48 ± 
2 hrs after the initiation of infusion. If 
irinotecan infusion time is between 45 min 
and 1 hour, then 1-hour sample is not needed, 
but all other time points apply. Irinotecan and 
SN-38 will be measured in the same sample.  
Blood for 
Genetic Analyses
X
To be collected pre-dose.
Blood for RNA 
Analyses
X
X
X
X
Blood sample for RNA analysis should be 
obtained pre-dose of Cycle 1 Day 1, Cycle 2 
Day 1, and Cycle 5 Day 1 and at the 
Treatment Discontinuation visit.
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Trial Period:
Screening 
Phase
Treatment Phase (3-Week Cycles)
End of Treatment
Post- Treatment
Notes
Treatment 
Cycle/Title
Screening 
(Visit 1)
1
2
3
4
5 to 35
Discon
Discon
Safety 
Follow 
Up
Follow-
up 
Visits
Survival 
Follow 
up
Treatment 
Days:
1
8
15
1
8
15
1
8
15
1
8
15
1
8
15
At time of 
Treatment 
discon
30 
days
Post 
last 
dose
Q9W 
Post-
discon
Q12W
Scheduling 
Window (Days):
-42 
to 
-29
-28 
to 
-1
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±14
Blood for Plasma 
Biomarker 
Analyses
X
X
X
X
Blood sample for plasma should be obtained 
pre-dose of Cycle 1 Day 1, Cycle 2 Day 1, 
and Cycle 5 Day 1 and at the Treatment 
Discontinuation visit.
Blood for Serum 
Biomarker 
Analyses
X
X
X
X
Blood sample for serum should be obtained 
pre-dose of Cycle 1 Day 1, Cycle 2 Day 1, 
and Cycle 5 Day 1 and at the Treatment 
Discontinuation visit.
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Pembrolizumab in Combination with FOLFIRI and Binimetinib (Cohort E)
Trial Period:
Screening 
Phase
Treatment Phase (3-Week Cycles)
End of Treatment
Post- Treatment
Notes
Treatment 
Cycle/Title
Screening 
(Visit 1)
1
2
3
4
5 to 35
Discon
Discon
Safety 
Follow 
Up
Follow-
up 
Visits
Survival 
Follow 
up
Treatment 
Days:
1
8
15
1
8
15
1
8
15
1
8
15
1
8
15
At time of 
Treatment 
discon
30 days
Post 
last 
dose
Q9W 
Post-
discon
Q12W
Scheduling 
Window (Days):
-42 
to 
-29
-28 
to 
-1
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±14
Tumor Tissue 
Collection
Archival and/or 
Newly Obtained 
Tissue Collection
X
Post-treatment 
Tumor Biopsy 
(Optional)
X
Abbreviations:  aPTT/PTT= activated prothrombin time/partial thromboplastin time; β-hCG=human chorionic gonadotropin; BID=twice daily; CBC=complete blood count; CEA= carcinoembryonic 
antigen; Discon=discontinuation; dMMR= deficient mismatch repair; ECG=electrocardiogram; ECHO=echocardiogram; ECOG=Eastern Cooperative Oncology Group; EOT= end of trial; FBR=future 
biomedical research; FOLFIRI=(irinotecan [180 mg/m2]; leucovorin [calcium folinate] [400 mg/m2]; 5-FU 2400 mg/m2); FT3=free triiodothyronine; FT4=free thyroxine; IHC= immunohistochemistry; 
IV=intravenous; MSI/MMR= microsatellite instability/mismatch repair; MUGA= multigated acquisition; PCR= polymerase chain reaction; PT/INR = prothrombin time/International Normalized Ratio; 
Q8W=every 8 weeks; Q9W=every 9 weeks; Q12W= every 12 weeks; QTc =Q-T interval; RNA=ribonucleic acid; TSH=thyroid stimulating hormone.
a.
All screening laboratory tests should be performed within 10 days prior to the first dose of trial treatment.
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3. Introduction
Metastatic colorectal cancer continues to be a serious, life-threatening condition. In the US, it 
is the fourth most common type of cancer with approximately 130,000 new cases projected 
in 2015, and it is the second leading cause of cancer mortality with nearly 50,000 projected 
deaths in 2015 [Siegel, R. L., et al 2015]. Standard therapy in patients with unresectable 
mCRC includes combination regimens with cytotoxic and targeted agents. 
Despite recent advances, the intent of treatment for most of mCRC participants is palliative 
with few patients achieving long-term survival (5-year survival rate of 13.5%) [Centers for 
Disease Control and Prevention 2015]. Current SOC treatments for mCRC in the early-line 
setting include chemotherapy based on fluoropyrimidine, oxaliplatin, and irinotecan used in 
combination or sequentially, with option for monoclonal antibodies targeting VEGF (eg,
bevacizumab, ziv-aflibercept) or its receptors (eg, ramucirumab) and in patients with Ras 
wild-type tumors, monoclonal antibodies targeting the EGF receptor (eg, cetuximab, 
panitumumab). Although the ORR reported in early line studies ranged from 31% to 60%, 
the DOR was limited (7.1 - 10.4 months) [Comella, P., et al 2009] [Diaz-Rubio, E., et al 
2007] [Ducreux, M., et al 2011] [Porschen, R., et al 2007] [National Comprehensive Cancer 
Network 2015] [Colucci, G., et al 2005] [Tournigand, C., et al 2004] [Douillard, J. Y., et al 
2010] [Hurwitz, H., et al 2004] [Van Cutsem, E., et al 2015] [Heinemann, V., et al 2014].  
Ultimately, nearly all patients will require salvage therapies which have limited clinical 
benefit coupled with high toxicity. The ORR in the 2L setting for combination regimens 
(fluoropyrimidine plus oxaliplatin or irinotecan +/- anti-VEGF or anti-EGFR) is less than 
23% while durations of benefit are limited (median PFS ≤7 months) [Van Cutsem, E., et al 
2012] [Bennouna, J., et al 2013] [Tabernero, J., et al 2015] [Giantonio, B. J., et al 2007] 
[Iwamoto, S., et al 2015] [Masi, G., et al 2015] [Rothenberg, M. L., et al 2008].  
Treatment options for heavily pre-treated patients beyond the 2L setting are limited and 
associated toxicities can be severe. Although regorafenib and TAS-102 are the 2 commonly 
accepted SOC therapies for patients who have been treated with fluoropyrimidine-, 
irinotecan-, oxaliplatin-containing chemotherapies, anti-VEGF and an anti-EGFR agent (if 
KRAS wild-type) offer minimal benefits as ORR is ≤2% for both agents [Grothey, A., et al
2013] [U.S. Prescribing Information 2012]. Minimal durability of clinical benefit is 
evidenced by a 6-month PFS rate of ~15%.  Clearly, there is a high unmet medical need in 
developing novel combination regimens to improve the clinical outcome for patients with 
mCRC.  
Study Rationale 
Rationale for the Trial and Selected Participant Population 
Pembrolizumab and other anti- PD1 agents produced durable clinical benefit in patients with 
mCRC with the dMMR/MSI-H phenotype [Le, D. T., et al 2015]. In the heavily treated 
mCRC setting, pembrolizumab produced high ORR as well as evidence for durable clinical 
benefit [Le, D. T., et al 2015]. However, anti-cancer activity in the CRC population has been 
limited to cancers with the dMMR/MSI-H phenotype, which represents a minority (~5%) of 
the Stage IV mCRC population.  
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Given that approximately 95% of mCRC patients have tumors that are non-microsatellite 
instability high (non-MSI-H/ pMMR), there is a need to develop combination regimens that 
would provide durable clinical benefit of immunotherapy such as pembrolizumab. While 
high response rates are reported in previously untreated mCRC population with current 
standard therapies, durability of clinical benefit is limited. Further, prognosis is poor when 
patients experience progression of disease after the initial treatment with combination 
chemotherapy. Given that durable clinical benefit is the hallmark of pembrolizumab 
demonstrated in multiple tumor types, addressing resistance to pembrolizumab in non-MSI-H 
population could improve the clinical outlook. 
Emerging data suggest that combining PD1/PD-L1 inhibitors with other agents might 
sensitize tumors to immunotherapy and/or provide additive efficacy [Weinstock, M. 2015] 
[Bever, K. M. 2017].  Consequently, this trial is designed to assess safety, tolerability, PK, 
and explore preliminary efficacy in the following combinations in participants with non MSI-
H/pMMR mCRC:

Cohort A: Pembrolizumab in combination with binimetinib in mCRC participants 
previously treated with fluoropyrimidine, irinotecan, and oxaliplatin

Cohort B: Pembrolizumab in combination with mFOLFOX7 in previously untreated 
mCRC participants

Cohort C: Pembrolizumab in combination with mFOLFOX7 and binimetinib in 
previously untreated mCRC participants

Cohort D: Pembrolizumab in combination with FOLFIRI in mCRC participants 
previously treated with one line of a fluoropyrimidine plus oxaliplatin-based regimen

Cohort E: Pembrolizumab in combination with FOLFIRI and binimetinib in mCRC 
participants previously treated with one line of a fluoropyrimidine plus oxaliplatin-based 
regimen
Rationale for Cohort A: Pembrolizumab in Combination with Binimetinib in 
Previously-treated non-MSI-H/pMMR mCRC Population 
Preclinical data show that the combination of a MEK inhibitor and an anti-PD1 agent results 
in superior tumor growth inhibition relative to anti-PD1 or MEK inhibitor alone [Morrissey, 
K. M., et al 2016] [Vella, L. J., et al 2014].  Recently, published data suggest that combining 
a MEK inhibitor with an anti-PD1 agent can produce anti-tumor responses in non-MSI-H 
mCRC patients [Bendell, J. C., et al 2016]. 
The proposed mechanisms are:

MEK inhibition increases the number of active immune cells (eg, CD8+ cells) in the 
tumor.

MEK inhibition reduces the expression of immune suppressive factors in the tumor 
microenvironment.

MEK inhibition results in tumor cell killing leading to release of tumor antigen.
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Recent clinical data supporting this hypothesis were presented at the ASCO meeting in 2016 
[Bendell, J. C., et al 2016]. Atezolizumab (a PD-L1 inhibitor) in combination with 
cobimetinib (a MEK inhibitor) produced a 17% ORR (N=23) with evidence of durable 
clinical benefit, 6-month PFS of 35%, and 6-month OS of 72% in heavily treated non-MSI-H 
mCRC [Bendell, J. C., et al 2016]. These data suggest possible synergy between 2 agents 
since MEK inhibitors (eg, cobimetinib, AZD6244, RO49887655, binimetinib) have shown 
0% ORR in mCRC clinical trials and 0% ORR was reported with pembrolizumab [Le, D. T., 
et al 2016] and nivolumab [Overman, M. J., et al 2016] in non-MSI-H mCRC population. A 
correlative study suggested the proposed mechanism to be an increase in the number of 
intratumoral CD8+ T-cell infiltration and major histocompatibility complex 1 (MHC1) 
expression with cobimetinib [Bendell, J. C., et al 2016]. 
In the previously described Phase 1 dose escalating trial of atezolizumab and cobimetinib and 
in mCRC [Bendell, J. C., et al 2016], no dose-limiting toxicities were observed, and 
expansion occurred at atezolizumab 800 mg Q2W and cobimetinib 60 mg. Median follow-up 
for safety in CRC patients was 3.78 months (range, 1.1-11.7). The most common treatment-
related AEs included diarrhea (69.6%), fatigue (52.2%), dermatitis acneiform (43.5%), rash 
(34.8%), maculopapular rash (26.1%), pruritus (26.1%) and nausea (26.1%). Incidence of 
treatment-related Grade 3-4 AEs was 34.8%. The only treatment-related Grade 3-4 AE in ≥ 2 
patients was diarrhea (8.7%). No Grade 5 AEs were reported.
In summary, preclinical and clinical data suggest that addition of binimetinib may enable 
non-MSI-H/pMMR mCRC to be susceptible to pembrolizumab.
Rationale for Cohorts B and C: Combination of Pembrolizumab plus
mFOLFOX7 With and Without Binimetinib in Previously Untreated Metastatic 
non MSI-H/pMMR mCRC Population
There is accumulating evidence demonstrating that chemotherapy agents including 5-FU and 
oxaliplatin that are commonly used to treat CRC may modulate the intrinsic immunogenicity 
of tumor and sensitize tumors to immunotherapy agents [Pfirschke, C., et al 2016] [Zhou, J., 
et al 2017]. Preclinical and clinical evidence suggest that conventional chemotherapies 
reactivate antitumor immune responses by increasing immunogenic cell death and antigen 
release, and/or by inhibiting immunosuppressive factors in the tumor microenvironment 
[Emens, L. A. 2015] [Galluzzi, L., et al 2015] [Vincent, J., et al 2010]. Further, 
chemotherapies can enhance tumor antigen presentation by upregulating the expression of 
tumor TCR themselves, or of the MHC1 molecules to which the TCRs bind [Emens, L. A. 
2015]. 
Although there are multiple therapeutic options for untreated patients with CRC, the majority 
of patients still experience disease progression and/or succumb to the disease in less than a 
year and there are few long term survivors.  As discussed below, a substantial body of 
scientific evidence has emerged to suggest that the efficacy of immunotherapy can be 
enhanced by chemotherapy such as fluorouracil (5-FU) and oxaliplatin. While KEYNOTE-
651 (KN651) will investigate the combination of pembrolizumab and mFOLFOX7 in 
untreated CRC patients, both safety and efficacy will be carefully monitored, with a pre-
defined efficacy futility criterion to ensure that expected efficacy in untreated patients is no 
worse than what would be expected with mFOLFOX7 alone.
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Recently, preclinical and clinical evidence suggest that conventional chemotherapies 
reactivate antitumor immune responses by increasing immunogenic cell death and antigen 
release, and/or by inhibiting immunosuppressive factors in tumor microenvironment [Emens, 
L. A. 2015] [Galluzzi, L., et al 2015] [Vincent, J., et al 2010]. As such, chemotherapy agents 
may modulate the intrinsic immunogenicity of tumor and sensitize tumors to immunotherapy 
agents by upregulating the expression of tumor TCR or the MHC1 molecules, and 
subsequently enhancing tumor antigen presentation to CD8+ T cells [Emens, L. A. 2015]. 
For example, 5-FU can increase the frequency of TIL including CTLs, upregulate MHC1 on 
cancer cells and decrease immunosuppressive myeloid derived suppressor cells [Apetoh, L., 
et al 2015], while oxaliplatin can increase immunogenicity of cancer cells and induce 
immunogenic cell death [Tesniere, A., et al 2010]. Indeed, FOLFOX plus bevacizumab 
combined with atezolizumab demonstrated an acceptable safety profile and promising 
activity (ORR, 52%; median PFS, 14.1 months; DOR, 11.4 months) [Wallin, J., et al 2016]. 
This study clearly demonstrated increase of PD-L1 expression, enhanced intra tumoral 
infiltration CD8+ of T cells, and upregulation of immune gene signature in tumor by use of 
FOLFOX alone or in combination with atezolizumab [Wallin, J., et al 2016]. Further, there 
was an association between an increase in immune gene signature and durability of clinical 
benefit. Results from several clinical trials have demonstrated that chemotherapies can be 
safely combined with anti- PD1/PD-L1 agents with promising anti-cancer activity [Reck, M., 
et al 2016] [Langer, C. J., et al 2016] [Wallin, J., et al 2016].
An investigator-initiated, Phase II study (NCT02375672) was designed to evaluate the 
combination of pembrolizumab 200 mg intravenous (IV) every 3 weeks (Q3W) and 
mFOLFOX6 in advanced untreated CRC patients.  Updated data were presented at ASCO 
2017 (data cutoff date of 01-MAY-2017). While this study utilizes mFOLFOX6, which is 
known to induce neutropenia in approximately 40% to 45% and neutropenic fever in 
approximately 2% to 5% of patients [Douillard, J. Y., et al 2010] [Cassidy, J., et al 2011], the 
dose limiting toxicity definition did not have provision for this known chemotherapy-related 
toxicity the in the protocol.  During the run-in phase for the safety cohort of 6 patients, 
because 2 reported events of febrile neutropenia, the institutional Data Safety Monitoring 
Committee recommended dose reduction of mFOLFOX6 as per protocol. The study 
successfully completed enrolling an additional 24 patients who were treated with 
pembrolizumab 200 mg Q3W and dose reduced mFOLFOX6 with oxaliplatin 65 mg/m2 IV, 
leucovorin 400 mg/m2 IV, 5-FU 320 mg/m2 IV bolus, then 5-FU 1920 mg/m2 IV over 46 
hours.  At the median follow up of 34 weeks, the best objective response rate for the 30 
patients was 40% (n = 30) and median PFS was 16.9 months, which appears promising in 
comparison with reported ORR of 46% and median PFS of 9.3 months for FOLFOX6 in 
untreated patients [Ducreux, M., et al 2011].
Results from several clinical trials have demonstrated that chemotherapies can be safely 
combined with PD-L1 agents and demonstrated promising anti-cancer activity [Reck, M., et 
al 2016] [Langer, C. J., et al 2016] [Wallin, J., et al 2016]. Various chemotherapies including 
pemetrexed and platinum were combined with pembrolizumab in NSCLC and produced 
promising activity in the previously untreated NSCLC population [Reck, M., et al 2016]. In 
KN-021, addition of pembrolizumab to carboplatin and pemetrexed showed superior PFS 
outcomes to carboplatin and pemetrexed without pembrolizumab (HR, 0.53; p=0.01) 
[Langer, C. J., et al 2016].  On the other hand, FOLFOX plus bevacizumab was combined 
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with atezolizumab and demonstrated an acceptable safety profile and promising activity 
(ORR, 52%; median PFS, 14.1 months; DOR, 11.4 months) [Wallin, J., et al 2016]. In this 
study, there was a clear demonstration of increase of PD-L1 expression, enhanced intra 
tumoral infiltration of CD8+ T cells, and upregulation of an immune gene signature in tumor 
by use of FOLFOX alone or in combination with atezolizumab [Wallin, J., et al 2016]. 
Further, there was an association between an increase in immune gene signature and 
durability of clinical benefit. 
In summary, accumulating evidence suggest that chemotherapies, including agents used in 
mCRC population, may be combined with pembrolizumab and improve efficacy in IL
treatment of mCRC. Together with the encouraging data from atezolizumab/cobimetinib 
mCRC study, adding MEK inhibitor binimetinib to pembrolizumab/mFOLFOX7 may further
enhance patient outcomes in this setting without added toxicity. While safety will be 
carefully monitored in the study, a futility analysis will be conducted to ensure that expected 
efficacy in untreated patients is no worse than that expected with mFOLFOX7 treatment 
alone.  
Rationale for Cohorts D and E: Combination of Pembrolizumab plus FOLFIRI
With and Without Binimetinib in Previously-treated non MSI-H/pMMR mCRC 
Population
As previously discussed in Section 3.1.2, there is accumulating evidence demonstrating that 
chemotherapy agents including 5-FU and oxaliplatin that are commonly used to treat CRC 
may modulate the intrinsic immunogenicity of tumor and sensitize tumors to immunotherapy 
agents [Pfirschke, C., et al 2016] [Zhou, J., et al 2017]. Although evidence of similar 
immune-modulating effect and synergy from clinical studies is scant for irinotecan, FOLFIRI 
may potentially sensitize tumors to checkpoint inhibitors that its combination with anti-PD-1 
warrants study in 2L treatment of mCRC because FOLFIRI is a commonly used regimen in 
this setting. A study involving 27 patients with mCRC who received FOLFOX (n=17) or 
FOLFIRI (n=10) showed that the percentage and the number of CD4(+)FoxP3(+) T-regs 
were significantly reduced after FOLFOX and FOLFIRI in the patients who had high levels 
of T-regs before chemotherapy, suggesting FOLFOX and FOLFIRI may enhance antitumor 
immunity via suppression of T-regs [Maeda, K., et al 2011]. On the other hand, the total 
number of lymphocytes and the population of CD4(+) T lymphocytes were unchanged. As 
discussed above in Section 3.1.2, the addition of binimetinib may sensitize non-MSI-H CRC 
to pembrolizumab. Therefore, the combination of FOLFIRI plus binimetinib may further 
change tumor microenvironment favorably for immunotherapy and sensitize non MSI-H 
CRC to pembrolizumab.
A Phase Ib study, PembroPlus, was one of the first reported multi-arm systemic 
chemotherapy study in combination with PD-1 inhibitors across diverse advanced solid 
tumors. Twelve patients (2 small-cell lung cancer, 8 NSCLC, 1 CRC, 1 gastric cancer) were 
treated with pembrolizumab 2 mg/kg and irinotecan 300 mg/m2 Q3W. The only mCRC 
patient enrolled in this arm had PD. Overall this combination were associated with Grade 1-2 
fatigue (41.7%), diarrhea (75%), nausea (75%), vomiting (33.3%), rash not otherwise 
specified (25%), and anorexia (25%), and Grade 3-4 neutropenia (25%). Immune-related 
adverse events (likely or definitely related) were reported in 33.3% of patients treated with 
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this combination. A Grade 3 rash and papilloedema was a DLT and led to a dose reduction
[Weiss, G. J., et al 2017].
Background
Pembrolizumab is a potent humanized IgG4 mAb with high specificity of binding to the 
programmed cell death 1 (PD-1) receptor, thus inhibiting its interaction with PD-L1 and 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 IV immunotherapy for advanced malignancies. Keytruda®
(pembrolizumab) is indicated for the treatment of patients across a number of indications 
because of its mechanism of action to bind the PD-1 receptor on the T cell. Refer to the 
pembrolizumab 
IB/approved 
labeling
for 
detailed 
background 
information 
on 
pembrolizumab.  Refer to the binimetinib IB for detailed background information on 
binimetinib. Also refer to the respective approved labeling for detailed background 
information on SOC chemotherapies.
Pharmaceutical and Therapeutic Background
Pembrolizumab Background
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades [Disis, M. L. 2010].  Accumulating evidence 
shows a correlation between tumor-infiltrating lymphocytes in cancer tissue and favorable 
prognosis in various malignancies.  In particular, the presence of CD8+ T-cells and the ratio 
of CD8+ effector T-cells/FoxP3+ T-regs correlates with improved prognosis and long-term 
survival in solid malignancies, such as ovarian, colorectal, pancreatic cancer, hepatocellular 
carcinoma, malignant melanoma, and renal cell carcinoma.  Tumor-infiltrating lymphocytes 
can be expanded ex vivo and reinfused, inducing durable objective tumor responses in 
cancers such as melanoma [Dudley, M. E., et al 2005] [Hunder, N. N., et al 2008].
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 
immunoglobulin superfamily member related to cluster of differentiation 28 (CD28) and 
CTLA-4 that has been shown to negatively regulate antigen receptor signaling upon 
engagement of its ligands (PD-L1 and/or PD-L2) [Greenwald, R. J., et al 2005] [Okazaki, T., 
et al 2001].
The structure of murine PD-1 has been resolved [Zhang, X., et al 2004].  Programmed death 
1 and its family members are type 1 transmembrane glycoproteins containing an Ig variable–
type domain responsible for ligand binding and a cytoplasmic tail responsible for the binding 
of signaling molecules.  The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling 
motifs, an immunoreceptor tyrosine-based inhibition motif, and an immunoreceptor tyrosine-
based switch motif.  Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases, 
SHP-1 and SHP-2, to the immunoreceptor tyrosine-based switch 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 
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[Chemnitz, J. M., et al 2004] [Sheppard, K-A, et al 2004] [Riley, J. L. 2009] [Okazaki, T., et 
al 2001].  The mechanism by which PD-1 down-modulates T-cell responses is similar to, but 
distinct from, that of CTLA-4, because both molecules regulate an overlapping set of 
signaling proteins [Parry, R. V., et al 2005] [Francisco, L. M., et al 2010].  
Pembrolizumab Pre-clinical Studies
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 monotherapy or in combination with other treatment 
modalities.  Anti-mouse PD-1 or anti-mouse PD-L1 antibodies have demonstrated antitumor 
responses as a monotherapy in models of squamous cell carcinoma, pancreatic carcinoma, 
melanoma, and colorectal carcinoma [Nomi, T., et al 2007] [Blank, C. and Mackensen, A. 
2007] [Iwai, Y., et al 2002] [Pölcher, M., et al 2010] [Korman, A., et al 2007].  Blockade of 
the PD-1 pathway effectively promoted CD8+ T-cell infiltration into the tumor and the 
presence of interferon gamma, granzyme B, and perforin, indicating that the mechanism of 
action involved local infiltration and activation of effector T-cell function in vivo [Ropponen, 
K. M., et al 1997].  Experiments have confirmed the in vivo efficacy of PD-1 blockade as a 
monotherapy as well as in combination with chemotherapy in syngeneic mouse tumor 
models (see the current version of the IB for further details).
Pembrolizumab Clinical Trials
Clinical trials have demonstrated efficacy in patients with metastatic melanoma, metastatic 
NSCLC, metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%), recurrent or 
metastatic HNSCC, bladder cancer, refractory classical Hodgkin lymphoma, and other tumor 
types.  
Pembrolizumab is an immunomodulatory agent, and based on this mechanism of action, 
immune-mediated AEs are of primary concern. The important identified AEs for 
pembrolizumab are of an immune-mediated nature, and are: pneumonitis; colitis; hepatitis; 
nephritis; endocrinopathies that include hypophysitis, thyroid disorder, and Type I diabetes 
mellitus; uveitis; myositis; Guillain-Barré syndrome; pancreatitis; myocarditis; myasthenic 
syndrome; severe skin reactions including Stevens-Johnson syndrome and toxic epidermal 
necrolysis, some with fatal outcome; encephalitis, sarcoidosis, and “solid organ transplant 
rejection following pembrolizumab treatment in donor organ recipients”.  The majority of
immune-mediated AEs were mild to moderate in severity, manageable with appropriate
care, and rarely required discontinuation of therapy (see the current version of the IB for 
further details).
Based on safety data of pembrolizumab evaluated in 2799 patients in controlled and 
uncontrolled studies, the 5 most frequently reported AEs considered drug related by the 
investigator were fatigue, pruritus, rash, diarrhea, and nausea (see the current version of the 
IB for further details).
Pembrolizumab Ongoing Clinical Trials
Ongoing clinical trials with pembrolizumab are being conducted in multiple solid tumors. In 
addition, multiple combinations with pembrolizumab are also being investigated. 
Furthermore, there are several ongoing trials to investigate activity of pembrolizumab as 
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monotherapy and in combination with other agents in patients with mCRC.  For trial details 
please refer to the current version of the IB.
Binimetinib Background
Binimetinib (also known as MEK162 or ARRY-438162) is a potent and selective allosteric, 
ATP-uncompetitive inhibitor of MEK1/2 that is active in inhibiting pERK and growth of 
BRAF-mutant cancer cells in the low nanomolar range. In oncology settings, binimetinib is 
currently being investigated both as a single agent and in combination with RAF or PI3K or 
inhibitors in patients with selected advanced or metastatic solid tumors, including biliary 
cancer, CRC, and melanoma.
Binimetinib Pre-clinical Studies
Acute, subchronic, chronic and reproductive toxicity, genotoxicity, and phototoxicity studies 
were completed in rats and monkeys to support the chronic administration of binimetinib to 
adult patients. There was no evidence of a genotoxic potential in vitro or in vivo. The adverse 
effects of MEK inhibitors in humans are similar to those observed in rats and monkeys, with 
the exception of ocular findings. These adverse effects include gastro-intestinal intolerance 
and diarrhea, rash (skin findings in rats only), retinal events (only seen in humans) and RVO 
(rarely seen in humans). In vitro and in vivo phototoxicity studies conducted in mice indicate 
that binimetinib has a low risk of weak phototoxic potential at therapeutic doses. 
Furthermore, there has been no evidence of phototoxicity or photosensitivity in humans 
being treated with binimetinib for cancer or for rheumatoid arthritis. 
Given the embryo-lethal effects seen in rats and rabbits and the teratogenic effects seen in 
rabbits, binimetinib should not be used in pregnant women. Women of child-bearing 
potential must be advised to use highly effective contraception methods.
For further details, please refer to the current binimetinib IB.
Binimetinib Clinical Studies
As of 20-JAN-2017, a total of 2750 healthy participants and patients have received at least 
1 dose of binimetinib and are therefore eligible for inclusion in the overall safety population 
of binimetinib, which comprises 229 healthy participants, 164 patients with rheumatoid 
arthritis, 17 patients with hepatic dysfunction, 6 participants with renal dysfunction and 2334 
patients with advanced cancer. Binimetinib demonstrated benefit over SOC agents in 
advanced melanoma as monotherapy as well as in combination with BRAF inhibitor
[Ascierto, P. A., et al 2016] [Dummer, R., et al 2016] [Dummer, R., et al 2017]. The 
binimetinib clinical development program also includes ongoing trials in patients with 
mCRC including a Phase I trial investigating binimetinib in combination with mFOLFOX7 
and a Phase I trial investigating binimetinib in combination with FOLFIRI.
In a Phase I dose-escalation study of oral binimetinib in patients with advanced solid tumors, 
common AEs (all grades) included combined rash, nausea, vomiting, diarrhea, peripheral 
edema, and fatigue. Ocular events were reported in 19% of patients. Most patients 
experienced Grade 2 (41%) or Grade 3 (49%) events. The most common Grade 3 events 
included anemia (11%), and abdominal pain and dehydration (4% each). Grade 4 AEs were 
reported for 6% of patients; those that occurred in at least 2 patients included anemia (3%). 
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There were no Grade 5 events. Laboratory abnormalities included increases in CPK and liver 
function tests [Bendell, J. C., et al 2017]. Of note, rash, ocular events, gastrointestinal events, 
increased CK, and edema are known class effects of MEK inhibitors [Larkin, J., et al 2014] 
[Bennouna, J., et al 2011] [Infante, J. R., et al 2012].
A Phase I trial was conducted to combine binimetinib and mFOLFOX7 in previously treated 
mCRC patients was recently presented [Thet Cho, M., et al 2016]. The study demonstrated 
that addition of 30 mg BID or 45 mg BID binimetinib was well tolerated without DLT in 
heavily treated mCRC participants; Treatment-related ≥ Grade 3 toxicities included 
anaphylaxis due to oxaliplatin (n=1), CPK elevation (n=2), neutropenia (n=1), peripheral 
neuropathy (n=3), thrombocytopenia (n=1), retinal vascular disorder (n=1), and acneiform 
rash (n=1). The combination showed promise in this heavily pretreated population who had 
been exposed to mFOLFOX7 before as 10/16 participants achieved stable disease at 
2 months, 5 of whom with stabilizations of > 4 months (4-10 months). Similarly, there is an 
ongoing study where FOLFIRI is being combined with binimetinib; while study data are not 
yet mature [ClinicalTrials.gov 2017].
For further details, please refer to the current binimetinib IB.
FOLFOX as First Line Therapy 
FOLFOX have been established as SOC 1L and 2L chemotherapy options for mCRC;
however, FOLFOX is more frequently used in the 1L setting.  Oxaliplatin combined with 
infusional 5-FU and leucovorin administered Q2W (FOLFOX) has been shown to be 
effective [Tournigand, C., et al 2004] and the mFOLFOX7 regimen is considered one of the 
SOC regimens for 1L treatment of mCRC [National Comprehensive Cancer Network 2017]. 
The most common AE overall was PSN (76.0%), followed by fatigue (70.9%), nausea 
(63.7%), diarrhea (53.6%), constipation (39.7%), and vomiting (31.3%); other AEs occurred 
in <30% of subjects. The most common SAE was neutropenia (16.7%), PSN (11.1%), 
diarrhea (8.3%), lymphopenia (2.8%), hypertension (2.8%), vomiting (2.8%), and fatigue 
(2.8%) [Hochster, H. S., et al 2014]. Neutropenia/neutropenic fever is a known toxicity 
associated with mFOLFOX6 chemotherapy and may be related to the 5-FU bolus for this 
regimen, which is known to be associated with myelosuppression. Hochster et al. reported 
18.2% Grade 3/4 neutropenia with mFOLFOX7 (without 5-FU bolus), while FOLFOX 
regimens that contain 5-FU bolus reported significantly higher frequency of approximately 
44% to 47% [Hochster, H. S., et al 2014] [Cassidy, J., et al 2011] [Douillard, J. Y., et al 
2010].  For this reason in KN651, Sponsor elected to use the mFOLFOX7 regimen, which 
lacks a 5-FU bolus and is associated with less neutropenia than mFOLFOX6.  
FOLFIRI as Second Line Therapy
FOLFIRI have been established as SOC 1L and 2L chemotherapy options for mCRC.  
However, FOLFIRI is more frequently used in the 2L setting after oxaliplatin-based 1L
therapies. Irinotecan combined with infusional 5-FU and leucovorin administered Q2W 
(FOLFIRI) has been shown to be more effective than when irinotecan is combined with bolus 
5-FU [Fuchs, C. S., et al 2007]. The regimen is considered one of the SOC regimens in 2L
mCRC [National Comprehensive Cancer Network 2017] and has also been shown to be 
effective in previously untreated patients [Bekaii-Saab, T. 2014]. For example, in the 
randomized Phase II/III FIRIS study comparing FOLFIRI vs irinotecan/S-1 (IRIS) in 2L
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treatment of mCRC, FOLFIRI was associated with ORR of 16.7% and median PFS of 5.1 
months. The incidence of Grade 3 or 4 neutropenia was 52.1%. The most common non-
hematological toxicities were diarrhea (4.7%), anorexia (5.2%), nausea (4.3%), fatigue 
(3.3%), and febrile neutropenia (0.9%), all at Grade 3. One treatment-related death from 
hypotension due to shock was reported in the FOLFIRI group within 28 days after the end of 
treatment [Muro, K., et al 2010]. 
Benefit/Risk Assessment
Participants in clinical trials generally cannot expect to receive direct benefit from 
treatment/vaccination during participation, as clinical trials are designed to provide 
information about the safety and effectiveness of an investigational medicine.
Additional details regarding specific benefits and risks for participants participating in this 
clinical trial may be found in the accompanying binimetinib and pembrolizumab IB, in the 
respective product labeling for SOC chemotherapy, and in the Informed Consent documents.
Given the unmet medical need that exists for patients with mCRC, described in Section 3.1, 
the objective of the current trial is to assess safety and tolerability of 5 different novel 
combinations that includes pembrolizumab. Extended duration of clinical benefit coupled 
with favorable tolerability and toxicity have been the hallmark of pembrolizumab in many 
tumor types including MSI-H/pMMR mCRC. Combination regimens being examined in the 
current trial have a potential to provide improvement of efficacy without increase of toxicity.
Potential Overlapping Toxicities
The combination of pembrolizumab with binimetinib and/or chemotherapy proposed in this 
protocol potentially may increase overlapping toxicities, and the potential overlapping 
toxicities for each cohort is presented in Table 1. The most likely overlapping toxicities are 
described in detail below.
Table 1
Potential Overlapping Toxicities for Each Cohort
Adverse Event
Pembrolizumab +
Binimetinib
mFOLFOX7
mFOLFOX7 + 
Binimetinib
FOLFIRI
FOLRIRI + 
Binimetinib
Diarrhea
Nausea
Vomiting
Neutropenia
Peripheral 
sensory 
neuropathy
Rash
Ocular toxicity
Liver test 
abnormalities
Pneumonitis
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Sections 5.4.1.3, 6.2, 7.2.1, 9.3, and 12.5 provide guidance, requirements, and mitigation 
strategies to minimize the possibility of overlapping toxicities. 
Pneumonitis
In pooled studies of pembrolizumab, all grade pneumonitis as irAE was reported in 3.4%
patients (among which 0.1% were Grade 5), and it is the most frequently reported SAEs 
considered drug-related by the investigator was pneumonitis (1.6%). In the pooled studies of 
single-agent binimetinib in patients with advanced cancer (N = 566), pneumonitis events 
were observed in 15 (2.7%) patients. No individual preferred term was reported for >1.0% of 
patients, and pneumonitis was the most common event (0.9%). Grade 3/4 pneumonitis events 
were reported for 4 (0.7%) patients, including pneumonitis, hypoxia, interstitial lung disease,
and wheezing. Pneumonitis events were SAEs for 5 (0.9%) patients and resulted in 
binimetinib discontinuation for 2 (0.4%) patients (MEK162 IB Version 14). Thus, combining 
pembrolizumab and binimetinib may increase incidence or severity of pneumonitis in 
participants to be treated in Cohort A. Rare cases of pulmonary toxicities including 
pneumonitis, organizing pneumonia, pulmonary fibrosis, and interstitial lung disease have 
been reported with FOLFOX or FOLFIRI treatment [Lee, Y. J. 2014] [Moskovitz, M. 2015] 
[Katsuta, E. 2011]. Thus, early recognition of pneumonitis and initiation of systemic 
corticosteroids is critical to reduce the risk of complications.
Liver Test Abnormalities
In pooled studies of pembrolizumab, Grade 2-4 hepatitis as irAE was reported in 0.7% 
patients. Autoimmune hepatitis is the fifth most frequently reported SAEs (0.3%) considered 
drug-related by the investigator (pembrolizumab current IB). In the pooled studies of single-
agent binimetinib in patients with advanced cancer (N = 566), incidence of AST increased 
and ALT increased were 14.8% and 10.8%, respectively. Grade 3/4 liver events were 
reported for 6.9% of subjects, including AST increased (3.0%), ALT increased (2.3%), 
gamma glutamyl transferase increased (1.6%), INR increased (0.7%), ascites (0.5%), blood 
bilirubin increased and hyperbilirubinemia (0.4% each), and acute hepatic failure, hepatic 
failure, hepatic function abnormal, hepatic pain and liver injury (0.2% each; binimetinib IB). 
On the other hand, 5-FU, a thymidylate synthetase inhibitor, when given intravenously, is not 
only converted in tissues to its active form, 5-fluoro-deoxyuridine-monophosphate, but also 
catabolized, primarily in the liver, by the dihydrouracil dehydrogenase and then cleaved to 
α-fluoro-β-alanine, ammonia, urea and carbon dioxide, as in the degradation of uracil. In 
spite of this well-known liver-mediated catabolism, only mild hepatotoxicity and steatosis 
have been reported when the drug is given intravenously [Peppercorn, P. D. 1998]. The 
active metabolite of irinotecan, SN-38, is inactivated by glucuronidation in the liver and can 
lead to steatosis [Robinson, S. M., et al 2012]. Thus, combination of 5-FU with irinotecan 
potentially can cause overlapping liver toxicity; however, it is not a common AE associated 
with FOLFIRI in CRC patients [Vincenzi, B., et al 2015] [Peeters, M. 2015]. In summary, 
liver test abnormalities or liver toxicities may occur as potential overlapping toxicity in any 
of the drug combinations proposed in this study, and will be closely monitored. For suspected 
autoimmune hepatitis, investigators are required to treat with systemic corticosteroids per 
Table 6 of the protocol, as specified in protocol Section 7.2.1.2, in addition to appropriate 
diagnostic tests and supportive care. 
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Diarrhea
Diarrhea is a common AE related to mFOLFOX7, FOLFIRI, binimetinib, and 
pembrolizumab. In addition, colitis and diarrhea reported as drug-related SAE by the 
investigator were 0.9%, and 0.6%, respectively, in patients treated with pembrolizumab. The 
incidence of diarrhea may increase in any of these drug combinations. Thus, all diarrhea 
events will be closely monitored. For suspected immune related colitis, investigators are 
required to adequately evaluate and confirm etiology or exclude other causes, and treat with 
systemic corticosteroids per Table 6 of the protocol, as specified in protocol Section 7.2.1.2. 
Additional procedures or tests such as colonoscopy and biopsy may be included as part of the 
evaluation. Supportive care is outlined in Section 7.7.1 and Table 8 of the protocol.
Other Risks
The addition of pembrolizumab and binimetinib may cause toxicities that require dose 
reduction, interruption and or discontinuation of the approved drugs (mFOLFOX7/FOLFIRI) 
which have been demonstrated to provide benefit to participants.
4. Objectives/Hypotheses and Endpoints
The objectives and endpoints apply to the study population of adult male and female 
participants with non-MSI-H/pMMR mCRC.
Objective/Hypothesis
Endpoint
Primary
Objectives: 

To 
determine 
the 
safety 
and 
tolerability and to establish a 
preliminary RP2D for the following 
cohorts:
o
Cohort A: (pembrolizumab in 
combination with binimetinib in 
mCRC participants previously 
treated with fluoropyrimidine, 
irinotecan, and oxaliplatin).

Determined by incidence of DLTs 
o
Cohort B: (pembrolizumab in 
combination with mFOLFOX7 
in previously untreated mCRC 
participants)
o
Cohort C: (pembrolizumab in 
combination with mFOLFOX7 
and binimetinib in previously 
untreated mCRC participants).
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Objective/Hypothesis
Endpoint
o
Cohort D: (pembrolizumab in 
combination with FOLFIRI in 
mCRC participants previously 
treated with one line of a 
fluoropyrimidine 
plus 
oxaliplatin-based regimen).
o
Cohort E: (pembrolizumab in 
combination with FOLFIRI and 
binimetinib 
in 
mCRC 
participants previously treated 
with 
one 
line 
of 
fluoropyrimidine 
plus 
oxaliplatin-based regimen)
Secondary

To evaluate the ORR based on 
RECIST 1.1 as assessed by the 
investigator for each cohort

(ORR, 
defined 
as 
the 
proportion 
of 
participants in the analysis population who 
experience CR or PR as assessed by the 
investigator based on RECIST Version 1.1. 
Tertiary/Exploratory

To evaluate serum levels of protein 
biomarkers (eg, CEA) before and 
after 
administration 
of 
pembrolizumab 
in 
combination 
with 
chemotherapy 
and/or 
binimetinib for each cohort

Determination 
of 
molecular/proteomic 
markers indicative of clinical response, safety 
or mechanism of action of pembrolizumab 
and other study treatments

To evaluate the DOR, DCR, PFS 
based on RECIST 1.1 as assessed 
by the investigator and OS for each 
cohort

DOR, defined as the time from first 
documented evidence of CR or PR until 
disease progression or death due to any 
cause, whichever occurs first, as assessed by 
the investigator per RECIST 1.1 criteria.

DCR, defined as and the percentage of 
participants who have achieved CR or PR or 
have demonstrated SD prior to any evidence 
of progression as assessed by the investigator 
per RECIST 1.1 criteria.

PFS, defined as the time from allocation to 
the first documented disease progression or 
death due to any cause, whichever occurs 
first, as assessed by the investigator based on 
RECIST Version 1.1

OS, defined as the time from the date of 
allocation to the date of death due to any 
cause.
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Objective/Hypothesis
Endpoint

To evaluate the DOR, ORR, DCR, 
and PFS based on iRECIST as 
assessed by the investigator for 
each cohort

DOR, ORR, DCR, and PFS as assessed by 
the investigator per iRECIST 1.1 criteria

To identify molecular (genomic, 
metabolic 
and/or 
proteomic) 
biomarkers that may be indicative 
of 
clinical 
response/resistance, 
safety, pharmacodynamic activity, 
and/or the mechanism of action of 
pembrolizumab 
in 
combination 
with 
chemotherapy 
and/or 
binimetinib for each cohort

Germline genetic variation, genetic (DNA) 
mutations from tumor, tumor and blood RNA 
variation, proteomics and IHC, and other 
blood-derived biomarkers

Tumor RNA immune cell activation and 
MHC molecule expression, proteomics and 
IHC to assess immune cells (CD8 T cell) 
infiltration, proliferation, and activation

To 
explore 
the 
effects 
of 
binimetinib 
on 
the 
pharmacokinetics of irinotecan and 
SN-38, conversely, to estimate the 
effects of irinotecan and SN-38 on 
the 
PK 
of 
binimetinib 
for 
participants in Cohort A, D, and E

Blood samples of binimetinib, irinotecan and 
SN-38 will be obtained to measure PK of 
binimetinib, irinotecan, and SN-38, and 
appropriate methods will be applied to assess 
the PK interactions.
5. Study Design 
Overall Design 
This is a multicenter, worldwide, open label, non-randomized, Phase 1b trial of 
pembrolizumab in combination with chemotherapy and/or MEK inhibitor binimetinib in 
participants with a histologically confirmed diagnosis of mCRC (Stage IV) that are non-MSI-
H or pMMR.  This trial includes 2 parts: Part 1 will be a dose finding phase and Part 2 will 
be a dose confirmation phase to further examine safety and explore efficacy.  There are a 
total of 5 cohorts. Each of the 5 cohorts will participate in Part 1 and Part 2. The study will 
evaluate safety, tolerability and efficacy in the following 5 cohorts that will enroll participant 
with non-MSI-H/pMMR mCRC:

Cohort A: Pembrolizumab in combination with binimetinib in mCRC participants 
previously treated with fluoropyrimidine, irinotecan, and oxaliplatin

Cohort B: Pembrolizumab in combination with mFOLFOX7 in previously untreated 
mCRC participants

Cohort C: Pembrolizumab in combination with mFOLFOX7 and binimetinib in 
previously untreated mCRC participants

Cohort D: Pembrolizumab in combination with FOLFIRI in mCRC participants
previously treated with one line of a fluoropyrimidine plus oxaliplatin-based regimen 
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
Cohort E: Pembrolizumab in combination with FOLFIRI and binimetinib in mCRC 
participants previously treated with one line of fluoropyrimidine plus oxaliplatin-
based regimen
There is no intent to compare Cohorts B and C or Cohorts D and E. Each cohort will have 
independent objectives and will be analyzed separately.
The MSI or MMR status must be known prior to enrollment and the participants must be non 
MSI-H (or pMMR). Local documentation of non MSI-H/pMMR status using one method ie,
IHC or PCR will be sufficient to meet eligibility criteria, as defined in Section 5.4.1.6 to be 
eligible for this study.
Pre-treatment tumor tissue is required to be provided prior to allocation into the study. If not 
available, a tumor biopsy must be obtained prior to entry in the study. 
In both parts of the trial, participants will be allocated using an IVRS/IWRS. Pembrolizumab 
(200 mg) will be administered by IV infusion on Day 1 of each 21-day cycle; the dose of 
pembrolizumab will remain constant for all cohorts.  Chemotherapy (mFOLFOX7 and 
FOLFIRI) will be administered by IV infusion every 14 days.  Binimetinib will be 
administered orally BID. For additional details on study treatment administration, please see 
Section 7.1.  
Study Design
Part 1 (Dose Finding)
An mTPI design [Ji Y, Li Y, Bekele BN 2007] with a target DLT rate of approximately 30% 
will be applied to identify a preliminary RP2D in each cohort. 
Dose escalation and de-escalation decisions are based on the mTPI design as outlined in 
Table 1.  
For Cohort A, the DLT observation period is the first 21-days of Cycle 1 and the next dose 
level may open for enrollment once the 21-days DLT observation period of the previous dose 
is completed and a dose escalation decision is made.
For Cohorts B, C, D, and E, the DLT observation period is the first 28-days to 
accommodate the chemotherapy schedule and the next dose level may open for enrollment 
once the 28-days DLT observation period of the previous dose is completed and a dose 
decision (escalation or de-escalation) is made.
During dose finding, a minimum of 3 participants are required at each dose level, and up to 
6 participants may be enrolled in the same cycle at each new dose. In Table 2, the columns 
indicate the numbers of participants treated at the current dose level, and the rows indicate 
the numbers of participants experiencing DLT.  The entries in the table are the dose-finding 
decisions: E, S, D, and DU represent escalating the dose, staying at the same dose, de-
escalating the dose, and excluding the dose from the trial due to unacceptable toxicity, 
respectively.  
Based on the mTPI design, the number of participants who are enrolled at a dose but are not 
yet fully evaluable for DLT assessment may not exceed the number of remaining participants 
who are at risk of developing a DLT before the dose would be considered unacceptably toxic 
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(Table 2). For example, if 1 out of 3 participants at a given dose level experiences a DLT, no 
more than an additional 3 participants may be enrolled at this dose level until additional DLT 
data are available since this dose would be considered unacceptably toxic if all 3 of the 
additional participants experience a DLT (ie, 4 out of 6 participants).  New participants will 
be enrolled to the next dose level based on the decision as outlined in the mTPI design (see 
Table 2). There will be no intra-participant dose level escalation or dose level de-escalation 
for participants enrolled in this study (ie, 1 participant will be assigned to 1 dose level of the 
study drug).  The definition of DLTs and the criteria for dose modification are outlined in 
Sections 5.1.3 and 7.2, respectively. The dose with an estimated DLT rate closest to 30% 
may be treated as a preliminary RP2D. Based on the emerging safety and/or efficacy signals, 
an alternate dose level may be explored.
The totality of the data will be considered before deciding on the dose(s) to carry forward to 
Part 2. 
Treatment allocation will be accomplished by non-random assignment. If a participant meets 
the eligibility criteria for Cohorts B and C (i.e., previously untreated) or Cohorts D and E 
(i.e., previously treated with one line of fluoropyrimidine-based therapy) then IVRS/IWRS 
will alternate assignments between the 2 cohorts with the same eligibility criteria.  Treatment 
for each cohort in Part 2 will begin once a preliminary RP2D for that cohort is identified in 
Part 1.
CCI
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Cohort A: Pembrolizumab plus Binimetinib (Participants Previously Treated 
with Fluoropyrimidine, Irinotecan, and Oxaliplatin)
The dose of pembrolizumab will remain constant at 200 mg Q3W (see Section 5.5.1.1.1).  
Two dose levels of binimetinib will be explored: 30 mg BID and 45 mg BID. The starting 
dose of binimetinib will be 30 mg BID and is described in Section 5.5.1.1.2. The dose level 
of binimetinib will be escalated to 45 mg BID, based upon the mTPI design rules, as outlined 
in Section 5.1.1. 
Abbreviations: DL = dose level; 5-FU = fluorouracil; mTPI = modified toxicity probability interval; RP2D = 
recommended Phase 2 dose; Q3W = every 3 weeks.
Figure 1
Study Diagram (Cohort A)
Cohort B: Pembrolizumab plus mFOLFOX7 (Previously Untreated
Participants)
mFOLFOX7 in combination with pembrolizumab will be explored.  The starting dose for 
mFOLFOX7 is the standard dose routinely used in clinical practice and is described in 
Section 5.5.1.1.3. There will be no dose escalation of the standard dose of mFOLFOX7.  If 
the standard dose mFOLFOX7 is deemed too toxic per mTPI, the dose of mFOLFOX7 may
be de-escalated per Figure 2, as outlined in Section 5.1.1.  The dose of pembrolizumab will 
remain constant at 200 mg Q3W.  
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Abbreviations: BID = twice daily; DL = dose level; 5-FU = fluorouracil; mTPI = modified toxicity probability 
interval; RP2D = recommended Phase 2 dose; Q2W = every 2 weeks; Q3W = every 3 weeks.
Notes: DL1: standard dose.  Please see Section 5.1.2 – Tolerability Evaluation Rules and Dose Finding.
DL-1: de-escalation dose
Figure 2
Study Diagram (Cohort B)
Cohort C: Pembrolizumab plus mFOLFOX7 plus Binimetinib (Previously 
Untreated Participants)
Participant may initiate enrollment in Cohort C after the preliminary RP2D decision has been 
made in Cohort B (pembrolizumab plus mFOLFOX7). Two dose levels of binimetinib (in 
combination with pembrolizumab and mFOLFOX7) will be explored. The starting dose of 
binimetinib will be 30 mg BID. The dose level of binimetinib will be escalated to 45 mg 
BID, based upon the occurrence of DLTs and the mTPI design rules as outlined in Section 
5.1.1. 
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Abbreviations: BID = twice daily; DL = dose level; 5-FU = fluorouracil; mTPI = modified toxicity probability 
interval; RP2D = recommended Phase 2 dose; Q2W=every 2 weeks; Q3W=every 3 weeks.
Notes: DL1: standard dose.  Please see Section 5.1.2 – Tolerability Evaluation Rules and Dose Finding.
DL2: escalation dose
Figure 3
Study Diagram (Cohort C)
Cohort D: Pembrolizumab plus FOLFIRI (Participants Previously Treated 
With One Line of Fluoropyrimidine plus Oxaliplatin-Based Therapy)
FOLFIRI in combination with pembrolizumab will be explored.  The starting dose of 
pembrolizumab will remain constant at 200 mg Q3W.  The starting standard dose for 
FOLFIRI is the dose routinely used in clinical practice and is described in Section 5.5.1.1.4.  
There will be no dose escalation of the standard dose of FOLFIRI. The dose level of 
FOLFIRI may be de-escalated per Figure 4 based upon occurrence of DLTs and the mTPI 
design rules as outlined in Section 5.1.1.
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Abbreviations: BID = twice daily; DL = dose level; 5-FU = fluorouracil; mTPI = modified toxicity probability 
interval; RP2D = recommended Phase 2 dose; Q2W = every 2 weeks; Q3W = every 3 weeks.
Notes: DL1: standard dose. DL-1: de-escalation dose.
Figure 4
Study Diagram (Cohort D)
Cohort E: Pembrolizumab plus FOLFIRI plus Binimetinib (Participants 
Previously Treated With One Line of Fluoropyrimidine plus Oxiplatin-Based 
Therapy)
Participant may initiate enrollment in Cohort E after the preliminary RP2D decision has been 
made in Cohort D (pembrolizumab plus FOLFIRI). Two dose levels of binimetinib (in 
combination with pembrolizumab and FOLFIRI) will be explored. The starting dose of 
binimetinib will be 30 mg BID. The dose level of binimetinib will be escalated to 45 mg 
BID, based upon the occurrence of DLTs and the mTPI design rules as outlined in Section 
5.1.1.    
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Abbreviations: BID = twice daily; DL = dose level; 5-FU = fluorouracil; mTPI = modified toxicity probability 
interval; RP2D = recommended Phase 2 dose; Q2W = every 2 weeks; Q3W = every 3 weeks.
Notes: DL1: standard dose.  Please see Section 5.1.2 – Tolerability Evaluation Rules and Dose Finding.
DL2: escalation dose
Figure 5
Study Diagram (Cohort E)
Part 2 (Dose Confirmation)
Each cohort can proceed to Part 2 independently after a preliminary RP2D for that cohort is 
identified in Part 1.  In Part 2, approximately 16 additional participants per cohort will be 
treated at the doses identified using the mTPI design in Part 1 to ensure at least 30 
participants are treated at RP2D.
Part 1 and Part 2
Participants in both parts of the trial may receive up to 2 years of treatment with 
pembrolizumab (35 administrations) and binimetinib and treatment will continue until 
disease progression, unacceptable AE(s), intercurrent illness that prevents further 
administration of treatment, investigator’s decision to withdraw treatment, participant 
withdrawal of consent, pregnancy of the participant, noncompliance with trial treatment or 
procedure requirements, participant completes treatment, or administrative reasons requiring 
cessation of treatment. Treatment with SOC chemotherapy (mFOLFOX7 or FOLFIRI) will 
continue per Investigator’s decision.
Participants will be monitored for the development of AEs, and for clinical and/or 
radiographic evidence of disease progression according to RECIST Version 1.1.  However 
iRECIST could be used by the investigator for treatment decision.  In participants who have 
initial evidence of radiological PD by RECIST Version 1.1, it will be at the discretion of the 
investigator whether or not to continue a participant on study treatment until repeat imaging 
is obtained to determine whether participant’s disease is progressing or the initial evidence 
represents a ‘pseudoprogression or tumor flare’. This clinical judgment decision should be 
based on the participant’s overall clinical condition, including performance status, clinical 
symptoms, and laboratory data.  Participants may continue to receive study treatment until 
tumor assessment is repeated ≥4 weeks later in order to confirm PD by iRECIST per site 
assessment.
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Time period and frequency for collecting AE, SAE and other reportable safety event 
information is outlined in Section 9.3.1.
Participants who discontinue treatment for reasons other than confirmed disease progression 
will have post-treatment follow-up for disease status until disease progression, initiating a 
new anticancer therapy, withdrawing consent for trial participation, or becoming lost to 
follow-up, whichever occurs first.
After confirmed disease progression, each participant will be contacted (eg, by telephone) 
every 12 weeks for survival until withdrawal of consent to participate in the trial, becoming 
lost to follow-up, death, or end of the trial, whichever occurs first.
The trial will be conducted in conformance with GCP. Adverse events will be evaluated 
according to criteria outlined in the NCI CTCAE, Version 4.0 or later.
Specific procedures to be performed during the trial, as well as their prescribed times and 
associated visit windows, are outlined in the Schedule of Activities - Section 2.0. Details of 
each procedure are provided in Section 9.0 – Study Assessments and Procedures.
Tolerability Evaluation Rules and Dose Finding
Two dose levels of binimetinib and the dose levels for SOC chemotherapies (mFOLFOX7 
and FOLFIRI) are provided in Table 3. Dose escalation will continue as outlined above 
(Section 5.1.1) according to mTPI dose finding rules.  
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Table 3
Dose Levels in Cohorts A, B, C, D, and E (Parts 1 [Dose Finding] and 2 [Dose 
Confirmation])
Regimen
Cohort
Dose 
Level
Part 1 (Dose Finding)
Part 2 
(Dose Confirmation)
Cohort A
Pembrolizumab 
+ Binimetinib 
DL1

Pembrolizumab 200 mg IV Q3W 

Binimetinib 30 mg (oral) BID
Pembrolizumab 200 mg 
IV Q3W + binimetinib 
(preliminary RP2D) (oral)
BID
DL2

Pembrolizumab 200 mg IV Q3W 

Binimetinib 45 mg (oral) BID
Cohort B
Pembrolizumab 
+ mFOLFOX7 
DL1

Pembrolizumab 200 mg IV Q3W 

mFOLFOX7 (oxaliplatin [85 mg/m2]; 
leucovorin [calcium folinate] [400 mg/m2]; 
5-FU [2400 mg/m2 over 46-48 hrs]) IV Q2W
Pembrolizumab 200 mg 
IV Q3W + mFOLFOX7 
(preliminary RP2D) IV 
Q2W
DL-1

Pembrolizumab 200 mg IV Q3W 

mFOLFOX7 (oxaliplatin [70 mg/m2]; 
leucovorin [calcium folinate] [400 mg/m2]; 
5-FU [2000 mg/m2 over 46-48 hrs]) IV Q2W
Cohort C
Pembrolizumab
+ mFOLFOX7
+ Binimetinib 
DL1

Pembrolizumab 200 mg IV Q3W 

mFOLFOX7 (preliminary RP2D determined 
in Cohort B) IV Q2W

Binimetinib 30 mg (oral) BID
Pembrolizumab 200 mg 
IV Q3W + mFOLFOX7 
(preliminary RP2D 
determined in Cohort B)
IV Q2W + binimetinib 
(preliminary RP2D) (oral)
BID
DL2

Pembrolizumab 200 mg IV Q3W 

mFOLFOX7 [preliminary RP2D determined 
in Cohort B] IV Q2W

Binimetinib 45 mg (oral) BID
Cohort D
Pembrolizumab
+ FOLFIRI 
DL1

Pembrolizumab 200 mg IV Q3W 

FOLFIRI (irinotecan [180 mg/m2]; 
leucovorin [calcium folinate] [400 mg/m2]; 
5-FU [2400 mg/m2 over 46-48 hrs]) IV Q2W
Pembrolizumab 200 mg 
IV Q3W + FOLFIRI 
(preliminary RP2D) IV 
Q2W
DL-1

Pembrolizumab 200 mg IV Q3W 

FOLFIRI (irinotecan [150 mg/m2]; 
leucovorin (calcium folinate) [400 mg/m2]; 
5-FU [2000 mg/m2 over 46-48 hrs]) IV Q2W
Cohort E
Pembrolizumab 
+ FOLFIRI + 
Binimetinib
DL1

Pembrolizumab 200 mg IV Q3W 

FOLFIRI [preliminary RP2D determined in 
Cohort D] IV Q2W

Binimetinib 30 mg BID
Pembrolizumab 200 mg 
IV Q3W + FOLFIRI 
(preliminary RP2D 
determined in Cohort D) 
IV Q2W + binimetinib 
(preliminary RP2D) BID
DL2

Pembrolizumab 200 mg IV Q3W 

FOLFIRI [preliminary RP2D determined in 
Cohort D] IV Q2W

Binimetinib 45 mg (oral) BID
Abbreviations: BID=twice daily; DL=dose level; DL1=standard dose;
DL-1=de-escalation dose; 
DL2=escalation dose; 5-FU = fluorouracil; hrs = hours; Q2W = every 2 weeks; Q3W = every 3 weeks.
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Individual participant dose interruptions and modifications may be implemented based on 
toxicity as described in Section 7.2.1.  However, dose adjustments should not be made during 
the DLT observation period without discussion with the Sponsor.   
The decision to enroll participants in the next dose level will be made by the sponsor in 
consultation with the participating investigators after reviewing the safety data.  
Participants may continue on treatment until disease progression, unacceptable toxicity, 
investigator’s decision to withdraw the participant, withdrawal of consent, development of an 
inter-current condition precluding further administration of study treatment, pregnancy of the 
participant, failure to comply with dosing evaluations or other study requirements, or 
administrative reasons.
Definition of Dose Limiting Toxicity
All toxicities will be graded using NCI CTCAE Version 4.0 based on the investigator 
assessment.  The DLT window of observation will be during first 21-days of treatment for 
Cohort A and first 28-days of treatment for Cohorts B, C, D, and E to align with 
chemotherapy regimen.  
The occurrence of any of the following toxicities will be considered a DLT, if assessed by 
the investigator to be possibly, probably or definitely related to study drug administration, 
excluding toxicities clearly not related to the drug, such as disease progression, 
environmental factors, unrelated trauma, etc.:
1. Grade 4 non-hematologic toxicity (not laboratory).
2. Grade 4 hematologic toxicity lasting >7 days.
3. Grade 3 thrombocytopenia associated with clinically significant bleeding.
4. Any non-hematologic AE Grade ≥3 in severity despite optimal supportive care should be 
considered a DLT, with the following exceptions: 

Grade 3 fatigue lasting ≤3 days; 

Grade 3 diarrhea, nausea, or vomiting without use of anti-emetics or anti-diarrheals 
per SOC; 

Grade 3 rash without use of corticosteroids or anti-inflammatory agents per SOC.
5. Any Grade 3 or Grade 4 non-hematologic laboratory value if:

Medical intervention is required to treat the participant, or

The abnormality leads to hospitalization, or

The abnormality persists for >1 week.
6. Febrile neutropenia Grade 3 or Grade 4:

Grade 3 is defined as ANC <1000/mm3 with a single temperature of >38.3°C (101°F) 
or a sustained temperature of ≥38°C (100.4°F) for more than 1 hour.
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
Grade 4 is defined as ANC <1000/mm3 with a single temperature of >38.3 degrees C 
(101 degrees F) or a sustained temperature of ≥38 degrees C (100.4 degrees F) for 
more than 1 hour, with life-threatening consequences and urgent intervention 
indicated.
7. Any prolonged delay (>2 weeks) in initiating study therapy due to a treatment-related AE 
that started during the DLT period:
8. Any treatment-related toxicity that causes the participant to discontinue treatment during 
the DLT period.
9. Missing >25% of binimetinib doses as a result of drug-related AE(s) during the DLT 
period.
10. Grade 5 toxicity
11. Cardiac disorders

Absolute decrease in LVEF >10% compared with baseline and the LVEF is below 
the institution’s lower limit of normal

Left ventricular systolic dysfunction Grade ≥3

Other cardiac disorders Grade ≥3
12. Vascular disorders

Hypertension CTCAE Grade ≥3 requiring more than 1 drug or more intensive therapy

Grade 4 hypertension
13. Eye disorders
Retinal

Retinopathy or retinal detachment Grade ≥3, confirmed by ophthalmic examination

Retinal vein disorder including RVO, confirmed by ophthalmic examination
Visual disturbances without ocular (retinal) changes

Blurred vision, flashing lights, floaters: Grade ≥3
Other specify

Grade ≥3 for >21 consecutive days

Grade 4 confirmed by ophthalmic examination
If a participant experiences a DLT, trial treatment may be discontinued following discussion 
between the sponsor and Investigator.  However, if the participant is deriving clinical benefit 
as determined by the Investigator from the trial treatment, the participant may be allowed to 
continue after discussion between the sponsor and the Investigator.
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Replacement of Participants in DLT Period
To fully evaluate the safety of the combination therapy in this study, all participants enrolled 
must meet the criteria for evaluability during the DLT period. Participants are considered 
non-evaluable and will be replaced if:

They are enrolled but not treated,

They discontinue from the trial prior to completing all safety evaluations due to 
reasons other than drug-related AEs,

They received <90% of the total pembrolizumab infusion during the DLT period (eg, 
because the infusion had to be discontinued due to an infusion reaction) and did not 
experience a drug-related event, 

They received <90% of the total SOC (mFOLFOX7 and FOLFIRI) infusion during 
the DLT period (eg, if the infusion had to be discontinued due to an infusion reaction) 
and did not experience a DLT,

They received ≤75% of binimetinib doses intended for the trial during the DLT 
period and did not experience a drug-related event,

They must take a prohibited concomitant medication during the DLT period, unless 
this medication is used to treat a study drug-related AE,

They must undergo medical/surgical procedures or have logistical issues not related 
to study therapy (eg, elective surgery, unrelated medical events) during the DLT 
period.
Non-evaluable participants will not be counted toward the cohort total for DLT evaluation.   
Specific procedures to be performed during the trial, as well as their prescribed times and 
associated visit windows, are outlined in the Trial SoA - Section 2. Details of each procedure 
are provided in Section 9 – Study Assessments and Procedures.
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Study Diagram
Abbreviations: n=number of participants; RP2D = recommended Phase 2 dose.
Figure 6
Study Diagram
Number of Participants
A maximum of approximately 220 participants will be enrolled (Parts 1 and 2).  A target 
sample size of 159 participants will be used for trial planning purposes.
Beginning and End of Study Definition
The overall trial begins when the first participant signs the informed consent form (ICF).  
The overall trial ends when the last participant completes the last study-related phone-call or 
visit, withdraws from the trial or is lost to follow-up (i.e. the participant is unable to be 
contacted by the investigator).
Once the participant has achieved the study objective or study has ended, the participant is 
discontinued from this study and may be enrolled in an extension study to continue protocol-
defined assessments and treatment.
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
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3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential 
health hazard to participants
4. Plans to modify or discontinue the development of the study drug
In the event of Sponsor decision to no longer supply study drug, ample notification will be 
provided so that appropriate adjustments to participant treatment can be made.
A primary objective of this early Phase I trial is to identify the maximum safe and well-
tolerated dose and/or dosing regimen that achieve pharmacokinetic, pharmacodynamic and/or 
biologic targets in humans based on preclinical or early clinical data.  Therefore, it is possible 
that trial participants may not receive all doses specified in the protocol if this objective is 
achieved at lesser dose levels in this trial.  This would not be defined as early termination of 
the trial, but rather an earlier than anticipated achievement of the trial objective(s).  If a 
finding (eg, pharmacokinetic, pharmacodynamic, efficacy, biologic targets, etc.) from 
another preclinical or clinical trial using the study treatment(s), comparator(s), drug(s) of the 
same class, or methodology(ies) used in this trial, results in the trial(s) or program being 
stopped for non-safety reasons, this also does not meet the definition of early trial 
termination.
Early trial termination is defined as a permanent discontinuation of the trial due to 
unanticipated concerns of safety to the trial participants arising from clinical or preclinical
trials with the study treatment(s), comparator(s), drug(s) of the same class or 
methodology(ies) used in this trial.
Scientific Rationale for Study Design 
Rationale for Endpoints
Efficacy Endpoints
This trial will use ORR based on RECIST 1.1 as assessed by investigator as the secondary 
endpoint. RECIST 1.1 is a validated tool in assessing anti-cancer activity of an 
investigational agent. 
Exploratory endpoints include DCR, DOR, and PFS as assessed by the investigator based on 
RECIST 1.1, ORR, DOR, DCR, and PFS as assessed by the investigator based on iRECIST
as well as OS for each cohort.  
A central imaging vendor will be used to collect, clean, and hold tumor imaging.  Images will 
be collected for possible analysis by blinded, independent central review.
Safety Endpoints
The primary safety endpoint is the incidence of DLTs.  Safety and tolerability will be 
assessed by clinical review throughout the trial. The toxicities and grades experienced by 
participants who have received study treatment, including AEs, SAEs and ECIs will be 
summarized.  Other safety measures evaluated in study include laboratory tests, ECGs, 
ECHO/MUGA, vital signs, ECG measurements,
physical examinations, and eye 
examination.
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Pharmacokinetic Endpoints
Binimetinib was found to be a weak inhibitor of human liver microsomal UGT1A-mediated 
SN-38 conjugation, with an IC50 value greater than 25 μM. Irinotecan (pro-drug) is a 
substrate of extensive metabolic conversion by various enzyme systems, including 
carboxylesterases to form the active metabolite SN-38, and UGT1A1 mediating 
glucuronidation of SN-38 to form the inactive glucuronide metabolite SN-38G. The effects 
of binimetinib on the PK of irinotecan and SN-38, conversely, to estimate the effects of 
irinotecan and SN-38 on the PK of binimetinib will be explored.  Blood samples of 
binimetinib, irinotecan and SN-38 will be obtained to measure PK of binimetinib, irinotecan, 
and SN-38.
Pharmacodynamic Endpoints
Not applicable.
Planned Exploratory Biomarker Research
Cancer immunotherapies represent an important and novel class of antitumor agents. 
However, the mechanism of action of these exciting new therapies is not completely 
understood and much remains to be learned regarding how best to leverage these new drugs 
in treating participants. Thus, to aid future participants, it is important to investigate the 
determinants of response or resistance to cancer immunotherapy, as well as determinants of 
AEs in the course of our clinical trials. These efforts will identify novel predictive/PD 
biomarkers and generate information that will better guide single-agent and combination 
therapy with immuno-oncology drugs. To identify novel biomarkers, biospecimens (ie, blood 
components, tumor material) will be collected to support analyses of cellular components 
(eg, protein, DNA, RNA, metabolites) and other circulating molecules.
Investigations may include but are not limited to:

Germline (blood) genetic analyses (eg, SNP analyses, whole exome sequencing, whole 
genome sequencing):  This research will evaluate whether genetic variation within a 
clinical trial population correlates with response to the treatment(s) under evaluation.

Genetic (DNA) analyses from tumor:  The application of new technologies, such as next 
generation sequencing, has provided scientists the opportunity to identify tumor-specific 
DNA changes (eg, mutations, methylation status, MSI).  Key molecular changes of 
interest to immune-oncology drug development include (for example) the mutational 
burden of tumors and the clonality of T-cells in the tumor microenvironment.  Increased 
mutational burden (sometimes referred to as a “hyper-mutated” state) may generate neo-
antigen presentation in the tumor microenvironment.  To conduct this type of research, it 
is important to identify tumor-specific mutations that occur across all genes in the tumor 
genome.  Thus, genome wide approaches may be used for this effort.  Note that in order 
to understand tumor-specific mutations; it is necessary to compare the tumor genome 
with the germline genome.
CCI
CCI
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
Pretreatment and posttreatment tumor (when obtained) and blood samples collected in 
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 binimetinib and pembrolizumab combination therapy and 
other immunologic targets. 

Tumor and blood RNA analyses: Both genome-wide and targeted mRNA expression 
profiling and sequencing in tumor tissue and in blood may be performed to define gene 
signatures that correlate to clinical response to treatment with pembrolizumab or other 
immunotherapies. 

Proteomics and IHC using blood or tumor: tumor and blood samples from this study may 
undergo proteomic analyses (eg, PD-L1 IHC). 
 Tumor tissue may, therefore, be subjected to proteomic 
analyses using a variety of platforms that could include but are not limited to 
immunoassays and liquid chromatography/mass spectrometry.  This approach could 
identify novel protein biomarkers that could aid in participant selection for 
pembrolizumab therapy.

Other blood derived biomarkers: In addition to expression on tumor tissue, PD-L1 and 
other tumor derived proteins can be shed from tumors and released into the blood.  
Assays such as enzyme-linked immunoassay measure such proteins in serum.  
Correlation of expression with response to pembrolizumab therapy may identify new 
approaches for predictive biomarkers in blood, representing a major advance from 
today’s reliance on assessing tumor biomarkers.  This research would serve to develop 
such assays for future clinical use.
Planned Genetic Analysis
Genetic variation may impact a participant’s response to therapy, susceptibility to, and 
severity and progression of disease. Variable response to therapy may be due to genetic 
determinants that impact drug absorption, distribution, metabolism, and excretion; 
mechanism of action of the drug; disease etiology; and/or molecular subtype of the disease 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
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being treated. Therefore, where local regulations and IRB/IEC allow, a sample will be 
collected for DNA analysis from consenting participants.
DNA samples will be used for research related to the study treatment(s), the disease under 
study and related diseases. They may also be used to develop tests/assays including 
diagnostic tests related to the disease under study, related diseases and study drug(s). Genetic 
research may consist of the analysis of 1 or more candidate genes or the analysis of genetic 
markers throughout the genome [or analysis of the entire genome] (as appropriate). DNA 
samples will be analyzed for variation across the entire genome. Analyses may be conducted 
if it is hypothesized that this may help further understand the clinical data. The samples may 
be analyzed as part of a multi-study assessment of genetic factors involved in the response to 
understand study disease or related conditions.
Microsatellite Instability Testing
Mismatch repair proteins, or MSI loci testing for CRC is already clinically indicated as per 
NCCN [National Comprehensive Cancer Network 2017], ESMO [Van Cutsem, E., et al 
2016], and ASCO guidelines [Sepulveda, A. R., et al 2017]. MMR or MSI status will be 
performed locally. Archived tumor samples or newly obtained biopsies will be used for 
determining MSI/MMR status by the site’s local laboratory.
MMR or MSI status is determined by examining either 1) protein expression by IHC of 4 
MMR enzymes (MLH1/MSH2/MSH6/PMS2) or 2) 5 tumor microsatellite loci using PCR-
based assay, respectively.
Tumors are classified as MSI-H when at least 2 allelic shifts among the 5 analyzed 
microsatellite markers are detected by PCR, or absence of at least 1 of 4 MMR proteins 
expression is detected by IHC (also called mismatch repair deficient, dMMR). Confirmation 
of non-MSI-H/pMMR status by one testing method (either PCR or IHC) is sufficient for 
eligibility. However, both methods should indicate pMMR and non-MSI-H status in 
participants who had both tests done. Sponsor consultation is required if further investigation 
led to confirmation of pMMR/non MSI-H status by the investigator.
Future Biomedical Research
The Sponsor will conduct Future Biomedical Research on specimens consented for future 
biomedical research 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, depending on which specimens are consented for future 
biomedical research.
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 participants. The objective of collecting/retaining specimens for 
Future Biomedical Research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. The overarching goal is to use 
such information to develop safer, more effective drugs/vaccines, and/or to ensure that 
participants receive the correct dose of the correct drug/vaccine at the correct time.  The 
details of Future Biomedical Research are presented in Appendix 7 – Collection and 
Management of Specimens for Future Biomedical Research.
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Rationale for The Use of Comparator/Placebo
This study does not include comparators or placebo.  
Justification for Dose 
Starting Dose for This Trial
Justification for Treatment Regimen
Rationale for Fixed Dose Pembrolizumab
The planned dose of pembrolizumab for this study is 200 mg every 3 weeks (Q3W). Based 
on the totality of data generated in the Keytruda development program, 200 mg Q3W is the 
appropriate dose of pembrolizumab for adults across all indications and regardless of tumor 
type. As outlined below, this dose is justified by:

Clinical data from 8 randomized studies demonstrating flat dose- and exposure-efficacy 
relationships from 2 mg/kg Q3W to 10 mg/kg every 2 weeks (Q2W), 

Clinical data showing meaningful improvement in benefit-risk including overall survival 
at 200 mg Q3W across multiple indications, and

Pharmacology data showing full target saturation in both systemic circulation (inferred 
from pharmacokinetic [PK] data) and tumor (inferred from physiologically-based 
pharmacokinetic [PBPK] analysis) at 200 mg Q3W
Among the 8 randomized dose-comparison studies, a total of 2262 participants were enrolled 
with melanoma and NSCLC, covering different disease settings (treatment naïve, previously 
treated, PD-L1 enriched, and all-comers) and different treatment settings (monotherapy and 
in combination with chemotherapy). Five studies compared 2 mg/kg Q3W versus 10 mg/kg 
Q2W (KN001 Cohort B2, KN001 Cohort D, KN002, KN010, and KN021), and 3 studies 
compared 10 mg/kg Q3W versus 10 mg/kg Q2W (KN001 Cohort B3, KN001 Cohort F2 and 
KN006). All of these studies demonstrated flat dose- and exposure-response relationships 
across the doses studied representing an approximate 5- to 7.5-fold difference in exposure. 
The 2 mg/kg (or 200 mg fixed-dose) Q3W provided similar responses to the highest doses 
studied. Subsequently, flat dose-exposure-response relationships were also observed in other 
tumor types including head and neck cancer, bladder cancer, gastric cancer and classical 
Hodgkin Lymphoma, confirming 200 mg Q3W as the appropriate dose independent of the 
tumor type. These findings are consistent with the mechanism of action of pembrolizumab, 
which acts by interaction with immune cells, and not via direct binding to cancer cells.
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W. First, PK 
data in KN001 evaluating target-mediated drug disposition (TMDD) conclusively 
demonstrated saturation of PD-1 in systemic circulation at doses much lower than 200 mg 
Q3W. Second, a PBPK analysis was conducted to predict tumor PD-1 saturation over a wide 
range of tumor penetration and PD-1 expression. This evaluation concluded that 
pembrolizumab at 200 mg Q3W achieves full PD-1 saturation in both blood and tumor.
Finally, population PK analysis of pembrolizumab, which characterized the influence of 
body weight and other participant covariates on exposure, has shown that the fixed-dosing 
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provides similar control of PK variability as weight based dosing, with considerable overlap 
in the distribution of exposures from the 200 mg Q3W fixed dose and 2 mg/kg Q3W dose. 
Supported by these PK characteristics, and given that fixed-dose has advantages of reduced 
dosing complexity and reduced potential of dosing errors, the 200 mg Q3W fixed-dose was 
selected for evaluation across all pembrolizumab protocols.
Binimetinib Starting Dose
The starting dose of binimetinib will be 30 mg oral BID and the dose will be escalated to 45 
mg oral BID per the mTPI rule. Rationale for these doses is based on studies conducted in 
patients with solid tumors. ARRAY-162-111 was a Phase I, open-label, dose-escalation study 
of oral binimetinib in patients with advanced solid tumors followed by expansion cohorts in 
patients with advanced or metastatic biliary cancer or KRAS- or BRAF-mutant mCRC. A 
total of 93 participants received at least 1 dose of binimetinib. Nineteen patients with 
advanced solid tumors received binimetinib in the dose-escalation phase. Four dose levels 
were evaluated: 30 mg BID, 45 mg BID, 60 mg BID and 80 mg BID. Two of the 
4 participants receiving 80 mg BID experienced DLTs (Grade 3 chorioretinopathy and Grade 
3 dermatitis acneiform despite maximal treatment measures), thus the 80 mg BID dose was 
declared non-tolerable. Seven participants were enrolled at 60 mg BID and no DLTs were 
observed, therefore, 60 mg BID was declared the MTD. Following completion of the Dose-
escalation Phase, a total of 74 participants were enrolled in the Expansion Phase, 
28 participants in the biliary cancer cohort, 31 participants in KRAS-mutant CRC cohort and 
15 participants in the BRAF-mutant CRC cohort. After initiation of the Expansion Phase, a 
higher-than-expected frequency of ocular AEs affected the ability to treat participants 
continuously at the MTD, thus a reduced dose of 45 mg BID was implemented for the 
remainder of newly enrolled participants in the expansion phase cohorts. 
Study CMEK162X1101 was an open-label, dose escalation, Phase I study of binimetinib as a 
single agent in Japanese participants with advanced solid tumors with the expansion part in 
participants whose tumors harbored RAS or BRAF mutations. Twenty-one participants were 
enrolled and treated with at least 1 dose of binimetinib (6 participants with 30 mg BID and 
15 participants with 45 mg BID). Dose-limiting toxicities were reported during the dose 
escalation part for determination of the MTD. A total of 2 participants in the 45 mg BID dose 
level cohort reported 2 DLTs, both of which were recurrent Grade 2 detachment of retinal 
pigment epithelium. These events were judged as DLTs due to recurrence of the toxicity at 
the same grade while the dose of study drug was reduced. Therefore, 45 mg BID was 
declared the MTD in Japanese participants. No DLT was reported in participants enrolled in 
the expansion part.
In addition, a Phase I study evaluated binimetinib 30 mg BID and 45 mg BID dose in 
combination with mFOLFOX7 in heavily treated metastatic CRC patients (Section 5.5.1.1.2), 
and these 2 doses of binimetinib were well tolerated.  Taken together, 30 mg BID and 45 
BID doses are appropriate doses to be explored in the current trial [Thet Cho, M., et al 2016].
mFOLFOX7 Starting Dose
The starting dose of mFOLFOX7 (oxaliplatin 85 mg/m2 IV infusion, leucovorin 400 mg/m2
IV infusion, 5-FU 2400 mg/m2 IV infusion over 46 to 48-hour infusion) Q2W, which is 
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considered a globally accepted SOC [National Comprehensive Cancer Network 2017]
[Hochster, H. S., et al 2014].  
FOLFIRI Starting Dose
The starting dose of FOLFIRI (irinotecan 180 mg/m2 IV over 30-90 minutes, leucovorin 
400 mg/m2 IV infusion, 5-FU 2400 mg/m2 IV over 46 to 48-hour infusion) Q2W, which is 
considered globally accepted SOC [National Comprehensive Cancer Network 2017].  
Maximum Dose/Exposure for This Trial
The dose of pembrolizumab will be 200 mg administered intravenously Q3W and will 
remain constant.
The dose of pembrolizumab is based on single agent doses tested as well as the highest doses 
tested in combination in Phase I to II trials (See Section 5.5.1.1 and package insert for 
KEYTRUDA™).
The maximum dose of binimetinib for this trial will be 45 mg administered orally BID 
(maximum 90 mg total per day). The maximum dose of binimetinib is based on the single 
agent doses tested in participants with advanced solid tumors followed by expansion cohorts 
in participants with advanced or metastatic biliary cancer of KRAS-or BRAF-mutant mCRC 
in Study ARRAY-162 [Thet Cho, M., et al 2016] (See Section 5.5.1.1.2).
The maximum dose of mFOLFOX7 and FOLFIRI is the starting dose as outlined in Sections 
5.5.1.1.3 and 5.5.1.1.4, respectively.
6. Study Population
Male and female participants with non-MSI-H/pMMR mCRC will be enrolled in this trial.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
1. Male and female participants who are at least 18 years of age on the day of signing 
consent will be eligible for enrollment in the study.
2. Have a histologically-confirmed, unresectable or metastatic (Stage IV American Joint 
Committee on Cancer seventh edition) CRC. 
3. Have a locally determined non-MSI-H/pMMR tumor status (Section 5.4.1.6).
4. Have at least 1 radiologically measurable lesion as defined by RECIST 1.1.
5. Have an ECOG performance status of 0 or 1 prior to treatment initiation.
6. Have a life expectancy of at least 3 months.
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7. Participants must have the ability to swallow and retain oral medication and not have any 
clinically significant gastrointestinal abnormalities that might alter absorption.
8. Have adequate organ function as defined in Table 4.  All screening labs should be 
performed   within 10 days prior to the first dose of trial treatment.
Table 4
Inclusion Criteria Laboratory Parameters
Hematological
Absolute neutrophil count (ANC)
≥1,500/mcL
Platelets
≥100,000/mcL
Hemoglobin
≥9.0 g/dL or ≥5.6 mmol/L 
Renal
Serum creatinine OR 
Calculated* 
serum 
creatinine 
clearance
(GFR can be used in place of 
creatine or creatinine clearance)
≤1.5 X upper limit of normal (ULN) OR
≥60 mL/min for participants with creatinine levels 
>1.5 X institutional ULN
Hepatic
Serum total bilirubin
≤1.5 X ULN or
direct bilirubin ≤ULN for 
participants with total bilirubin >1.5 ULN
AST (SGOT) and ALT (SGPT)
≤2.5 X ULN OR ≤5.0 X ULN for participants with 
liver metastases
Albumin
≥3.0 g/L
Coagulation
International 
Normalized 
Ratio 
(INR) or prothrombin time (PT) or 
activated 
partial 
thromboplastin 
time (aPTT)
≤1.5X 
ULN 
unless 
participant 
is 
receiving 
anticoagulant therapy as long as the PT or aPTT is 
within the therapeutic range for the intended use of 
the anticoagulants
*Calculate serum creatinine clearance using the standard Cockcroft-Gault formula.
Abbreviations:  ALT=alanine aminotransferase; AST=aspartate aminotransferase; GFR= glomerular 
filtration rate; INR=International Normalized Ratio; SGOT=serum glutamic oxaloacetic transaminase; 
SGPT= serum glutamic-pyruvic transaminase; ULN = upper limit of normal.
Participants for Cohort A
9. Must have been previously treated with fluoropyrimidine, irinotecan, and oxaliplatin.
Note: Adjuvant chemotherapy counts as a first line of prior systemic therapy if there 
is documented disease progression within 12 months of chemotherapy completion.
Participants for Cohorts B and C
10. Must not have received prior systemic chemotherapy for Stage IV CRC.
Note: Participants who have received adjuvant chemotherapy for non-Stage IV CRC 
and have documented disease progression within 12 months of chemotherapy 
completion will not be eligible as these participants may have relative resistance to 
the proposed 1L regimen, which may undermine the adequate efficacy assessment of 
this 1L combination.
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Participants for Cohorts D and E
11. Must have been previously treated with 1 line of therapy including a fluoropyrimidine 
plus an oxaliplatin-based regimen.
Note: Adjuvant chemotherapy counts as 1 line of prior systemic therapy if there is 
documented disease progression within 12 months of chemotherapy completion. 
Participants for Cohorts A, C, and E
12. Participants must have a 12-lead ECG and ECHO or MUGA scan performed by the 
investigator or other qualified person to evaluate cardiac function prior to enrollment in 
the study. Adequate cardiac function will be assessed by:
a) LVEF ≥50% as determined by MUGA scan or ECHO; and
b) QT interval calculated according to the Fridericia method (QTcF) value ≤480 msec 
(mean of 3 measurements corrected for heart rate using Fridericia’s formula).
Contraception
Male participants:
13. A male participant must agree to use a contraception as detailed in Appendix 5 of this 
protocol during the treatment period and for at least 180 days, after the last dose of study 
treatment and refrain from donating sperm during this period.
a) Male participants with pregnant partners must agree to use a condom. 
b) No additional method of contraception is required for the pregnant partner.
Female participants:
14. A female participant is eligible to participate if she is not pregnant (see Appendix 6), not 
breastfeeding, 
and 
at 
least 
one 
of 
the 
following 
conditions 
applies: 
a) Not a woman of childbearing potential (WOCBP) as defined in Appendix 6
OR 
b) A WOCBP who agrees to follow the contraceptive guidance in Appendix 6 during the 
treatment period and for at least 180 days after the last dose of study treatment.
Informed Consent
15. The participant (or legally acceptable representative if applicable) provides written 
informed consent for the trial. The participant may also provide consent for Future 
Biomedical Research. However, the participant may participate in the main trial without 
participating in Future Biomedical Research.
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply:
1. Is currently participating and receiving study therapy in a study of an investigational 
agent or has participated and received study therapy in a study of an investigational agent 
or has used an investigational device within 28 days of administration of MK-3475.
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Note:  Participants who have entered the follow-up phase of an investigational study
may participate as long as it has been 4 weeks since the last dose of the previous 
investigational agent.
2. Has had chemotherapy, definitive radiation, or biological cancer therapy within 4 weeks 
(2 weeks for palliative radiation) prior to the first dose of study therapy, or has not 
recovered to CTCAE Grade 1 or better from any adverse events that were due to cancer 
therapeutics administered more than 4 weeks earlier (this includes participants with 
previous immunomodulatory therapy with residual immune-related adverse events).  
Participants receiving ongoing replacement hormone therapy for endocrine immune-
related adverse events will not be excluded from participation in this study.
3. Has a history of a second malignancy, unless potentially curative treatment has been 
completed with no evidence of malignancy for 2 years.
Note: The time requirement does not apply to participants who underwent successful 
definitive resection of basal cell carcinoma of the skin, superficial bladder cancer or 
in situ cervical cancer, or other in-situ cancers.
4. Has clinically active CNS metastases and/or carcinomatous meningitis. Participants with 
previously treated brain or meningeal metastases may participate and be eligible for 
treatment provided they are stable and asymptomatic (without evidence of progression by 
MRI of the brain separated by at least 4 weeks after treatment), have no evidence of new 
or enlarging brain metastases, are evaluated within 4 weeks prior to first study treatment 
administration, and are off immunosuppressive doses of systemic steroids at least 2 
weeks prior to enrollment. 
5. Has a known hypersensitivity, intolerability or contraindication to any component of 
study treatment (eg, known deficiency of the enzyme DPD), including premedication.
6. Has any active infection requiring systemic therapy.
7. Has a history of (non-infectious) pneumonitis that required steroids or has current 
pneumonitis.
8. Has received prior therapy with compounds targeting PD-1, PD-L1, PD-L2, or a MAPK 
pathway inhibitor (eg, BRAF, MEK, ERK inhibitors).
9. Has an autoimmune disease that has required systemic treatment in the past 2 years with 
use of disease modifying agents, corticosteroids, or immunosuppressive drugs. 
Replacement therapy (eg, thyroxine, insulin, physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency) is not considered a form of systemic 
treatment.
10. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any 
other form of immunosuppressive therapy within 7 days prior to randomization.
11. Has known history of HIV infection. No HIV testing is required unless mandated by local 
health authority.
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12. Has a known history of Hepatitis B (defined as HBSAg reactive) or known active 
Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection.
Note: No testing for Hepatitis B and Hepatitis C is required unless mandated by local 
health authority.
13. Has received live vaccine within 30 days of the planned start of study therapy. 
Note:  Seasonal influenza vaccines for injection are generally inactivated flu vaccines 
and are allowed; however intranasal influenza vaccines (eg, Flu-Mist®) are live 
attenuated vaccines, and are not allowed.
14. Has undergone major surgery and has not recovered adequately from any toxicity and/or 
complications from the intervention prior to starting study therapy.
15. Has baseline peripheral neuropathy/paresthesia
a.
Grade >1 for potential participants for Cohort A, D or E in Part 1
b. Grade >0 for potential participants for Cohort B or C in Part 1 (oxaliplatin containing 
cohorts)
c.
Grade >2 for potential participants for Cohort A, D or E in Part 2
d. Grade >1 for potential participants for Cohort B or C in Part 2 (oxaliplatin containing 
cohorts)
16. Have any medical, psychiatric, cognitive, or other conditions that may compromise the 
participant’s ability to understand the participant information, give informed consent, 
comply with the study protocol, or complete the study.
17. Has symptomatic CHF (i.e. Grade 2 or higher), history or current evidence of clinically 
significant cardiac arrhythmia and/or conduction abnormality ≤6 months prior to start of 
study treatment, except atrial fibrillation and PSVT. 
18. Have a history of acute or chronic pancreatitis.
19. Have existing uncontrolled arterial hypertension (SBP ≥150 mm Hg or DBP ≥100 mm
Hg) despite appropriate medical therapy.
20. Have a history of thromboembolic or cerebrovascular events within 6 months prior to 
registration, including TIAs, CVAs, deep vein thrombosis, or pulmonary embolism.
21. Have neuromuscular disorders associated with an elevated creatine kinase (eg, 
inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal 
muscular atrophy.
Potential Participants for Cohorts A, C or E who are to Receive Binimetinib:
22. Have a history of, or current, RVO or current risk factors for RVO (eg, uncontrolled 
glaucoma, ocular hypertension, history of hyperviscosity, or hypercoagulability 
syndromes).
23. Have retinal degenerative disease.
Potential Participants for Cohorts A, C, D or E:
24. Have a known history of Gilbert’s Syndrome.
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Potential Participants for Cohorts D or E:
25. Has a previous treatment with irinotecan will be excluded. 
26. Has plans to use, or is using, any herbal medications/supplements or any medications or 
foods that are strong inhibitors or inducers of cytochrome P450 3A 4/5 ≤1 week prior to 
the start of study treatment.
Pregnancy Exclusion
27. A WOCBP who has a positive urine pregnancy test within 24 hours before the first dose 
of study treatment (see Appendix 6).  If the urine test cannot be confirmed as negative, a 
serum pregnancy test is required.  In such cases, the participant must be excluded from 
participation if the serum pregnancy result is positive.
Lifestyle Restrictions
Participants receiving 5-FU (mFOLFOX7 or FOLFIRI) must avoid exposure to sunlight due 
drug-induced photosensitivity. 
Meals and Dietary Restrictions
Participants should maintain a normal diet unless modification is required to manage AEs 
such as diarrhea, nausea, or vomiting.
Caffeine, Alcohol, and Tobacco
There are no study specific restrictions regarding caffeine, alcohol, and tobacco.
Activity
There are no study specific restrictions.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently entered in the study.  A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any adverse events or serious adverse events 
(SAE) meeting reporting requirements as outlined in the entry guidelines.
Participant Replacement Strategy
If a participant withdraws from the trial, a replacement participant may be enrolled if deemed 
appropriate by the investigator and Sponsor.  The replacement participant will generally 
receive the same treatment or treatment sequence (as appropriate) as the participant being 
replaced. The replacement participant will be assigned a unique treatment number. The trial 
site should contact the Sponsor for the replacement participant’s treatment number.
Please see Section 5.1.4 regarding replacement of participants during the DLT period.
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7. Treatments
Study treatment is defined as any investigational treatment(s), marketed product(s), placebo,
or medical device(s) intended to be administered to a study participant according to the study 
protocol.
Clinical supplies [study treatment(s) provided by the Sponsor] will be packaged to support 
enrollment and replacement participants as required.  When a replacement participant is 
required, the Sponsor or designee needs to be contacted prior to dosing the replacement 
supplies.  Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
Treatments Administered
The study treatment(s) to be used in this trial are outlined below in Table 5.
Table 5
Study Treatment(s)
Study Treatment Name
Dosage 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administra-
tion
Sourcing
Pembrolizumab (MK-3475)
Solution 
for 
Infusion
100 mg/4 mL
200 mg Q3W
IV infusion
Provided 
centrally by the 
Sponsor
Binimetinib
Tablet
15 mg
30 mg BID 
Oral
Provided 
centrally by the 
Sponsor
45 mg BID
mFOLFOX7
Oxaliplatin
Solution 
for 
Infusion 
5 mg/mL 
85 mg/m2 
Q2W
IV infusion
Provided 
centrally by the 
Sponsor 
or 
locally 
by 
the 
trial 
site, 
subsidiary, 
or 
designee
70 mg/m2
Q2W
Leucovorin 
(Calcium 
Folinate)
Solution 
for 
Injection
10 mg/mL 
400 mg/m2
Q2W
5-FU
Solution 
for 
Injection
50 mg/mL
2400 mg/m2
Q2W
2000 mg/m2
Q2W
FOLFIRI
Irinotecan
Solution 
for 
Infusion
20 mg/mL
180 mg/m2
Q2W
IV infusion
Provided centrally 
by the Sponsor or 
locally 
by 
the 
trial 
site, 
subsidiary, 
or 
designee
150 mg/m2
Q2W
Leucovorin 
(Calcium 
Folinate)
Solution 
for 
Injection
10 mg/mL 
400 mg/m2
Q2W
5-FU
Solution 
for 
Injection
50 mg/mL
2400 mg/m2
Q2W
2000 mg/m2
Q2W
Abbreviations:  BID=twice daily; FOLFIRI = (irinotecan [180 mg/m2]; leucovorin [calcium folinate] [400 
mg/m2]; 5-FU 2400 mg/m2); mFOLFOX7 = (oxaliplatin [85 mg/m2]; leucovorin [calcium folinate] [400 
mg/m2]; 5-FU 2400 mg/m2); 5-FU=Fluorouracil; IV=intravenous; Q2W= every 2 weeks; Q3W=every 3 weeks.
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All supplies indicated in Table 5 will be provided per the ‘Sourcing’ row depending upon 
local country operational requirements.  Every attempt should be made to source these 
supplies from a single lot/batch number. The trial site is responsible for recording the lot 
number, manufacturer, and expiry date for any locally purchased product as per local 
guidelines unless otherwise instructed by the Sponsor.
Refer to section 9.1.8 for details regarding administration of the study treatment.
Dose Modification (Escalation/Titration/Other) 
Guideline for Dose Modification
Guidelines for dose delay and dose modification are described below and are applicable to 
the start of each cycle as well as during the cycle if treatment-related toxicities occur. If 
treatment-related toxicities occur that require supportive care including steroid use follow the 
general recommendations in Section 7.7.1 - Rescue Medications & Supportive Care.
Dosing interruptions are permitted after Cycle 1 in the case of medical/surgical events or 
logistical reasons not related to study therapy (eg, elective surgery, unrelated medical events, 
participant vacation, and/or holidays). 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 participant’s study record.
Dose Modification Due to Adverse Events
The CTCAE Version 4.0 must be used to grade the severity of adverse events. The 
Investigator may attribute each toxicity event to pembrolizumab alone, binimetinib alone, or 
to any of the components of the standard of care chemotherapies (mFOLFOX7 and 
FOLFIRI), or to any component of the combination therapy, and follow corresponding dose 
modification guidelines described in Section 7.2.1.2 to Section 7.2.1.5.
If a participant experiences overlapping toxicities that may be attributed to the combination 
regimen as a whole rather than to a single drug, Investigators should consider dose 
reduction/interruption/discontinuation of all the drugs in the combination, in addition to 
considering the discontinuation of the drug that most likely causes the toxicities, and/or 
consult with the Sponsor. Early recognition of immune related adverse effect and initiation of 
systemic corticosteroids is critical to reduce the risk of complications. Investigators should 
follow individual guidelines described in Table 6 (pembrolizumab), Table 7 (binimetinib), 
Section 7.2.1.4 (mFOLFOX7), or Section 7.2.1.5 (FOLFIRI), respectively, and/or consult 
with the Sponsor, to determine whether and when to resume the withheld/interrupted drug(s).
All AEs should be followed as clinically appropriate until stabilization or resolution.
The drug to which the investigator is attributing to the AE must be documented (AE eCRF, 
patient notes, etc.).
Exceptional circumstances to following the dose modification tables below should be 
consulted with the Sponsor.
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Immune-Related Events and Dose Modification (Withhold, Treat, Discontinue)
Dose Modification and Toxicity Management for Immune-related AEs Associated with 
Pembrolizumab
AEs associated with pembrolizumab exposure may represent an immune-related response. 
These 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 monotherapy, coformulations, or IO combinations are provided in Table 6.
See Section 7.7.1.4 for supportive care guidelines, including the use of corticosteroids.
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Table 6
Dose Modification and Toxicity Management Guidelines for Immune-related Adverse Events Associated with 
Pembrolizumab Monotherapy, Coformulations or IO Combinations
General instructions:
1.    Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive treatment should 
begin if the irAEs are not controlled by corticosteroids.
2.    Pembrolizumab monotherapy, coformulations or IO combinations must be permanently discontinued if the irAE does not resolve or the corticosteroid 
dose is not ≤10 mg/day within 12 weeks of the last treatment. 
3.    The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks.
4.    If pembrolizumab monotherapy, coformulations or IO combinations have been withheld, treatment may resume after the irAE decreased to ≤Grade 1 
after corticosteroid taper.
irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Pneumonitis 
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
Recurrent Grade 2 
or Grade 3 or 4 
Permanently 
discontinue
Diarrhea / Colitis 
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.
Recurrent Grade 3 
or Grade 4
Permanently 
discontinue
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irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
AST / ALT 
Elevation or 
Increased 
Bilirubin
Grade 2
Withhold
   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
   Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper
T1DM or 
Hyperglycemia
New onset T1DM 
or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of β-cell 
failure
Withhold a
   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
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 
discontinue a
Hyperthyroidism 
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 
discontinue a
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irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Hypothyroidism
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
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
Grade 1 
Withhold
   Based on severity of AE 
administer corticosteroids
   Ensure adequate evaluation to confirm etiology 
and/or exclude other causes
Grade 2, 3 or 4
Permanently 
discontinue
All Other irAEs
Persistent Grade 2
Withhold
   Based on severity of AE 
administer corticosteroids
   Ensure adequate evaluation to confirm etiology or 
exclude other causes
Grade 3
Withhold or 
discontinue b
Recurrent Grade 3 
or Grade 4 
Permanently 
discontinue
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for Adverse Events; DRESS=Drug Rash 
with Eosinophilia and Systemic Symptom; GI=gastrointestinal; IO=immuno-oncology; ir=immune related; IV=intravenous; SJS=Stevens-Johnson Syndrome; T1DM=type 
1 diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal.
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations.
a     The decision to withhold or permanently discontinue pembrolizumab monotherapy, coformulations or IO combinations is at the discretion of the investigator or treating 
physician. If control achieved or ≤ Grade 2, pembrolizumab monotherapy, coformulations or IO combinations may be resumed.
b     Events that require discontinuation include, but are not limited to: Guillain-Barre Syndrome, encephalitis, myelitis, DRESS, SJS, TEN and other clinically important irAEs
(eg, vasculitis and sclerosing cholangitis).
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Binimetinib
The starting dose level for binimetinib is 30 mg BID, and a dose reduction below 30 mg BID 
is not allowed. Participants requiring additional reductions must discontinue binimetinib
treatment.  Dose interruptions of more than 21 days are not allowed.  In the cases of the dose 
interruption of longer than 21 days due to an AE, discontinuation of binimetinib should be 
considered. 
For participants who do not tolerate the 45 mg BID dosing schedule, dose adjustment to 30 
mg BID is permitted in order to allow the participant to continue on study drug. 
Missed/skipped doses will not be made up (ie, the participant should not double their dose if 
the previous dose was missed). When the toxicity that resulted in a dose reduction improves 
to and remains stable at Grade 1 or less for a minimum of 21 days, the dose can be re-
escalated at the investigators discretion provided there are no other concomitant toxicities. 
No dose re-escalation of binimetinib is allowed after dose reduction due to left ventricular
dysfunction or prolonged QTcF ≥501 msec. 
No dose re-escalation of binimetinib is allowed after a dose reduction due to retinal toxicity 
≥Grade 2.
Dose reduction/interruption/discontinuation decisions should be based on the CTCAE grade 
of the toxicity and the guidelines provided below. In general, doses should not be reduced or 
interrupted for Grade 1 toxicities, but treatment to control symptoms should be provided as 
appropriate. 
Please refer to Table 7 for dose adjustment recommendations for binimetinib-induced 
toxicities.
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Table 7
Dose Modification Guideline for Binimetinib
Toxicity
Dose Adjustment for Binimetinib
Eye disorders- Retinal Events (including serous detachment of the retina)
Grade 1
Maintain dose level of binimetinib and repeat ophthalmic monitoring including 
visual acuity assessment and ocular coherence tomography (OCT) within 10 
days.
Grade 2
Interrupt binimetinib dosing and refer the participant to ophthalmologist within 
1 week and obtain OCT within 10 days:

If resolved to baseline or Grade ≤ 1 within 10 days, resume treatment at 
current dose level and continue schedule of visual assessments established 
per protocol.

If not resolved to baseline or Grade ≤ 1 within 10 days, resume treatment at 
reduced dose level and continue the schedule of events of visual 
assessments established per protocol.
Grade 3
Interrupt binimetinib and refer the participant to ophthalmologist within 1 
week and obtain OCT:

If resolved to baseline or Grade ≤ 2 within 7 days, resume treatment at 
current dose level and continue schedule of visual assessments established 
per protocol.

If not resolved to baseline or Grade ≤ 2 within 7 days, continue to hold the 
binimetinib dose and repeat ophthalmic assessment in 10 days.
o
If resolved to baseline or Grade ≤ 2, resume treatment at reduced dose 
level and continue schedule of visual assessments established per
protocol.
o
If remains Grade 3, permanently discontinue binimetinib.
Grade 4
Permanently discontinue binimetinib and immediately follow up with 
ophthalmic monitoring.
Eye disorder - RVO
Any Grade
Permanently discontinue binimetinib.
Other eye disorders (i.e. Non-retinal Events)
Grade 1-2
Maintain dose level of binimetinib and increase frequency of ophthalmic 
monitoring to at least 14 days until stabilization or resolution.
Grade 3
Interrupt binimetinib and refer participant to ophthalmologist within 1 week:

If resolved to Grade ≤ 1 in ≤ 21 days, reduce 1 dose level of binimetinib.

If not resolved to Grade ≤ 1 in ≤ 21 days, permanently discontinue 
binimetinib.
Grade 4
Permanently discontinue binimetinib.
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Toxicity
Dose Adjustment for Binimetinib
Liver-related adverse events
Grade 1 AST or 
ALT (> ULN - 3 
x ULN)
Maintain dose level of binimetinib.
Grade 2 AST or 
ALT (> 3 - 5.0 x 
ULN 
or 
3 
x 
baseline 
value) 
AND 
blood 
bilirubin ≤ 2.0 x 
ULN
Interrupt dose of binimetinib until resolved to Grade ≤ 1 (or Grade ≤ 2 in case 
of liver metastasis), then:

If resolved in ≤ 14 days, maintain dose level of binimetinib.

If resolved in > 14 days, reduce dose level of binimetinib.
Recurrence: 

Interrupt dosing of binimetinib until resolved to Grade ≤1 (or Grade ≤ 2 in 
case of liver metastasis), then resume treatment at a reduced dose.
Grade 2 AST or 
ALT (> 3 - 5.0 x 
ULN 
or 
3 
x 
baseline 
value) 
AND 
blood 
bilirubin > 2.0 x 
ULN
Interrupt dose of binimetinib until resolved to Grade ≤ 1 (or Grade ≤ 2 in case 
of liver metastasis), then:

If resolved in ≤ 7 days, resume treatment at a reduced dose of binimetinib.

If not resolved in ≤ 7 days, permanently discontinue binimetinib.
Grade 3 AST or 
ALT (> 5.0 - 8.0 
x 
ULN) 
AND 
blood bilirubin ≤ 
2.0 x ULN
Interrupt dose of binimetinib until resolved to Grade ≤ 1 (or Grade ≤ 2 in case 
of liver metastasis), then:

If resolved in ≤ 14 days, maintain dose level of binimetinib.

If resolved in > 14 days, reduce dose level of binimetinib.
Recurrence: 

Interrupt dosing of binimetinib until resolved to Grade ≤1 (or Grade ≤ 2 in 
case of liver metastasis), then resume treatment at a reduced dose.
AST or ALT (>8 
x 
ULN) 
AND 
blood bilirubin* 
≤ 2.0 x ULN
Permanently discontinue binimetinib.
AST or ALT (> 
5.0 x ULN) AND 
blood bilirubin* 
> 2.0 x ULN
Permanently discontinue binimetinib.
AST 
or 
ALT 
Grade 4 (> 20.0 x 
ULN)
Permanently discontinue binimetinib.
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Toxicity
Dose Adjustment for Binimetinib
Cardiac disorders
Left 
ventricular 
systolic 
dysfunction 
Asymptomatic 
decrease 
of 
>10% in LVEF 
compared 
to 
baseline and the 
LVEF is below 
the 
institution’s 
lower 
limit 
of 
normal
Interrupt dose of binimetinib and repeat evaluation of LVEF within 2 weeks. 

If the LVEF recovers (defined as LVEF ≥ 50% or ≥ LLN and absolute 
decrease ≤ 10% compared to baseline) ≤ 3 weeks, reduce 1 dose level after 
approval of the Sponsor Medical Monitor. Monitor LVEF 2 weeks after 
restarting on binimetinib, every 4 weeks for 12 weeks and subsequently as 
per protocol. 

If the LVEF does not recover within 3 weeks, permanently discontinue 
participant from study treatment. Closely monitor LVEF until resolution 
(or 16 weeks).
Grade 3-4
Permanently discontinue participant from binimetinib. Closely monitor LVEF 
until resolution (or 16 weeks).
CK elevation
Grade 1-2
Continue treatment on same dose level.  Ensure patient is adequately hydrated. 
Monitor closely CK and serum creatinine levels.
(If total CK ≥ 3 X ULN, measure isoenzymes and myoglobin in blood and 
urine).
Grade 3 (> 5.0 -
10.0 
x 
ULN) 
without 
renal 
impairment 
(ie, 
serum creatinine 
< 1.5 x ULN or 
1.5 x baseline)
If asymptomatic, maintain dose of binimetinib. Monitor closely and measure 
isoenzymes and myoglobin in blood and urine.
If symptomatic (muscle pain/spasms or muscle weakness), interrupt dose of 
binimetinib until resolved to CTCAE Grade ≤ 1 and monitor closely, then:

If resolved in ≤ 21 days, reduce 1 dose level of binimetinib.

If resolved in > 21 days, permanently discontinue binimetinib.
Grade 4
without 
renal 
impairment 
(ie, 
serum creatinine 
< 1.5 x ULN or 
1.5 x baseline)
If asymptomatic, interrupt dose of binimetinib and monitor closely.  Ensure 
patient is adequately hydrated and monitor and measure isoenzymes and 
myoglobin in blood or urine, and serum creatinine.

If resolved in ≤ 21 days, reduce 1 dose level of binimetinib.

If resolved in > 21 days, permanently discontinue binimetinib.
If symptomatic, permanently discontinue binimetinib.
If symptomatic (muscle pain/spasms), permanently discontinue binimetinib.
Grade 3 or 4 
with 
renal 
impairment 
(ie, 
serum creatinine 
≥ 1.5 x ULN or 
1.5 x baseline)
Interrupt binimetinib dose until resolved to Grade < 1 or baseline level.  Ensure 
patient is adequately hydrated.  Monitor isoenzymes and myoglobin in blood 
or urine, and serum creatinine, then:

If resolved in ≤ 21 days, reduce 1 dose level of binimetinib.

If resolved in > 21 days, permanently discontinue binimetinib.
Recurrence:

Permanently discontinue binimetinib
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Toxicity
Dose Adjustment for Binimetinib
Rash
Grade 1
Treatment with binimetinib should be maintained at the current dose. 
Initiate prophylactic regimen if it was not already and monitor closely.
Grade 2
First occurrence: Treatment with binimetinib should be maintained at the 
current dose and rash should be closely monitored. Initiate prophylactic 
regimen if it was not already started. 
Reassess within a maximum of 2 weeks. If rash worsens or does not improve, 
interrupt dosing until improvement to Grade ≤ 1. Resume treatment at the same 
dose level.
Second occurrence: Reassess within a maximum of 2 weeks. If rash worsens or 
does not improve, interrupt dosing until improvement to Grade ≤ 1. Resume 
treatment at a reduced dose level.
Only one dose reduction is permitted.
Grade 3
First occurrence: Treatment with binimetinib should be interrupted.  Reassess 
the participant weekly. Consider referral to dermatologist and manage rash per 
dermatologist’s recommendation.
Interrupt treatment until improvement to Grade ≤ 1. Resume treatment with 
binimetinib at the same dose level.
Second occurrence: Interrupt treatment until improvement to Grade ≤ 1. 
Resume treatment with binimetinib at a reduced dose level. If participant is at 
the lowest dose, participant should be discontinued.
Consider referral to dermatologist and manage rash per dermatologist’s 
recommendation.
Grade 4
Permanently discontinue binimetinib.
Diarrhea
Uncomplicated 
Grade 1-2
Consider temporary interruption of binimetinib until resolved to Grade ≤ 1. 
Treatment with binimetinib may then be resumed at the same dose level.
Complicated 
Grade 1-2
Temporarily interrupt binimetinib treatment until resolved to Grade ≤ 1. 
Restart binimetinib at one reduced dose level. If participant is at the lowest 
dose, participant should be discontinued.
Grade 3-4
Temporarily interrupt binimetinib treatment until resolved to Grade ≤ 1. 
Restart binimetinib at a reduced dose level. If participant is at the lowest dose, 
participant should be discontinued.
Nausea/Vomiting
Grade 1-2
Treatment with binimetinib should be maintained at the current dose. 
Promptly institute antiemetic measure. 
Grade 3
Temporarily interrupt binimetinib treatment until resolved to Grade ≤ 1. 
Resume treatment with binimetinib at the same dose if, in the judgment of the 
investigator, the toxicity is considered to be unrelated to binimetinib, or at one 
reduced dose level. 
Note: Interrupt dose for ≥ Grade 3 vomiting or Grade 3 nausea only if the 
vomiting or nausea cannot be controlled with optimal antiemetics (as per local 
practice).
Grade 4
Permanently discontinue binimetinib treatment
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Toxicity
Dose Adjustment for Binimetinib
Interstitial lung disease/pneumonitis
Grade 1
Maintain dose level of binimetinib. Monitor weekly.
Grade 2
Withhold binimetinib for up to 3 weeks.
If improved to Grade 0 or 1, resume treatment at 1 reduced dose level of 
binimetinib.
If not resolved within 3 weeks, permanently discontinue binimetinib.
Grade 3-4
Permanently discontinue binimetinib.
Venous Thromboembolism
Uncomplicated 
DVT or PE
Withhold binimetinib for up to 3 weeks.

If improved to Grade 0 or 1, resume at reduced dose.
If not improved, permanently discontinue.
Life threatening 
PE
Permanently discontinue binimetinib.
All other adverse events (suspected to be related)
Grade 1-2
If the event is a persistent Grade 2 AE not responsive to a specific therapy, 
consider study drug interruption or reduction.
Grade 3
For other AEs, interrupt study drug until resolution to Grade ≤1 or to pre-
treatment/baseline level. If the event resolves within 21 days then study drug 
may be restarted at a lower dose (one level below that previously received) 
based upon the Investigator’s discretion.
Grade 4
Permanently discontinue study drug.
Abbreviations: AE=adverse event; ALT=alanine aminotransferase; AST=aspartate aminotransferase; BID= 
twice daily; CK=creatine kinase; CTC=Common Terminology Criteria; ECG=electrocardiogram; LLN= lower 
limit of normal; LVEF=left ventricular ejection fraction; OCT= ocular coherence tomography; RVO=retinal 
vein occlusion; QTc=Q-T interval QTcF=QT interval calculated according to the Fridericia method; ULN= 
upper limit of normal.
mFOLFOX7 
Dose delays and treatment restarts will be made at the discretion of the site investigator 
according to institutional guidelines or local standard practice. The recommended dose 
reduction is stepwise by 20%. Discontinuation of treatment should be considered if dose 
reduction below the following dosage is required: Oxaliplatin 50 mg/m2 and 5-FU infusion
1600 mg/m2 46 to 48 hours.  
FOLFIRI
Dose delays and treatment restarts will be made at the discretion of the site investigator 
according to institutional guidelines or local standard practice. The recommended dose 
reduction is stepwise by 20%.
Discontinuation of treatment should be considered if dose 
reduction below the following dosage is required: Irinotecan 120 mg/m2 and 5-FU infusion
1600 mg/m2 46 to 48 hours.
Method of Treatment Assignment 
Treatment allocation will be accomplished by non-random assignment. There are 5 planned 
treatment cohorts in Part 1 (dose finding) and Part 2 (dose confirmation). This is an open-
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label trial. Treatment allocation will be accomplished by non-random assignment. If a 
participant meets the eligibility criteria for Cohorts B and C (ie, previously untreated) or 
Cohorts D and E (ie, previously treated with one line of fluoropyrimidine-based therapy),
then IVRS/IWRS will alternate assignments between the 2 cohorts with the same eligibility 
criteria. Treatment for each cohort in Part 2 will begin once a preliminary RP2D for that 
cohort is identified in Part 1.
Stratification
No stratification based on age, sex or other characteristics will be used in this trial.
Blinding 
This is an open-label trial; therefore, the Sponsor, investigator and participant will know the 
study drug administered.
Preparation/Handling/Storage/Accountability
Dose Preparation
The rationale for selection of doses to be used in this trial is provided in Section 3.2 –
Background.  
Pembrolizumab
The Pharmacy Manual contains specific instructions for preparation of the pembrolizumab 
infusion fluid and administration.
Binimetinib
Binimetinib is an oral medication, and it is supplied as film-coated tablets in dosage strength 
of 15 mg. There are no specific calculations or evaluations required to be performed in order 
to administer the proper dose to each participant.
Standard of Care Chemotherapies (mFOLFOX7 and FOLFIRI)
Preparation of SOC chemotherapies must follow local standards.
Handling, Storage and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are reported 
and resolved before use of the study treatment.
Only participants enrolled in the study may receive study treatment and only authorized site 
staff may supply or administer study treatment. All study treatments must be stored in a 
secure, environmentally controlled, and monitored (manual or automated) area in accordance 
with the labeled storage conditions with access limited to the investigator and authorized site 
staff.
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The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all trial sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate.  Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The trial site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product as per local guidelines unless otherwise instructed by the 
Sponsor.
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 study 
treatments in accordance with the protocol and any applicable laws and regulations.
Treatment Compliance
Pembrolizumab and SOC chemotherapies will be administered by the investigator and/or 
study staff according to the specifications within the pharmacy manual. The total volume of 
study medication infused will be compared with the total volume prepared to determine 
compliance with each dose administered.
Participants receiving binimetinib should be instructed to bring their study drug supply and 
bottles, to the site at each study visit.  Compliance will be evaluated at each visit by review of 
an accounting of returned study drug.
Interruptions from the protocol specified treatment plan for ≥12 weeks require consultation 
between the investigator and the Sponsor and written documentation of the collaborative 
decision on participant management.
Concomitant Therapy
If a participant does not discontinue all prior medications within 14 days of the first dose of 
study treatment, he/she may be included in the study if the investigator can rationalize that 
the specific use of a prior medication is not clinically relevant within the context of the trial.
Concurrent use of any prescription or non-prescription medication, or concurrent vaccination, 
during the course of the trial (ie, after randomization or treatment allocation) must first be 
discussed between the investigator and Sponsor prior to administration, unless appropriate 
medical care necessitates that therapy or vaccination should begin before the investigator and 
Sponsor can consult.  The participant will be allowed to continue in the trial if both the 
Sponsor and the investigator agree.
Listed below are specific restrictions for concomitant therapy during the course of the trial:
Participants are prohibited from receiving the following therapies during the Screening and 
Treatment Phases (including retreatment for post- CR relapse) of this trial: Participants who, 
in the assessment of the investigator, require the use of any of the treatments mention for 
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clinical management should be discontinued from treatment. Participants may receive other 
medications that the investigator deems to be medically necessary.

Antineoplastic systemic chemotherapy or biological therapy not specified in this study

Immunotherapy not specified in this protocol

Chemotherapy not specified in this protocol

Investigational agents other than pembrolizumab and binimetinib

Radiation therapy 
Note:  Radiation therapy to a symptomatic solitary lesion or to the brain may be allowed 
at the investigator’s discretion. 

Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial. Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and 
typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live 
attenuated vaccines and are not allowed.

Systemic glucocorticoids for any purpose other than to modulate symptoms from an ECI 
that is suspected to have an immunologic etiology. The use of physiologic doses of 
corticosteroids may be approved after consultation with the Sponsor.

Glucocorticoids (inhaled steroids as part of a stable regimen for the treatment of asthma/
COPD are permitted) for any purpose other than to modulate symptoms from an AE.  The 
use of physiologic doses of corticosteroids may be approved after consultation with the 
Sponsor.  Additionally, a short limited course of steroids may be used to treat medical 
conditions and/or AEs during the study after sponsor notification and consultation. 
Note:  Use of prophylactic corticosteroids to avoid allergic reactions (eg, IV contrast dye)
and as a part of anti-emetic therapy for chemotherapy is permitted.

Participants who, in the assessment of the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial. 
Participants may receive other medications that the investigator deems to be medically 
necessary.
Participants who, in the assessment of the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the study. 
All treatments that the investigator considers necessary for a participant’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 eCRF including all 
prescription, over-the-counter products, herbal supplements, and IV medications and fluids. 
If changes occur during the study period, documentation of drug dosage, frequency, route, 
and date should also be included on the eCRF.
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All concomitant medications received within 28 days prior to the first dose of study treatment 
and up to 30 days after the last dose of study treatment should be recorded. Concomitant 
medications administered 30 days after the last dose of study treatment should be recorded 
for SAEs and ECIs as defined in Section 9.3.7.
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing study. If there is a clinical indication for any medication or vaccination 
specifically prohibited during the study, discontinuation from study therapy or vaccination 
may be required. The investigator should discuss any questions regarding this with the 
Sponsor. The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the participant's primary physician. However, the decision to continue the 
participant on study treatment requires the mutual agreement of the investigator, the Sponsor 
and the participant.
Rescue Medications & Supportive Care
For adverse events included in the protocol, if the investigator cannot definitively attribute to 
any particular component of the regimen, supportive care including steroid use should follow 
general recommendations below. 
Participants 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 are outlined along with the dose modification guidelines in 
Section 7.2 and Table 6. 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 pembrolizumab. 
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 8 in Section 
7.7.1.1 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. 
Supportive Care Guidelines for Pembrolizumab
Dose Modification and Toxicity Management of Infusion-Reactions Related to 
Pembrolizumab
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 8. 
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Table 8
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 
participant
is 
deemed 
medically stable in the opinion of the investigator.
None
Grade 2
Requires therapy or infusion 
interruption 
but 
responds 
promptly 
to 
symptomatic 
treatment (eg, 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 
participant
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 (eg, from 100 
mL/hr to 50 mL/hr).  Otherwise dosing will be 
held until symptoms resolve and the participant
should be premedicated for the next scheduled 
dose.
Participants who develop Grade 2 toxicity 
despite adequate premedication should be 
permanently 
discontinued 
from 
further 
treatment with pembrolizumab
Participant
may 
be 
premedicated 1.5 h (± 
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).
Grades 3 or 4
Grade 3:
Prolonged (ie,
not rapidly 
responsive 
to 
symptomatic 
medication 
and/or 
brief 
interruption 
of 
infusion); 
recurrence 
of 
symptoms 
following initial improvement; 
hospitalization indicated for 
other clinical sequelae (eg,
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:
Epinephrine**
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Increase monitoring of vital signs as medically 
indicated 
until 
the 
participant
is 
deemed 
medically stable in the opinion of the investigator.
Hospitalization may be indicated.
**In cases of anaphylaxis, epinephrine should be 
used immediately.
Participant is permanently discontinued from 
further treatment with pembrolizumab.
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
Abbreviations: CTCAE = Common Terminology Criteria for Adverse Events; IV = intravenous; NCI = National Cancer 
Institute; NSAIDs = nonsteroidal anti-inflammatory drugs; PO = oral.
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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.
Supportive Care Guidelines for Binimetinib
Hypertension 
It is recommended that additional blood pressure monitoring occur for participants who may 
be at risk (participants with hypertension at baseline) or those with antecedents of 
hypertension or those treated with antihypertensive medication. Early initiation of treatment 
is recommended after diagnosis, with aggressive management of emergent hypertension.
Nausea and/or vomiting
Because nausea and vomiting have been reported for binimetinib, it is recommended that 
participants are educated on the possibility of occurrence of these side effects prior to starting 
study treatment. Participant education as well as proper management of nausea and/or 
vomiting at the first sign is important. Clinical judgment and experience of the treating 
physician should guide the management plan of each participant. Participants experiencing 
nausea and/or vomiting CTCAE Grade ≥1 should receive antiemetics at the discretion of the 
treating physician (as per local guideline). It is recommended that participants be provided a 
prescription for antiemetics, and are instructed on the use of antiemetics on the first day of 
study drug treatment. Prophylactic antiemetics such as dexamethasone 8 mg, 
prochlorperazine, or metoclopramide may be administered to participants on an "as needed" 
basis. 
Dose interruption/reduction decisions for nausea and/or vomiting should be based on the 
CTCAE grade of the toxicity and the guidelines provided in Section 7.2.1.
As guidance for recommendations on supportive measures for the prevention and/or 
management of nausea and/or vomiting, the published recommendation from ASCO
[Sepulveda, A. R., et al 2017], ESMO [Van Cutsem, E., et al 2016], and MASCC can be used 
[Basch, E., et al 2011] [Roila, F., et al 2010].
Diarrhea
In order to effectively manage diarrhea and mitigate the escalation in severity or duration of 
diarrhea, participant education as outlined above as well as proper management of diarrhea is 
important. 
Management of diarrhea should be instituted at the first sign of abdominal cramping, loose 
stools or overt diarrhea. All concomitant therapies used for treatment of diarrhea must be 
recorded on the Concomitant Medications section of the participant record. It is 
recommended that participants be provided loperamide tablets and are instructed on the use 
of loperamide on the first day of binimetinib treatment. In addition to the binimetinib-
induced diarrhea dosing guidelines, these instructions should be provided at each visit and 
the site should ensure that the participant understands the instructions. 
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Explain the frequency of diarrhea and its relationship to NCI CTCAE grading. 
Rule out other or concomitant causes which may include: 

Infection with Candida, Salmonella, Clostridium difficile, Campylobacter, Giardia, 
Entamoeba and Cryptosporidium species can lead to severe infections in 
immunosuppressed participants 

Medication-induced diarrhea 

Malabsorption/lactose intolerance 

Fecal impaction, partial bowel obstruction 
For uncomplicated Grade 1/2 diarrhea 

Stop all lactose-containing products, alcohol and eat frequent small meals that include 
bananas, rice, applesauce, or toast) 

Stop laxatives, bulk fiber (ie, Metamucil®) and stool softeners (eg, docusate sodium; 
Colace®) 

Stop high-osmolar food supplements such as Ensure® Plus and Jevity® Plus (with fiber) 

Drink 8 to 10 large glasses of clear liquids per day (eg, water, Pedialyte®, Gatorade® or 
broth) 

Consider administration of standard dose of loperamide: initial administration 4 mg, then 
2 mg every 4 hours (maximum of 16 mg/day) or after each unformed stool

Discontinue loperamide after 12-hours diarrhea-free (Grade 0) interval

If uncomplicated Grade 1 to 2 diarrhea persists for more than 24 hours, escalate to high
dose loperamide: 2 mg every 2 hours (max. of 16 mg/day) or after each unformed stool. 
Note: Oral antibiotics may be started as prophylaxis for infections under the discretion of the 
physician. 

If uncomplicated Grade 1 to 2 diarrhea persists after 48 hours of treatment with 
loperamide, discontinue loperamide and begin a 2L agent which can be an opiate (opium 
tincture or paregoric), octreotide acetate or steroid (budesonide).
For complicated Grade 1/2 diarrhea or any Grade 3 to 4 diarrhea 

The participant must call the investigator immediately 

If loperamide has not been initiated, initiate loperamide immediately. Initial 
administration 4 mg, then 2 mg every 4 hours (maximum of 16 mg/day) or after each 
unformed stool. 

Administer IV fluids and electrolytes as needed. In case of severe dehydration, replace 
loperamide by octreotide. 

Monitor/continue IV fluids and antibiotics as needed. Intervention should be continued 
until the participant is diarrhea free for at least 24 hours. 

Hospitalization may need to be considered. 
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Note: (see Section 7.2.1.2 for pembrolizumab dose modification)
Skin Toxicity
Clinical judgment and experience of the treating physician should guide the management 
plan of each participant. In general, the following interventions are in addition to the rash 
dosing adjustment guidelines in Table 7: 

Prophylaxis of skin toxicity to be initiated 24 hours prior to the first treatment with study 
drug or later as needed.

Application of topical agents to the most commonly affected skin areas such as face, 
scalp, neck, upper chest and upper back.
Topical agents include non-oily sunscreen (PABA free, SPF ≥ 30, UVA/UVB protection), 
topical steroids (preferably mometasone cream ie, Elocon®) and topical erythromycin (ie,
Eryaknen® or topical pimecrolimus).
Note: Topical agents should be applied on a daily basis starting on Day 1 of study treatment 
or 24 hours prior to the first dose, and more often as needed. 

Possibly oral doxycycline (100 mg daily) for the first 2-3 weeks of study drug 
administration.
Other effective medications are antihistamines, other topical corticosteroids, other topical 
antibiotics and low-dose systemic corticosteroids. 
The treatment algorithm based on CTCAE grade is as follows:
Mild rash (CTCAE Grade 1) 

Consider prophylactic rash treatment if not already started.

Topical or other topical corticosteroid (ie, mometasone cream) and/or topical antibiotic 
(ie, erythromycin 2%) are recommended. 

The participant should be reassessed within a maximum of 2 weeks or as per investigator 
opinion. 
Moderate rash (CTCAE Grade 2)

Use of topical erythromycin or clindamycin (1%) plus topical mometasone or 
pimecrolimus cream (1%) plus oral antibiotics such as: lymecycline (408 mg QD], 
doxycycline (100 mg BID) or minocycline (50 to 100 mg QD).

Although there has been no evidence of phototoxicity or photosensitivity in participants 
being treated with binimetinib, doxycycline (or minocycline as 2L) should be used with 
thorough UV protection (ie, avoidance of direct exposure to sunlight, use of sunscreen 
and sunglasses).

Use of acitretin is not recommended
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Severe rash (CTCAE Grade 3-4)
CTCAE Grade 3 

In addition to the interventions recommended for moderate rash, consider oral 
prednisolone at a dose of 0.5 mg/kg. Upon improvement, taper the dose in a stepwise 
manner (25 mg for 7 days, subsequently decreasing the dose by 5 mg/day every day). 

Alternatively, in addition to the interventions recommended for moderate rash, consider 
oral isotretinoin (low doses, ie, 0.3 to 0.5 mg/kg) [Lacouture, M. E., et al 2011]. 

Use of acitretin is not recommended.
CTCAE Grade 4

Immediately discontinue the participant from study drug and treat the participant with 
oral and topical medications (see recommendation CTCAE Grade 3).
Symptomatic Treatment:

It is strongly recommended that participants who develop rash/skin toxicities receive 
symptomatic treatment:
o
For pruritic lesions, use cool compresses and oral antihistaminic agents
o
For fissuring, use Monsel’s solution, silver nitrate, or zinc oxide cream. If not 
sufficient use mild steroid ointments or combinations of steroids and antibiotics such 
as Fucicort®
o
For desquamation, use emollients with mild pH 5/neutral (best containing urea 10%)
o
For paronychia, antiseptic bath and local potent corticosteroids, use oral antibiotics 
and if no improvement is seen, refer to a dermatologist or surgeon
o
For infected lesions, obtain bacterial and fungal cultures and treat with topical or 
systemic antibiotics based on sensitivity of culture
Supportive Care Guidelines for mFOLFOX7
Please refer to local guidelines and the label regarding supportive care for participants treated 
with SOC chemotherapies.
Supportive Care Guidelines for FOLFIRI
Participants should receive appropriate supportive care measures as deemed necessary by the 
site investigator including but not limited to the items outlined below:
Early Diarrhea:

Occurring during or shortly after infusion of irinotecan is usually transient and 
infrequently severe.  Early diarrhea may be prevented or treated.  Consider prophylactic 
or therapeutic administration of 0.25 mg to 1 mg of IV or subcutaneous atropine (unless 
clinically contraindicated).
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Late Diarrhea:

Occurring more than 24 hours after administration of irinotecan.  Use loperamide 4 mg at 
the onset of diarrhea, then 2 mg every 2 hours until the participant is diarrhea-free for at 
least 12 hours.
Colitis/Ileus:

Participants experiencing ileus should receive prompt antibiotic support.
Treatment After the End of the Study 
There is no study-specified treatment following the end of the study.
Clinical Supplies Disclosure
This trial is open-label; therefore, the participant, the trial site personnel, the Sponsor and/or 
designee are not blinded. Study treatment (name, strength or potency) is included in the label 
text; random code/disclosure envelopes or lists are not provided.
8. Discontinuation/Withdrawal Criteria 
Discontinuation of Study Treatment 
Discontinuation of study treatment does not represent withdrawal from the study.
As certain data on clinical events beyond study treatment discontinuation may be important 
to the study, they must be collected through the participant’s last scheduled follow-up, even 
if the participant has discontinued study treatment.  Therefore, all participants who 
discontinue study treatment prior to completion of the protocol-specified treatment period
will still continue to participate in the study as specified in Section 2 - SoA and Section 
9.10.3 – Discontinued Participants Continuing to be Monitored in the Study.
Participants may discontinue study treatment at any time for any reason or be dropped from 
the study treatment at the discretion of the investigator should any untoward effect occur.  In 
addition, a participant may be discontinued from study treatment by the investigator or the 
Sponsor if study treatment is inappropriate, the trial plan is violated, or for administrative 
and/or other safety reasons.  Specific details regarding procedures to be performed at study 
treatment discontinuation are provided in Section 9.1.9 – Withdrawal/Discontinuation.
A participant must be discontinued from study treatment but continue to be monitored in the 
study for any of the following reasons:
○
The participant or participant’s legally acceptable representative requests to discontinue 
study treatment.
o
The participant has a confirmed positive serum pregnancy test
o
The participant is non-compliant with study treatment or procedures 
o
The participant has confirmed radiographic disease progression with the exception of the 
Sponsor approving treatment continuation as outlined in Section 9.2 - Efficacy 
Assessments 
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o
The participant experiences unacceptable AEs as described in Section 9.3 - Adverse 
Events, Serious Adverse Events and Other Reportable Safety Events 
o
The participant develops an intercurrent illness other than another malignancy that 
prevents further administration of treatment 
o
The investigator decides to withdraw the participant
o
The participant experiences recurrent Grade 2 pneumonitis
o
Discontinuation of treatment may be considered for participants who have attained a 
confirmed CR by local investigator assessments and have been treated for at least 8 
cycles (at least 24 weeks), receiving 2 cycles of the combination including 2 doses of 
pembrolizumab and at least 80% of the planned doses of binimetinib beyond the date 
when the initial CR was declared. SOC chemotherapies may continue administered at the 
discretion of the investigator.
o
Noncompliance with study treatment or procedure requirements
o
The participant experiences progression or recurrence of any malignancy or any 
occurrence of another malignancy that requires active treatment
o
The participant completes 35 treatments (approximately 2 years) with pembrolizumab.   
Note: The number of treatments is calculated starting with the first dose.
For participants who are discontinued from study treatment but continue to be monitored in 
the trial, see Section 2 – SoA, and Section 9.10.3 – Discontinued Participants Continuing to 
be Monitored in the Study for those procedures to be completed at each specified visit.
Participants may be allowed to begin study treatment again if deemed medically appropriate.
Withdrawal from the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study treatment or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, as well as specific details regarding withdrawal from Future Biomedical Research are 
outlined in Section 9.1.9 – Withdrawal/Discontinuation. The procedures to be performed 
should a participant repeatedly fail to return for scheduled visits and/or if the study site is 
unable to contact the participant are outlined in Section 8.3.
Lost to Follow Up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
o
The site must attempt to contact the participant and reschedule the missed visit.  If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
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o
The investigator or designee must make every effort to regain contact with the 
participant at each missed visit (eg, phone calls and/or a certified letter to the 
participant’s last known mailing address or locally equivalent methods). These 
contact attempts should be documented in the participant’s medical record.
o
Note:  A participant is not considered lost to follow-up until the last scheduled visit 
for the individual participant.  The amount of missing data for the participant will be 
managed via the pre-specified data handling and analysis guidelines.
9. Study Assessments and Procedures
●
Study procedures and their timing are summarized in the SoA. 
●
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
●
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log 
to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable. 
●
Procedures conducted as part of the participant’s routine clinical management (eg, 
blood count) and obtained before signing of ICF may be utilized for screening or 
baseline purposes provided the procedure met the protocol-specified criteria and were 
performed within the time frame defined in the SoA.
The approximate amount of blood collected from each participant over the duration of the 
study, including any extra assessments can be found in the procedures manual.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
Administrative and General Procedures
Informed Consent
The investigator or qualified designee must obtain documented consent from each potential 
participant or each participant’s legally acceptable representative prior to participating in a 
clinical trial or Future Biomedical Research. If there are changes to the participant’s status 
during the trial (eg, health or age of majority requirements), the investigator or qualified 
designee must ensure the appropriate consent is in place. 
General Informed Consent
Consent must be documented by the participant’s dated signature or by the participant’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 participant before 
participation in the trial.
The initial ICF, any subsequent revised written ICF and any written information provided to 
the participant must receive the IRB/IEC’s approval/favorable opinion in advance of use.  
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The participant or his/her legally acceptable representative should be informed in a timely 
manner if new information becomes available that may be relevant to the participant’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 participant’s dated signature or by the participant’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/IEC requirements, applicable laws and regulations 
and Sponsor requirements.
Consent and Collection of Specimens for Future Biomedical Research
The investigator or qualified designee will explain the Future Biomedical Research consent 
to the participant, answer all of his/her questions, and obtain written informed consent before 
performing any procedure related to Future Biomedical Research.  A copy of the informed 
consent will be given to the participant.
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the participant qualifies for the trial.
Participant Identification Card
All participants will be given a Participant 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 participant with a Participant Identification Card 
immediately after the participant provides written informed consent. At the time of treatment 
allocation/randomization, site personnel will add the treatment/randomization number to the 
Participant Identification Card.
The participant identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about study 
treatment in emergency situations where the investigator is not available.
Medical History
A medical history will be obtained by the Investigator or qualified designee. 
The medical history will collect all active conditions and any condition diagnosed within the 
prior 10 years that the Investigator considers to be clinically significant. Details regarding the
disease for which the participant has enrolled in this trial will be recorded separately and not
listed as medical history.
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Prior and Concomitant Medications Review
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 participant 
within 28 days before starting the trial. Treatment for the disease for which the participant
has enrolled in this trial will be recorded separately and not listed as a prior medication.
Disease Status and Prior Cancer Treatment History
The investigator or qualified designee will also review the participant’s current disease 
status. They will also review all prior anti-cancer treatments including systemic treatments, 
radiation, and surgeries.  
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the trial. The investigator or qualified designee will record medication, if any, taken 
by the participant during the study through the Safety Follow-up visit.
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur prior to treatment allocation.  Each 
participant will be assigned only one screening number.  Screening numbers must not be re-
used for different participants.
Any participant who is screened multiple times will retain the original screening number 
assigned at the initial screening visit.
Assignment of Treatment/Randomization Number
All eligible participants will be allocated, by non-random assignment and will receive a 
treatment/randomization number.  The treatment/randomization number identifies the 
participant for all procedures occurring after treatment allocation/randomization.  Once a 
treatment/randomization number is assigned to a participant, it can never be re-assigned to 
another participant.
Once the participant has achieved the study objective or study has ended, the participant is 
discontinued from this study and may be enrolled in an extension study to continue protocol-
defined assessments and treatment.
Treatment Administration
Pembrolizumab and the components of the mFOLFOX7 and FOLFIRI chemotherapy 
regimens will be administered by the investigator and/or study staff according to the 
specifications within the pharmacy manual. 
When the treatment assignment includes pembrolizumab and one of the chemotherapy 
regimens (Cohorts B and C and Cohorts D and E) pembrolizumab is to be administered first. 
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The components of the chemotherapy regimens cannot be given through the same IV line and 
cannot be given concurrently with pembrolizumab. 
Binimetinib (BID dosing): Participants should be instructed to take binimetinib tablets 12 ± 
2 hours apart with a large glass of water (~250 mL) in the morning and in the evening at 
approximately the same times every day. Doses of binimetinib that are omitted for AEs or 
any other reason should not be made up later in the day, or at the end of the dosing period.
Standard mFOLFOX7 regimen:  oxaliplatin 85 mg/m2 given concurrently with leucovorin 
400 mg/m2 by IV infusion over 2 hours, 5-FU 2400 mg/m2 by IV infusion given over 46 to 
48 hours. 
Standard FOLFIRI regimen: irinotecan 180 mg/m2 given by IV infusion over 30-90 minutes, 
leucovorin 400 mg/m2 given by IV infusion over 2 hours, 5-FU 2400 mg/m2 by IV infusion 
over 46 to 48 hours. 
Timing of Dose Administration
Pembrolizumab Administration
Pembrolizumab 200 mg 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).
The Pharmacy Manual contains specific instructions for pembrolizumab preparation of the 
infusion fluid and administration.
Every effort should be made to begin the first dose of study treatment on the day of 
randomization, but if this is not achieved, trial therapy should be initiated no later than 3 days 
from the date of randomization.
All subsequent cycles of study treatment may be administered up to 3 days before or 3 days 
after the scheduled Day 1 of each cycle due to administrative reasons per the Investigator’s 
judgment.  
All study treatments will begin on Day 1 of each cycle after all pre-dose study procedures 
and assessments have been completed as detailed on the SoA – Section 2.0.
All study treatments will be administered on an outpatient basis.
Standard of Care
mFOLFOX7 is a regimen containing oxaliplatin, leucovorin, and 5-FU. Oxaliplatin 
85 mg/m2 is administered over 2 hours on Day 1. Leucovorin 400 mg/m2 IV is administered 
over 2 hours on Day 1. 5-FU 2400 mg/m2 is administered as an IV over 46 to 48 hours IV 
continuous infusion.  mFOLFOX7 is repeated Q2W. 
FOLFIRI is a regimen containing irinotecan, leucovorin, and 5-FU. Irinotecan 180 mg/m2 is 
administered over 30-90 minutes on Day 1. Leucovorin 400 mg/m2 IV infusion is 
administered to match duration of irinotecan infusion on Day 1. 5-FU is administered as 
1200 mg/m2/day for 2 days (total 2400 mg/m2 over 46-48 hours) IV continuous infusion.  
FOLFIRI is repeated Q2W.
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All study treatments will be administered on an outpatient basis.
Binimetinib
Participants should be instructed to take binimetinib tablets 12 ± 2 hours apart with a large 
glass of water (~250 mL) in the morning and in the evening at approximately the same times 
every day.
Withdrawal/Discontinuation
Participants who discontinue study treatment prior to completion of the treatment period
should be encouraged to continue to be followed for all remaining study visits.
When a participant withdraws from participation in the trial, all applicable activities 
scheduled for the final trial visit should be performed at the time of withdrawal.  Any adverse 
events which are present at the time of withdrawal should be followed in accordance with the 
safety requirements outlined in Section 9.3 - Adverse Events.
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for Future Biomedical Research.  Participants 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@MSD.com).  Subsequently, 
the participant's consent for Future Biomedical Research will be withdrawn.  A letter will be 
sent from the Sponsor to the investigator confirming the withdrawal. It is the responsibility of 
the investigator to inform the participant of completion of withdrawal.  Any analyses in 
progress at the time of request for withdrawal 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 (eg, 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 
participant’s personal information and their specimens.  In this situation, the request for 
specimen withdrawal cannot be processed.
Participant Blinding/Unblinding
This is an open label trial; there is no blinding for this trial.
Domiciling
Not applicable.
Calibration of Critical Equipment
The investigator or qualified designee has the responsibility to ensure that any critical device 
or instrument used for a clinical evaluation/test during a clinical trial that provides important 
information about inclusion/exclusion criteria and/or safety or efficacy parameters shall be 
suitably calibrated and maintained to ensure that the data obtained is reliable and/or 
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reproducible.  Documentation of equipment calibration must be retained as source 
documentation at the trial site.
Critical Equipment for this trial includes:
No critical equipment is required. To qualify, sites must have standard equipment and 
procedures for monitoring vital signs, administering IV medication, and responding to 
emergencies. 
Efficacy Assessments 
Tumor Imaging and Assessment of Disease
The process for image collection and transmission to the central imaging vendor can be 
found in SIM. Tumor imaging is strongly preferred to be acquired by CT. For the abdomen 
and pelvis, contrast-enhanced MRI may be used when CT with iodinated contrast is 
contraindicated, or when mandated by local practice. MRI is the strongly preferred modality 
for imaging the brain. The same imaging technique regarding modality, ideally the same 
scanner, and the use of contrast should be used in a participant throughout the study to 
optimize the reproducibility of the assessment of existing and new tumor burden and improve 
the accuracy of the assessment of response or progression based on imaging. Note: for the 
purposes of assessing tumor imaging, the term “investigator” refers to the local investigator 
at the site and/or the radiological reviewer located at the site or at an offsite facility.
Initial Tumor Imaging
Initial tumor imaging at Screening must be performed within 28 days prior to the date of 
allocation. The site study team must review screening images to confirm the participant has 
measurable disease per RECIST 1.1
Tumor Imaging During the Study
The first on-study imaging assessment should be performed at 9 weeks (63 days ±7 days) 
from the date of allocation. Subsequent tumor imaging should be performed every 9 weeks 
(63 days ±7 days) or more frequently if clinically indicated. Imaging timing should follow 
calendar days and should not be adjusted for delays in cycle starts. Imaging should continue 
to be performed until disease progression is identified by the investigator (unless the 
investigator elects to continue treatment and follow iRECIST), the start of new anticancer 
treatment, withdrawal of consent, or death, whichever occurs first. Response will be based on 
RECIST Version 1.1 (Appendix 8) as assessed by investigator/local radiology review. A 
central imaging vendor will be used to collect, clean, and hold tumor imaging.  Images will 
be collected for possible analysis by blinded, independent central review. The same imaging 
technique should be used at each time point and the schedule of disease assessment should 
not be adjusted for delays, if any, in cycle starts of disease assessment.
Objective response should be confirmed by a repeat imaging assessment. Tumor imaging to 
confirm PR or CR should be performed at least 4 weeks after the first indication of a 
response is observed. Participants will then return to regular scheduled imaging, starting with 
the next scheduled imaging time point. Participants who receive additional imaging for 
confirmation do not need to undergo the next scheduled tumor imaging if it is less than 
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4 weeks later; tumor imaging may resume at the subsequent scheduled imaging time point. 
Note:  Response does not typically need to be verified in real time by the central imaging 
vendor.
Per iRECIST (Section 9.2.1.5), disease progression should be confirmed by the site 4 to 8 
weeks after site-assessed first radiologic evidence of PD in clinically stable participants. 
Participants who have unconfirmed disease progression may continue on treatment at the 
discretion of the investigator until progression is confirmed by the site, provided they have 
met the conditions detailed in Section 9.2.1.5. Participants who receive confirmatory imaging 
do not need to undergo the next scheduled tumor imaging if it is less than 4 weeks later; 
tumor imaging may resume at the subsequent scheduled imaging time point, if clinically 
stable. Participants who have confirmed disease progression by iRECIST, as assessed by the 
site, will discontinue study treatment. Exceptions are detailed in Section 9.2.1.5.
End of Treatment and Follow-up Tumor Imaging
For participants who discontinue study treatment, tumor imaging should be performed at the 
time of treatment discontinuation (±4 week window). If previous imaging was obtained 
within 4 weeks prior to the date of discontinuation, then imaging at treatment discontinuation 
is not mandatory. For participants who discontinue study treatment due to documented 
disease progression, this is the final required tumor imaging if the investigator elects not to 
implement iRECIST.
For participants who discontinue study treatment without documented disease progression, 
every effort should be made to continue monitoring disease status by tumor imaging using 
the same imaging schedule used while on treatment (every 9 weeks) until the start of a new 
anticancer treatment, disease progression, death, withdrawal of consent, or the end of the 
study, whichever occurs first.
RECIST 1.1 Assessment of Disease
RECIST 1.1 will be used by BICR as the primary measure for assessment of tumor response, 
date of disease progression, and as a basis for all protocol guidelines related to disease status 
(eg, discontinuation of study treatment). Although RECIST 1.1 references a maximum of 
5 target lesions in total and 2 per organ, it will be modified for this study.  When more than 
one measurable lesion is present at baseline all lesions up to a maximum of 10 lesions total 
(and a maximum of 5 lesions per organ) representative of all involved organs should be 
identified as target if a broader sampling of lesions is needed to provide a more meaningful 
assessment of overall tumor burden. 
iRECIST Assessment of Disease
iRECIST is based on RECIST 1.1, but adapted to account for the unique tumor response seen 
with immunotherapeutic drugs. iRECIST will be used by the investigator to assess tumor 
response and progression, and make treatment decisions. When clinically stable, participants 
should not be discontinued until progression is confirmed by the investigator, working with 
local radiology, according to the rules outlined in Appendix 8. This allowance to continue 
treatment despite initial radiologic PD takes into account the observation that some 
participants can have a transient tumor flare in the first few months after the start of 
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immunotherapy, and then experience subsequent disease response. This data will be captured 
in the clinical database.
Clinical stability is defined as the following: 

Absence of symptoms and signs indicating clinically significant progression of
disease

No decline in ECOG performance status 

No requirements for intensified management, including increased analgesia, 
radiation, or other palliative care
Any participant deemed clinically unstable should be discontinued from study treatment at 
site-assessed first radiologic evidence of PD, and is not required to have repeat tumor 
imaging for confirmation of PD by iRECIST.
If the investigator decides to continue treatment, the participant may continue to receive 
study treatment and the tumor assessment should be repeated 4 to 8 weeks later to confirm 
PD by iRECIST, per investigator assessment. Images should continue to be sent in to the 
central imaging vendor for potential retrospective BICR. 
If repeat imaging does not confirm PD per iRECIST, as assessed by the investigator, and the 
participant continues to be clinically stable, study treatment may continue and follow the 
regular imaging schedule. If PD is confirmed, participants will be discontinued from study 
treatment.
If a participant has iCPD as defined in Appendix 9, study treatment should be discontinued; 
however, if the participant is achieving a clinically meaningful benefit, an exception to 
continue study treatment may be considered following consultation with the Sponsor. In this 
case, if study treatment is continued, tumor imaging should continue to be performed 
following the intervals as outlined in Section 2 and submitted to the central imaging vendor. 
A description of the adaptations and iRECIST process is provided in Appendix 9, with 
additional details in the iRECIST publication [Seymour, L., et al 2017]. A summary of 
imaging and treatment requirements after first radiologic evidence of progression is provided 
in Table 9.
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Table 9
Imaging and Treatment after First Radiologic Evidence of Progressive Disease
Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
First radiologic evidence of PD 
by RECIST 1.1 
Repeat imaging at 4 to 
8 weeks to confirm PD.
May continue study treatment at the 
investigator’s discretion while 
awaiting confirmatory tumor 
imaging by site by iRECIST.
Repeat imaging at 4 to 
8 weeks to confirm PD per 
investigator’s discretion only.
Discontinue treatment
Repeat tumor imaging 
confirms PD (iCPD) by 
iRECIST per investigator 
assessment
No additional imaging 
required.
Discontinue treatment (exception is 
possible upon consultation with 
Sponsor).
No additional imaging 
required.
Not applicable
Repeat tumor imaging shows 
iUPD by iRECIST per 
investigator assessment
Repeat imaging at 4 to 
8 weeks to confirm PD. May 
occur at next regularly 
scheduled imaging visit.
Continue study treatment at the 
investigator’s discretion.
Repeat imaging at 4 to 
8 weeks to confirm PD per 
investigator’s discretion only.
Discontinue treatment
Repeat tumor imaging shows 
iSD, iPR, or iCR by iRECIST 
per investigator assessment.
Continue regularly scheduled 
imaging assessments.
Continue study treatment at the 
investigator’s discretion.
Continue regularly scheduled 
imaging assessments.
May restart study treatment if 
condition has improved and/or 
clinically stable per investigator’s 
discretion. Next tumor imaging 
should occur according to the 
regular imaging schedule.
iCPD=iRECIST confirmed progressive disease; iCR=iRECIST complete response; iRECIST=modified Response Evaluation Criteria in Solid Tumors 1.1 for immune-based 
therapeutics; iSD=iRECIST stable disease; iUPD=iRECIST unconfirmed progressive disease; PD=progressive disease; RECIST 1.1=Response Evaluation Criteria in Solid 
Tumors 1.1.
Note:  If progression has been centrally verified, further management is by the site, based on iRECIST. Any further imaging should still be submitted to the central imaging 
vendor, but no rapid review will occur.
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Adverse Events, Serious Adverse Events and Other Reportable Safety Events 
The definitions of an adverse event (AE) or serious adverse event (SAE), as well as the 
method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting AE, SAE and other reportable safety event reports can be 
found in Appendix 5.
Progression of the cancer under study is not considered an adverse event as described in 
Section 9.3.5 – Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as 
AEs or SAEs, and Appendix 5. Sponsor will closely monitor all AEs, including potential 
irAEs and overlapping toxicities from drug combination that is tested in this study, and 
encourage prompt report of any signs and symptoms suggestive of overlapping toxicities, and 
management of toxicities. Periodic meetings (teleconferences) between the Sponsor and the 
investigators will be scheduled to discuss the AE findings. On days without a clinic visit 
during a Cycle (ie, Days 8, 15), AEs should be assessed by telephone.  
AE, SAEs, and other reportable safety events will be reported by the participant (or, when 
appropriate, by a caregiver, surrogate, or the participant's legally authorized representative). 
The investigator, who is a qualified physician, and any designees are responsible for 
detecting, assessing, documenting, and reporting events that meet the definition of an AE or 
SAE as well as other reportable safety events. Investigators remain responsible for following 
up AE, SAEs and other reportable safety events for outcome according to Section 9.3.3.
Adverse events will not be collected for participants during the pre-screening period (for 
determination of archival tissue status) as long as that participant has not undergone any 
protocol-specified procedure or intervention.  If the participant requires a blood draw, fresh 
tumor biopsy etc., the participant is first required to provide consent to the main study and 
AEs will be captured according to guidelines for standard AE reporting.
Time Period and Frequency for Collecting AE, SAE and Other Reportable 
Safety Event Information 
All AEs, SAEs and other reportable safety events that occur after the consent form is signed 
but before treatment allocation/randomization must be reported by the investigator if the 
participant is receiving placebo run-in or other run-in treatment, if the event cause the 
participant 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, or a procedure. 
●
All AEs from the time of treatment allocation/randomization through 30 days following 
cessation of study treatment must be reported by the investigator. 
●
All AEs meeting serious criteria, from the time of treatment allocation/randomization 
through 90 days following cessation of study treatment, or 30 days following cessation of 
study treatment if the participant initiates new anticancer therapy, whichever is earlier must 
be reported by the investigator. 
●
All pregnancies and exposure during breastfeeding, from the time of treatment 
allocation/randomization through 120 days following cessation of study treatment, or 30 days 
following cessation of study treatment if the participant initiates new anticancer therapy  
must be reported by the investigator. 
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●
Additionally, any SAE brought to the attention of an investigator at any time outside of 
the time period specified above must be reported immediately to the Sponsor if the event is 
considered to be drug-related.
Investigators are not obligated to actively seek AE or SAE or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study treatment or study participation, the 
investigator must promptly notify the sponsor.
All initial and follow-up AEs, SAEs and other reportable safety events will be recorded and 
reported to the sponsor or designee within the timeframes as indicated in Table 10.
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Table 10
Reporting Time Periods and Timeframes for Adverse Events and Other Reportable Safety Events
Type of Event
Reporting Time Period:
Consent to Randomization/ 
Allocation
Reporting Time Period:
Randomization/ Allocation 
through Protocol-Specified 
Follow-up Period
Reporting Time Period:
After the Protocol 
Specified Follow-up 
Period
Timeframe to 
Report Event and 
Follow-up 
Information to 
SPONSOR:
Non-Serious Adverse 
Event (NSAE) 
Report if:
- due to protocol-specified 
intervention
- causes exclusion
- participant is receiving placebo 
run-in or other run-in treatment
Report all
Not required
Per data entry 
guidelines
Serious Adverse Event 
(SAE) including Cancer 
and Overdose
Report if:
- due to protocol-specified 
intervention
- causes exclusion
- participant is receiving placebo 
run-in or other run-in treatment
Report all
Report if:
- drug/vaccine related.
(Follow ongoing to 
outcome)
Within 24 hours of 
learning of event
Pregnancy/Lactation 
Exposure
Report if:
- due to intervention
- causes exclusion
Report all
Previously reported –
Follow to 
completion/termination; 
report outcome
Within 24 hours of 
learning of event
Event of Clinical Interest 
(require regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report
- Potential DILI
- Require regulatory 
reporting
Not required
Within 24 hours of 
learning of event
Event of Clinical Interest 
(Do not require regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report
- non-DILI ECIs and those 
not requiring regulatory 
reporting
Not required
Within 5 calendar 
days of learning of 
event
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Method of Detecting AE, SAE and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AE and/or SAE and other reportable 
safety events. Open-ended and non-leading verbal questioning of the participant is the 
preferred method to inquire about AE occurrence.
Follow-up of AE, SAE and Other Reportable Safety Event Information 
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AE, SAE and other reportable safety events 
including pregnancy and exposure during breastfeeding, ECI, Cancer and Overdose will be 
followed until resolution, stabilization, until the event is otherwise explained, or the 
participant is lost to follow-up (as defined in Section 8.3). In addition, the investigator will 
make every attempt to follow all non-serious AEs that occur in randomized participants for 
outcome.  Further information on follow-up procedures is given in Appendix 5.
Regulatory Reporting Requirements for SAE

Prompt notification (within 24 hours) by the investigator to the sponsor of SAE is 
essential so that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study treatment under clinical investigation are met. 

The sponsor has a legal responsibility to notify both the local regulatory authority 
and other regulatory agencies about the safety of a study treatment under clinical 
investigation. All Adverse Events will be reported to regulatory authorities, 
IRB/IECs and investigators in accordance with all applicable global laws and 
regulations, i.e., per ICH Topic E6 (R1) Guidelines for Good Clinical Practice.

Investigator safety reports must be prepared for suspected unexpected serious 
adverse reactions (SUSAR) according to local regulatory requirements and sponsor 
policy and forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (eg, summary or listing of SAE) from the sponsor will 
file it along with the Investigator’s Brochure and will notify the IRB/IEC, if 
appropriate according to local requirements.
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs 
or SAEs
Progression of the cancer under study is not considered a reportable event. 
The Sponsor will monitor aggregated efficacy endpoint events and safety data to ensure the 
safety of the participants 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.
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered adverse 
events, any pregnancy or infant exposure during breastfeeding in a participant (spontaneously 
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reported to the investigator or their designee) that occurs during the trial are reportable to the 
Sponsor.
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.
Although pregnancy and infant exposure during breastfeeding are not considered adverse 
events, any pregnancy or infant exposure during breastfeeding in a participant (spontaneously 
reported to the investigator or their designee), including the pregnancy of a male participant's 
female partner, that occurs during the trial are reportable to the Sponsor.
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.
Events of Clinical Interest (ECI)
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported to the Sponsor.
Events of clinical interest for this trial include: 
1. an overdose of Sponsor's product, as defined in Section 9.4 – Treatment of Overdose, 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).
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 participant
must be reported within 24 hours to the Sponsor if it causes the participant 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 30 days
following cessation of treatment, 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 
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guidelines.  Paper reporting procedures can be found in the Investigator Trial File Binder (or 
equivalent).
Monitoring Overlapping Toxicities
To ensure the safety of all participants, sponsor will closely monitor all AEs, including irAEs 
and potential overlapping toxicities from drug combination that is tested in this study, and 
encourage prompt reporting of any signs and symptoms suggestive of overlapping toxicities, 
and management of toxicities according to the protocol and local guidelines. Periodic 
meetings (teleconferences) between the Sponsor and the investigators will be scheduled to 
discuss the AE findings. Incidence of potential overlapping toxicities in each combination 
will be closely monitored and compared to that reported in relevant clinical studies. Most 
importantly, all AEs of unknown etiology associated with drug exposure will be evaluated by 
investigators to determine if those are possibly immune-related. For suspected irAEs, 
investigators are required to adequately evaluate and confirm etiology or exclude other 
causes. Additional procedures or tests may be included as part of the evaluation. Based on 
the severity of irAEs, withhold or permanently discontinue pembrolizumab alone or 
discontinue all study treatment, as described in Section 7.2.1.
Treatment of Overdose
For purposes of this trial, an overdose will be defined as any dose exceeding the prescribed 
dose for binimetinib >80 mg BID. For participants treated with pembrolizumab, an overdose 
will be defined as any dose exceeding ≥1000 mg. For SOC chemotherapy overdose, please 
refer to the prescribing information and local guidelines. No specific information is available 
on the treatment of overdose of pembrolizumab. In the event of overdose, the drug should be 
discontinued and the participant should be observed closely for signs of toxicity.  
Appropriate supportive treatment should be provided if clinically indicated.
Safety 
Details regarding specific safety procedures/assessments to be performed in this trial are 
provided below. The total amount of blood/tissue to be drawn/collected over the course of 
the trial (from pre-trial to post-trial visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per participant can be found in Section 9.
Planned time points for all safety assessments are provided in the SoA.
Physical Examinations
Full Physical Examination
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 exams are described in Section 2. After the first 
dose of study treatment, new clinically significant abnormal findings should be recorded as 
AEs.  
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Directed Physical Examination
For cycles that do not required a full physical exam as defined in Section 2, the investigator 
or qualified designee will perform a directed physical exam as clinically indicated prior to the 
administration of the study treatment. New clinically significant abnormal findings should be 
recorded as AEs.
Full Ophthalmic Examination
Full ophthalmic examination, including best corrected visual acuity for distance testing, 
automated visual field testing, slit lamp examination, intraocular pressure and dilated 
fundoscopy with attention to retinal abnormalities, especially RPED, serous detachment of 
the retina and RVO, will be performed by an ophthalmologist at screening, Cycle 2 Day 1 
and then every 8 weeks from Cycle 2 Day 1 and EOT for participants in Cohorts A, C, and E.  
An ophthalmic examination at the 30-day follow up is only required if there was a clinically 
significant abnormality noted at EOT.  For all participants, ophthalmic assessments may be 
performed more frequently per SOC or if clinically indicated for evaluation of any visual 
signs or symptoms.
Additional Testing
Participants with clinical suspicion of retinal abnormalities (ie, RPED, serous detachment of 
the retina, RVO, photopsia, metamorphopsia, impairment of visual acuity), must complete at 
least one of the following additional assessments: 

For non-vascular abnormalities: OCT of the macula (spectral domain OCT 
recommended) 

For vascular abnormalities: fluorescein angiography of the central 30 degrees. 

Images/results of the ophthalmic examinations (at a minimum, OCT and/or 
fluorescein angiography) should be sent to the study site and be maintained in the 
participant’s source document file. These images/results may be requested to be sent 
to the Sponsor or designee.
Vital Signs
Vital signs (temperature, pulse rate, respiratory rate, and blood pressure) will be assessed.
The same method of temperature measurement must be used for all participants and must 
remain the same for each participant. Height will be measured at Visit 1 only.
Blood pressure and pulse measurements should be performed with a completely automated 
device. Manual techniques will be used only if an automated device is not available. The 
participant should be in a semi-recumbent or supine position for at least 10 minutes prior to 
having the measurement performed. The correct size of the blood pressure cuff and correct 
positioning of the participant’s arm are essential to the accuracy of the blood pressure 
measurement.
Electrocardiograms

A standard 12-lead ECG will be performed using local standard procedure.
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
The ECG measurement performed at the Screening Visit will be used to determine 
eligibility.

The ECG measurement at any time point should be used for AE grading and 
recommended dose modifications.

When an ECG is to be performed at the same time point as a blood collection, the ECG is 
to be performed first.
Cohorts A, C, and E

Triplicate 12-lead ECGs will be obtained at screening only. 
o
Three individual ECG tracings should be obtained as closely as possible in 
succession, but no more than 2 minutes apart. The full set of triplicates should be 
completed in less than 4 minutes. Refer to Section 6.1 (Inclusion Criterion # 12
for QTc withdrawal criteria).

ECG will be performed predose at every visit starting at Cycle 2 Day 1.
Cohort B and D
ECG will be performed one time during screening using local standard procedures. 
Additional time points may be performed as clinically necessary.
Echocardiogram/Multigated Acquisition Scan
Cardiac ejection fraction will be assessed by transthoracic ECHO or MUGA scans at the time 
points specified in Section 2.0 - SoA. The same method should be used throughout the study. 
Participants who develop signs/symptoms of CHF at any point during the study are required 
to have an evaluation of LVEF measurement by ECHO or MUGA.
Eastern Cooperative Oncology Group (ECOG) Performance Status
The investigator or qualified designee will assess ECOG Performance Status (see 
Appendix 2) at screening within 7 days prior to the first dose of trial treatment.  ECOG 
Performance Status will be assessed prior to dosing ±3 days of Day 1 of each subsequent 
treatment cycle, and at discontinuation of trial treatment as specified in the Section 2.0 -
Schedule of Activities.
Clinical Safety Laboratory Assessments
Refer to Appendix 3 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency. 
●
The investigator must review the laboratory report, document this review, and record 
any clinically relevant changes occurring during the study in the AE section of the 
CRF. The laboratory reports must be filed with the source documents. Clinically 
significant abnormal laboratory findings are those which are not associated with the 
underlying disease, unless judged by the investigator to be more severe than expected 
for the participant's condition.
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●
All protocol-required laboratory assessments, as defined in Appendix 3, must be 
conducted in accordance with the laboratory manual and the SoA.
●
If laboratory values from non-protocol specified laboratory assessments performed at 
the institution’s local laboratory require a change in study participant management or 
are considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).
●
For any laboratory tests with values considered clinically significantly abnormal 
during participation in the study or within 30 days after the last dose of study 
treatment, every attempt should be made to perform repeat assessments until the 
values return to normal or baseline or if a new baseline is established as determined 
by the investigator. 
Pregnancy test will be performed only on women of child bearing potential. For women of 
reproductive potential, a urine pregnancy test will be performed at Screening and within 24 
hours prior to receiving the first dose of study medication.  Additional urine/serum pregnancy 
tests may be performed if clinically warranted, or as defined by local regulations.  If a urine 
pregnancy test cannot be confirmed as negative, a serum pregnancy test is required.
NOTE: Monthly pregnancy testing should be conducted as per local regulations where 
applicable.  
Local Laboratory Assessments
All required laboratory tests are specified in Table 11.  The schedule of individual laboratory 
tests is shown in the SoA in Section 2.0.
Table 11
Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Hematocrit 
Albumin 
Specific gravity
Thyroid stimulating hormone 
(TSH)
Hemoglobin 
Alkaline phosphatase 
Microscopic exam, if 
abnormal results are 
noted
Serum β-human chorionic 
gonadotropin (β-hCG)a
Platelet count 
Lactate dehydrogenase 
(LDH)
Protein
Serum tumor markers (CEA)
White blood cell 
(WBC) count  
(total and 
differential)b
Alanine aminotransferase 
(ALT) 
Glucose
Total triiodothyronine (T3) or 
Free T3 (FT3)c
Absolute 
neutrophil countd 
Aspartate aminotransferase 
(AST) 
Blood
Free thyroxine (FT4)
Absolute 
lymphocyte countd 
Bicarbonate or Carbon 
dioxidee 
Protein
PT (INR) 
Calcium 
Specific gravity
Activated partial 
thromboplastin time (aPTT)
Chloride 
Microscopic exam, if 
abnormal results are 
noted
Blood for RNA Analyses
Serum Creatinine 
Blood for Plasma Biomarker 
Analyses
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Hematology
Chemistry
Urinalysis
Other
Creatine phosphokinase 
(CPK)
Blood for Serum Analyses
Glucose 
Binimetinib pharmacokinetics 
(PK)
Potassium 
Blood for Genetics Analyses
Sodium 
Blood for Biomarkers
Total bilirubin  
Irinotecan and SN-38 PK
Direct bilirubin, if total 
bilirubin is elevated above 
the ULN
Total protein 
Blood urea nitrogen/Ureaf
a.
Perform on women of childbearing potential only.  Serum pregnancy test is required. 
b.
Absolute results will be requested for the clinical database.
c.
T3 is preferred; if not available free T3 may be tested. If the local laboratory is unable to perform either of 
these tests the site should submit the sample to the central laboratory for testing; details are provided in 
the Procedures Manual. 
d.
Results should be calculated per local standard of practice.
e.
If these tests are not done as part of standard of care in your region then these test do not need to be 
performed.
f.
Blood Urea Nitrogen is preferred; if not available urea may be tested.
Pharmacokinetics
Blood Collection for Binimetinib 
Plasma pharmacokinetic studies for binimetinib will be obtained from consenting participants 
in both Part 1 and Part 2 in Cohort A and E, respectively.  Serial plasma samples for PK
analysis of binimetinib will be collected at pre-dose, 0.5, 1, 1.5, 2, 4, 6 hours (all ±10 min) on 
Day 15, pre-dose (24 ± 2 hours from the first binimetinib PK collection) on Day 16 and pre-
dose (48 ± 2 hr from the first binimetinib PK collection) on Day 17 in Cycle 1. The exact 
time of sample collection and time of administration of binimetinib will be recorded. In 
Cohort E, only one sample is collected at each time point to measure concentrations of 
binimetinib, irinotecan and active metabolite of irinotecan (SN-38). Sample collection, 
storage and shipment instructions for plasma samples will be provided in the procedure 
manual.
Blood Collection for Irinotecan and an Active Metabolite of Irinotecan (SN-38)
Plasma PK studies for irinotecan and an active metabolite of irinotecan (SN-38) will be 
obtained from consenting participants in both Part 1 and Part 2 in Cohort D and E.  Serial 
plasma samples for PK analysis of irinotecan and an active metabolite of irinotecan (SN-38) 
will be collected before (pre-infusion), the end of infusion, 1, 1.5, 2, 4, 6 (all ±10 min), 24 ± 
2, and 48 ± 2 hours after the initiation of infusion. If irinotecan infusion time is between 
45 minutes and 1-hour, then 1-hour sample is not needed, but all other time points apply.  
The exact time of sample collection (irinotecan and SN-38 will be measured in the same 
sample) and time of irinotecan administration will be recorded. Sample collection, storage 
and shipment instructions for plasma samples will be provided in the procedure manual.
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Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
Future Biomedical Research Sample Collection 
The following specimens are to be obtained as part of Future Biomedical Research:

DNA for future research

Leftover RNA

Leftover plasma from biomarker analyses

Leftover serum from biomarker analyses

Leftover main study tumor
Biomarkers
To identify novel biomarkers, the following biospecimens to support exploratory analyses of 
cellular components (eg, protein, RNA, DNA, metabolites) and other circulating molecules 
will be collected from all participants in this study as specified in the SoA – Section 2. 
Sample collection, storage, and shipment instructions for the exploratory biomarker 
specimens will be provided in the laboratory manual.

Blood for Genetic Analysis

Blood for RNA Analyses

Blood for plasma biomarker analyses

Blood for serum biomarker analyses

Archival or Newly Obtained Tumor Tissue collection

Post-treatment Tumor Biopsy
Tumor Tissue Collection
Participants will be requested at screening to provide a tumor sample (archival or newly 
obtained) for biomarker analysis.
The MSI/MMR status must be known prior to enrollment and the participants must be non 
MSI-H/pMMR. If not known, MSI/MMR status must be performed by the sites’ local 
laboratory using one method ie, IHC or PCR prior to enrollment.
Participants may also agree to provide an optional post-treatment biopsy, for biomarker 
analysis as outlined in the Schedule of Activities (Section 2). On-study biopsy should be 
collected on Cycle 2 Day 1 (±3 days).
Sample collection, storage, and shipment instructions for tumor samples will be provided in 
the Procedures Manual.  Archival samples are not required to be submitted within the 
screening period but must be obtained by the site at the earliest convenient time.
Any leftover samples will be stored for FBR if the participant signs the FBR consent.  
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Planned Genetic Analysis Sample Collection
Sample collection, storage and shipment instructions for Planned Genetic Analysis samples 
will be provided in the Procedure Manual. This sample should be drawn for planned analysis 
of the association between genetic variants in DNA and drug response. This sample will not 
be collected at the site if there is either a local law or regulation prohibiting collection, or if 
the IRB/IEC does not approve the collection of the sample for these purposes. If the sample 
is collected, leftover extracted DNA will be stored for FBR if the participant signs the FBR 
consent. If the planned genetic analysis is not approved, but FBR is approved and consent is 
given, this sample will be collected for the purpose of FBR.
Visit Requirements
Visit requirements are outlined in Section 2 – Schedule of Activities (SoA).  Specific 
procedure-related details are provided above in Section 9 – Study Assessments and 
Procedures.
Screening
Approximately 28 of days prior to treatment allocation, potential participants will be 
evaluated to determine that they fulfill the entry requirements as set forth in Sections 6.1 
(Inclusion Criteria) and 6.2 (Exclusion Criteria).  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 participant signing consent as part of routine 
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 trial 
treatment except for the following:

Laboratory tests are to be performed within 10 days prior to the first dose of trial 
treatment. An exception is hepatitis testing, which may be done up to 28 days prior to 
the first dose of trial treatment.

Evaluation of ECOG is to be performed within 7 days prior to the first dose of trial 
treatment.

For women of reproductive potential, a urine or serum pregnancy test will be 
performed within 72 hours prior to the first dose of trial treatment. If urine pregnancy 
results cannot be confirmed as negative, a serum pregnancy test will be required 
(performed by the local study site laboratory).

Archival tumor sample collection is not required to be obtained within 28 days prior 
to the first dose of trial treatment. Newly obtained tumor tissue may be obtained 
within 90 days of treatment initiation.
Treatment Period
Visit requirements are outlined in Section 2 – Schedule of Activities (SoA). Specific 
procedure-related details are provided above in Section 9 – Study Assessments and 
Procedures.
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Discontinued Participants Continuing to be Monitored in the Study
When a participant discontinues study treatment in the treatment or retreatment period, 
procedures for discontinuation will be performed.
The Discontinuation Visit should occur at the time study treatment is discontinued for any 
reason. If the Discontinuation Visit occurs 30 days from the last dose of study treatment, at 
the time of the mandatory Safety Follow-up Visit, the Discontinuation Visit procedures and 
any additional Safety Follow-up procedures should be performed. Visit requirements are 
outlined in Section 2 - Schedule of Activities. Additional details regarding participant 
withdrawal and discontinuation are presented in Section 8 –Discontinuation/Withdrawal 
Criteria.
Post-Study
Participants will be required to return to clinic approximately 30 days after the last dose of 
study treatment for the post-trial visit.  If the post-trial visit occurs less than 30 days after the 
last dose of study treatment, a subsequent follow-up phone call should be made at 30 days 
post the last dose of study treatment to determine if any adverse events have occurred since 
the post-trial clinic visit
Safety Follow-up Visits
The mandatory Safety Follow-up Visit should be conducted approximately 30 days after the 
last dose of trial treatment or before the initiation of new anti-cancer treatment, whichever 
comes first.  All AEs that occur prior to the Safety Follow-up Visit should be recorded.  
Participants with an AE of Grade >1 will be followed until the resolution of the AE to Grade 
0-1 or until the beginning of a new anti-cancer therapy, whichever occurs first.  SAEs that 
occur within 90 days of the end of treatment or before initiation of a new anti-cancer 
treatment should also be followed and recorded.
Imaging Follow-up Visits
Subjects who discontinue treatment for reasons other than verified PD should continue with 
imaging assessments per the protocol-defined schedule until: (1) PD is verified or further 
confirmed by the investigator, (2) initiation of a new anti-cancer treatment, (3) death, (4) 
withdrawal of consent, or (5) study conclusion or early termination, whichever occurs first.
Follow-up Visits
Participants who discontinue trial treatment for reasons other than disease progression will 
move into the Follow-up Phase and should be assessed Q9W by radiological imaging to 
monitor disease status.  Every effort should be made to collect information regarding disease 
status until the start of a new anti-cancer therapy, disease progression, death, or the end of the 
study.
Information regarding post-study anti-cancer treatment will be collected if new treatment is 
initiated.
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Survival Follow-up Contacts
Participant survival follow-up status will be assessed approximately Q12W until death, 
withdrawal of consent, or the end of the study, whichever occurs first.  
The first survival follow-up assessment should be scheduled as described below: 
•
For participants who discontinue treatment intervention and who will not enter the 
efficacy follow-up phase, the first survival follow-up contact will be scheduled 12 
weeks after the discontinuation visit and/or safety follow-up visit (whichever is last).  
•
For participants who completed assessments in the efficacy follow-up phase, the first 
survival follow-up contact will be scheduled 12 weeks after the last efficacy 
assessment follow-up visit has been performed.
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 external Data 
Monitoring Committee (eDMC) review, interim and/or final analysis.  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 that have a previously recorded death event in the collection tool).
10. Statistical Analysis Plan 
This section outlines the statistical analysis strategies and procedures for the primary and 
secondary analyses of the study.  Exploratory and other non-confirmatory analyses will be 
outlined in a separate sSAP. 
If, after the study has begun, changes are made to primary and/or secondary objectives, or the 
statistical methods related to those objectives, then the protocol will be amended (consistent 
with ICH Guideline E9).  Changes to exploratory or other non-confirmatory analyses made 
after the protocol has been finalized, but prior to the conduct of any analyses, will be 
documented in the sSAP as needed and referenced in the Clinical Study Report (CSR) for the 
study.  Post hoc exploratory analyses will be clearly identified in the CSR.
Statistical Analysis Plan Summary
Trial Design Overview
A Phase 1b Multi-cohort Study of Pembrolizumab (MK-3475) in 
Combination With Binimetinib and/or Chemotherapy in Participants With 
Metastatic Colorectal Cancer (KEYNOTE-651)
Analysis Populations
Safety (Primary): All-Participants-as-Treated (APaT)
Efficacy (Secondary & Exploratory): Full Analysis Set (FAS)
Primary Endpoint(s)
Safety: Dose-limiting toxicities (DLTs)
Secondary Endpoints
ORR based on RECIST 1.1 as assessed by the investigator for each cohort.
Statistical Methods for 
Key Efficacy
The point estimate and 95% CI for ORR will be evaluated separately for each 
cohort, using exact binomial distribution.
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Treatment Assignment
The trial is an open-label trial. Treatment allocation will be accomplished by 
non-random assignment. If a participant meets the eligibility criteria for 
Cohorts B and C (ie, previously untreated) or Cohorts D and E (ie,
previously treated with one line of fluoropyrimidine-based therapy) then 
IVRS/IWRS will alternate assignments between the 2 cohorts with the same 
eligibility criteria.  Treatment for each cohort in Part 2 will begin once a 
preliminary RP2D for that cohort is identified in Part 1.
Statistical Methods for 
Key Safety Analyses
Summary statistics (counts, percentages, means, standard deviations, etc.) 
will be provided for the safety endpoints as appropriate. The estimates of the 
DLT rates among participants treated at the RP2D and the 80% Bayesian 
credible intervals based on a prior distribution of Beta (1,1) for the estimates 
will be provided.
Interim Analyses
In this study, data will be examined on a continuous basis to allow for 
preliminary RP2D decisions (Part 1) and confirmation of RP2D (Part 2).  
Interim analyses will be conducted at the Sponsor’s discretion to enable future 
trial planning. Futility analyses will be performed in the first 14 evaluable 
participants treated at the RP2D for each cohort.
Multiplicity
No multiplicity adjustment is planned.
Sample Size and Power 
The actual sample size depends on the safety profiles and number of doses to 
be studied. A target sample size of 159 participants will be used for trial 
planning purposes.
Responsibility for Analyses/In-House Blinding
The statistical analyses of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
The trial is open-label, ie, Participants, Investigators, and Sponsor personnel will be aware of 
participant treatment assignment after each participant is enrolled and treatment is assigned.  
Allocation to treatment will not be randomized.
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 4.
Analysis Endpoints
Efficacy Endpoints
Objective response rate is the secondary endpoint of the trial. Objective response rate is 
defined as the proportion of participants in the analysis population who experience CR or PR 
using RECIST 1.1 criteria as assessed by investigator review. Other efficacy endpoints (eg,
DOR, DCR and PFS based on RECIST 1.1 as assessed by the investigator, ORR, DOR, 
DCR, and PFS based on iRECIST 1.1 as assessed by the investigator and OS) are exploratory 
endpoints in this trial and will be defined in the sSAP.
A description of efficacy assessments is provided in Section 9.2.
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Safety Endpoints
The primary safety endpoint is the incidence of DLTs.  Safety and tolerability will be 
assessed by clinical review throughout the trial. The toxicities and grades experienced by 
participants who have received study treatment, including AEs, SAEs and ECIs will be 
summarized.  Other safety measures evaluated in study include laboratory tests, ECGs, 
ECHO/MUGA, vital signs, ECG measurements,
physical examinations, and eye 
examination.
A description of safety measures is provided in Section 9.3.
Analysis Populations
Safety Analysis Population
The APaT population will be used for the analysis of safety data in this study. The APaT
population consists of all participants who received at least 1 dose of study treatment for each 
cohort.  In case of treatment administration errors, participants will be analyzed according to 
the treatment they actually received.  For DLT evaluation, APaT who were observed for 
safety for 21 days (Cohort A) or 28 days (Cohorts B, C, D, and E) after the first dose of 
assigned treatment or experienced a DLT prior to 21 days (Cohort A) or 28 days (Cohort B, 
C, D, and E) after the first dose of assigned treatment will be used.
At least one laboratory or vital sign measurement obtained subsequent to at least 1 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.
Efficacy Analysis Population
The FAS population will be used for the analyses of efficacy data in this study.  The FAS 
population consists of all evaluable participants for each cohort with a baseline scan with 
measurable disease by investigator assessment and received at least 1 dose of study 
treatment.
Statistical Methods
This section describes the statistical methods that address the primary and secondary 
objectives.  Methods related to exploratory endpoints will be described in the sSAP.
Statistical Methods for Efficacy Analysis
Full Analysis Set population treated at RP2D in each cohort, the point estimate of ORR will 
be summarized along with a 95% CI using exact binominal method proposed by Clopper and 
Pearson (1934) [Clopper, C. J. and Pearson, E. S. 1934]. Statistical methods for other 
efficacy analyses will be documented in the sSAP.
Statistical Methods for Safety Analysis
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, SAEs, ECIs, laboratory tests, vital signs, ECG measurements, and physical 
examinations.
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Adverse events will be summarized by counts and frequencies for each dose level.  
Laboratory tests, vital signs, and other safety endpoints will be summarized as appropriate.
For Part 1 in each cohort: DLTs will be listed, and further summarized by dose level.  The 
estimates of the DLT rates among participants treated at the RP2D and the 80% Bayesian 
credible intervals based on a prior distribution of Beta (1,1) for the estimates will be 
provided.
Interim Analyses
In this study, data will be examined on a continuous basis to allow for preliminary RP2D 
decisions (Part 1) and confirmation of RP2D (Part 2).  Interim analyses will be conducted at 
the Sponsor’s discretion to enable future trial planning.
Multiplicity
There will be no multiplicity control in this study.
Sample Size and Power Calculations
For each of the combinations, for Part 1 – dose finding phase: With sample size capped at 14 
in each dose level, the maximum sample size in Part 1 is expected to be approximately 28 
evaluable participants.  In Part 2
–
dose confirmation phase, approximately 16
additional participants per cohort will be treated at the RP2D identified in Part 1 to bring the 
total number of evaluable participants in Part 1 and Part 2 treated at RP2D to approximately 
30 for each cohort. The actual sample size depends on the safety profiles and number of 
doses to be studied. A target sample size of 159 participants will be used for trial planning 
purposes.  The key efficacy endpoint will be ORR based on the investigator assessment per 
RECIST 1.1. Table 12 shows the ORR estimate and 95% CI (Clopper-Pearson interval) in 
each cohort.
CCI
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Table 12
Estimate and 95% Confidence Interval of Objective Response Rate in Each 
Cohort
Abbreviations: CI=confidence interval; CR=complete response; ORR=objective response rate; PR=partial 
response.
Subgroup Analyses
Subgroup analyses of efficacy endpoints will be documented in the sSAP.
Compliance (Medication Adherence)
Drug accountability data for study treatment will be collected during the trial.  Any deviation 
from protocol-directed administration will be reported.
Extent of Exposure
The extent of exposure will be summarized as duration of treatment in cycles.
CCI
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11. References
[Apetoh, L., et al 2015]
Apetoh L, Ladoire S, Coukos G, Ghiringhelli F. 
Combining immunotherapy and anticancer agents: 
the right path to achieve cancer cure? Ann Oncol. 
2015 Sep;26(9):1813-23.
[04HN6L]
[Ascierto, P. A., et al 
2016]
Ascierto PA, Di Giacomo AM, Rutkowski P, 
Vecchio MD, Thomas L, Hogg D, et al. 
Management of MEK inhibitor (MEKi) toxicities 
of Binimetinib (BINI) in the NEMO trial. Poster 
session presented at: 13th International Congress 
of the Society for Melanoma Research; 2016 Nov 
6-9; Boston, MA.
[04MW44]
[Basch, E., et al 2011]
Basch E, Hesketh PJ, Kris MG, Prestrud AA, 
Temin S, Lyman GH. Antiemetics: American 
Society of Clinical Oncology clinical practice 
guideline update. J Oncol Pract 2011;7(6):395-8.
[03XVKC]
[Bekaii-Saab, T. 2014]
Bekaii-Saab T, Wu C. Seeing the forest through 
the trees: a systematic review of the safety and 
efficacy of combination chemotherapies used in 
the treatment of metastatic colorectal cancer. Crit 
Rev Oncol Hematol. 2014 Jul;91(1):9-34.
[04MCX7]
[Bendell, J. C., et al 
2016]
Bendell JC, Kim TW, Goh BC, Wallin J, Oh DY, 
Han SW. Clinical activity and safety of 
cobimetinib (cobi) and atezolizumab in colorectal 
cancer (CRC) [abstract]. J Clin Oncol. 2016;34. 
Abstract no.3502.
[04MHLD]
[Bendell, J. C., et al 
2017]
Bendell JC, Javle M, Bekaii-Saab TS, Finn RS, 
Wainberg ZA, Laheru DA, et al. A phase 1 dose-
escalation and expansion study of binimetinib 
(MEK162), a potent and selective oral MEK1/2 
inhibitor. Br J Cancer. 2017 Feb 28;116(5):575-
583.
[04MV9T]
[Bennouna, J., et al 
2011]
Bennouna J, Lang I, Valladares-Ayerbes M, Boer 
K, Adenis A, Escudero P, et al. A Phase II, open-
label, randomised study to assess the efficacy and 
safety of the MEK1/2 inhibitor AZD6244 (ARRY-
142886) versus capecitabine monotherapy in 
patients with colorectal cancer who have failed 
one or two prior chemotherapeutic regimens. 
Invest New Drugs. 2011 Oct;29(5):1021-8.
[04S3B4]
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[Bennouna, J., et al 
2013]
Bennouna J, Sastre J, Arnold D, Osterlund P, Greil 
R, Van Cutsem E, et al. Continuation of 
bevacizumab after first progression in metastatic 
colorectal cancer (ML18147): a randomised phase 
3 trial. Lancet Oncol. 2013 Jan;14(1):29-37.
[04FXZC]
[Bever, K. M. 2017]
Bever KM, Le DT. An expanding role for 
immunotherapy in colorectal cancer. J Natl Compr 
Canc Netw. 2017 Mar;15(3):401-410.
[04NCRK]
[Blank, 
C. 
and 
Mackensen, A. 2007]
Blank C, Mackensen A. Contribution of the PD-
L1/PD-1 pathway to T-cell exhaustion: an update 
on implications for chronic infections and tumor 
evasion. Cancer Immunol Immunother. 2007 
May;56(5):739-45.
[00VMND]
[Cassidy, J., et al 2011]
Cassidy J, Clarke S, Diaz-Rubio E, Scheithauer W, 
Figer A, Wong R, et al. XELOX vs FOLFOX-4 as 
first-line therapy for metastatic colorectal cancer: 
NO16966 updated results. Br J Cancer. 2011 Jun 
28;105(1):58-64.
[04RQ5S]
[Centers for Disease 
Control and Prevention 
2015]
Centers for Disease Control and Prevention. 
United States Cancer Statistics: 1999-2012 Cancer 
Incidence and Mortality Data [Internet]. Atlanta 
(GA): National Cancer Institute; c2015. Available 
from: www.cdc.gov/uscs.
[04FZ6L]
[Chemnitz, J. M., et al 
2004]
Chemnitz JM, Parry RV, Nichols KE, June CH, 
Riley JL. SHP-1 and SHP-2 associate with 
immunoreceptor tyrosine-based switch motif of 
programmed death 1 upon primary human T cell 
stimulation, but only receptor ligation prevents T 
cell activation. J Immunol 2004;173:945-54.
[00VMPN]
[ClinicalTrials.gov 
2017]
ClinicalTrials.gov. A trial of mFOLFIRI with 
MEK162 in patients with advanced KRAS 
positive metastatic colorectal cancers [Internet]. 
Washington: U.S. Department of Health & Human 
Services; 
2017. 
Available 
from: 
https://clinicaltrials.gov/ct2/show/NCT02613650.
[04NQ7Y]
[Clopper, C. J. and 
Pearson, E. S. 1934]
Clopper CJ, Pearson ES. The use of confidence or 
fiducial limits illustrated in the case of binomial. 
Biometrika 1934;26(4):404-13.
[03RMKM]
08JTB4


Product:  MK-3475 
135
Protocol/Amendment No.: 651-04
MK-3475-651-04 Final Protocol
08-Jun-2022
Confidential
[Colucci, 
G., 
et 
al 
2005]
Colucci G, Gebbia V, Paoletti G, Giuliani F, 
Caruso M, Gebbia N, et al. Phase III randomized 
trial of FOLFIRI versus FOLFOX4 in the 
treatment of advanced colorectal cancer: a 
multicenter study of the Gruppo Oncologico 
Dell'Italia Meridionale. J Clin Oncol. 2005 Aug 
1;23(22):4866-75.
[045QKJ]
[Comella, P., et al 
2009]
Comella P, Massidda B, Filippelli G, Farris A, 
Natale D, Barberis G, et al. Randomised trial 
comparing 
biweekly 
oxaliplatin 
plus 
oral 
capecitabine versus oxaliplatin plus i.v. bolus 
fluorouracil/leucovorin in metastatic colorectal 
cancer patients: results of the Southern Italy 
Cooperative Oncology study 0401. J Cancer Res 
Clin Oncol. 2009 Feb;135(2):217-26.
[04FZ6M]
[Diaz-Rubio, E., et al 
2007]
Diaz-Rubio E, Tabernero J, Gomez-Espana A, 
Massuti B, Sastre J, Chaves M, et al. Phase III 
study of capecitabine plus oxaliplatin compared 
with 
continuous-infusion 
fluorouracil 
plus
oxaliplatin as first-line therapy in metastatic 
colorectal cancer: final report of the Spanish 
Cooperative Group for the Treatment of Digestive 
Tumors 
Trial. 
J 
Clin 
Oncol. 
2007 
Sep 
20;25(27):4224-30.
[04FZ6S]
[Disis, M. L. 2010]
Disis ML. Immune regulation of cancer. J Clin 
Oncol 2010;28(29):4531-8.
[058SQL]
[Douillard, J. Y., et al 
2010]
Douillard JY, Siena S, Cassidy J, Tabernero J, 
Burkes R, Barugel M, et al. Randomized, phase III 
trial of panitumumab with infusional fluorouracil, 
leucovorin, and oxaliplatin (FOLFOX4) versus 
FOLFOX4 alone as first-line treatment in patients 
with previously untreated metastatic colorectal 
cancer: the PRIME study. J Clin Oncol. 2010 Nov 
1;28(31):4697-705.
[04G2DC]
[Ducreux, M., et al 
2011]
Ducreux M, Bennouna J, Hebbar M, Ychou M, 
Lledo G, Conroy T, et al. Capecitabine plus 
oxaliplatin 
(XELOX) 
versus 
5-
fluorouracil/leucovorin 
plus 
oxaliplatin 
(FOLFOX-6) as first-line treatment for metastatic 
colorectal cancer. Int J Cancer. 2011 Feb 
1;128(3):682-90.
[04FZ6Y]
08JTB4


Product:  MK-3475 
136
Protocol/Amendment No.: 651-04
MK-3475-651-04 Final Protocol
08-Jun-2022
Confidential
[Dudley, M. E., et al 
2005]
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.
[00VMPR]
[Dummer, R., et al 
2016]
Dummer R, Ascierto PA, Gogas HJ, Arance A, 
Mandala M, Liszkay G, et al. Results of 
COLUMBUS Part 1: A phase 3 trial of 
Encorafenib (ENCO) Plus Binimetinib (BINI) 
versus Vemurafenib (VEM) or ENCO in BRAF-
Mutant Melanoma. Poster session presented at: 
13th International Congress of the Society for 
Melanoma Research; 2016 Nov 6-9; Boston, MA.
[04MW47]
[Dummer, R., et al 
2017]
Dummer R, Schadendorf D, Ascierto PA, Arance 
A, Dutriaux C, Di Giacomo AM, et al. Binimetinib 
versus dacarbazine in patients with advanced 
NRAS-mutant melanoma (NEMO): a multicentre, 
open-label, randomised, phase 3 trial. Lancet 
Oncol. 2017 Mar 8. pii: S1470-2045(17)30180-8. 
[Epub ahead of print].
[04MW49]
[Emens, L. A. 2015]
Emens LA, Middleton G. The interplay of 
immunotherapy and chemotherapy: harnessing 
potential synergies. Cancer Immunol Res. 2015 
May;3(5):436-43.
[04BLP8]
[Francisco, L. M., et al 
2010]
Francisco LM, Sage PT, Sharpe AH. The PD-1 
pathway in tolerance and autoimmunity. Immunol 
Rev 2010;236:219-42.
[058SQP]
[Fuchs, C. S., et al 
2007]
Fuchs CS, Marshall J, Mitchell E, Wierzbicki R, 
Ganju V, Jeffery M, et al. Randomized, controlled 
trial of irinotecan plus infusional, bolus, or oral 
fluoropyrimidines 
in 
first-line 
treatment 
of 
metastatic colorectal cancer: results from the 
BICC-C 
Study. 
J 
Clin 
Oncol. 2007 
Oct 
20;25(30):4779-86.
[045QL4]
[Galluzzi, L., et al 
2015]
Galluzzi L, Buque A, Kepp O, Zitvogel L, 
Kroemer 
G. 
Immunological 
effects 
of 
conventional 
chemotherapy 
and 
targeted 
Anticancer agents. Cancer Cell. 2015 Dec 
14;28(6):690-714.
[04NCRQ]
08JTB4


Product:  MK-3475 
137
Protocol/Amendment No.: 651-04
MK-3475-651-04 Final Protocol
08-Jun-2022
Confidential
[Giantonio, B. J., et al 
2007]
Giantonio BJ, Catalano PJ, Meropol NJ, O'Dwyer 
PJ, Mitchell EP, Alberts SR, et al. Bevacizumab in 
combination with oxaliplatin, fluorouracil, and 
leucovorin (FOLFOX4) for previously treated 
metastatic colorectal cancer: results from the 
Eastern Cooperative Oncology Group Study 
E3200. J Clin Oncol. 2007 Apr 20;25(12):1539-
44.
[04FXZN]
[Greenwald, R. J., et al 
2005]
Greenwald RJ, Freeman GJ, Sharpe AH. The B7 
family revisited. Annu Rev Immunol 2005;23:515-
48.
[00VMQL]
[Grothey, A., et al 
2013]
Grothey A, Van Cutsem E, Sobrero A, Siena S, 
Falcone A, Ychou M, et al. Regorafenib 
monotherapy for previously treated metastatic 
colorectal cancer (CORRECT): an international, 
multicentre, 
randomised, 
placebo-controlled, 
phase 3 trial. Lancet. 2013 Jan 26;381(9863):303-
12.
[043VF0]
[Heinemann, V., et al 
2014]
Heinemann V, von Weikersthal LF, Decker T, 
Kiani A, Vehling-Kaiser U, Al-Batran SE, et al. 
FOLFIRI plus cetuximab versus FOLFIRI plus 
bevacizumab as first-line treatment for patients 
with metastatic colorectal cancer (FIRE-3): a 
randomised, open-label, phase 3 trial. Lancet 
Oncol. 2014 Sep;15(10):1065-75.
[045QM0]
[Hochster, H. S., et al 
2014]
Hochster HS, Grothey A, Hart L, Rowland K, 
Ansari R, Alberts S, et al. Improved time to 
treatment failure with an intermittent oxaliplatin 
strategy: results of CONcePT. Ann Oncol. 2014 
Jun;25(6):1172-8.
[04N4DY]
[Hunder, N. N., et al 
2008]
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.
[00VMPX]
[Hurwitz, H., et al 
2004]
Hurwitz H, 
Fehrenbacher L, Novotny 
W, 
Cartwright T, Hainsworth J, Heim W, et al. 
Bevacizumab plus irinotecan, fluorouracil, and 
leucovorin for metastatic colorectal cancer. N Engl 
J Med. 2004 Jun 3;350(23):2335-42.
[045QMB]
08JTB4


Product:  MK-3475 
138
Protocol/Amendment No.: 651-04
MK-3475-651-04 Final Protocol
08-Jun-2022
Confidential
[Infante, J. R., et al 
2012]
Infante 
JR,
Fecher 
LA, 
Falchook 
GS, 
Nallapareddy S, Gordon MS, Becerra C, et al. 
Safety, pharmacokinetic, pharmacodynamic, and 
efficacy data for the oral MEK inhibitor 
trametinib: a phase 1 dose-escalation trial. Lancet 
Oncol. 2012 Aug;13(8):773-81.
[04S3B7]
[Iwai, Y., et al 2002]
Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, 
Minato N. Involvement of PD-L1 on tumor cells in 
the escape from host immune system and tumor 
immunotherapy by PD-L1 blockade. Proc Natl 
Acad Sci U S A 2002;99(19):12293-7.
[00VMNR]
[Iwamoto, S., et al 
2015]
Iwamoto S, Takahashi T, Tamagawa H, Nakamura 
M, Munemoto Y, Kato T, et al. FOLFIRI plus 
bevacizumab as second-line therapy in patients 
with metastatic colorectal cancer after first-line 
bevacizumab plus oxaliplatin-based therapy: the 
randomized phase III EAGLE study. Ann Oncol. 
2015 Jul;26(7):1427-33.
[04FXZD]
[Ji Y, Li Y, Bekele BN 
2007]
Ji Y, Li Y, Bekele BN. Dose-finding in phase l 
clinical trials based on toxicity probability 
intervals. Clin Trials 2007;4:235-44.
[03TFYL]
[Katsuta, E. 2011]
Katsuta E, Kaneko J, Someno Y, Saguchi M, 
Aoyagi H, Yoshida T, et al. A case of interstitial 
pneumonia 
induced 
by 
CPT-11 
for 
local 
recurrence of rectal cancer [abstract]. Gan To 
Kagaku Ryoho. 2011 Jul;38(7):1225-7.
[04S6P5]
[Korman, A., et
al 
2007]
Korman A, Chen B, Wang C, Wu L, Cardarelli P, 
Selby M. Activity of anti-PD-1 in murine tumor 
models: role of "host" PD-L1 and synergistic 
effect of anti-PD-1 and anti-CTLA-4 [Abstract]. J 
Immunol 2007;178:48.37.
[00VMPZ]
[Lacouture, M. E., et al
2011]
Lacouture ME, Anadkat MJ, Bensadoun RJ, Bryce 
J, Chan A, Epstein JB, et al. Clinical practice 
guidelines for the prevention and treatment of 
EGFR inhibitor-associated dermatologic toxicities. 
Support Care Cancer. 2011 Aug;19(8):1079-95.
[04MPRX]
08JTB4


Product:  MK-3475 
139
Protocol/Amendment No.: 651-04
MK-3475-651-04 Final Protocol
08-Jun-2022
Confidential
[Langer, C. J., et al 
2016]
Langer 
CJ, 
Gadgeel 
SM, 
Borghaei 
H, 
Papadimitrakopoulou VA, Patnaik A, Powell SF, 
et al. Carboplatin and pemetrexed with or without 
pembrolizumab for advanced, non-squamous non-
small-cell lung cancer: a randomised, phase 2 
cohort of the open-label KEYNOTE-021 study. 
Lancet Oncol. 2016 Oct 9. [Epub ahead of print].
[04JNLW]
[Larkin, J., et al 2014]
Larkin J, Ascierto PA, Dreno B, Atkinson V, 
Liszkay G, Maio M, et al. Combined vemurafenib 
and cobimetinib in BRAF-mutated melanoma. N
Engl J Med. 2014 Nov 13;371(20):1867-76.
[04B8P2]
[Le, D. T., et al 2015]
Le DT, Uram JN, Wang H, Bartlett BR, 
Kemberling H, Eyring AD, et al. PD-1 Blockade 
in Tumors with Mismatch-Repair Deficiency. N 
Engl J Med. 2015 May 30. [Epub ahead of print]
[0462RS]
[Le, D. T., et al 2016]
Le DT, Uram JN, Wang H, Bartlett B, Kemberling 
H, Eyring A, et al. Programmed death1 blockade 
in mismatch repair deficient colorectal cancer 
[abstract]. Abstracts of the 2016 ASCO Annual 
Meeting; 2016 Jun 3-7; Chicago, IL: ASCO; 2016. 
p. 1- 2.
[04P9RH]
[Lee, Y. J. 2014]
Lee YJ, Kim JH, Kim SW, Kang WC, Kim SJ, 
Kim JH, Kim SJ. A Case of Organizing 
Pneumonia 
Associated 
with 
FOLFIRI 
Chemotherapy. Tuberc Respir Dis (Seoul). 2014 
Dec;77(6):262-5.
[04S6MH]
[Maeda, K., et al 2011]
Maeda K, Hazama S, Tokuno K, Kan S, Maeda Y, 
Watanabe Y, et al. Impact of chemotherapy for 
colorectal cancer on regulatory T-cells and tumor 
immunity. Anticancer Res. 2011 Dec;31(12):4569-
74.
[04S6PK]
[Masi, G., et al 2015]
Masi G, Salvatore L, Boni L, Loupakis F, 
Cremolini C, Fornaro L, et al. Continuation or 
reintroduction of bevacizumab beyond progression 
to first-line therapy in metastatic colorectal cancer: 
final results of the randomized BEBYP trial. Ann 
Oncol. 2015 Apr;26(4):724-30.
[04FXRS]
08JTB4


Product:  MK-3475 
140
Protocol/Amendment No.: 651-04
MK-3475-651-04 Final Protocol
08-Jun-2022
Confidential
[Morrissey, K. M., et al 
2016]
Morrissey KM, Yuraszeck TM, Li CC, Zhang Y, 
Kasichayanula S. Immunotherapy and Novel 
Combinations in Oncology: Current Landscape, 
Challenges, and Opportunities. Clin Transl Sci. 
2016 Apr;9(2):89-104.
[04MHLG]
[Moskovitz, M. 2015]
Moskovitz M, Wollner M, Haim N. Oxaliplatin-
Induced Pulmonary Toxicity in Gastrointestinal 
Malignancies: Two Case Reports and Review of 
the 
Literature. 
Case 
Rep 
Oncol 
Med. 
2015;2015:341064.
[04S6MN]
[Muro, K., et al 2010]
Muro K, Boku N, Shimada Y, Tsuji A, Sameshima 
S, Baba H, et al. Irinotecan plus S-1 (IRIS) versus 
fluorouracil and folinic acid plus irinotecan 
(FOLFIRI) as second-line chemotherapy for 
metastatic colorectal cancer: a randomised phase 
2/3 non-inferiority study (FIRIS study). Lancet 
Oncol. 2010 Sep;11(9):853-60.
[04S4GC]
[National 
Comprehensive Cancer 
Network 2015]
National Comprehensive Cancer Network. Clinical 
Practice 
Guidelines 
in 
Oncology 
(NCCN 
Guidelines): 
Colon 
Cancer 
version 
2.2016 
[Internet]. 
Fort 
Washington 
(PA): 
National 
Comprehensive Cancer Network; c2015. Available 
from: www.nccn.org/patients.
[04FZ74]
[National 
Comprehensive Cancer 
Network 2017]
National 
Comprehensive 
Cancer 
Network 
(NCCN). Clinical practice guidelines in oncology: 
Colon cancer: version 1.2017. Fort Washington, 
PA: NCCN; 2017.
[04MCXK]
[Nomi, T., et al 2007]
Nomi T, Sho M, Akahori T, Hamada K, Kubo A, 
Kanehiro H, et al. Clinical significance and 
therapeutic potential of the programmed death-1 
ligand/programmed death-1 pathway in human 
pancreatic 
cancer. 
Clin 
Cancer 
Res 
2007;13(7):2151-7.
[00VMNS]
[Okazaki, T., et al 
2001]
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. Proc Natl Acad 
Sci U S A 2001;98(24):13866-71.
[00VMQ6]
08JTB4


Product:  MK-3475 
141
Protocol/Amendment No.: 651-04
MK-3475-651-04 Final Protocol
08-Jun-2022
Confidential
[Overman, M. J., et al 
2016]
Overman MJ, Kopetz S, McDermott RS, Leach J, 
Lonardi S, Lenz H, et al. Nivolumab ± ipilimumab 
in treatment (tx) of patients (pts) with metastatic 
colorectal cancer (mCRC) with and without high 
microsatellite instability (MSIH): CheckMate142 
interim results [abstract]. Abstracts of the 2016 
ASCO Annual Meeting; 2016 Jun 3-7; Chicago, 
IL: ASCO; 2016. p. 1- 2.
[04P9RQ]
[Parry, R. V., et al 
2005]
Parry RV, Chemnitz JM, Frauwirth KA, Lanfranco 
AR, Braunstein I, Kobayashi SV, et al. CTLA-4 
and PD-1 receptors inhibit T-cell activation by 
distinct 
mechanisms. 
Mol 
Cell 
Biol 
2005;25(21):9543-53.
[00VMQ7]
[Peeters, M. 2015]
Peeters M, Oliner KS, Price TJ, Cervantes A, 
Sobrero AF, Ducreux M, et al. Analysis of 
KRAS/NRAS Mutations in a Phase III Study of 
Panitumumab with FOLFIRI Compared with 
FOLFIRI Alone as Second-line Treatment for 
Metastatic Colorectal Cancer. Clin Cancer Res. 
2015 Dec 15;21(24):5469-79.
[04S0R7]
[Peppercorn, 
P. 
D. 
1998]
Peppercorn PD, Reznek RH, Wilson P, Slevin ML, 
Gupta RK. Demonstration of hepatic steatosis by 
computerized tomography in patients receiving 5-
fluorouracil-based therapy for advanced colorectal 
cancer. Br J Cancer. 1998 Jun;77(11):2008-11.
[04S0R8]
[Pfirschke, C., et al 
2016]
Pfirschke C, Engblom C, Rickelt S, Cortez-
Retamozo V, Garris C, Pucci F, Et al. 
Immunogenic chemotherapy sensitizes tumors to 
checkpoint blockade therapy. Immunity. 2016 Feb 
16;44(2):343-54.
[04S3LQ]
[Pölcher, M., 
et al 
2010]
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(6):909-19.
[00VMQ8]
08JTB4


Product:  MK-3475 
142
Protocol/Amendment No.: 651-04
MK-3475-651-04 Final Protocol
08-Jun-2022
Confidential
[Porschen, R., et al 
2007]
Porschen R, Arkenau HT, Kubicka S, Greil R, 
Seufferlein T, Freier W, et al. Phase III study of 
capecitabine plus oxaliplatin compared with 
fluorouracil and leucovorin plus oxaliplatin in 
metastatic colorectal cancer: a final report of the 
AIO Colorectal Study Group. J Clin Oncol. 2007 
Sep 20;25(27):4217-23.
[04FZ7C]
[Reck, M., et al 2016]
Reck M, Rodriguez-Abreu D, Robinson AG, Hui 
R, Csoszi T, Fulop A, et al. Pembrolizumab versus 
Chemotherapy for PD-L1-Positive Non-Small-Cell 
Lung Cancer. N Engl J Med. 2016 Oct 8. [Epub 
ahead of print].
[04JNM3]
[Riley, J. L. 2009]
Riley JL. PD-1 signaling in primary T cells. 
Immunol Rev 2009;229:114-25.
[00VMQ9]
[Robinson, S. M., et al 
2012]
Robinson SM, Wilson CH, Burt AD, Manas DM, 
White SA. Chemotherapy-associated liver injury 
in patients with colorectal liver metastases: a 
systematic review and meta-analysis. Ann Surg 
Oncol. 2012 Dec;19(13):4287-99.
[04S09G]
[Roila, F., et al 2010]
Roila F, Herrstedt J, Aapro M, Gralla RJ, Einhorn 
LH, Ballatori E, et al. Guideline update for 
MASCC and ESMO in the prevention of 
chemotherapy- and radiotherapy-induced nausea 
and vomiting: results of the Perugia consensus 
conference. Ann Oncol 2010;21(suppl 5):v232-
v243.
[03RC6L]
[Ropponen, K. M., et al 
1997]
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(3):318-24.
[00VMQT]
[Rothenberg, M. L., et 
al 2008]
Rothenberg ML, Cox JV, Butts C, Navarro M, 
Bang YJ, Goel R, et al. Capecitabine plus 
oxaliplatin (XELOX) versus 5-fluorouracil/folinic 
acid plus oxaliplatin (FOLFOX-4) as second-line 
therapy 
in 
metastatic 
colorectal 
cancer: 
a 
randomized phase III noninferiority study. Ann 
Oncol. 2008 Oct;19(10):1720-6.
[04FXRN]
08JTB4


Product:  MK-3475 
143
Protocol/Amendment No.: 651-04
MK-3475-651-04 Final Protocol
08-Jun-2022
Confidential
[Sepulveda, A. R., et al 
2017]
Sepulveda AR, Hamilton SR, Allegra CJ, Grody 
W, Cushman-Vokoun AM, Funkhouser  WK, et al. 
Molecular biomarkers for the evaluation of 
colorectal cancer: Guideline from the American 
Society for Clinical Pathology, college of 
American Pathologists, Association for Molecular 
Pathology, and American Society of Clinical 
Oncology. J Mol Diagn. 2017 Mar;19(2):187-225.
[04MNGL]
[Seymour, L., et al 
2017]
Seymour L, Bogaerts J, Perrone A, Ford R, 
Schwartz LH, Mandrekar S, et al. iRECIST: 
guidelines for response criteria for use in trials 
testing immunotherapeutics. Lancet Oncol. 2017 
Mar;18(3):e143-52.
[04P9RV]
[Sheppard, K-A, et al 
2004]
Sheppard K-A, Fitz LJ, Lee JM, Benander C, 
George JA, Wooters J, et al. PD-1 inhibits T-cell 
receptor 
induced 
phosphorylation 
of 
the 
ZAP70/CD3zeta signalosome and downstream 
signaling to PKCtheta. FEBS Lett. 2004;574:37-
41.
[00VMQC]
[Siegel, R. L., et al 
2015]
Siegel RL, Miller KD, Jemal A. Cancer statistics, 
2015. CA Cancer J Clin. 2015 Jan;65(1):5-29.
[043NDC]
[Tabernero, J., et al 
2015]
Tabernero J, Yoshino T, Cohn AL, Obermannova 
R, Bodoky G, Garcia-Carbonero R, et al. 
Ramucirumab versus placebo in combination with 
second-line FOLFIRI in patients with metastatic 
colorectal carcinoma that progressed during or 
after 
first-line 
therapy 
with 
bevacizumab, 
oxaliplatin, and a fluoropyrimidine (RAISE): a 
randomised, double-blind, multicentre, phase 3 
study. Lancet Oncol. 2015 May;16(5):499-508.
[04FXSK]
[Tesniere, A., et al 
2010]
Tesniere A, Schlemmer F, Boige V, Kepp O, 
Martins I, Ghiringhelli F, et al. Immunogenic 
death of colon cancer cells treated with oxaliplatin. 
Oncogene. 2010 Jan 28;29(4):482-91.
[04RQ5V]
08JTB4


Product:  MK-3475 
144
Protocol/Amendment No.: 651-04
MK-3475-651-04 Final Protocol
08-Jun-2022
Confidential
[Thet Cho, M., et al 
2016]
Thet Cho M, Lim D, Synold TW, Frankel PH, 
Leong LA, Chao J, et al. A phase I study of 
MEK162 and FOLFOX in chemotherapy-resistant 
metastatic colorectal cancer [abstract]. Abstracts 
of the 2016 Gastrointestinal Cancers Symposium; 
2016 Jan 21-23; San Francisco, CA: ASCO; 2016. 
p. 1-2.
[04MCNF]
[Tournigand, C., et al 
2004]
Tournigand C, Andre T, Achille E, Lledo G, Flesh 
M, Mery-Mignard D, et al. FOLFIRI followed by 
FOLFOX6 or the reverse sequence in advanced 
colorectal cancer: a randomized GERCOR study. J 
Clin Oncol. 2004 Jan 15;22(2):229-37.
[04780L]
[Tournigand, C., et al 
2004]
Tournigand C, AndréT, Achille E, Lledo G, Flesh 
M, Mery-Mignard D, et al. FOLFIRI followed by 
FOLFOX6 or the reverse sequence in advanced 
colorectal cancer: A randomized GERCOR study. 
J Clin Oncol 2004;22(2):229-37.
[03QBYN]
[U.S. 
Prescribing 
Information 2012]
U.S. 
Prescribing 
Information: 
STIVARGA 
(regorafenib) tablets, oral: September 2012.
[044H62]
[Van Cutsem, E., et al 
2012]
Van Cutsem E, Tabernero J, Lakomy R, Prenen H, 
Prausova J, Macarulla T, et al. Addition of 
aflibercept 
to 
fluorouracil, 
leucovorin, 
and 
irinotecan improves survival in a phase III 
randomized trial in patients with metastatic 
colorectal cancer previously treated with an 
oxaliplatin-based regimen. J Clin Oncol. 2012 Oct 
1;30(28):3499-506.
[04FXSM]
[Van Cutsem, E., et al 
2015]
Van Cutsem E, Lenz HJ, Kohne CH, Heinemann 
V, Tejpar S, Melezinek I, et al. Fluorouracil, 
leucovorin, 
and 
irinotecan 
plus 
cetuximab 
treatment and RAS mutations in colorectal cancer. 
J Clin Oncol. 2015 Mar 1;33(7):692-700.
[04FZ7K]
[Van Cutsem, E., et al 
2016]
Van Cutsem E, Cervantes A, Adam R, Sobrero A, 
Van Krieken JH, Aderka D, et al. ESMO 
consensus guidelines for the management of 
patients with metastatic colorectal cancer. Ann 
Oncol. 2016 Aug;27(8):1386-422.
[04MMYZ]
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[Vella, L. J., et al 2014]
Vella LJ, Pasam A, Dimopoulos N, Andrews M, 
Knights A, Puaux AL, et al. MEK inhibition, alone 
or in combination with BRAF inhibition, affects 
multiple functions of isolated normal human 
lymphocytes and dendritic cells. Cancer Immunol 
Res. 2014 Apr;2(4):351-60.
[04NCRW]
[Vincent, J., et al 2010]
Vincent J, Mignot G, Chalmin F, Ladoire S, 
Bruchard M, Chevriaux A, et al. 5-Fluorouracil 
selectively kills tumor-associated myeloid-derived 
suppressor cells resulting in enhanced T cell-
dependent antitumor immunity. Cancer Res. 2010 
Apr 15;70(8):3052-61.
[04NCS5]
[Vincenzi, B., et al 
2015]
Vincenzi B, Imperatori M, Picardi A, Vespasiani 
Gentilucci U, Gallo P, Fausti V, et al. Liver 
toxicity in colorectal cancer patients treated with 
first-line FOLFIRI-containing regimen: a single 
institution experience. Expert Rev Anticancer 
Ther. 2015;15(8):971-6.
[04S09H]
[Wallin, J., et al 2016]
Wallin J, Pishvaian MJ, Hernandez G, Yadav M, 
Jhunjhunwala S, Delamarre L, et al. Clinical 
activity and immune correlates from a phase Ib 
study evaluating atezolizumab (anti-PDL1) in 
combination with FOLFOX and bevacizumab 
(anti-VEGF) in metastatic colorectal carcinoma 
[abstract]. Clinical Research. 2016 Jul;76(14 
Suppl). Abstract no. 2651.
[04N6CV]
[Weinstock, M. 2015]
Weinstock M, McDermott D. Targeting PD-1/PD-
L1 in the treatment of metastatic  renal cell 
carcinoma. Ther Adv Urol. 2015 Dec;7(6):365-77.
[04N47S]
[Weiss, G. J., et al 
2017]
Weiss GJ, Waypa J, Blaydorn L, Coats J, 
McGahey K, Sangal A, et al. A phase Ib study of 
pembrolizumab plus chemotherapy in patients 
with advanced cancer (PembroPlus). Br J Cancer. 
2017 Jun 27;117(1):33-40.
[04S4H2]
[Zhang, X., et al 2004]
Zhang X, Schwartz J-CD, Guo X, Bhatia S, Cao E, 
Chen L, et al. Structural and functional analysis of 
the costimulatory receptor programmed death-1. 
Immunity 2004;20:337-47.
[00VMQJ]
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[Zhou, J., et al 2017]
Zhou J, Yang T, Liu L, Lu B. Chemotherapy 
oxaliplatin sensitizes prostate cancer to immune 
checkpoint blockade therapies via stimulating 
tumor immunogenicity. Mol Med Rep. 2017 
Sep;16(3):2868-2874.
[04S3LR]
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12. Appendices
Appendix 1: Abbreviations and Trademarks
Abbreviation
Definition
1L
first line
2L
second line
5-FU
fluorouracil
AE
adverse event
ALT
alanine aminotransferase
ANC
absolute neutrophil count
aPTT
activated partial thromboplastin time
APaT
All-Participants-as-Treated
ASCO
American Society of Clinical Oncology
AST
aspartate aminotransferase
ATP
Adenosine triphosphate 
BCRP
breast cancer resistance protein 
β-hCG
human chorionic gonadotropin 
BICR
Blinded Independent Central Review
BID
twice daily
CEA
carcinoembryonic antigen
CD3ζ
CD3 zeta
CHF
congestive heart failure
CI
confidence interval
CNS
central nervous system
CONSORT
Consolidated Standards of Reporting Trials
COPD
chronic obstructive pulmonary disease
CPK
creatine phosphokinase
CR
complete response
CRC
colorectal cancer
CRF
case report form
CSR
Clinical Study Report
CT
computerized tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTL
cytotoxic T lymphocytes
CTL-4
cytotoxic T lymphocytes-associated protein 4
CVA
cerebrovascular accidents
DCR
disease control rate
DILI
drug-induced liver injury
DBP
diastolic blood pressure
DL
dose level
DL1
Standard dose
DL-1
de-escalation dose
DL2
escalation dose
DLT
dose-limiting toxicity
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Abbreviation
Definition
dMMR
deficient mismatch repair
DNA
deoxyribonucleic acid
DOR
duration of response
ECG
electrocardiogram
ECI
events of clinical interest
ECOG
Eastern Cooperative Oncology Group
ECHO
echocardiogram
EDC
electronic data capture
EGF
epidermal growth factor
EGFR
epidermal growth factor receptor
EOT
end of trial
ESMO
European Society for Medical Oncology
FAS
Full Analysis Set
FBR
Future Biomedical Research
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FOLFIRI
(irinotecan [180 mg/m2]; leucovorin [calcium folinate] [400 mg/m2]; 5-
FU 2400 mg/m2)
FOLFOX, 
mFOLFOX6, 
mFOLFOX7
(oxaliplatin [85 mg/m2]; leucovorin [calcium folinate] [400 mg/m2]; 5-
FU 2400 mg/m2)
5-FU
fluorouracil 
GCP
Good Clinical Practice
HBsAG
Hepatitis B surface antigen
HCV
Hepatitis C virus
HIV
human immunodeficiency virus
HLA
human leukocyte antigen
HNSCC
head and neck squamous cell carcinoma
IB
Investigator’s Brochure
IC50
half maximal inhibitory concentration
ICF
informed consent form
ICH
International Conference on Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use
iCPD
iRECIST confirmed progressive disease
iCR
iRECIST complete response
IgG4
immunoglobulin G4
IHC
immunohistochemistry
INR
International Normalized Ratio
irAE
immune-related adverse event
IRB/IEC
Institutional Review Board/Independent Ethics Committee
iRECIST
modified Response Evaluation Criteria in Solid Tumors 1.1 for 
immune-based therapeutics 
iSD
iRECIST stable disease
iUPD
iRECIST unconfirmed progressive disease
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Abbreviation
Definition
IV
intravenous
IVRS/IWRS
interactive voice response system, integrated web response system
LVEF
left ventricular ejection fraction;
mAb
monoclonal antibody
MASCC
Multinational Association  of Supportive Care
mCRC
metastatic colorectal cancer
MHC1
major histocompatibility complex1
MMR
mismatch repair
MRI
magnetic resonance imaging
mRNA
messenger RNA
MSI
microsatellite instability
MSI-H
microsatellite instability high
MTD
maximum tolerated dose
mTPI
modified toxicity probability interval
MUGA
multigated acquisition
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NSCLC
non-small cell lung cancer
OCT
optical coherence tomography
ORR
objective response rate
OS
overall survival
PABA
para-aminobenzoic acid
PBPK
physiologically-based pharmacokinetic
PCR
polymerase chain reaction
PD
progressive disease
PD-1
programmed death 1
PD-L1
programmed cell death ligand 1
PD-L2
programmed cell death ligand 2
PET
positron emission tomography
PFS
Progression-free survival
P-gp
P-glycoprotein
PK
pharmacokinetic
PKCθ
protein kinase C-theta
pMMR
proficient mismatch repair
PO
oral
PSN
peripheral sensory neuropathy
PSVT
paroxysmal supraventricular tachycardia
PT
prothrombin time
PTT
partial thromboplastin time
QD
once daily
Q2W
every 2 weeks
Q3W
every 3 weeks
Q9W
every 9 weeks
Q12W
every 12 weeks
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Abbreviation
Definition
QTc
Q-T interval
QTcF
QT interval calculated according to the Fridericia method
RECIST 1.1
Response Evaluation Criteria In Solid Tumors 1.1
RP2D
recommended Phase 2 dose
RPED
retinal pigment epithelial detachment
RNA
ribonucleic acid
RVO
retinal vein occlusion
SAE
serious adverse event
SAP
statistical analysis plan
SBP
systolic blood pressure
SIM
Site Imaging Manual
SNP
single nucleotide polymorphism
SoA
schedule of activities
SOC
standard of care
sSAP
supplemental statistical analysis plan
T3, T4
triiodothronine, thyroxine
TCR
T-cell receptor
TIA
transient ischemic attacks
TIL
tumor infiltrating lymphocyte
TMDD
target-mediated drug disposition
TPS
tumor proportion score
T-reg
Regulatory T cells
TSH
thyroid stimulating hormone
ULN
upper limit of normal
UVA
ultraviolet A
UVB
ultraviolet B
VEGF
vascular endothelial growth factor
VEGFR
vascular endothelial growth factor receptor
WOCBP
woman of childbearing potential
ZAP70
zeta-chain-associated protein kinase
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Appendix 2: ECOG Performance Status
Grade
Description
0
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction.
1
Symptoms, but ambulatory. Restricted in physically strenuous activity, 
but ambulatory and able to carry out work of a light or sedentary nature 
(eg, light housework, office work).
2
In bed < 50% of the time. Ambulatory and capable of all self-care, but 
unable to carry out any work activities. Up and about more than 50% 
of waking hours.
3
In bed > 50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair.
5
Dead.
* As published in Am. J. Clin. Oncol.: Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden 
ET, Carbone PP: Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin 
Oncol. 1982;5:649-655. The Eastern Cooperative Oncology Group, Robert Comis M.D., Group Chair.
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Appendix 3: Clinical Laboratory Tests 

The tests detailed in Table 13 will be performed by the local laboratory. 

Protocol-specific requirements for inclusion or exclusion of participants are detailed 
in Sections 6.1 and 6.2 of the protocol.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.
Table 13
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
RBC Indices:
MCV
MCH
WBC count (total and 
differential)a:
Absolute neutrophil 
countb
Absolute lymphocyte 
countb Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Chemistry
Blood Urea 
Nitrogen 
(BUN)c
Potassium
Aspartate 
Aminotransferase 
(AST)/Serum Glutamic-
Oxaloacetic Transaminase 
(SGOT)
Total bilirubin (and 
direct bilirubin, if total 
bilirubin is elevated 
above the upper limit of 
normal)
Albumin
Bicarbonate 
or Carbon 
dioxided
Chloride
LDH
Creatinine
Sodium
Alanine Aminotransferase 
(ALT)/Serum Glutamic-
Pyruvic Transaminase 
(SGPT)
Total Protein
Glucose 
Calcium
Alkaline phosphatase
Creatine 
phosphokinase 
(CPK)
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood

Microscopic examination (if blood or protein is abnormal)
Other 
Screening 
Tests

Thyroid stimulating hormone (TSH)

Serum tumor markers (CEA [carcinoembryonic antigen])

Total triiodothyronine (T3) or Free T3 (FT3)e

Free thyroxine (FT4)

PT (INR) 

aPTT 

Serum or urine β human chorionic gonadotropin (β-hCG) pregnancy test (as needed for 
women of childbearing potential)f

Serology [(HIV antibody, hepatitis B surface antigen [HBsAg], and hepatitis C virus 
antibody)] [if applicable] 

All study-required laboratory assessments will be performed by a local laboratory, with 
the exception of: Blood for ribonucleic acid (RNA) analyses, blood for plasma 
biomarker analyses, binimetinib pharmacokinetics (PK), Blood for genetics analyses, 
and irinotecan and SN-38 PK
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Laboratory 
Assessments
Parameters
NOTES:
a.
Absolute results will be requested for the clinical database.
b.
Results should be calculated per local standard of practice.
c.
Blood Urea Nitrogen is preferred; if not available urea may be tested.
d.
If these tests are not done as part of standard of care in your region then these test do not need to be performed.
e.
T3 is preferred; if not available free T3 may be tested. If the local laboratory is unable to perform either of these 
tests the site should submit the sample to the central laboratory for testing; details are provided in the Procedures 
Manual.
f.
Perform on women of childbearing potential only.  Serum pregnancy test is required.
Investigators must document their review of each laboratory safety report.
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Appendix 4: Study Governance Considerations
Code of Conduct for Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, 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 participants in clinical trials is the 
overriding concern in the design and conduct of clinical trials. In all cases, MSD clinical trials will be conducted 
in compliance with local and/or national regulations (including all applicable data protection laws and 
regulations), and International Council for Harmonisation Good Clinical Practice (ICH-GCP), and also in 
accordance with the ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD 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 that are observational in nature, or 
which are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the 
full control of MSD.
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 MSD or comparator products. Alternatively, MSD 
may conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to 
determine patient preferences, etc.
The design (i.e., participant population, duration, statistical power) must be adequate to address the specific 
purpose of the trial and shall respect the data protection rights of all participants, trial site staff and, where 
applicable, third parties. All trial protocols are and will be assessed for the need and capability to enroll 
underrepresented groups. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
MSD’s clinical trials are conducted globally in many different countries and in diverse populations, including 
people of varying age, race, ethnicity, gender, and accounting for other potential disease related factors. MSD 
selects investigative sites based on medical expertise, access to appropriate participants, adequacy of facilities 
and staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial initiation, 
sites are evaluated by MSD personnel (or individuals acting on behalf of MSD) to assess the ability to 
successfully conduct the trial.
Where appropriate, and in accordance with regulatory authority guidance, MSD will make concerted efforts 
to raise awareness of clinical trial opportunities in various communities. MSD will seek to engage 
underrepresented groups and those disproportionately impacted by the disease under study. MSD will support 
clinical trial investigators to enroll underrepresented groups and expand access to those who will ultimately 
use the products under investigation.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and Good Clinical Practice 
(GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data are verified versus 
source documentation according to standard operating procedures. Per MSD policies and procedures, if 
potential fraud, scientific/research misconduct, privacy incidents/breaches or Clinical Trial-related 
Significant Quality Issues are reported, such matters are investigated. When necessary, appropriate corrective 
and/or preventative actions are defined and regulatory authorities and/or ethics review committees are 
notified.
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B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the pre-specified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important 
to patients, physicians, and payers. 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 such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). 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. MSD funding of a trial will be acknowledged in 
publications.
III. Participant Protection
A. Regulatory Authority and Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics 
Committee [IEC])
All 
protocols 
and protocol 
amendments 
will 
be 
submitted 
by 
MSD 
for 
regulatory 
authority 
acceptance/authorization prior to implementation of the trial or amendment, in compliance with local and/or 
national regulations.
The protocol, protocol amendment(s), informed consent form, investigator’s brochure, and other relevant trial 
documents must be reviewed and approved by an IRB/IEC before being implemented at each site, in compliance 
with local and/or national regulations. Changes to the protocol that are required urgently to eliminate an 
immediate hazard and to protect participant safety may be enacted in anticipation of ethics committee approval. 
MSD will inform regulatory authorities of such new measures to protect participant safety, in compliance with 
local and/or national regulations.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance. 
Potential participants 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.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Participants may withdraw from an MSD 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
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible, as well as all 
applicable data protection rights. Unless required by law, only the investigator, Sponsor (or individuals acting on 
behalf of MSD), ethics committee, and/or regulatory authorities will have access to confidential medical records 
that might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD does not pay incentives to 
enroll participants in its trials. However, when enrollment is particularly challenging, additional payments may be 
made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent 
on chart review and medical evaluation to identify potentially eligible participants.
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B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may 
wish to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD 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.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
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Financial Disclosure
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 
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. 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.
Data Protection
Participants will be assigned a unique identifier by the sponsor. Any participant records or 
datasets that are transferred to the sponsor will contain the identifier only; participant names 
or any information which would make the participant identifiable will not be transferred. 
The participant must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
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/IEC) 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 Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, 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 participant 
agrees to this process.  If trial documents will be photocopied during the process of verifying 
worksheet/case report form information, the participant will be identified by unique code 
only; full names/initials will be masked prior to transmission to the Sponsor.
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By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this trial in accordance with all applicable privacy laws, rules 
and regulations.
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC 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.
Publication Policy
The results of this study may be published or presented at scientific meetings. The sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the sponsor before submission.  This allows the sponsor to protect 
proprietary information and to provide comments.  
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
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.  MSD, as Sponsor of this trial, will 
review this protocol and submit the information necessary to fulfill these requirements. MSD
entries are not limited to FDAAA or the EMA clinical trial directive mandated trials.  
Information posted will allow participants 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.
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 (eg, International Conference on Harmonization of Technical Requirements 
for Registration of Pharmaceuticals for Human Use Good Clinical Practice: Consolidated 
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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 MSD, is provided in this appendix 
under the Code of Conduct for Clinical Trials.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers or from government programs for procedures included as part of the trial 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this trial.
The Investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting from 
regulatory authority inspection, and will provide the Sponsor with a copy of the proposed response 
for consultation before submission to the regulatory authority. 
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.
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data). The investigator or 
qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF. 
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
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 
requested by the Sponsor or regulatory authority as a result of an audit or inspection to cure 
deficiencies in the trial documentation and worksheets/case report forms.
The sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
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source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements. 
Records and documents, including signed ICF, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the sponsor. 
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available.
Study and Site Closure
The sponsor or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP. 
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will 
promptly notify that trial site’s IRB/IEC.
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Appendix 5: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
Definition of AE
AE Definition
●
An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study treatment, whether or not considered 
related to the study treatment.
●
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study treatment.
●
NOTE: for purposes of AE definition, study treatment (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, device, 
diagnostic agent or protocol specified procedure whether investigational (including 
placebo or active comparator product) or marketed, manufactured by, licensed by, 
provided by or distributed by the sponsor for human use in this study.
Events Meeting the AE Definition 
●
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator.
●
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.
●
New conditions detected or diagnosed after study treatment administration even though 
it may have been present before the start of the study.
●
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
●
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication. 
●
For all reports of overdose (whether accidental or intentional) with an associated 
adverse event, the AE term should reflect the clinical symptoms or abnormal test 
result.  An overdose without any associated clinical symptoms or abnormal laboratory 
results is reported using the terminology “accidental or intentional overdose without 
adverse effect.”
●
Any new cancer (that is not a condition of the study). 
Note: Progression of the cancer under study is not a reportable event. Refer to Section 
9.3.5 for additional details.
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Events NOT Meeting the AE Definition 
●
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads 
to the procedure is the AE.
●
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
●
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
●
Surgery planned prior to informed consent to treat a pre-existing condition that has not 
worsened.
●
Refer to section 9.3.5 for protocol specific exceptions
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met 
A SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b. Is life-threatening
●
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing 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 MSD product and is documented in the 
patient’s medical history.
d. Results in persistent or significant disability/incapacity
●
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
●
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
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e.
Is a congenital anomaly/birth defect
●
in offspring of participant taking the product regardless of time to diagnosis
f.
Other important medical events:
●
Medical or scientific judgment should be exercised in deciding whether SAE reporting 
is appropriate in other situations such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
participant or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These events should usually be considered 
serious.
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency or 
drug abuse.
Additional Events reported in the same manner as SAE
Additional Events which require reporting in the same manner as SAE
●
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.
Recording AE and SAE
AE and SAE Recording
●
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related 
to the event.
●
The investigator will record all relevant AE/SAE information on the Adverse Event 
case report forms/worksheets at each examination.
●
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
●
There may be instances when copies of medical records for certain cases are requested 
by the Sponsor. In this case, all participant identifiers, with the exception of the 
participant number, will be blinded on the copies of the medical records before 
submission to the Sponsor.
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●
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
●
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe.
●
The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) 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.
●
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.
Assessment of Causality
●
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 product 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:
●
Exposure:  Is there evidence that the participant 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?
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●
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
●
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; (3) the trial is a single-dose drug trial); or (4) Sponsor's 
product(s) is/are only used one time.)
●
Rechallenge:  Was the participant re-exposed to the Sponsor's product in this 
trial?
●
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 RE-EXPOSURE TO THE SPONSOR'S PRODUCT POSES 
ADDITIONAL POTENTIAL SIGNIFICANT RISK TO THE PARTICIPANT THEN 
THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR 
CLINICAL DIRECTOR AS PER DOSE MODIFICATION GUIDELINES IN THE 
PROTOCOL, 
AND 
IF 
REQUIRED, 
THE 
INSTITUTIONAL 
REVIEW 
BOARD/INDEPENDENT ETHICS COMMITTEE.
●
Consistency with Study 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.
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●
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:
Participant 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 participant with overdose without an associated AE.)
●
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
●
There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the Sponsor. However, it is very 
important that the investigator always make an assessment of causality for every event 
before the initial transmission of the SAE data to the Sponsor.
●
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.
●
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements
●
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 event to the 
single agent.
Follow-up of AE and SAE
●
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
●
New or updated information will be recorded in the CRF.
●
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
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Reporting of AE, SAE, and Other Reportable Safety Events to the Sponsor 
AE, SAE, and Other Reportable Safety Event Reporting to Sponsor via Electronic 
Data Collection Tool
●
The primary mechanism for reporting to the Sponsor will be the electronic data 
collection (EDC) tool.  
●
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
●
If the electronic system is unavailable for more than 24 hours, then the site will use the 
paper AE Reporting form.  
●
Reference section 9.3.1 – Time Period and Frequency for Collecting AE and SAE and 
Other Reportable Safety Event Information for reporting time requirements 
●
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
●
After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data.
●
If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form or by 
telephone (see next section).
●
Contacts for SAE reporting can be found in the Investigator Trial File Binder (or 
equivalent).
SAE Reporting to the Sponsor via Paper CRF
●
If the electronic data collection tool is not operational, facsimile transmission or secure 
e-mail of the SAE paper CRF is the preferred method to transmit this information to 
the Sponsor.
●
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
●
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
●
Contacts and instructions for SAE reporting and paper reporting procedures can be 
found in the Investigator Trial File Binder (or equivalent).
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Appendix 6: Contraceptive Guidance and Pregnancy Testing
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below) 
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
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 hormonal 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 non-hormonal 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.
Contraception Requirements
Male Participants:
Male participants with female partners of childbearing potential are eligible to participate if 
they agree to one of the following during the protocol defined time frame in section 6.1: 
●
Be abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent
●
Use a male condom plus partner use of a contraceptive method with a failure rate of <1% 
per year as described in Table 14 when having penile-vaginal intercourse with a woman of 
childbearing potential who is not currently pregnant.
○
Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile-vaginal intercourse or use a male condom during each episode of penile 
penetration.
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Female Participants:
Female participants of childbearing potential are eligible to participate if they agree to use 
one of the contraception methods described in Table 14 consistently and correctly during the 
protocol-defined time frame in Section 6.1.
Table 14
Contraceptive Methods
Acceptable Contraceptive Methods 
Failure rate of >1% per year when used consistently and correctly.
●
Male or female condom with or without spermicide
●
Cervical cap, diaphragm or sponge with spermicide
Highly Effective Contraceptive Methods That Are User Dependent a
Failure rate of <1% per year when used consistently and correctly.
●
Combined (estrogen- and progestogen- containing) hormonal contraceptionb
○
Oral 
○
Intravaginal 
○
Transdermal 
○
Injectable
●
Progestogen-only hormonal contraception b
○
Oral 
○
Injectable 
Highly Effective Methods That Have Low User Dependency 
Failure rate of <1% per year when used consistently and correctly.
●
Progestogen- only contraceptive implant b, c
●
Intrauterine hormone-releasing system (IUS) b
●
Intrauterine device (IUD)
●
Bilateral tubal occlusion
●
Vasectomized partner 
A vasectomized partner 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. 
●
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 treatment. 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.) 
Notes: 
Use should be consistent with local regulations regarding the use of contraceptive methods for participants 
of clinical studies.
a) Typical use failure rates are higher than perfect-use failure rates (i.e. when used consistently and 
correctly). 
b) If hormonal contraception efficacy is potentially decreased due to interaction with study treatment, 
condoms must be used in addition to the hormonal contraception during the treatment period and for at least 
120 days after the last dose of study treatment.
c) If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable 
hormonal contraceptives are limited to those which inhibit ovulation. 
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Pregnancy Testing
WOCBP should only be included after a negative highly sensitive urine or serum pregnancy 
test.
Pregnancy testing will be performed whenever an expected menstrual cycle is missed or 
when pregnancy is otherwise suspected.
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Appendix 7: 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 specimens consented and/or collected in this trial as outlined in Section 9.8 – Future 
Biomedical Research Samples will be used in various experiments to understand:
o
The biology of how drugs/vaccines work
o
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
o
Other pathways drugs/vaccines may interact with
o
The biology 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 the Sponsor or those working for 
or with the Sponsor.
3. Summary of Procedures for Future Biomedical Research
a.
Participants for Enrollment
All participants enrolled in the clinical trial will be considered for enrollment in Future 
Biomedical Research.
b. Informed Consent
Informed consent for specimens (i.e., DNA, RNA, protein, etc.) will be obtained during 
screening for protocol enrollment from all participants 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 participants on the visit designated in the trial flow 
chart.  If delayed, present consent at next possible Participant Visit.  Consent forms 
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signed by the participant will be kept at the clinical trial site under secure storage for 
regulatory reasons.  
A template of each trial site’s approved informed consent will be stored in the Sponsor’s 
clinical document repository.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for Future Biomedical Research will be captured in 
the electronic Case Report Forms (eCRFs). Any specimens for which such an informed 
consent cannot be verified will be destroyed.
d. Future Biomedical Research Specimen(s)
Collection of specimens for Future Biomedical Research will be performed as outlined in 
the trial flow chart. In general, if additional blood specimens are being collected for 
Future Biomedical Research, these will usually be obtained at a time when the participant 
is having blood drawn for other trial purposes.
4. Confidential Participant 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 participant' 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 participant 
characteristics like gender, age, medical history and treatment outcomes are critical to 
understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for Future 
Biomedical Research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below. 
At the clinical trial site, unique codes will be placed on the Future Biomedical Research 
specimens.  This code is a random number which does not contain any personally 
identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the trial site.  No personal identifiers will 
appear on the specimen tube.  
5. Biorepository Specimen Usage
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices.  Analyses utilizing the Future Biomedical Research specimens may be 
performed by the Sponsor, or an additional third party (eg, a university investigator) 
designated by the Sponsor. The investigator conducting the analysis will follow the 
Sponsor’s privacy and confidentiality requirements. Any contracted third party analyses 
will conform to the specific scope of analysis outlined in Future Biomedical Research 
and consent. Future Biomedical Research specimens remaining with the third party after 
specific analysis is performed will be reported to the Sponsor.
6. Withdrawal From Future Biomedical Research 
Participants may withdraw their consent for Future Biomedical Research and ask that 
their biospecimens not be used for Future Biomedical Research.  Participants may 
withdraw consent at any time by contacting the principal investigator for the main trial. If 
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medical records for the main trial are still available, the investigator will contact the 
Sponsor using the designated mailbox (clinical.specimen.management@MSD.com). 
Subsequently, the participant's specimens will be flagged in the biorepository and 
restricted to main study use only. If specimens were collected from study participants 
specifically for Future Biomedical Research, these specimens will be removed from the 
biorepository and destroyed. Documentation will be sent to the investigator confirming 
withdrawal and/or destruction, if applicable. It is the responsibility of the investigator to 
inform the participant of completion of the withdrawal and/or destruction, if applicable.  
Any analyses in progress at the time of request for withdrawal/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 (eg, 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 participant’s personal information and their specimens. In this situation, 
the request for withdrawal of consent and/or destruction cannot 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 the end of the main study. 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 Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
trial, the trial site will ship directly to the Sponsor-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 Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated trial administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Participants
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include: Lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
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rapidly report this information to doctors and participants.  Participants will not be 
identified by name in any published reports about this study or in any other scientific 
publication or presentation.
10. Future Biomedical Research Study Population
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical trials for Future Biomedical Research.
11. Risks Versus Benefits of Future Biomedical Research 
For future biomedical research, risks to the participant have been minimized. No 
additional risks to the participant have been identified as no additional specimens are 
being collected for Future Biomedical Research (ie, only leftover samples are being 
retained).]
The Sponsor has developed strict security, policies and procedures to address participant 
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.
12. Questions
Any questions related to the future biomedical research should be e-mailed directly to 
clinical.specimen.management@MSD.com.
13. References
1. National Cancer Institute: http://www.cancer.gov/dictionary/?searchTxt=biomarker
2. International Conference on Harmonization: DEFINITIONS FOR GENOMIC 
BIOMARKERS, PHARMACOGENOMICS, PHARMACOGENETICS, GENOMIC 
DATA 
AND 
SAMPLE 
CODING 
CATEGORIES 
-
E15; 
http://www.ich.org/LOB/media/MEDIA3383.pdf
3. Industry Pharmacogenomics Working Group. Understanding the Intent, Scope and 
Public Health Benefits of Exploratory Biomarker Research: A Guide for IRBs/IECs 
and Investigational Site Staff. Available at http://i-pwg.org/
4. Industry Pharmacogenomics Working Group. Pharmacogenomics Informational 
Brochure for IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/
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Appendix 8: Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 
Criteria for Evaluating Response in Solid Tumors
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. Details are provided in the Image Acquisition Guidelines.
* As published in the European Journal of Cancer:
New response evaluation criteria in solid tumours: revised RECIST guideline (Version 1.1). 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck 
S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij 
J. New response evaluation criteria in solid tumors: Revised RECIST guideline (Version 
1.1). Eur J Cancer. 2009 Jan;45(2):228-247. 
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Appendix 9: Description of the iRECIST Process for Assessment of Disease 
Progression
Assessment at Screening and Prior to RECIST 1.1 Progression
Until radiographic disease progression based on RECIST 1.1, there is no distinct iRECIST 
assessment.
Assessment and Decision at RECIST 1.1 Progression
For participants who show evidence of radiological PD by RECIST 1.1, the investigator will 
decide whether to continue a participant on study treatment until repeat imaging is obtained 
(using iRECIST for participant management) (see Table 9). This decision by the investigator 
should be based on the participant’s overall clinical condition.
Clinical stability is defined as the following: 

Absence of symptoms and signs indicating clinically significant progression of
disease

No decline in ECOG performance status 

No requirements for intensified management, including increased analgesia, 
radiation, or other palliative care
Any participant deemed clinically unstable should be discontinued from study treatment at 
site-assessed first radiologic evidence of PD, and is not required to have repeat tumor 
imaging for confirmation of PD by iRECIST.
If the investigator decides to continue treatment, the participant may continue to receive 
study treatment and the tumor assessment should be repeated 4 to 8 weeks later to confirm 
PD by iRECIST, per investigator assessment. Images should continue to be sent in to the 
central imaging vendor for potential retrospective BICR.
Tumor flare may manifest as any factor causing radiographic progression per RECIST 1.1, 
including:

Increase in the sum of diameters of target lesion(s) identified at baseline to ≥20% and 
≥5 mm from nadir
o
Note: the iRECIST publication uses the terminology “sum of measurements,” but 
“sum of diameters” will be used in this protocol, consistent with the original 
RECIST 1.1 terminology.

Unequivocal progression of non-target lesion(s) identified at baseline

Development of new lesion(s)
iRECIST defines new response categories, including iUPD and iCPD. For purposes of 
iRECIST assessment, the first visit showing progression according to RECIST 1.1 will be 
assigned a visit (overall) response of iUPD, regardless of which factors caused the 
progression.
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At this visit, target and non-target lesions identified at baseline by RECIST 1.1 will be 
assessed as usual.
New lesions will be classified as measurable or non-measurable, using the same size 
thresholds and rules as for baseline lesion assessment in RECIST 1.1. From measurable new 
lesions, up to 5 lesions total (up to 2 per organ), may be selected as New Lesions – Target.  
The sum of diameters of these lesions will be calculated and kept distinct from the sum of 
diameters for target lesions at baseline. All other new lesions will be followed qualitatively 
as New Lesions – Non-target.
Assessment at the Confirmatory Imaging
On the confirmatory imaging, the participant will be classified as progression confirmed 
(with an overall response of iCPD), or as showing persistent unconfirmed progression (with 
an overall response of iUPD), or as showing disease stability or response (iSD/iPR/iCR).
Confirmation of Progression
Progression is considered confirmed, and the overall response will be iCPD, if ANY of the 
following occurs:

Any of the factors that were the basis for the initial iUPD show worsening
o
For target lesions, worsening is a further increase in the sum of diameters of 
≥5 mm, compared to any prior iUPD time point
o
For non-target lesions, worsening is any significant growth in lesions overall, 
compared to a prior iUPD time point; this does not have to meet the 
“unequivocal” standard of RECIST 1.1
o
For new lesions, worsening is any of these:

An increase in the new lesion sum of diameters by ≥5 mm from a prior iUPD 
time point 

Visible growth of new non-target lesions 

The appearance of additional new lesions

Any new factor appears that would have triggered PD by RECIST 1.1
Persistent iUPD
Progression is considered not confirmed, and the overall response remains iUPD, if:

None of the progression-confirming factors identified above occurs AND

The target lesion sum of diameters (initial target lesions) remains above the initial PD 
threshold (by RECIST 1.1)
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Additional imaging for confirmation should be scheduled 4 to 8 weeks from the imaging on 
which iUPD is seen. This may correspond to the next visit in the original visit schedule. The 
assessment of the subsequent confirmation imaging proceeds in an identical manner, with 
possible outcomes of iCPD, iUPD, and iSD/iPR/iCR.
Resolution of iUPD
Progression is considered not confirmed, and the overall response becomes iSD/iPR/iCR, if:

None of the progression-confirming factors identified above occurs, AND

The target lesion sum of diameters (initial target lesions) is not above the initial PD 
threshold. 
The response is classified as iSD or iPR (depending on the sum of diameters of the target 
lesions), or iCR if all lesions resolve.
In this case, the initial iUPD is considered to be pseudo-progression, and the level of 
suspicion for progression is “reset”. This means that the next visit that shows radiographic 
progression, whenever it occurs, is again classified as iUPD by iRECIST, and the 
confirmation process is repeated before a response of iCPD can be assigned.
Management Following the Confirmatory Imaging
If repeat imaging does not confirm PD per iRECIST, as assessed by the investigator, and the 
participant continues to be clinically stable, study treatment may continue and follow the 
regular imaging schedule. If PD is confirmed, participants will be discontinued from study 
treatment. Detection of Progression at Visits after Pseudo-progression Resolves
After resolution of pseudo-progression (ie, achievement of iSD/iPR/iCR), iUPD is indicated 
by any of the following events:

Target lesions
o
Sum of diameters reaches the PD threshold (≥20% and ≥5 mm increase from 
nadir) either for the first time, or after resolution of previous pseudo-progression. 
The nadir is always the smallest sum of diameters seen during the entire trial, 
either before or after an instance of pseudo-progression.

Non-target lesions
o
If non-target lesions have never shown unequivocal progression, their doing so for 
the first time results in iUPD.
o
If non-target lesions have shown previous unequivocal progression, and this 
progression has not resolved, iUPD results from any significant further growth of 
non-target lesions, taken as a whole.
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
New lesions
o
New lesions appear for the first time
o
Additional new lesions appear
o
Previously identified new target lesions show an increase of ≥5 mm in the new 
lesion sum of diameters, from the nadir value of that sum
o
Previously identified non-target lesions show any significant growth
If any of the events above occur, the overall response for that visit is iUPD, and the iUPD 
evaluation process (see Assessment at the Confirmatory Imaging above) is repeated. 
Progression must be confirmed before iCPD can occur.
The decision process is identical to the iUPD confirmation process for the initial PD, with 
one exception:  if new lesions occurred at a prior instance of iUPD, and at the confirmatory 
imaging the burden of new lesions has increased from its smallest value (for new target 
lesions, the sum of diameters is ≥5 mm increased from its nadir), then iUPD cannot resolve 
to iSD or iPR. It will remain iUPD until either a decrease in the new lesion burden allows 
resolution to iSD or iPR, or until a confirmatory factor causes iCPD.
Additional details about iRECIST are provided in the iRECIST publication [Seymour, L., et 
al 2017].
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