Conditions: Colorectal Carcinoma
Keywords: Programmed Cell Death Receptor 1 (PD-1) Programmed Cell Death Receptor Ligand 1 (PD-L1, PDL1)
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 307
Healthy volunteers: no

Brief summary:
In this study, participants with stage IV Microsatellite Instability-High (MSI-H) or Mismatch Repair Deficient (dMMR) colorectal carcinoma (CRC) will be randomly assigned to receive either pembrolizumab or the Investigator's choice of 1 of 6 standard of care (SOC) chemotherapy regimens for the treatment of advanced colorectal carcinoma. The primary study hypothesis is that pembrolizumab will prolong progression-free survival (PFS) or overall survival (OS) compared to current SOC chemotherapy.

Detailed description:

Arms:
arm 1: Participants receive pembrolizumab 200 mg intravenously (IV) on Day 1 of each 21-day cycle (Q3W) for up to 35 treatments (approximately 2 years). Participants that have stopped the initial course of pembrolizumab and have stable disease but progress after discontinuation can initiate a second course of pembrolizumab for up to 17 cycles (approximately 1 year additional). arm 2: Participants receive 1 of 6 possible standard chemotherapy regimens: mFOLFOX6, or mFOLFOX6+bevacizumab 5 mg/kg IV on Day 1 of each 2-week cycle, or mFOLFOX6+cetuximab 400 mg/m\^2 IV over 2 hours then 250 mg/m\^2 over 1 hour weekly in each 2-week cycle, or FOLFIRI, or FOLFIRI+bevacizumab 5 mg/kg IV on Day 1 of each 2-week cycle, or FOLFIRI+cetuximab 400 mg/m\^2 IV over 2 hours then 250 mg/m\^2 over 1 hour weekly in each 2-week cycle. Participants with documented disease progression following chemotherapy can crossover to receive pembrolizumab for up to 35 cycles (approximately 2 years). Participants that have stopped pembrolizumab and have stable disease but progress after discontinuation can initiate a second course of pembrolizumab for up to 17 cycles (approximately 1 year additional).

Interventions: intervention 1: mFOLFOX6 intervention 2: FOLFIRI intervention 3: Pembrolizumab intervention 4: Bevacizumab intervention 5: Cetuximab
Intervention descriptions: intervention 1: Regimen consists of oxaliplatin 85 mg/m\^2 IV on Day 1, leucovorin 400 mg/m\^2 or levoleucovorin 200 mg/m\^2 IV on Day 1, 5-fluorouracil (5-FU) 400 mg/m\^2 IV bolus on Day 1 and then 1200 mg/m\^2/day IV over 2 days for total dose of 2400 mg/m\^2 in each 2-week cycle intervention 2: Regimen consists of irinotecan 180 mg/m\^2 IV on Day 1, leucovorin 400 mg/m\^2 or levoleucovorin 200 mg/m\^2 IV on Day 1, 5-FU 400 mg/m\^2 IV bolus on Day 1 and then 1200 mg/m\^2/day IV over 2 days for total dose of 2400 mg/m\^2 in each 2-week cycle intervention 3: IV infusion intervention 4: IV infusion intervention 5: IV infusion

Protocol document:
Prot_SAP_001.pdf: 
Official Protocol Title:
NCT number:
Document Date:
A Phase III Study of Pembrolizumab (MK-3475)
vs. Chemotherapy in Microsatellite Instability-
High (MSI-H) or Mismatch Repair Deficient
(dMMR) Stage IV Colorectal Carcinoma
(KEYNOTE-177)
NCT02563002
12-Oct-2022


Product:  MK-3475 
1
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
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).
SPONSOR:
Merck Sharp & Dohme LLC 
(hereafter called the Sponsor or MSD)
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA 
Protocol-specific Sponsor Contact information can be found in the Investigator Trial File 
Binder (or equivalent).
TITLE:
A Phase III Study of Pembrolizumab (MK-3475) vs. Chemotherapy in Microsatellite 
Instability-High (MSI-H) or Mismatch Repair Deficient (dMMR) Stage IV Colorectal 
Carcinoma (KEYNOTE-177)
IND NUMBER:  123,482 
EudraCT NUMBER:  2015-002024-89
08GT0T


Product:  MK-3475 
2
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
TABLE OF CONTENTS
DOCUMENT HISTORY ..................................................................................................... 11
SUMMARY OF CHANGES................................................................................................ 12
1.0
TRIAL SUMMARY.................................................................................................. 17
2.0
TRIAL DESIGN........................................................................................................ 18
Trial Design ........................................................................................................... 18
Trial Diagram........................................................................................................ 21
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 22
Primary Objective(s) & Hypothesis(es).............................................................. 22
Secondary Objective(s) & Hypothesis(es)........................................................... 22
Exploratory Objectives......................................................................................... 22
4.0
BACKGROUND & RATIONALE.......................................................................... 23
Background ........................................................................................................... 23
Pharmaceutical and Therapeutic Background .................................................... 23
Preclinical and Clinical Studies .......................................................................... 24
Ongoing Clinical Studies .................................................................................... 24
Information on Other Study-Related Therapy .................................................... 24
Rationale................................................................................................................ 27
Rationale for the Trial and Selected Subject Population .................................... 27
Proof of Concept: Keynote 016 (KN016)........................................................... 28
Overview of Efficacy in KN016 study ........................................................ 28
Overview of Safety in KN016 Study........................................................... 32
Rationale for Dose Selection/Regimen/Modification......................................... 33
Rationale for the Use of Comparator........................................................... 34
Rationale for Endpoints ...................................................................................... 34
Efficacy Endpoints....................................................................................... 34
Exploratory Endpoints ................................................................................. 35
4.2.4.2.1
Immune-Related RECIST (irRECIST)................................................. 35
4.2.4.2.2
Subject Reported Outcomes (PRO)...................................................... 35
08GT0T


Product:  MK-3475 
3
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
Safety Endpoints.......................................................................................... 36
Microsatellite Instability Testing................................................................. 36
Planned Exploratory Biomarker Research................................................... 37
Future Biomedical Research........................................................................ 38
Benefit/Risk ........................................................................................................... 38
5.0
METHODOLOGY ................................................................................................... 39
Entry Criteria........................................................................................................ 39
Diagnosis/Condition for Entry into the Trial...................................................... 39
Subject Inclusion Criteria.................................................................................... 39
Subject Exclusion Criteria .................................................................................. 41
Trial Treatment(s) ................................................................................................ 43
Dose Selection .................................................................................................... 45
Dose Selection (Preparation) ....................................................................... 45
Dose Modification (Escalation/Titration/Other).......................................... 45
5.2.1.2.1
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue).......................................................................................... 45
Timing of Dose Administration.......................................................................... 50
Pembrolizumab (MK-3475) Administration................................................ 50
Standard of Care .......................................................................................... 51
Trial Blinding/Masking....................................................................................... 51
Randomization ...................................................................................................... 52
Stratification.......................................................................................................... 52
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 52
Acceptable Concomitant Medications and Therapy ........................................... 52
Prohibited Concomitant Medications and Therapy ............................................ 52
Prohibited Concomitant Medications and Therapies for UK Only ............. 53
Rescue Medications & Supportive Care............................................................. 54
Supportive Care Guidelines for Pembrolizumab (MK-3475)............................. 54
Diet/Activity/Other Considerations..................................................................... 55
Diet...................................................................................................................... 55
Contraception...................................................................................................... 55
Use in Pregnancy ................................................................................................ 58
08GT0T


Product:  MK-3475 
4
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
Use in Nursing Women....................................................................................... 58
UK Only:  Sun Exposure Caution....................................................................... 58
Subject Withdrawal/Discontinuation Criteria................................................... 58
Discontinuation of Pembrolizumab (MK-3475) after Complete Response........ 60
Subject Replacement Strategy............................................................................. 60
Beginning and End of the Trial ........................................................................... 60
Clinical Criteria for Early Trial Termination ................................................... 60
6.0
TRIAL FLOW CHART ........................................................................................... 62
Initial Treatment Phase: Pembrolizumab (MK-3475) Arm ............................. 62
Initial Treatment Phase: SOC Chemotherapy Arm.......................................... 66
Second Course Treatment Phase: Pembrolizumab (MK-3475) Arm and 
SOC Chemotherapy Arm following Crossover.................................................. 70
Crossover Phase:  SOC Chemotherapy Arm..................................................... 72
7.0
TRIAL PROCEDURES ........................................................................................... 74
Trial Procedures ................................................................................................... 74
Administrative Procedures.................................................................................. 74
Informed Consent......................................................................................... 74
7.1.1.1.1
General Informed Consent.................................................................... 74
7.1.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research................................................................................................ 75
Inclusion/Exclusion Criteria ........................................................................ 75
Subject Identification Card .......................................................................... 75
Medical History ........................................................................................... 75
Disease Details............................................................................................. 75
Prior and Concomitant Medications Review............................................... 76
7.1.1.6.1
Prior Medications.................................................................................. 76
Prior Treatment Details for Colorectal Carcinoma ........................ 76
7.1.1.6.2
Concomitant Medications..................................................................... 76
Assignment of Screening Number............................................................... 76
Assignment of Treatment/Randomization Number..................................... 76
Trial Compliance (Medication/Diet/Activity/Other)................................... 77
Clinical Procedures/Assessments........................................................................ 77
08GT0T


Product:  MK-3475 
5
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
Adverse Event Monitoring........................................................................... 77
Electronic Subject Reported Outcomes (ePROs) ........................................ 77
Physical Exam.............................................................................................. 77
7.1.2.3.1
Full Physical Exam ............................................................................... 77
7.1.2.3.2
Directed Physical Exam........................................................................ 78
Height, Weight, and Vital Signs .................................................................. 78
12-Lead Electrocardiogram ......................................................................... 78
Eastern Cooperative Oncology Group (ECOG) Performance Status .......... 78
Post-study Anticancer Therapy Status......................................................... 78
Laboratory Procedures/Assessments .................................................................. 78
Local Laboratory Assessments .................................................................... 79
7.1.3.1.1
Hematology, Chemistry, Urinalysis, and Other Labs........................... 79
7.1.3.1.2
Serum β-hCG........................................................................................ 80
Central Laboratory Assessments.................................................................. 80
7.1.3.2.1
Pharmacokinetic Evaluations................................................................ 80
7.1.3.2.2
Planned Genetic Analysis Sample Collection ...................................... 80
7.1.3.2.3
Blood for Correlative and Biomarker Studies ...................................... 80
Tumor Tissue for Exploratory Analyses ........................................ 81
Future Biomedical Research Sample Collection ......................................... 81
Efficacy Measurements....................................................................................... 81
Tumor Imaging and RECIST Assessment................................................... 81
Initial Tumor Imaging.................................................................................. 81
On Study Tumor Imaging............................................................................ 82
End of Treatment and Follow-up Tumor Imaging....................................... 83
RECIST 1.1 Assessment of Disease............................................................ 83
Immune-related RECIST (irRECIST) Assessment of Disease (for 
subjects on Pembrolizumab (MK-3475) ONLY) ........................................ 84
Other Procedures................................................................................................. 86
Withdrawal/Discontinuation........................................................................ 86
7.1.5.1.1
Withdrawal From Future Biomedical Research ................................... 87
Blinding/Unblinding .................................................................................... 87
Calibration of Critical Equipment................................................................ 87
Visit Requirements.............................................................................................. 87
08GT0T


Product:  MK-3475 
6
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
Screening...................................................................................................... 88
Treatment Period.......................................................................................... 88
Second Course Phase for Subjects Receiving Pembrolizumab (MK-
3475) in the Initial Treatment Phase or Crossover from SOC Treatment 
Phase............................................................................................................ 88
Crossover Phase for Subjects in the Chemotherapy Arm with 
Documented Disease Progression................................................................ 90
Post Treatment Visits................................................................................... 92
7.1.6.5.1
Safety Follow-up Visits ........................................................................ 92
7.1.6.5.2
Follow-up Visits ................................................................................... 92
7.1.6.5.3
Survival Follow-up ............................................................................... 92
Survival Status ............................................................................................. 92
Assessing and Recording Adverse Events .......................................................... 93
Definition of an Overdose for This Protocol and Reporting of Overdose to 
the Sponsor.......................................................................................................... 94
Reporting of Pregnancy and Lactation to the Sponsor ....................................... 94
Immediate Reporting of Adverse Events to the Sponsor.................................... 95
Serious Adverse Events ............................................................................... 95
Events of Clinical Interest............................................................................ 96
Protocol-Specific Exceptions to Serious Adverse Event Reporting............ 97
Evaluating Adverse Events................................................................................. 97
Sponsor Responsibility for Reporting Adverse Events .................................... 100
Data Monitoring Committee............................................................................. 100
8.0
STATISTICAL ANALYSIS PLAN ...................................................................... 100
Statistical Analysis Plan Summary ................................................................... 100
Responsibility for Analyses/In-House Blinding ............................................... 102
Hypotheses/Estimation....................................................................................... 102
Analysis Endpoints ............................................................................................. 103
Efficacy Endpoints............................................................................................ 103
Safety Endpoints ............................................................................................... 104
Analysis Populations........................................................................................... 104
Efficacy Analysis Populations .......................................................................... 104
Safety Analysis Populations ............................................................................. 104
08GT0T


Product:  MK-3475 
7
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
Statistical Methods.............................................................................................. 104
Statistical Methods for Efficacy Analyses........................................................ 104
Progression-Free Survival.......................................................................... 105
Overall Survival (OS) ................................................................................ 106
Overall Response Rate (ORR)................................................................... 107
Statistical Methods for Safety Analyses ........................................................... 107
Summaries of Demographic and Baseline Characteristics ............................... 109
Interim Analyses ................................................................................................. 109
Multiplicity .......................................................................................................... 110
Sample Size and Power Calculations ................................................................ 111
Subgroup Analyses and Effect of Baseline Factors ......................................... 112
Compliance (Medication Adherence)................................................................ 112
Extent of Exposure.............................................................................................. 112
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ............................................................................................................... 113
Investigational Product ...................................................................................... 113
Packaging and Labeling Information ............................................................... 114
Clinical Supplies Disclosure............................................................................... 114
Storage and Handling Requirements................................................................ 114
Discard/Destruction/Returns and Reconciliation ............................................ 114
Standard Policies................................................................................................. 114
10.0
ADMINISTRATIVE AND REGULATORY DETAILS..................................... 115
Confidentiality..................................................................................................... 115
Confidentiality of Data ..................................................................................... 115
Confidentiality of Subject Records................................................................... 115
Confidentiality of Investigator Information...................................................... 115
Confidentiality of IRB/IEC Information........................................................... 116
Compliance with Financial Disclosure Requirements..................................... 116
Compliance with Law, Audit and Debarment ................................................. 116
Compliance with Trial Registration and Results Posting Requirements...... 118
Quality Management System............................................................................. 118
Data Management............................................................................................... 119
08GT0T


Product:  MK-3475 
8
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
Publications ......................................................................................................... 119
11.0
LIST OF REFERENCES....................................................................................... 120
12.0
APPENDICES......................................................................................................... 125
Code of Conduct for Clinical Trials.................................................................. 125
Collection and Management of Specimens for Future Biomedical 
Research............................................................................................................... 128
Understanding the Intent, Scope and Public Health Benefits of 
Exploratory Biomarker Research: A Guide for IRBs/IECs and 
Investigational Site Staff .................................................................................... 132
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1....................... 143
ECOG Performance Status................................................................................ 144
Common Terminology Criteria for Adverse Events v4.0 ............................... 145
List of Abbreviations .......................................................................................... 146
13.0
SIGNATURES......................................................................................................... 149
Sponsor's Representative ................................................................................... 149
Investigator.......................................................................................................... 149
08GT0T


Product:  MK-3475 
9
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
LIST OF TABLES
Table 1
Studies of Approved Drugs for Colorectal Cancer.............................................. 26
Table 2
Objective Responses for Subjects Enrolled in KN 016....................................... 29
Table 3
Adverse Event Summary: KN016....................................................................... 33
Table 4
Adequate Organ Function Lab Values ................................................................ 40
Table 5
Study Medication................................................................................................. 43
Table 6
Dose Modification and Toxicity Management Guidelines for Immune-
related Adverse Events Associated with Pembrolizumab Monotherapy, 
Coformulations or IO Combinations................................................................... 46
Table 7
Infusion Reaction Treatment Guidelines............................................................. 49
Table 8
Laboratory Tests.................................................................................................. 79
Table 9
Imaging and Treatment after First Radiologic Evidence of PD for Subjects 
Receiving Pembrolizumab (MK-3475) (management per irRECIST)................ 85
Table 10
Evaluating Adverse Events.................................................................................. 98
Table 11
Censoring rules for Primary and Sensitivity Analyses of PFS.......................... 106
Table 12
Analysis Strategy for Key Efficacy Endpoints.................................................. 107
Table 13
Analysis Strategy for Safety Parameters........................................................... 109
Table 14
Timing, Sample Size, and Decision Guidance.................................................. 110
Table 15
Product Descriptions ......................................................................................... 113
08GT0T


Product:  MK-3475 
10
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
LIST OF FIGURES
Figure 1
Study Design ....................................................................................................... 21
Figure 2
Biochemical Responses....................................................................................... 30
Figure 3
Radiographic Responses...................................................................................... 30
Figure 4
Duration of Objective Response.......................................................................... 31
Figure 5
Duration of Disease Control................................................................................ 31
Figure 6
A and B Progression-Free Survival..................................................................... 32
Figure 7
C and D Overall Survival .................................................................................... 32
Figure 8
Imaging and Treatment after First Radiologic Evidence of PD.......................... 86
Figure 9
Multiplicity Strategy.......................................................................................... 111
08GT0T


Product:  MK-3475 
11
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
3475-177-07
12 Oct 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. In addition, extension study language was added.
3475-177-06
19 Apr 2021
To update the dose modification and toxicity management guidelines for 
irAEs.
3475-177-05
17 Dec 2019
Change in timing of Interim Analysis 2 and Final Analysis
3475-177-04
30 Apr 2018
Change in timing of PFS interim analyses
3475-177-03
20 Nov 2017
Addition of Overall Survival as a primary dual endpoint
3475-177-02
16 Mar 2016
Response to UK Health Authority Requests
3475-177-01
17 Mar 2016
Response to France Health Authority Requests
3475-177-00
11 Sept 2015
Original Protocol
08GT0T


Product:  MK-3475 
12
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
SUMMARY OF CHANGES
PRIMARY REASON(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title(s)
Description of Change (s)
Rationale
Title Page 
12.1 
Throughout
Title Page
Code of Conduct for Clinical 
Trials
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.
5.10 
Beginning and End of the Trial
Added 
that 
upon 
study 
completion, 
participants 
are 
discontinued 
and 
may 
be 
enrolled in a pembrolizumab 
extension study, if available.
To 
allow 
participants 
to 
continue 
pembrolizumab 
treatment in an extension study. 
ADDITIONAL CHANGES FOR THIS AMENDMENT:
Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
1.0
5.1.2 
5.10
6.1
6.2
Trial Summary
Subject Inclusion Criteria
Beginning and End of the Trial
Initial 
Treatment 
Phase: 
Pembrolizumab (MK-3475) Arm
Initial Treatment Phase: SOC 
Chemotherapy Arm
Updated consent language to 
refer to documented informed 
consent 
instead 
of 
written 
informed consent, to refer to 
legally acceptable representative 
where applicable, and to refer to 
last study-related contact instead 
of specifying telephone call or 
visit.
To revise the informed consent 
language in alignment with 
updates made in response to 
COVID-19–related situations.
08GT0T


Product:  MK-3475 
13
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
7.1.1.1
7.1.1.1.1
7.1.1.1.2
7.1.1.3
7.1.3.2.2
7.1.3.2.3
7.1.3.2.3.1
7.1.6.1
7.2
7.2.2
7.2.3.1
7.2.3.2
Informed Consent
General Informed Consent
Consent 
and 
Collection 
of 
Specimens for Future Biomedical 
Research
Subject Identification Card
Planned Genetic Analysis Sample 
Collection 
Blood 
for 
Correlative 
and 
Biomarker Studies
Tumor Tissue for Exploratory 
Analyses
Screening
Assessing and Recording Adverse 
Events
Reporting 
of 
Pregnancy 
and 
Lactation to the Sponsor
Serious Adverse Events
Events of Clinical Interest
08GT0T


Product:  MK-3475 
14
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
4.2.4.6
7.1.1.1.2
12.2
Future Biomedical Research
Consent 
and 
Collection 
of 
Specimens for Future Biomedical 
Research
Collection and Management of 
Specimens for Future Biomedical 
Research
Removed reference to future 
biomedical research (FBR) as a 
sub-trial to the clinical protocol.
Due to European Union (EU) 
Clinical 
Trials 
Regulation
(CTR) changes that will require 
FBR results to be reported if 
FBR is indicated as a sub-trial
to the clinical protocol.
5.1.2
Subject Inclusion Criteria
In Inclusion Criteria Nos. 8 and 
9, 
removed 
“and 
preferred 
contraception” from the note.
To clarify that abstinence is an 
acceptable 
method 
of 
contraception only if this is the 
usual lifestyle of the subject. 
5.1.2
5.7.2 
7.1.6.3
7.1.6.4
Subject Inclusion Criteria
Contraception
Second Course Phase for Subjects 
Receiving Pembrolizumab (MK-
3475) in the Initial Treatment 
Phase or Crossover from SOC 
Treatment Phase
Crossover Phase for Subjects in 
the Chemotherapy Arm with 
Documented Disease Progression
Removed requirement for male 
subjects to use contraception for 
120 days after the last dose of 
pembrolizumab (MK-3475).
To 
align 
with 
current 
pembrolizumab 
prescribing 
information. 
08GT0T


Product:  MK-3475 
15
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
5.1.3
Subject Exclusion Criteria
In 
exclusion 
criterion 
#17, 
clarified 
that 
requirements 
regarding the SOC arm apply to 
male and female subjects, while 
requirements 
regarding 
the 
pembrolizumab (MK-3475) arm 
apply to female participants 
only.
Clarification 
regarding 
pregnancy and breastfeeding, 
and conceiving or fathering 
children during the study.
5.5.2
Prohibited 
Concomitant 
Medications and Therapy
Clarified that live attenuated 
vaccines 
are 
not 
permitted 
during the study.
Added a note that licensed 
COVID-19 
vaccines 
are
allowed, 
but 
investigational 
vaccines are not allowed.
Clarification of which vaccines 
are permitted.
7.1.1.9
Trial Compliance (Medication/
Diet/Activity/Other)
Reworded text regarding study 
medication administration to be 
monitored instead of witnessed.
To reflect standard clinical 
practice and administration of 
study 
medication 
more 
accurately.
7.1.1.3
Subject Identification Card
Added that at the time of 
intervention randomization, the 
treatment/randomization number
should be added to the Subject 
Identification Card.
Clarify timing of action.
08GT0T


Product:  MK-3475 
16
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
Throughout Document
-
Minor 
administrative, 
formatting, grammatical, and/or 
typographical 
changes 
were 
made throughout the document.
To ensure clarity and accurate 
interpretation of the intent of 
the protocol.
08GT0T


Product:  MK-3475 
17
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
1.0 TRIAL SUMMARY
Abbreviated Title
A Phase III Study of Pembrolizumab (MK-3475) vs Chemotherapy in 
Microsatellite Instability-High or Mismatch Repair Deficient Stage IV 
Colorectal Carcinoma 
Trial Phase
Phase III
Clinical Indication
Microsatellite Instability-High
or Mismatch Repair Deficient
Colorectal Carcinoma
Trial Type
Interventional
Type of control
Active control without placebo
Route of administration
Intravenous
Trial Blinding
Unblinded Open-label
Treatment Groups

Arm 1: Pembrolizumab (MK-3475) 200 mg IV every 3 weeks 
(Q3W)
OR

Arm 2: Standard of Care (SOC): Investigator’s choice of the 
following:
o
mFOLFOX6, or
o
mFOLFOX6 + bevacizumab, or
o
mFOLFOX6+ cetuximab, or
o
FOLFIRI, or
o
FOLFIRI+ bevacizumab, or
o
FOLFIRI+ cetuximab
Number of trial subjects
Approximately 300 subjects will be enrolled.
Estimated duration of trial
The Sponsor estimates that the trial will require approximately 
65 months (Note: the study period in Japan is from November 2016 to
April 2021) from the time the first subject (or their legally acceptable 
representative) provides documented informed consent until the last 
subject’s last study-related contact.
Duration of Participation
Each subject will participate in the study from the time that the subject 
provides documented informed consent through the final protocol-
specified contact. After a screening phase of up to 42 days, eligible 
subjects can be randomized to either pembrolizumab (experimental 
arm) or standard of care chemotherapy (control arm). Subjects will 
receive pembrolizumab (MK-3475) beginning on Day 1 of each 
3-week dosing cycle or chemotherapy beginning on Day 1 of each 
2-week cycle. The chemotherapy to be used must be chosen before 
randomization.
Subjects will be randomized in a 1:1 fashion to standard chemotherapy 
per Investigator’s choice or to pembrolizumab (MK-3475). Treatment 
on study will continue until progressive disease (PD), unacceptable 
adverse events (AEs), intercurrent illness that prevents further 
administration of study medication, Investigator’s decision to 
discontinue the subject, subject withdraws consent, pregnancy of the 
subject, noncompliance with study medication
or procedure 
requirements, administrative reasons, or the subject had received
35 treatments (approximately 2 years; pembrolizumab arm only) (see 
Section 5.8). 
Subjects who stop pembrolizumab (MK-3475) as a result of obtaining 
a locally confirmed complete response (CR), or after receiving 
08GT0T


Product:  MK-3475 
18
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
35 treatments (approximately. 2 years) and have stable disease (SD) or 
better may be eligible, at the discretion of the Investigator, for an 
additional 17 treatments (approximately 1 year) after experiencing PD 
while off pembrolizumab (MK-3475) if they meet the criteria for 
re-treatment; this will be designated the Second Course Treatment 
Phase (see Section 7.1.6.3 for details). Subjects randomized to the 
chemotherapy arm will have the option to crossover and receive 
35 treatments with pembrolizumab (MK-3475) in the Crossover Phase 
(approximately 2 years) after verification of PD by a blinded 
independent central imaging vendor per Response Evaluation Criteria 
in Solid Tumors (RECIST 1.1) (see Section 7.1.4.5 for details). 
Subjects who stop pembrolizumab (MK-3475) in the crossover phase 
as a result of obtaining a locally confirmed CR, or after receiving 
35 treatments (approximately 2 years) and have SD or better may be 
eligible, at the discretion of the Investigator, for an additional 
17 treatments (approximately 1 year) in the Second Course Treatment 
Phase after experiencing PD while off pembrolizumab (MK-3475) if 
they meet the criteria for re-treatment (see Section 7.1.6.3 for details).
After the end of treatment, each subject will be followed for 30 days 
for AE monitoring. Serious adverse events (SAE) will be collected for 
90 days after the end of treatment or for 30 days after the end of 
treatment if the subject initiates new anticancer therapy, whichever is 
earlier. All subjects will have post-treatment follow-up for disease 
status, until initiating a non-study cancer treatment, experiencing 
disease progression, death, withdrawing consent, or becoming lost to 
follow-up. Subjects who experience confirmed disease progression or 
start a new anticancer therapy, will move into the Survival Follow-Up 
Phase and should be contacted by telephone approximately every 
9 weeks to assess for survival status until death, withdrawal of 
consent, or the end of the study, whichever occurs first. During the 
study, subjects may undergo resection of the primary tumor and 
metastasectomy with curative intent if deemed eligible per site 
institutional standard after achieving a response to study medication.
Randomization Ratio
1:1
A list of abbreviations used in this document can be found in Section 12.7.
2.0 TRIAL DESIGN
Trial Design
This is a two-arm, multicenter, international, randomized, open-label, controlled study of 
pembrolizumab (MK-3475) monotherapy versus standard chemotherapy in subjects who 
have stage IV Microsatellite Instability-High (MSI-H) or Mismatch Repair Deficient
(dMMR) colorectal carcinoma (CRC). MSI, a form of genomic instability, occurs through 
the insertion or deletion of repeating nucleotides during DNA replication and failure of the 
mismatch repair system to correct errors in nucleotide repeat markers (refer to Section 4.2.4.4
for further details). Subjects will be required to have at least 1 measurable lesion by 
Response Evaluation Criteria in Solid Tumors (RECIST 1.1) for response assessment. 
Subjects will be randomized in a 1:1 ratio to receive pembrolizumab (experimental arm) or 
the Investigator’s choice of standard of care (SOC) chemotherapy (control arm). The 
chemotherapy to be used must be chosen before randomization. 
08GT0T


Product:  MK-3475 
19
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
Pembrolizumab
(MK-3475)
arm subjects will receive up to 35 administrations of 
pembrolizumab (approximately 2 years) in the Initial Treatment Phase. Subjects who stop 
pembrolizumab (MK-3475) with locally confirmed complete response (CR), or stable disease 
(SD) or better at the end of the Initial Treatment Phase may be treated in a Second Course 
Treatment Phase with up to 17 administrations of pembrolizumab (MK-3475) if they meet 
criteria outlined in Section 7.1.6.3. 
Control arm subjects with progressive disease (PD) per RECIST 1.1 as verified by a blinded 
independent central imaging vendor who meet all crossover criteria will have an option to 
receive pembrolizumab (MK-3475) in the Crossover Phase. See Section 7.1.6.4 for crossover 
criteria and guidance.
This may be followed by 17 additional treatments in the Second 
Course Treatment Phase if criteria as outlined in Section 7.1.6.3 are met.
The primary objectives of the study are progression-free survival (PFS) per RECIST 1.1 
assessed by an independent central imaging vendor based on the first radiologic PD from the 
primary treatment to which subjects are randomized and overall survival (OS). On-study 
imaging assessments, performed every 9 weeks (Q9W), will be calculated from the date of 
randomization and independent of treatment delays for both treatment arms. RECIST 1.1 will 
be used by the site for the treatment decisions until verification of initial site-assessed PD by 
the blinded independent central imaging vendor. For subjects receiving pembrolizumab
(MK-3475), following verification of PD by the central imaging vendor, further treatment 
decisions may be made by the adaptation of RECIST 1.1 as described in Section 4.2.4.2.1
termed immune-related RECIST (irRECIST) to accommodate for the tumor response 
patterns seen with pembrolizumab (MK-3475) treatment (eg, tumor flare). For a clinically 
stable subject with first radiologic evidence of PD per RECIST 1.1 as verified by the central 
imaging vendor, per irRECIST, it is at the discretion of the site Investigator to continue 
treating the subject with pembrolizumab (MK-3475) until PD is confirmed at least 4 weeks 
from the date of first radiologic PD by RECIST 1.1. If radiologic PD is confirmed by the 
subsequent tumor imaging, the subject should be discontinued from treatment unless, in the 
opinion of the Investigator, the subject is achieving a clinically meaningful benefit, in which 
case an exception to continue treatment may be considered following consultation with the 
Sponsor (see Section 7.1.4.6). France only:  If radiologic PD is confirmed by the subsequent 
tumor imaging, the subject must be discontinued from treatment.
Subjects will continue to be treated with study medication until PD, unacceptable adverse 
events (AEs), intercurrent illness that prevents further administration of treatment, 
investigator’s decision to discontinue the subject, subject withdraws consent, pregnancy of 
the subject, noncompliance with study medication or procedure requirements, administrative 
reasons, or the subject has received 35 treatments (approximately 2 years; pembrolizumab
arm only).
Subjects may undergo resection of the primary tumor and metastasectomy with curative 
intent after achieving a response to study medication converting unresectable to resectable 
disease if deemed eligible per Investigator’s discretion in a multidisciplinary approach 
according to his/her institutional standard. After surgery, subjects in the SOC arm may 
resume the same therapy that they were receiving pre-operatively when clinically 
appropriate. For instance, only mFOLFOX6/Bevacizumab may be used post-operatively (at 
08GT0T


Product:  MK-3475 
20
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
the investigator’s discretion) if a subject was assigned to the FOLFOX/ Bevacizumab arm 
pre-operatively. The duration of post-operative therapy is at the investigator’s discretion per 
institutional standard. Pembrolizumab (MK-3475) subjects may also resume therapy post-
operatively, and receive up to 35 total treatments inclusive of both pre- and post-operative 
periods. Pembrolizumab subjects who progress post-operatively will have an option to 
receive pembrolizumab (MK-3475) in the Second Treatment Course Phase with up to 
17 administrations (approximately 1 year) of pembrolizumab (MK-3475) if clinically 
appropriate. Subjects in the SOC arm who progress post-operatively may have an option to 
receive pembrolizumab (MK-3475) in the Crossover Phase with up to 35 administrations 
(approximately 2 years) of pembrolizumab (MK-3475), followed by 17 administrations of 
pembrolizumab (MK-3475) in the Second Treatment Course, also if clinically appropriate.
Subjects from both arms of the study who develop isolated lesion/tumor growth in the setting 
of overall clinical benefit may resume the assigned therapy after completing local treatment 
for the isolated lesion/tumor growth provided there is mutual agreement between the 
Investigator and Sponsor.
Subjects who receive pembrolizumab (MK-3475) and attain locally confirmed CR per 
RECIST 1.1 or irRECIST by 2 tumor imaging assessments at least 4 weeks apart and who 
have received at least 8 treatments (approximately 6 months) with pembrolizumab
(MK-3475) may discontinue treatment at the discretion of the Investigator after receiving at 
least 2 treatments beyond the initial determination of a CR.
Adverse events will be 
monitored throughout the study and graded in severity according to the guidelines outlined in 
the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 (Section 12.6). Each subject will be monitored for AEs for 30 days 
after discontinuation of study medication. Serious adverse events (SAEs) will be collected 
for 90 days after the end of treatment or 30 days after the end of treatment if the subject 
initiates new anticancer therapy, whichever is earlier.  
All subjects (including subjects who have received the maximum 35 pembrolizumab 
treatments) will have post-treatment follow-up for disease status, until initiating a non-study 
cancer treatment, experiencing disease progression, death, withdrawing consent, or becoming 
lost to follow-up. Subjects who experience confirmed disease progression or start a new 
anticancer therapy, will move into the Survival Follow-Up Phase and should be contacted by 
telephone approximately every 9 weeks to assess for survival status until death, withdrawal 
of consent, or the end of the study, whichever occurs first.
This study will be conducted in conformance with Good Clinical Practices (GCP).
Specific procedures to be performed during the trial, as well as their prescribed times and 
associated visit windows, are outlined in the Trial Flow Chart - Section 6.0. Details of each 
procedure are provided in Section 7.0 – Trial Procedures.
Details regarding interim analyses are provided in Section 8.7. An external data monitoring 
committee (eDMC) will serve as the primary reviewer of the treatment-level results and will 
make recommendations for discontinuation of the study or modification to an executive 
oversight committee of the SPONSOR. The eDMC responsibilities and review schedules will 
be outlined in the eDMC charter.
08GT0T


Product:  MK-3475 
21
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
Trial Diagram
The study design is depicted in Figure 1 below.
*For pembrolizumab (MK-3475) treatment discontinuation after CR, please refer to 
Section 5.8.1.
Figure 1
Study Design
08GT0T


Product:  MK-3475 
22
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
Primary Objective(s) & Hypothesis(es)
In subjects with stage IV MSI-H or dMMR CRC treated with first-line (1L) pembrolizumab
(MK-3475) versus SOC chemotherapies,
1) Objective:  To compare Progression-Free Survival (PFS) per RECIST 1.1 by central
imaging vendor.
Hypothesis (H1):  Pembrolizumab (MK-3475) prolongs PFS per RECIST 1.1 by 
central imaging vendor compared to SOC chemotherapies.
2) Objective:  To compare Overall Survival (OS).
Hypothesis (H2): 
Pembrolizumab (MK-3475) prolongs OS compared to SOC 
chemotherapies.
The study is considered to have met its primary objective if pembrolizumab is superior to 
SOC chemotherapies in either of the 2 primary endpoints.
Secondary Objective(s) & Hypothesis(es)
In subjects with stage IV MSI-H or dMMR CRC treated with 1L pembrolizumab (MK-3475) 
versus SOC chemotherapies, 
1) Objective: To compare Overall Response Rate (ORR) per RECIST 1.1 by central
imaging vendor.
Hypothesis (H3):
Pembrolizumab (MK-3475) improves ORR compared to SOC 
chemotherapies
2) Objective:  To evaluate the safety and tolerability profiles.
Exploratory Objectives
1) Objective:  To evaluate Progression-Free Survival 2 (PFS2).
2) Objective: To evaluate Progression-Free Survival (PFS) per irRECIST by central 
imaging vendor.
3) Objective:
To evaluate Duration of Response (DOR) per RECIST 1.1 by central
imaging vendor.
4) Objective: 
To evaluate score change of health-related quality-of-life using the 
European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 
and the EORTC QLQ-CR29
from baseline among subjects treated with 
pembrolizumab (MK-3475) compared to SOC chemotherapies.
08GT0T


Product:  MK-3475 
23
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
5) Objective: To characterize utilities using EuroQoL EQ-5D among subjects treated 
with pembrolizumab (MK-3475) compared to SOC chemotherapies.
6) Objective: To explore the relationship between genetic variation and response to the 
treatment(s) administered. Variation across the human genome (germline and tumor)
will be analyzed for association with clinical data collected in this study.  
7) Objective:
To evaluate the surgical conversion rate among subjects treated with 
pembrolizumab (MK-3475) compared to SOC chemotherapies.
4.0 BACKGROUND & RATIONALE
Background
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody 
(mAb) with high specificity of binding to the programmed cell death 1 (PD-1), thus,
inhibiting its interaction with programmed cell death ligand 1 (PD-L1) and programmed cell 
death ligand 2 (PD-L2). Based on preclinical in vitro data, pembrolizumab has high affinity 
and potent receptor blocking activity for PD-1. Pembrolizumab has an acceptable preclinical 
safety profile and is in clinical development as an intravenous (IV) immunotherapy for 
advanced malignancies. Keytruda™ (pembrolizumab) is indicated for the treatment of 
patients across a number of indications. For more details on specific indications refer to the 
current Investigator Brochure (IB).
Pharmaceutical and Therapeutic Background
Microsatellite instability (MSI) is the molecular hallmark of mismatch repair deficiency, 
which results in high mutational load in MSI tumors and creates tumor-specific neo-antigens 
[1] [2], highly activated Th1- and cytotoxic T cell (CTL)-rich microenvironment with 
elevated expression of the gene encoding interferon gamma (IFNγ). Importantly however, 
offsetting this active Th1/CTL microenvironment, MSI-H tumors selectively demonstrate 
highly upregulated expression of multiple immune checkpoints, including programmed death 
1 (PD-1), programmed death ligand 1 (PD-L1), cytotoxic T-lymphocyte-associated protein-4 
(CTLA-4), lymphocyte-activation gene 3 (LAG-3), and indoleamine 2,3-dioxygenase (IDO), 
indicating the active immune microenvironment primed by neo-antigens is counterbalanced 
by immune inhibitory signals that hinder tumor elimination. [3], [1], [2] Pembrolizumab
(MK-3475) is a potent and highly selective humanized monoclonal antibody (mAb) of the 
immunoglobulin G4 (IgG4)/kappa isotype designed to directly block the interaction between 
PD-1 and its ligands, PD-L1 and PD-L2 to restore the function of the host immune response 
in facilitating immune mediated tumor regression and ultimately rejection – a scientifically 
rational therapeutic approach for MSI-H colorectal cancer. The efficacy of pembrolizumab
(MK-3475) was recently studied in pretreated subjects with advanced MSI-H CRC; its 
impressive results are reported in the proof of concept KEYNOTE 016 (Section 4.2.2).
08GT0T


Product:  MK-3475 
24
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
Preclinical and 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 ultimately 
leads 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. Blockade of the PD-1 pathway effectively promoted 
CD8+ T-cell infiltration into the tumor and the presence of IFNγ, granzyme B, and perforin, 
indicating that the mechanism of action involved local infiltration and activation of effector 
T-cell in vivo [4] [5] [6] [7] [8] [9]. Experiments have confirmed the in vivo efficacy of PD-1 
blockade as monotherapy as well as in combination with chemotherapy in syngeneic mouse 
tumor models (see the IB).
Clinical studies have demonstrated efficacy in subjects with advanced melanoma, non-small 
cell lung cancer, head and neck cancer, bladder cancer, Hodgkin’s lymphoma, triple-negative 
breast cancer, and gastric cancer. 
Ongoing Clinical Studies
Ongoing clinical studies of pembrolizumab (MK-3475) are being conducted in advanced 
melanoma, non-small cell lung cancer, and a number of other advanced solid tumor 
indications and hematologic malignancies. For study details please refer to the IB.
Information on Other Study-Related Therapy
Approved drugs for colorectal carcinoma in the 1L setting include chemotherapy 
(fluoropyrimidines, oxaliplatin, irinotecan) and monoclonal antibodies (anti-VEGF [vascular 
endothelial growth factor]: bevacizumab, or anti-EGFR [epidermal growth factor receptor]: 
cetuximab). Table 1 lists the studies of approved drugs for colorectal cancer.
FOLFOX or FOLFIRI as first line therapy
FOLFOX and FOLFIRI have been established as SOC 1L chemotherapy options for 
metastatic CRC, and may be used interchangeably depending on the physician’s 
recommendation per a subject’s profile as well as institutional and regional preference. 
Colucci et al. established the equivalency in clinical outcomes between FOLFOX4 and 
FOLFIRI in a Phase III study that randomized a total of 360 chemotherapy-naive subjects to 
either FOLFIRI or FOLFOX4. The median time to progression (TTP; 7 vs 7 months, 
respectively), and median overall survival (OS; 14 vs 15 months, respectively) were similar 
between the 2 regimens, without statistically significant difference. [10]
The concept of either FOLFOX or FOLFIRI being used in the 1L setting, to be sequenced by 
the other regimens upon progressive disease is further solidified in a Phase III study 
performed by GERCOR. In 1L therapy, FOLFIRI achieved 8.5 months median PFS, versus 
8.0 months for FOLFOX6 (p=0.26). The median survival for FOLFIRI followed by 
08GT0T


Product:  MK-3475 
25
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
FOLFOX6 was 21.5 months in 109 subjects versus 20.6 months in 111 subjects allocated to 
FOLFOX6 followed by FOLFIRI (p=0.99). [11]
Bevacizumab containing therapy
Bevacizumab was studied in subjects with untreated metastatic CRC who were randomly 
assigned to IFL or IFL and bevacizumab. Subjects receiving the combination of IFL and 
bevacizumab experienced better PFS compared to IFL, 10.6 months vs 6.2 months. Overall 
survival was 20.3 months in the IFL plus bevacizumab group compared to 15.6 months in the 
IFL group. [12]
BICC-C is a multi-cohort study evaluating 3 different irinotecan-containing regimens for 
subjects with untreated metastatic CRC. After bevacizumab was approved, this study was 
amended and an additional 117 subjects were randomly assigned to receive FOLFIRI plus 
bevacizumab or mIFL plus bevacizumab. Although the primary endpoint, PFS, was not 
significantly different (FOLFIRI plus bevacizumab: 11.2 months vs. mIFL
plus 
bevacizumab: 8.3 months; p=0.28), subjects receiving FOLFIRI and bevacizumab had a 
significantly better OS (not yet reached with a median follow-up of 22.6 months vs. 
19.2 months, p=0.007). As such, bevacizumab can be added to FOLFIRI in the 1L setting. 
[13]
Even though there is no direct clinical data, bevacizumab and FOLFOX became SOC after 
the Intergroup N9741 study reporting superior OS of FOLFOX versus IFL and IROX [14]. 
Subsequently, a Phase III study of untreated stage IV CRC was conducted; subjects were 
assigned in a 2x2 factorial design to CAPOX vs FOLFOX4 and then to bevacizumab vs 
placebo. In this study, median PFS was 9.4 months for subjects receiving either CAPOX or 
FOLFOX and bevacizumab, and 8 months for subjects receiving CAPOX or FOLFOX and 
placebo (p=0.0023). Median OS was 21.3 months for subjects receiving bevacizumab 
containing therapy and 19.9 months for subjects receiving placebo (p=0.077). [15]
Cetuximab containing therapies
In the CRYSTAL study, cetuximab was studied in subjects who were randomized to receive 
cetuximab in combination with FOLFIRI or FOLFIRI alone as 1L treatment. There was a 
statistically significant improvement in PFS in the combination arm compared to FOLFIRI 
alone (median PFS 8.9 vs 8.0 months; p=0.048). In KRAS wild-type subjects, the median 
PFS was 9.9 months in the combination arm compared to 8.7 months in the FOLIRI alone 
arm (p=0.03). [16]
In the OPUS study, subjects were randomly assigned to FOLFOX4 or FOLFOX4 plus 
cetuximab. There was no statistical difference in response rate or PFS. However, in the 
subset analysis of KRAS wild-type tumors, cetuximab was associated with a statistically 
significant improvement in PFS of 8.3 months vs 7.2 months (p=0.0064). [17]
More recently, in the Phase 3 FIRE3 study, subjects were randomized to FOLFIRI plus 
cetuximab or FOLFIRI plus bevacizumab. Median PFS was 10 months in the cetuximab
group and 10 months in the bevacizumab group (p=0.55). Median overall survival was 
08GT0T


Product:  MK-3475 
26
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
28.7 months in the cetuximab group compared with 25 months in the bevacizumab group 
(p=0.017) for KRAS exon 2 wild-type subjects. [18]
Table 1
Studies of Approved Drugs for Colorectal Cancer
Study Title
Treatment Arms
N
Efficacy Outcomes
HR, 95% CI
Phase III Randomized Study of FOLFIRI 
Versus
FOLFOX4 in the Treatment of Advanced 
Colorectal
Cancer: A Multicenter Study of the 
Gruppo Oncologico
Dell’Italia Meridionale
Arm A: FOLFOX4 
Arm B: FOLFIRI
Arm A: 164
Arm B: 172
TTR
Arm A: 7 months
Arm B: 7 months
OS
Arm A: 14 months vs. 
Arm B:15 months
FOLFIRI Followed by FOLFOX6 or the 
Reverse
Sequence 
in 
Advanced 
Colorectal 
Cancer: A
Randomized GERCOR Study 
ARM 
A: 
FOLFIRI 
followed by FOLFOX6 
Arm 
B: 
FOLFOX6 
followed by FOLFIRI
Arm A: 109
Arm B: 111
OS
Arm A: 21.5 months vs.
Arm 
B: 
20.6 
months 
(p=0.99)
In first-line therapy:
PFS
Arm A: 8.5 months vs.
Arm 
B: 
8.0 
months 
(p=0.26)
Randomized, 
Controlled 
Study
of 
Irinotecan Plus
Infusional, 
Bolus, 
or 
Oral 
Fluoropyrimidines in First-Line
Treatment 
of 
Metastatic 
Colorectal 
Cancer: Results From
the BICC-C Study
Arm A: FOLFIRI and 
bevacizumab 
Arm B:
mIFL and bevacizumab
Arm A: 57
Arm B: 60
OS at median follow-up of 
22.6 months
Arm A: not yet reached 
vs. 
Arm 
B:19.2 
months, 
(p=0.007)
PFS
Arm A: 11.2 months vs. 
Arm 
B: 
8.3 
months 
(p=0.28)
Bevacizumab 
in 
Combination 
With 
Oxaliplatin-Based 
Chemotherapy 
As 
First-Line 
Therapy 
in 
Metastatic 
Colorectal Cancer: A Randomized Phase 
III Study
Arm A:
CAPOX or FOLFOX 
and bevacizumab
Arm B:
CAPOX or FOLFOX 
and placebo
Arm A: 699
Arm B: 701
OS
Arm A: 21.3 months vs
Arm 
B: 
19.9 
months 
(p=0.077)
PFS
Arm A: 9.4 months vs 
Arm 
B: 
8.0 
months 
(p=0.0023)
Cetuximab and Chemotherapy as Initial
Treatment 
for 
Metastatic 
Colorectal 
Cancer
Arm A: FOLFIRI plus 
cetuximab
Arm B: FOLFIRI 
Arm A: 599
Arm B: 599
PFS for wild-type KRAS 
Arm A: 9.9 months vs
Arm 
B: 
8.7 
months 
(p=0.03)
OS for wild-type KRAS
Arm A: 24.9 months vs
Arm 
B: 
21 
months 
(p not reported)
Efficacy according to biomarker status of 
cetuximab
plus FOLFOX-4 as first-line treatment 
for metastatic
colorectal cancer: the OPUS study
Wild-type KRAS
Arm A: Cetuximab plus 
FOLFOX4 
Arm B: FOLFOX4 
Arm A: 82
Arm B: 97
PFS for wild-type KRAS:
Arm A: 8.3 months vs 
Arm 
B: 
7.2 
months 
(p=0.0064)
08GT0T


Product:  MK-3475 
27
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
Study Title
Treatment Arms
N
Efficacy Outcomes
HR, 95% CI
FOLFIRI 
plus 
cetuximab 
versus 
FOLFIRI plus bevacizumab as first-line 
treatment for subjects with metastatic 
colorectal 
cancer 
(FIRE-3): 
a 
randomized, open-label, Phase 3 study
Arm A:
FOLFIRI plus cetuximab 
Arm B: FOLFIRI plus 
bevacizumab
Arm A: 297
Arm B: 295
PFS
Arm A: 10.8 months vs
Arm 
B: 
10.3 
months 
(p=0.55)
OS
Arm A: 28.7 months vs
Arm 
B: 
25 
months 
(p=0.017)
Rationale
Rationale for the Trial and Selected Subject Population
In the United States (US), CRC is the third most common diagnosed cancer and the third 
leading cause of cancer death in both men and women [19]. The American Cancer Society 
estimated that 132,640 people will be diagnosed with CRC and 49,700 people will die from 
the disease in 2015. [20] Approximately 4.5% of men and women will be diagnosed with 
colon and rectum cancer at some point during their lifetime. [21] Based on the Surveillance, 
Epidemiology, and End Results (SEER) Program data from 2008 to 2012, the age-adjusted 
incidence rate was 42.4 per 100,000 population; the incidence was higher in men (48.9 per 
100,000 men) than in woman (37.1 per 100,000 women). [22] The incidence increased with 
age, from 0.1 per 100,000 in those between 10 and 14 years of age to 311.9 per 100,000 
among those above 85 years of age. [21] The median age at diagnosis was 68 years. 
Ethnically, colorectal cancer rates are highest in black men and women and lowest in Asian
and Pacific Islander (API) men and women. [21] The estimated age-adjusted prevalence 
proportion of colorectal cancer diagnosed in the previous 20 years on 01-JAN-2012 was 
0.2845%, with an overall complete prevalence count of 1,168,929 on the same date. [22]
Similar to incidence patterns, mortality rates declined most rapidly in the past decade. The 
annual overall mortality for colorectal cancer was 15.5 per 100,000, and men had a higher 
mortality (18.6 per 100,000 men) than women (13.1 per 100,000 women) [22]. On average, 
the 5-year survival was 65%, and survival was highest among those with localized lesions 
(90.1%), followed by those with regional lesions (70.8%), and was the lowest among those 
with distant lesions (13.1%). [21]
Colorectal cancers may be divided via molecular phenotyping into tumors with normal DNA 
mismatch repair (MMR) function and those with DNA MMR deficiency (MMR-D) [23]. 
Tumors showing the presence of MSI are classified as MSI-H (high) depending on the extent 
of instability in the markers tested, whereas tumors without this characteristic are classified 
as microsatellite-stable (MSS). [24] The prevalence estimates of MSI-H in all CRC subjects 
were similar across studies, ranging between 14% and 16%. In one population-based study, 
which included 2,080 persons diagnosed with incident invasive CRC between January 1998 
and June 2002, residing in one of the 3 counties of Washington State, US, approximately 
16% of all the cases had tumors that were MSI-H. [25]
08GT0T


Product:  MK-3475 
28
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
Germline mutations in MMR genes cause a cancer susceptibility syndrome called Lynch 
syndrome. Germline mutations in the MMR genes MLH1, MSH2, MSH6 and/or PMS2 or 
EpCAM are found in individuals with Lynch syndrome, which is responsible for 2% to 4% 
of colon cancer cases. [26] Many studies have found that some CRCs occurring in 
non-Lynch syndrome subjects also showed MSI (sporadic CRCs with MSI), and CRCs with 
MSI showed different clinical-pathological features, prognosis,
and response to 
chemotherapeutic agents compared to MSS CRCs. [27]
MSI-H CRC comprises approximately 15% of sporadic CRC and 5% of stage IV CRC, 
whereas MSS CRC comprises the remainder. [28] [29] The estimates for MSI-H CRC in 
stage IV subjects range from ~3.5% to 5%. Zsofia et al, indicated when assessed stage–by-
stage, the presence of MSI-H is noted in ~20% of stage I/II, ~12% of stage III, but only ~4% 
of stage IV subjects. [23] Data from the PETACC-3 study showed that tumor specimens 
characterized as MSI-H are more common in stage II disease than in stage III (22% vs. 12% 
respectively; p<0.0001).[30] The study by Koopman et al, indicated that the percentage of 
stage IV tumors characterized as MSI-H was only 3.5%. [31]
A recent study reported that once the disease recurs the prognostic advantage of MSI-H CRC 
is lost as the median OS after recurrence in stage II disease is 1.6 versus 2.2 years (MSI-H
CRC vs MSS CRC, respectively; hazard ratio (HR) 1.00, 95% confidence interval (CI), 
0.68-1.48; p>0.99) and after stage III disease is 1.2 versus 1.6 years (MSI-H CRC versus 
MSS CRC, respectively; HR 1.00, 95% CI, 0.85-1.17; p>0.99). The same group reported that 
there is actually a disadvantage in having MSI-H status in advanced disease. Five percent of 
the primary tumors of 3,063 subjects, pooled from 4 Phase III 1L studies in CRC, were found 
to be MSI-H. The median PFS and OS were significantly worse for subjects with MSI-H 
CRC compared with proficient MSS tumors (PFS: 6.2 vs 7.6 months; HR 1.33, 95% CI, 
1.12-1.57; p=0.001; OS: 13.6 vs 16.8; HR 1.35, 95% CI, 1.13-1.61; p=0.001). [32] These 
data emphasize that the prognosis for subjects with metastatic MSI-H CRC is poor despite
the current treatment options. Therefore, advanced or metastatic MSI-H CRC subjects 
represent a group of subjects with a high unmet medical need. 
Proof of Concept: Keynote 016 (KN016)
Overview of Efficacy in KN016 study
KN016 evaluated pembrolizumab (MK-3475) monotherapy in MSI-H CRC and MSS as well 
as MSI-H non-CRC subjects [33]. A total of 48 subjects were enrolled and treated during the 
period from September 2013 through May 2015. As of May 2015, the study accrued 13 MSI-
H, 25 MSS CRC, and 10 MSI-H non-CRC subjects. All CRC subjects had received >2 prior 
chemotherapy regimens (median=4) except for one MSS subject who had received 
1 chemotherapeutic and 1 immunotherapeutic (non-PD-1-based) regimen. The subjects
received pembrolizumab (MK-3475) 10mg/kg every 2 weeks. Radiologic assessments were 
made using RECIST v1.1 and immune-related response criteria (irRC) at 12 weeks and then 
every 8 weeks thereafter. 
Mismatch repair status was assessed in tumors through the evaluation of selected 
microsatellite sequences that are particularly prone to copying errors when mismatch repair is 
08GT0T


Product:  MK-3475 
29
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
compromised or by immunohistochemistry to determine expression of MMR proteins. Thus 
MSI tumor status was classified as MSI-H when ≥2 loci were present among the 5 analyzed 
microsatellite loci (NR-21, BAT-26, BAT-25, NR-24, and MONO-27) as detected by 
polymerase chain reaction (PCR) (Promega MSI analysis system) or if 1 or more of the 4 
(MLH1/MSH2/MSH6/PMS2)
mismatch repair protein expression [as
detected by
immunohistochemistry (IHC)] was absent.  
In the 13 subjects with MSI-H CRC, the ORR was 62%, whereas in 25 subjects with MSS 
CRC, no objective response was observed (ORR 0%). In the 10 MSI-H non-CRC subjects, 
the ORR was also 60%, demonstrating that pembrolizumab (MK-3475) is effective in all 
MSI-H subjects irrespective of the tumor type (Table 2). 
As shown in Figure 2, decreased serum tumor markers were observed in MSI-H CRC and 
non-CRC subjects, but not in MSS CRC subjects and reduction corresponded with clinical 
benefit. Radiographic responses are shown in Figure 3. The majority of MSI-H CRC (green 
bars) and MSI-H non-CRC subjects (black bars) experienced tumor shrinkage whereas MSS 
subjects (red bars) experienced no tumor shrinkage. 
Data presented in Figure 4 and Figure 5 show that the DOR observed in both MSI-H CRC 
and MSI-H non-CRC subjects is remarkably long in this advanced disease setting compared 
with MSS CRC subjects. In addition, none of the 8 out of 13 MSI-H CRC subjects with PR
have progressed at the time of this report (longest DOR is 16+ months).
Kaplan-Meier curves for PFS and OS are shown in Figure 6 Panels A and B and Figure 7
Panels C and D, respectively. For the subjects with MSI-H CRC, median PFS and median OS 
were not reached. In contrast, the subjects with MSS CRC had a median of PFS 2.3 months 
and a median of OS 7.6 months. The HR for PFS (MSI-H vs. MSS) is 0.13 (p<0.0001, 95% 
CI [0.07, 0.36]). The HR for OS (MSI-H vs. MSS) is 0.17 (p<0.007, 95% CI [0.09, 0.68]). 
Table 2
Objective Responses for Subjects Enrolled in KN 016
MSI-H CRC
MSS CRC
MSI-H non-
CRC
Type of Response-no. (%)
13
25
10
Complete Response1
0 (0)
0 (0)
1 (10)
Partial Response2
8 (62)
0 (0)
5 (50)
Stable Disease (Week 12)
4 (30)
4 (16)
1 (10)
Progressive Disease
1 (8)
14 (56)
2 (20)
Not Evaluable3
0 (0)
7 (28)
1 (10)
Objective response rate
62%
0%
60%
95% CI
32-86
0-14
26-88
Disease control rate4
92%
16%
70%
95% CI
64-100
5-36
35-93
1One endometrial subject in the MSI-H non-CRC cohort who was originally a PR achieved CR subsequently.
2Eight CRC subjects in the MSI-H CRC cohort and 5 subjects in the MSI-H non-CRC (endometrial, ampullary, 
duodenum, cholangio, and gastric cancers) achieved PR.
3Subjects were considered not evaluable if they did not undergo a 12-week scan due to clinical progression. Seven 
subjects in the MSS CRC cohort and 1 subject in the MSI-H non-CRC cohort were found to be not evaluable.
4The rate of disease control was defined as the percentage of subjects who had a complete response, partial response, or 
stable disease for 12 weeks or more.
08GT0T


Product:  MK-3475 
30
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
Figure 2
Biochemical Responses
Serum protein biomarker levels were measured with each cycle and the values represent 
percent change from baseline.  Subjects were included if baseline tumor marker values were 
greater than the upper limit of normal. CA-125 was used for a subject with endometrial 
cancer; CA19-9 was used for one cholangiocarcinoma and one ampullary cancer; and 
carcinoembryonic antigen (CEA) was used for all other subjects. Red, green, and black lines 
represent subjects with MSS, MSI-H CRC, and MSI-H non-CRC, respectively.  
Figure 3
Radiographic Responses
Tumor responses were measured at regular intervals and values show the best fractional 
change of the sum of longest diameters (SLD) from the baseline measurements of each 
measurable tumor. 
08GT0T


Product:  MK-3475 
31
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
Figure 4
Duration of Objective Response
Figure 5
Duration of Disease Control
08GT0T


Product:  MK-3475 
32
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
Figure 6
A and B Progression-Free Survival
Figure 7
C and D Overall Survival 
In summary, dMMR/MSI-H tumors were highly responsive to pembrolizumab (MK-3475). 
Biochemical response correlates with radiographic response as well as with PFS and OS. The 
overall results from the KN016 study suggest that MSI status predicts clinical benefit of 
immune checkpoint blockade with pembrolizumab (MK-3475) in both CRC and non-CRC 
subjects.
Overview of Safety in KN016 Study
Adverse events occurring in more than 5% of the subjects are listed in Table 3 below. Events 
of clinical interest included rash or pruritus (17%); thyroiditis, hypothyroidism (10%), 
hypophysitis (2%); and asymptomatic pancreatitis (15%). Although the numbers were small,
thyroid-function abnormalities were limited to the cohorts with mismatch repair–deficient 
cancer. There were no treatment-related serious adverse events. The overall adverse event 
summary as of 28-JAN-2015 appears in Table 3.
08GT0T


Product:  MK-3475 
33
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
Table 3
Adverse Event Summary: KN016
Adverse Event
All Grades
no. (%)
N=41
Grades 3 or 4
no. (%)
N=41
Any
21 (51)
4 (10)
Generalized symptoms
Fatigue
1 (2)
0 (0)
Myalgias
1 (2)
0 (0)
Arthalgias
1 (2)
0 (0)
Pancreatitis1
6 (15)
0 (0)
Pneumonitis
1 (2)
0 (0)
Endocrine disorders
Thyroiditis/hypothyroidism
4 (10)
0 (0)
Hypophysitis
1 (2)
0 (0)
Rash/pruritis
7 (17)
0 (0)
Thrombocytopenia
1 (2)
1 (2)
1 All cases of pancreatitis were asymptomatic.
Rationale for Dose Selection/Regimen/Modification
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 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 OS at 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 subjects were enrolled 
with melanoma and non-small-cell lung cancer (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 vs. 10 mg/kg Q3W (KN001 B2, KN001 D, KN002, KN010, and KN021), and 
3 studies compared 10 mg/kg Q3W vs. 10 mg/kg Q2W (KN001 B3, KN001 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. 
08GT0T


Product:  MK-3475 
34
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
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, pharmacologic 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. Secondly, 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 subject covariates on exposure, has shown that the fixed-dose regimen 
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 regimen and 2 mg/kg Q3W 
dose. Supported by these PK characteristics, and given that fixed-dose regimen has 
advantages of reduced dosing complexity and reduced potential of dosing errors, the 200 mg 
Q3W fixed-dose regimen was selected for evaluation across all pembrolizumab protocols.
A fixed-dose regimen is expected to simplify dosing (potentially reducing dosing errors), as 
well as provide convenience for physicians. A fixed-dose scheme will also reduce 
complexity in the logistical chain at treatment facilities, as well as waste.
Rationale for the Use of Comparator
Comparators in this study include mFOLFOX6 or FOLFIRI or respective combinations with 
bevacizumab or cetuximab; all are globally accepted standards of care as recommended by 
formal guidelines [National Comprehensive Cancer Network (NCCN), European Society for 
Medical Oncology (ESMO), and Japanese Society for Cancer of the Colon and Rectum
(JSCCR)].
Rationale for Endpoints
Efficacy Endpoints
This study will use PFS and OS as the primary endpoints. PFS is an acceptable measure of 
clinical benefit for a randomized Phase III study that demonstrates superiority of a new 
antineoplastic therapy, especially if the magnitude of effect is large and the therapy has an 
acceptable risk-benefit profile. The endpoint of OS is the standard for demonstrating 
superiority of antineoplastic therapy in oncology clinical studies.
RECIST 1.1, as assessed by the central imaging vendor, will be used to determine the dates 
of progression as this methodology is accepted by regulatory authorities. Since the treatment 
assignment is unblinded, images read by the central imaging vendor blinded to treatment 
assignment can minimize bias in the response assessments. In addition, final determination of 
radiologic PD will be based on the central imaging vendor assessment of PD, rather than 
local site Investigator/radiology assessment. Verification of PD will be expedited by the 
central imaging vendor and communicated to the site study team and Sponsor.
08GT0T


Product:  MK-3475 
35
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
Exploratory Endpoints
4.2.4.2.1 Immune-Related RECIST (irRECIST)
Immunotherapeutic agents such as pembrolizumab (MK-3475) may produce antitumor 
effects by potentiating endogenous cancer-specific immune responses. The response patterns 
seen with such an approach may extend beyond the typical time course of responses seen 
with cytotoxic agents, and can manifest a clinical response after an initial increase in tumor 
burden or even the appearance of new lesions. Standard RECIST 1.1 may, thus, not provide 
an accurate response assessment of immunotherapeutic agents such as pembrolizumab
(MK-3475). Based on an analysis of subjects with melanoma enrolled in KEYNOTE-001, 
7% of evaluable subjects experienced delayed or early tumor pseudoprogression. Of note, 
subjects who had progressive disease by RECIST 1.1, but not by irRC, had longer OS than 
subjects with PD by both criteria. Additionally, the data suggest that RECIST 1.1 may 
underestimate the benefit of pembrolizumab (MK-3475) in approximately 15% of subjects. 
These findings support the need to apply a modification to RECIST 1.1 that takes into 
account the unique patterns of atypical response in immunotherapy and enable treatment 
beyond initial radiographic progression. Immune-related RECIST (irRECIST) is RECIST 1.1 
adapted to account for the unique tumor response seen with immuno-therapeutics as 
described in [34]. The assessment of unidimensional target lesions and response categories 
per irRECIST are identical to RECIST 1.1. However, MSD has implemented an adaptation 
related to new lesions, non-target and tumor burden assessment in order to confirm 
radiographic progression. irRECIST will be used by local site Investigators to assess tumor 
response and progression, and make treatment decisions as well as by the central imaging 
vendor in support of the PFS endpoint. (see Section 7.1.4.6 for additional details on 
irRECIST assessments).
4.2.4.2.2 Subject Reported Outcomes (PRO)
As part of an exploratory analysis, subjects will provide information regarding their 
health-related quality-of-life (HRQoL) via the following EORTC assessment tools: EORTC 
QLQ-C30 and QLQ-CR29, and eEuroQol-5D3L (EQ5D-3L) questionnaires. These measures 
are not pure efficacy or safety endpoints because they are affected by both disease 
progression and treatment tolerability. 
eEORTC QLQ-C30 and eEORTC QLQ-CR29
The EORTC QLQ-C30 is the most widely used cancer-specific HRQoL instrument, which 
contains 30 items and measures 5 functioning dimensions (physical, role, cognitive, 
emotional, and social), 3 symptom items (fatigue, nausea/vomiting, pain), 6 single items 
(dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, and financial impact), and a 
global health and quality-of-life scale. [35] This instrument has been translated and validated 
into 81 languages and used in more than 3,000 studies worldwide.
The EORTC QLQ-CR29, a supplemental colorectal cancer-specific module, comprises 
multi-item and single-item measures of colorectal cancer-associated symptoms and impact. It 
includes 4 scales assessing urinary frequency, fecal seepage, stool consistency, and body 
08GT0T


Product:  MK-3475 
36
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
image, and single items assessing other common problems following treatment of colorectal 
cancer. 
eEuroQoL-5D 
The eEuroQol-5D-3L (eEQ5D-3L) is a standardized instrument for use as a measure of 
health outcome. The eEQ5D-3L will provide data for use in economic models and analyses 
including developing health utilities or quality adjusted life years (QALYs). The 5 health 
state dimensions in this instrument include the following: mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression. Each dimension is rated on a 3-point scale from 
1 (extreme problem) to 3 (no problem). The eEQ5D-3L also includes a graded (0 to 100) 
vertical visual analog scale on which the subject rates his or her general state of health at the 
time of the assessment. The eEQ5D-3L will always be completed by subjects first before 
completing the EORTC QLQ-C30 and QLQ-CR29 and is to be completed at various time 
points as specified in the Study Flow Chart, beginning with Cycle 1 until 30 days post-
treatment discontinuation. 
See flow chart for PRO assessment schedule. 
Safety Endpoints
The safety objective of this study is to characterize the safety and tolerability of 
pembrolizumab (MK-3475) in subjects with MSI-H or dMMR CRC. The primary safety 
analysis will be based on subjects who experienced toxicities as defined by CTCAE criteria. 
Safety will be assessed by quantifying the toxicities and grades experienced by subjects who 
have received pembrolizumab (MK-3475) compared to SOC including SAEs.
Safety will be assessed by reported adverse experiences using CTCAE, version 4.0. The 
attribution to drug, time-of-onset, duration of the event, its resolution, and any concomitant 
medications administered will be recorded. AEs will be analyzed including but not limited to 
all AEs, SAEs, fatal AEs, and laboratory changes. 
Microsatellite Instability Testing
Microsatellite instability (MSI), a form of genomic instability, occurs through the insertion or 
deletion of repeating nucleotides during DNA replication and failure of the mismatch repair 
system to correct errors in nucleotide repeat markers. MMR proteins, or MSI loci testing for 
CRC is clinically indicated as per NCCN, ESMO, and American Society of Clinical 
Oncology (ASCO) guidelines. [26] [36] [37] MMR or MSI status is determined by 
examining 
either 
1) 
protein 
expression 
by 
IHC 
of 
4 MMR 
enzymes 
(MLH1/MSH2/MSH6/PMS2) or 2) 3-5 tumor microsatellite loci using PCR-based assay, 
respectively.
Tumors are classified as MSI high when at least 2 allelic shifts among the 3-5 analyzed 
microsatellite markers are detected by PCR, or absence of at least 1 of 4 MMR enzymes’
protein expression is detected by IHC.
08GT0T


Product:  MK-3475 
37
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
Planned Exploratory Biomarker Research
Planned Genetic Analysis
Understanding genetic determinants of drug response is an important endeavor during 
medical research. This research will evaluate whether genetic variation within a clinical trial 
population correlates with response to the treatment(s) under evaluation. If genetic variation 
is found to predict efficacy or adverse events, the data might inform optimal use of therapies 
in the patient population. This research contributes to understanding genetic determinants of 
efficacy and safety associated with the treatments in this study.
Additional biomarker research to identify factors important for pembrolizumab (MK-3475) 
therapy may also be pursued. For example, tumor and blood samples from this study may 
undergo proteomic, genomic, metabolomics, and transcriptional analyses. Additional 
research may evaluate factors important for predicting responsiveness or resistance to 
pembrolizumab (MK-3475) therapy and other immunologic targets.
Assays may include but are not limited to:
Transcriptional Analyses
Messenger RNA (mRNA) expression profiling in archival material will be completed to 
assess expression of approximately 700 genes and attempt to define a gene set critical for 
clinical response to pembrolizumab (MK-3475). 
 Global profiling will also be pursued. Expression of individual genes related to the 
ystem may also be evaluated such as immune signatures and critical cytokines (eg,
IL-10). MicroRNA profiling may also be pursued in serum samples.
Proteomic analysis
Tissue derivatives can be subjected to proteomic profiling studies using a variety of 
platforms that could include but are not limited to immunoassay
and
liquid 
chromatography/mass spectrometry.
Gene Analyses
The application of new technologies, such as next-generation sequencing, has provided 
scientists the opportunity to define certain tumor types at the genetic level as being 
hypermutated (also known as increase mutational burden) or it can detect the presence of 
specific T-cell clones within the tumor microenvironment. Increased mutational burden is 
one of the major mechanisms of neo-antigen presentation in the context of a tumor. The 
increased presence of foreign-like peptides due to somatic mutations in the DNA of the 
tumor increases the chances that the tumor will be visible to the adaptive immune system 
through the major histocompatibility complex I (MHC-I) antigen presentation mechanism. 
There are a number of mechanisms by which a tumor can have increased mutational burden 
CCI
CCI
CCI
CCI
CCI
08GT0T


Product:  MK-3475 
38
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
such as defects in key genes related to DNA mismatch repair mechanisms or environmentally
induced factors such as smoking. Additionally, a DNA tetrapeptide neo-antigen mutational 
signature pattern can also be obtained by use of bioinformatics prediction tools of human 
leukocyte antigen (HLA)-restricted mutated peptide binding to MHC class I and to the T-cell. 
Future Biomedical Research
The Sponsor will conduct Future Biomedical Research on specimens collected 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.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main trial) and will only be conducted on specimens from 
appropriately consented subjects. The objective of collecting specimens for Future 
Biomedical Research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. The overarching goal is to use 
such information to develop safer, more effective drugs/vaccines, and/or to ensure that 
subjects receive the correct dose of the correct drug/vaccine at the correct time.  The details 
of this Future Biomedical Research are presented in Section 12.2 - Collection and 
Management of Specimens for Future Biomedical Research.  Additional informational 
material for institutional review boards/ethics committees (IRBs/ERCs) and investigational 
site staff is provided in Section 12.3.
Benefit/Risk
Subjects in clinical studies generally cannot expect to receive direct benefit from treatment 
during participation, as clinical studies are designed to provide information about the safety 
and effectiveness of an investigational medicine. France only:  It cannot be guaranteed that 
subjects in clinical studies will directly benefit from treatment during participation, as 
clinical studies are designed to provide information about the safety and effectiveness of an 
investigational medicine.
Additional details regarding specific benefits and risks for subjects participating in this 
clinical study may be found in the accompanying IB and informed consent documents.
Based on results from the ongoing clinical studies, there is no contraindication to the 
continued clinical investigation of pembrolizumab.
In addition, beneficial effects of pembrolizumab have been seen in several studies to date. 
Publications of a significantly positive benefit/risk ratio have been reported for melanoma 
both in a single-arm study encompassing nearly 1000 subjects (KEYNOTE 001), which led 
CCI
08GT0T


Product:  MK-3475 
39
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
to USFDA approval in September 2014, and in a randomized comparison to chemotherapy 
(KEYNOTE-002 – detailed in the IB). Additional potential benefits for CRC were 
demonstrated in the proof-of-concept study KEYNOTE-016, which showed that 
dMMR/MSI-H CRC were highly responsive to pembrolizumab (MK-3475) monotherapy 
(refer to Section 4.2.2.1). 
In conclusion, pembrolizumab demonstrates a promising anticancer
activity in 
MSI-H/dMMR CRC subjects with an acceptable safety profile compared to those of existing 
therapeutic options. Ongoing and planned studies will allow for a more comprehensive 
analysis of benefit/risk balance of pembrolizumab.
5.0 METHODOLOGY
Entry Criteria
Diagnosis/Condition for Entry into the Trial
Male/Female subjects with Microsatellite Instability-High (MSI-H) or Mismatch Repair 
Deficient (dMMR) Colorectal Cancer will be enrolled in this study.
Subject Inclusion Criteria
In order to be eligible for participation in this trial, the subject must:
1. Provide documented informed consent for the study.
2. Be male or female who is ≥ 18 years of age on the date of providing documented
informed consent.
3. Have locally confirmed MMR deficient (dMMR) or microsatellite instability-high 
(MSI-H) stage IV colorectal carcinoma (refer to Section 4.2.4.4 for details).
4. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
within 10 days prior to treatment initiation.
5. Have life expectancy of at least 3 months.
6. Have measurable disease at baseline based on RECIST 1.1 as determined by the local 
site Investigator/radiology assessment. 
7. Female subjects of childbearing potential must have a negative serum pregnancy test 
within 72 hours prior to receiving the first dose of study medication.
8. Female subjects of childbearing potential must be willing to use an adequate method 
of contraception as outlined in Section 5.7.2 – Contraception, for the course of the 
study starting with the first dose of study medication through 180 days after the last 
dose of study medication for the chemotherapy arm and 120 days for pembrolizumab
(MK-3475) arm, whichever is later. 
08GT0T


Product:  MK-3475 
40
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
Note: Abstinence is acceptable if this is the usual lifestyle for the subject.
9. Male subjects of childbearing potential must agree to use an adequate method of 
contraception as outlined in Section 5.7.2 – Contraception, starting with the first dose 
of study medication through 180 days after the last dose of study medication for the 
chemotherapy arm (no contraception requirement for pembrolizumab [MK-3475]
arm).
Note: Abstinence is acceptable if this is the usual lifestyle for the subject.
10. Demonstrate adequate organ function as defined in Table 4. All screening laboratory 
assessment should be performed within 10 days prior to treatment initiation.
Table 4
Adequate Organ Function Lab Values
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
≥1,500/µL
Platelets
≥100,000/µL
Hemoglobin
≥9 g/dL or ≥5.6 mmol/L 
Renal
Creatinine OR
Measured or calculateda  creatinine clearance
[Glomerular filtration rate (GFR) can also be used 
in place of creatinine or CrCl)]
≤1.5 × upper limit of normal (ULN) OR
≥60 mL/min for subject with creatinine levels >1.5 ×
institutional ULN
Hepatic
Total bilirubin
≤1.5 × ULN OR
Direct bilirubin ≤ULN for subjects with total 
bilirubin levels >1.5 ULN
Aspartate aminotransferase (AST) [Serum 
glutamic oxaloacetic transaminase (SGOT)] and 
Alanine Aminotransferase (ALT) [Serum 
Glutamic Pyruvic Transaminase (SGPT)]
≤2.5 × ULN OR
≤5 × ULN for subjects with liver metastases
Albumin
≥2.5 g/dL
Coagulation
International Normalized Ratio (INR) or 
Prothrombin Time (PT)
≤1.5 × ULN unless subject is receiving anticoagulant 
therapy
as long as PT or partial prothrombin time (PTT) is 
within therapeutic range of intended use of 
anticoagulants
Activated Partial Thromboplastin Time (aPTT)
≤1.5 × ULN unless subject is receiving anticoagulant 
therapy
as long as PT or PTT is within therapeutic range of 
intended use of anticoagulants
a Creatinine clearance should be calculated per institutional standard.
08GT0T


Product:  MK-3475 
41
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
Subject Exclusion Criteria
The subject must be excluded from participating in the trial if the subject:
1. Has received prior systemic therapy for stage IV CRC. Subjects may have received prior 
adjuvant chemotherapy for CRC as long as it was completed at least 6 months prior to 
randomization.
2. Is currently participating and receiving study medication in another study, or has 
participated in a study of an investigational agent and received study medication, or used 
an investigational device within 4 weeks of randomization.
3. Has an active autoimmune disease that has required systemic treatment in past 2 years 
(ie, with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). 
Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic 
treatment. 
4. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any 
other form of immunosuppressive therapy within 7 days prior to randomization.
5. Has had radiation therapy within 4 weeks prior to randomization of study medication and
who has not recovered to baseline from adverse events due to radiation therapy. Subjects 
who have been given palliative radiotherapy to peripheral sites (eg, bone metastasis) may 
enter the study before 4 weeks have elapsed but must have recovered from any acute 
adverse effects.
6. Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis. Subjects with previously treated brain metastases may participate provided 
they have stable brain metastases (without evidence of progression by imaging as 
confirmed by magnetic resonance imaging [MRI] if MRI was used at prior imaging, or 
confirmed by computed tomography [CT] imaging, if CT used at prior imaging, at least 
4 weeks prior to the first dose of study medication; also, any neurologic symptoms must 
have returned to baseline), and have not used steroids for brain metastases for at least 
28 days prior to study initiation. This exception does not include carcinomatous 
meningitis, as subjects with carcinomatous meningitis are excluded regardless of clinical 
stability.
7. Has had major surgical procedure, open biopsy, or significant traumatic injury within 
28 days prior to randomization.
8. Has received prior therapy with an immune checkpoint inhibitor (eg, anti-PD-1, 
anti-PD-L1, anti-PD-L2 agent, or anti-CTLA-4 agent, etc).
9. Has another malignancy that is progressing or requires active treatment. Exceptions 
include non-melanomatous skin cancer that has undergone potentially curative therapy
and in situ cervical carcinoma.
08GT0T


Product:  MK-3475 
42
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
10. Has received a live vaccine within 30 days of planned start of study medication (see 
Section 5.5.2).
11. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the study, interfere with the subject’s participation for 
the full duration of the study, or is not in the best interest of the subject to participate, in 
the opinion of the treating Investigator.

France and UK only:  Has a history or current evidence of any condition, (ie, known 
allergy, hypersensitivity, or contraindication to fluorouracil, leucovorin, oxaliplatin, 
irinotecan, bevacizumab, or cetuximab or any components used in their preparation if 
such is applicable in the investigator’s choice of chemotherapy for this study),
therapy, or laboratory abnormality that might confound the results of the study, 
interfere with the subject’s participation for the full duration of the study, or is not in 
the best interest of the subject to participate, in the opinion of the treating 
investigator.
12. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies), 
active chronic or acute Hepatitis B (eg, HBsAg reactive) or Hepatitis C (eg, HCV RNA 
[qualitative] is detected).
13. Has known history of, or any evidence of interstitial lung disease or active, 
non-infectious pneumonitis. 
14. Has a known history of active tuberculosis (TB; Bacillus tuberculosis).
15. Has an active infection requiring systemic therapy.
16. Has known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the study. 
17. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the study, starting with the screening visit through 180 days after 
the last dose of study medication for SOC (applicable for male and female subjects) or 
120 days after the last dose of study medication in the pembrolizumab (MK-3475) arm
(applicable for female subjects only).
08GT0T


Product:  MK-3475 
43
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
Trial Treatment(s)
The treatments to be used in this trial are outlined below in Table 5.
Table 5
Study Medication
Study 
Medication
Dose/Potency
Dose 
Frequency
Route of 
Administration
Use
Pembrolizumab
(MK-3475)
200 mg IV over 30 minutes
Q3W
IV infusion
Experimental
mFOLFOX6 
mFOLFOX6:
Oxaliplatin 85 mg/m2 IV over 2 hours, 
day 1
Leucovorin* 400 mg/m2 IV over 
2 hours, day 1
5-FU 400 mg/ m2 IV bolus, day 1, then 
5-FU 1200 mg/m2/day x 2 days 
(2400 mg/m2 over 46-48 hours) IV 
continuous infusion
Q2W
IV infusion
Standard of care
mFOLFOX6 + 
bevacizumab
mFOLFOX6:
Oxaliplatin 85 mg/m2 IV over 2 hours, 
day 1
Leucovorin* 400 mg/m2 IV over 
2 hours, day 1
5-FU 400 mg/m2 IV bolus, day 1, then 
5-FU 1200 mg/m2/day x 2 days 
(2400 mg/m2 over 46-48 hours) IV 
continuous infusion
Bevacizumab 5 mg/kg IV, day 1
Q2W
IV infusion
Standard of care
mFOLFOX6 + 
cetuximab
mFOLFOX6: 
Oxaliplatin 85 mg/m2 IV over 2 hours, 
day 1
Leucovorin* 400 mg/m2 IV over 
2 hours, day 1
5-FU 400 mg/m2 IV bolus, day 1, then 
5-FU 1200 mg/m2/day x 2 days 
(2400 mg/m2 over 46-48 hours) IV 
continuous infusion
Cetuximab: 400 mg/m2 IV over 2 hours 
first infusion, then 250 mg/m2 IV over 
1 hour weekly
Q2W
IV infusion
Standard of care
FOLFIRI
FOLFIRI:
Irinotecan 180 mg/m2 IV over 
30-90 minutes, day 1
Leucovorin* 400 mg/m2 IV infusion to 
match duration of irinotecan infusion, 
day 1 
5-FU 400 mg/m2 IV bolus day 1, then 
1200 mg/m2/day x 2 days (total 
2400 mg/m2 over 46-48 hours) IV 
continuous infusion
Q2W
IV infusion
Standard of care
08GT0T


Product:  MK-3475 
44
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
Study 
Medication
Dose/Potency
Dose 
Frequency
Route of 
Administration
Use
FOLFIRI 
+bevacizumab
FOLFIRI:
Irinotecan 180 mg/m2 IV over 
30-90 mins, day 1
Leucovorin* 400 mg/m2 IV infusion to 
match duration of irinotecan infusion, 
day 1 
5-FU 400 mg/m2 IV bolus day 1, then 
1200 mg/m2/day x 2 days (total 
2400 mg/ m2 over 46-48 hours) IV 
continuous infusion
Bevacizumab 5 mg/kg IV, day 1
Q2W
IV infusion
Standard of care
FOLFIRI 
+cetuximab
FOLFIRI:
Irinotecan 180 mg/m2 IV over 
30-90 mins, day 1
Leucovorin* 400 mg/m2 IV infusion to 
match duration of irinotecan infusion, 
day 1 
5-FU 400 mg/m2 IV bolus day 1, then 
1200 mg/m2/day x 2 days (total 
2400 mg/m2 over 46-48 hours) IV 
continuous infusion
Cetuximab:
400 mg/m2 IV over 2 hours first 
infusion, then 250 mg/m2 IV over 1 hour 
weekly 
Q2W
IV infusion
Standard of care
*or levoleucovorin 200mg/m2
Trial Treatment should begin within 3 days of randomization. However, every effort should 
be made to begin study medication on the day of randomization.
All supplies indicated in Table 5 above will be provided centrally by the Sponsor or locally 
by the trial site, subsidiary or designee, depending on local country operational or regulatory 
requirements.
For any commercially available product that is provided by the trial site, subsidiary or 
designee every attempt will be made to source these supplies from a single lot/batch number. 
Per local guidelines the trial site may be responsible for recording the lot number, 
manufacturer and expiry date of any locally purchased product.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of trial 
treatments in accordance with the protocol and any applicable laws and regulations.
08GT0T


Product:  MK-3475 
45
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
Dose Selection
Dose Selection (Preparation)
The rationale for selection of the dose of pembrolizumab (MK-3475) to be used in this study
is provided in Section 4.0, Background & Rationale. Details on preparation and 
administration of pembrolizumab (MK-3475) are provided in the Pharmacy Manual. 
Preparation and administration of SOC should follow local treatment guidelines.
Dose Modification (Escalation/Titration/Other)
SOC Arm
All SOC regimens must start at doses stipulated in the protocol. Dose modifications are 
permitted only if the modification is due to an AE/toxicity and must follow local treatment 
guidelines. Oxaliplatin may be stopped and restarted to prevent neuropathy per OPTIMOX
study after a minimum of 6 cycles of mFOLFOX [38].  Oxaliplatin should be resumed after 
12 cycles of 5FU/leucovorin if no neuropathy occurs. 
5.2.1.2.1 Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue)
Pembrolizumab (MK-3475) Arm
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 5.6.1 for supportive care guidelines, including use of corticosteroids.
08GT0T


Product:  MK-3475 
46
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
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
08GT0T


Product:  MK-3475 
47
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
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
08GT0T


Product:  MK-3475 
48
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
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).
08GT0T


Product:  MK-3475 
49
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
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. 
Table 7 provides treatment guidelines for subjects who experience an infusion reaction 
associated with administration of pembrolizumab (MK-3475).
Table 7
Infusion Reaction Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at Subsequent 
Dosing
Grade 1
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated
Increase monitoring of vital signs 
as medically indicated until the 
subject is deemed medically stable 
in the opinion of the Investigator.
None
Grade 2
Requires infusion interruption but 
responds promptly to symptomatic 
treatment (eg, antihistamines, 
NSAIDS, narcotics, IV fluids); 
prophylactic medications 
indicated for ≤24 hrs
Stop Infusion and monitor 
symptoms.
Additional appropriate medical 
therapy may include but is not 
limited to:
IV fluids
Antihistamines
NSAIDS
Acetaminophen
Narcotics
Increase monitoring of vital signs 
as medically indicated until the 
subject is deemed medically stable 
in the opinion of the Investigator.
If symptoms resolve within one 
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 
subject should be premedicated 
for the next scheduled dose.
Subjects who develop Grade 2 
toxicity despite adequate 
premedication should be 
permanently discontinued from 
further study medication
administration.
Subject may be premedicated 1.5h 
(± 30 minutes) prior to infusion of 
pembrolizumab (MK-3475) with:
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine).
Acetaminophen 500-1000 mg po 
(or equivalent dose of antipyretic).
08GT0T


Product:  MK-3475 
50
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
NCI CTCAE Grade
Treatment
Premedication at Subsequent 
Dosing
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:
IV fluids
Antihistamines
NSAIDS
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Epinephrine**
Increase monitoring of vital signs 
as medically indicated until the 
subject is deemed medically stable 
in the opinion of the Investigator.
Hospitalization may be indicated.
**In cases of anaphylaxis, 
epinephrine should be used 
immediately.
Subject is permanently 
discontinued from further study 
medication administration.
No subsequent dosing
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period 
of drug administration.
Other allowed dose interruption for pembrolizumab
Dosing interruptions are permitted with Sponsor consultation in the case of medical/surgical 
events or logistical reasons not related to study medication (eg, elective surgery (including
surgery for curative intent), unrelated medical events, subject vacation, and/or holidays). 
Subjects should be placed back on study medication within 3 weeks of the scheduled 
interruption, unless otherwise discussed with the Sponsor. As such, a maximum of 6 weeks
between doses of pembrolizumab and a maximum of 5 weeks between doses of SOC are 
allowed. A scheduled dosing interruption of longer than the aforementioned requires written 
Sponsor approval.
The reason for interruption should be documented in the subject’s study record.
Timing of Dose Administration
Pembrolizumab (MK-3475) Administration
Pembrolizumab (MK-3475) 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 (ie, infusion time is 30 minutes: -5 min/+10 min).
08GT0T


Product:  MK-3475 
51
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
The Pharmacy Manual contains specific instructions for pembrolizumab (MK-3475) 
preparation of the infusion fluid and administration.
Every effort should be made to begin the first dose of study medication on the day of 
randomization, but if this is not achieved, study medication should be initiated no later than 
3 days from the date of randomization.
All subsequent cycles of study medication 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 medications will begin on Day 1 of each cycle after all pre-dose study procedures 
and assessments have been completed as detailed on the Study Flow Chart – Section 6.0.
All study medications will be administered on an outpatient basis.
Standard of Care
mFOLFOX6 is a regimen containing oxaliplatin, leucovorin, and 5-fluorouracil (5-FU). 
Oxaliplatin 85 mg/m2 is administered over 2 hours on Day 1. Leucovorin 400 mg/m2 (or 
levoleucovorin 200 mg/m2) IV is administered over 2 hours on Day 1. 5-FU 400 mg/m2 is 
administered as an IV bolus on Day 1, then 1200 mg/m2/day for 2 days (total 2400 mg/m2
over 46-48 hours) IV continuous infusion. mFOLFOX6 is repeated every 2 weeks. 
FOLFIRI is a regimen containing irinotecan, leucovorin, and 5-FU. Irinotecan 180 mg/m2 is 
administered over 30 to 90 minutes on Day 1. Leucovorin 400 mg/m2 (or levoleucovorin 
200mg/m2) IV infusion is administered to match duration of irinotecan infusion on Day 1. 
5-FU 400 mg/m2 is administered as an IV bolus Day 1, then 1200 mg/m2/day for 2 days (total 
2400 mg/ m2 over 46-48 hours) IV continuous infusion. FOLFIRI is repeated every 2 weeks.
Bevacizumab 5mg/kg IV infusion is administered on Day 1 of every 2-week cycle. The first 
infusion is administered over 90 minutes. The second infusion is administered over 
60 minutes if the first infusion is tolerated. All subsequent infusions are administered over 
30 minutes if the infusion over 60 minutes is tolerated. Variations in infusion schedule per 
tolerability may be followed per institutional practice.
Cetuximab 400 mg/m2 IV infusion is administered over 120 minutes for the first infusion
on Day 1, then 250 mg/m2 IV infusion over 60 minutes weekly thereafter.
All study medications will be administered on an outpatient basis.
Trial Blinding/Masking
This is an open-label study; therefore, the Sponsor, Investigator and subject will know the 
treatment administered.
Imaging data will be centrally reviewed by independent radiologist(s) without knowledge of 
subject treatment assignment.
08GT0T


Product:  MK-3475 
52
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
Randomization
Treatment allocation/randomization will occur centrally using an interactive voice response 
system / integrated web response system (IVRS/IWRS).
There are 2 treatment arms.  
Subjects will be assigned randomly in a 1:1 ratio to pembrolizumab (MK-3475) or SOC,
respectively.
Stratification
No stratification based on age, sex, or other characteristics will be used in this study.
Concomitant Medications/Vaccinations (Allowed & Prohibited)
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for any medication or vaccination 
specifically prohibited during the trial, discontinuation from trial therapy or vaccination is 
required.  
Acceptable Concomitant Medications and Therapy
All treatments that the Investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the Investigator in keeping with the local and institutional 
standards of medical care. In addition, local therapy for palliation is permitted after 
consultation with the Sponsor. All concomitant medication will be recorded on the case 
report form (CRF) including all prescription, over-the-counter (OTC), herbal supplements, 
and IV medications and fluids. If changes occur during the study period, documentation of 
drug dosage, frequency, route, and date may also be included on the CRF.
All concomitant medications taken by the subject from the date of first dose of study 
medication and 30 days after the last dose of study medication should be recorded. 
Concomitant medications administered more than 30 days after the last dose of study 
medication should be recorded for SAEs as defined in Section 7.2.
Prohibited Concomitant Medications and Therapy
Subjects are prohibited from receiving the therapies listed below during the Screening and 
Treatment Phase (including retreatment for post-complete response relapse) of this study.  

Antineoplastic systemic chemotherapy or immunotherapy not specified in this 
protocol

Investigational agents other than pembrolizumab (MK-3475)

Local therapy for palliation after consultation with Sponsor

Live or live attenuated vaccines within 30 days prior to the first dose of study 
medication and while participating in the study. Examples of live vaccines include, 
but are not limited to, the following: measles, mumps, rubella, chickenpox, yellow 
08GT0T


Product:  MK-3475 
53
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
fever, rabies, Bacillus Calmette–Guérin (BCG), and typhoid (oral) 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.
Note: Any licensed COVID-19 vaccine (including for Emergency Use) in a particular 
country is allowed in the study as long as they are mRNA vaccines, replication-
incompetent adenoviral vaccines, or inactivated vaccines. These vaccines will be 
treated just as any other concomitant therapy.
Investigational vaccines (ie, those not licensed or approved for Emergency Use) are 
not allowed.

For pembrolizumab (MK-3475): 
glucocorticoids for any purpose other than to 
modulate symptoms from an event of suspected immunologic etiology. The use of 
physiologic doses of corticosteroids (prednisone 10 mg orally per day, or equivalent) 
may be approved after consultation with the Sponsor.

Note: Inhaled steroids are allowed for the management of asthma

Note: Use of prophylactic corticosteroids to avoid allergic reactions (eg, to IV 
contrast dye) is permitted.
Subjects may receive other medications that the Investigator deems to be medically 
necessary.
The Exclusion Criteria describes other medications that are prohibited in this study.
There are no prohibited therapies during the Post-Treatment Follow-up Phase.
Prohibited Concomitant Medications and Therapies for UK Only

For subjects receiving 5-FU:

5-FU may not be taken or used in conjunction with:
o
Brivudine, Sorivudine analogs, and other inhibitors of the enzyme 
dihydropyrimidine dehydrogenase (DPD)
o
Active immunizations
o
Polio vaccines

For subjects receiving Leucovorin:

Calcium folinate may not be mixed with 5-FU in the same intravenous 
injection or infusion since a precipitate can be formed
08GT0T


Product:  MK-3475 
54
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential

Calcium folinate solutions should not be mixed with infusions containing 
hydrogen carbonate due to chemical incompatibilities

Incompatibilities between the injected forms of calcium folinate and the 
injectable forms of Droperidol, 5-FU, Foscarnet, and Methotrexate were 
reported

For subjects receiving Oxaliplatin:

None

For subjects receiving Irinotecan:

Concomitant administration of inhibitors (eg, Ketoconazole) or inducers (eg,
Carbamazepine, Phenobarbital, Phenytoin, or Rifampicin) of cytochrome P-
450 isoenzyme 3A activity may alter the metabolism of Irinotecan and should 
be avoided

Hypericum perforatum (Hypericum, St John’s wort) preparations lower SN-38 
plasma levels. Consequently,
Hypericum preparations should not be 
administered with Irinotecan

For subjects receiving Bevacizumab:

None

For subjects receiving Cetuximab:

None
Rescue Medications & Supportive Care
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.
Supportive Care Guidelines for Pembrolizumab (MK-3475)
Suggested supportive care measures for the management of AEs with potential immunologic 
etiology are outlined in Section 5.2.1.2, Table 6. Where appropriate, these guidelines include 
the use of oral or intravenous 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 (MK-3475). 
08GT0T


Product:  MK-3475 
55
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
It may be necessary to perform conditional Procedures such as bronchoscopy, endoscopy, 
skin photography, and tissue biopsy as part of evaluation of the event. 
Diet/Activity/Other Considerations
Diet
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea, or vomiting.
Contraception
Pembrolizumab (MK-3475) may have adverse effects on a fetus in utero. Furthermore, it is 
not known if pembrolizumab (MK-3475) has transient adverse effects on the composition of 
sperm. 
For this study, male subjects will be considered to be of non-reproductive potential if they 
have azoospermia (whether due to having had a vasectomy or due to an underlying medical 
condition). 
Female subjects will be considered of non-reproductive potential if they meet 1 of the 
following criteria:

Are postmenopausal (defined as at least 12 months with no menses without an 
alternative medical cause. In women <45 years of age who are not using hormonal 
contraception or hormonal replacement therapy, a high follicle stimulating hormone 
(FSH) level in the postmenopausal range may be used to confirm a post-menopausal 
state. In the absence of 12 months of amenorrhea, a single FSH measurement is 
insufficient.

Have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or 
bilateral tubal ligation/occlusion, at least 6 weeks prior to screening.

Has a congenital or acquired condition that prevents childbearing.
Female subjects of reproductive potential must agree to avoid becoming pregnant while 
receiving pembrolizumab (MK-3475) and for 120 days after the last dose of study drug. For 
the chemotherapy arm, female and male subjects should start using birth control from the 
first dose of chemotherapy throughout the study period up to 180 days after the last dose of 
study drug. For subjects who cross over from chemotherapy to pembrolizumab (MK-3475), 
the aforementioned will apply to either 180 days after the last dose of chemotherapy or 
120 days after the last dose of pembrolizumab (MK-3475), whichever is later. Subjects must 
comply with one of the following:

Practice abstinence from heterosexual activity;
Abstinence (relative to heterosexual activity) can be used as the sole method of 
contraception if it is consistently employed as the subject’s preferred and usual 
08GT0T


Product:  MK-3475 
56
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
lifestyle and if considered acceptable by local regulatory agencies and European 
Research Councils (ERCs)/Institutional Review Boards (IRBs). Periodic abstinence 
(eg, calendar, ovulation, symptothermal, post-ovulation methods, etc.) and 
withdrawal are not acceptable methods of contraception.

Use (or have their partner use) acceptable contraception during heterosexual activity. 
Acceptable methods of contraception are‡:

Single method (1 of the following is acceptable):

Intrauterine device (IUD)

Vasectomy of a female subject’s male partner 

Contraceptive rod implanted into the skin

Combination method (requires use of 2 of the following):

Diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide)

Cervical cap with spermicide (nulliparous women only)  

Contraceptive sponge (nulliparous women only) 

Male condom or female condom (cannot be used together)

Hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or 
progestin-only pill), contraceptive skin patch, vaginal contraceptive ring, or 
subcutaneous contraceptive injection
‡If a contraceptive method listed above is restricted by local regulations/guidelines, then 
it does not qualify as an acceptable method of contraception for subjects participating at 
sites in this country/region.
Subjects should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study. In order to participate in 
the study, subjects of childbearing potential must adhere to the contraception requirement 
(described above) from the day of study medication initiation (or 14 days prior to the 
initiation of study medication for oral contraception) throughout the study period up to 
120 days after the last dose of pembrolizumab or 180 days after the last dose of 
chemotherapy. If there is any question that a subject of childbearing potential will not 
reliably comply with the requirements for contraception, that subject should not be entered 
into the study.
08GT0T


Product:  MK-3475 
57
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
For countries (eg, Sweden and Norway) or sites that follow the Clinical Study
Facilitation Group (CTFG) guidance, please use the following:
Pembrolizumab, bevacizumab, FOLFOX (5-FU, leucovorin, oxaliplatin), FOLFIRI 
(irinotecan + 5-FU + leucovorin), and cetuximab may have adverse effects on a fetus in 
utero. Furthermore, it is not known if these therapies have transient adverse effects on the 
composition of sperm. Therefore, non-pregnant, non-breastfeeding women may only be 
enrolled if they are willing to follow the CTFG Guidance (Final Version 2014-09-15, 
Sections 4.1 and 4.2) for highly effective birth control as outlined below, or are considered to 
be highly unlikely to conceive. Highly unlikely to conceive is defined as 1) surgically 
sterilized, or 2) postmenopausal (a woman who is ≥45 years of age and has not had menses 
for greater than 1 year will be considered postmenopausal), or 3) not heterosexually active 
for the duration of the study. Subjects should use birth control methods that can achieve a 
failure rate of less than 1% per year when used consistently and correctly and are considered 
as highly effective birth control methods. Such methods include:

Combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation:

Oral

Intravaginal

Transdermal

Progestogen-only hormonal contraception associated with inhibition of ovulation:

Oral

Injectable

Implantable

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)

Bilateral tubal occlusion

Vasectomized partner

Sexual abstinence
Subjects should start using birth control from study Visit 1 throughout the study period up to
180 days after the last dose of study medication.
Subjects should be informed that taking the study medication may involve unknown risks to
the fetus (unborn baby) if pregnancy were to occur during the study. In order to participate in 
08GT0T


Product:  MK-3475 
58
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
the study they must adhere to the contraception requirement (described above) for the
duration of the study and during the follow-up period defined in Section 7.2.2 – Reporting of
Pregnancy and Lactation to the Sponsor. If there is any question that a subject will not
reliably comply with the requirements for contraception, that subject should not be entered
into the study.
Monthly pregnancy testing is recommended per local standards if applicable.
Use in Pregnancy
If a subject inadvertently becomes pregnant while on treatment, the subject will immediately 
discontinue treatment and be removed from the study. The site will contact the subject at 
least monthly and document the subject’s status until the pregnancy has been completed or 
terminated. The outcome of the pregnancy will be reported to the Sponsor without delay and 
within 24 hours if the outcome is a serious adverse experience (eg, death, abortion, 
congenital anomaly, or other disabling or life-threatening complication to the mother or 
newborn). The study Investigator will make every effort to obtain permission to follow the 
outcome of the pregnancy and report the condition of the fetus or newborn to the Sponsor. If 
a male subject impregnates his female partner at any time during treatment, the study 
personnel at the site must be informed immediately and the pregnancy must be reported to 
the Sponsor and followed as described in Section 7.2.2 – Reporting of Pregnancy and 
Lactation to the Sponsor.
Use in Nursing Women
It is unknown whether pembrolizumab (MK-3475) is excreted in human milk. Since many 
drugs are excreted in human milk, and because of the potential for serious adverse reactions 
in the nursing infant, subjects who are breastfeeding are not eligible for enrollment.
Standard of care subjects should follow label guidance for use during nursing.
UK Only:  Sun Exposure Caution
Prolonged exposure to sunlight is not advisable in subjects treated with 5-FU due to the risk
of photosensitivity.
Subject Withdrawal/Discontinuation Criteria
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the 
trial plan is violated, or for administrative and/or other safety reasons.  Specific details 
regarding discontinuation or withdrawal procedures; including specific details regarding 
withdrawal from Future Biomedical Research, are provided in Section 7.1.5 – Other 
Procedures.
08GT0T


Product:  MK-3475 
59
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
In this trial, a subject may discontinue from treatment but continue to participate in the 
regularly scheduled activities, as long as the subject does not withdraw consent.  Once a 
subject has discontinued treatment, even though he/she continues to be monitored in the trial, 
he/she may be allowed to begin treatment again if deemed medically appropriate.
A subject must be discontinued from the trial for any of the following reasons:
●
The subject or legal representative (such as a parent or legal guardian) withdraws 
consent.

The subject is lost to follow-up

(France only):  Any progression or recurrence of another malignancy, or any 
occurrence of another malignancy that requires active treatment.
A subject must be discontinued from treatment but should continue to be monitored in the 
trial for any of the following reasons:

The subject or legal representative (such as a parent or legal guardian) withdraws 
consent for treatment

Confirmed radiographic PD as outlined in Section 7.1.4.5 for SOC arm and 
Section 7.1.4.6 for pembrolizumab (MK-3475) arm (exception if Sponsor approves 
treatment continuation for subjects on pembrolizumab) (France only:  exception does 
not apply).

Unacceptable adverse experiences as described in Section 7.2.

Intercurrent 
illness 
that 
prevents 
further 
administration 
of 
treatment
(France only:  other than another malignancy as noted above).

Investigator’s decision to discontinue the subject from treatment

The subject has a confirmed positive serum pregnancy test (refer to Section 5.7.3)

Administrative reasons

Completed 35 treatments (approx. 2 years) with pembrolizumab (MK-3475) (Initial 
Treatment/Crossover Phase)
The End of Treatment and Follow-up visit procedures are listed in Section 7.1.6.5 and 
Section 6.0 - Study Flow Chart. After the end of treatment, each subject will be followed for 
the occurrence of adverse events and spontaneously reported pregnancy as described in 
Section 7.2. See Section 7.2 for complete details of reporting requirements of adverse events 
and pregnancy/lactation.  
All subjects (including subjects who have received the maximum 35 pembrolizumab 
treatments) will have post-treatment follow-up for disease status, until initiating a non-study 
08GT0T


Product:  MK-3475 
60
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
cancer treatment, experiencing disease progression, death, withdrawing consent, or becoming 
lost to follow-up. Subjects who experience confirmed disease progression or start a new 
anticancer therapy, will move into the Survival Follow-Up Phase and should be contacted by 
telephone approximately every 9 weeks to assess for survival status until death, withdrawal 
of consent, or the end of the study, whichever occurs first.
Discontinuation of Pembrolizumab (MK-3475) after Complete Response
During the Initial Treatment Phase, discontinuation of pembrolizumab (MK-3475) may be 
considered for subjects who have attained a locally confirmed CR that have received at least 
8 pembrolizumab (MK-3475) treatments (approximately 6 months), and had at least 
2 treatments beyond the date when the initial CR was declared. Subjects who stop treatment 
and then experience radiographic PD may be eligible for up to 17 additional treatments 
(approximately 1 year) with pembrolizumab (MK-3475) in the Second Treatment Course 
Phase at the discretion of the Investigator if:
•
No cancer treatment was administered since the last dose of pembrolizumab (MK-3475)
•
The subject meets the parameters listed in the Inclusion/Exclusion criteria
•
The study is ongoing
Subjects will resume therapy at the same dose and schedule at the time of initial 
discontinuation. Additional details are provided in Section 7.1.6.3. Response or progression 
in this Second Course Phase will not count towards the primary endpoint in this study.
Subject Replacement Strategy
A subject who discontinues from the trial will not be replaced.
Beginning and End of the Trial
The overall trial begins when the first subject (or their legally acceptable representative) 
provides documented informed consent.  The overall trial ends when the last subject 
completes the last study-related contact, withdraws consent, or is lost to follow-up (ie, the 
subject is unable to be contacted by the investigator).
Upon study completion, participants are discontinued and may be enrolled in a 
pembrolizumab extension study, if available.
Clinical Criteria for Early Trial Termination
The clinical trial may be terminated early if the extent (incidence and/or severity) of 
emerging effects/clinical endpoints is such that the risk/benefit ratio to the trial population as 
a whole is unacceptable.  In addition, further recruitment in the trial or at (a) particular trial 
site(s) may be stopped due to insufficient compliance with the protocol, GCP and/or other 
applicable regulatory requirements, procedure-related problems or the number of 
discontinuations for administrative reasons is too high.
08GT0T


Product:  MK-3475 
61
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
Early trial termination will be the result of the criteria specified below:
1. Quality or quantity of data recording is inaccurate or incomplete
2. Poor adherence to protocol and regulatory requirements
3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential 
health hazard to subjects
4. Plans to modify or discontinue the development of the study drug. 
In the event of Sponsor decision to no longer supply study drug, ample notification will be 
provided so that appropriate adjustments to subject treatment can be made.
08GT0T


Product:  MK-3475 
62
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
6.0 TRIAL FLOW CHART
Initial Treatment Phase: Pembrolizumab (MK-3475) Arm
Details regarding the procedures listed in this table are outlined in Section 7.0.
Study Period:
Screening Phase
Treatment Cycles (3-Week Cycles)
End of 
Treatment
Post-treatment
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-upa
At time of 
discon
30 days 
post-
discon
Q9W
post-discon
Q9W
Scheduling Window (Days)b:
-42 to -29
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 7
± 7
± 7
Administrative Procedures
Informed Consent
X
Informed Consent for Future Biomedical 
Research (optional)
X
Inclusion/Exclusion Criteria
X
Subject Identification Card
X
Demographics and Medical History
X
Prior and Concomitant Medication Review
X
X
X
X
X
X
X
X
X
X
X
Survival Statusc
X
Clinical Procedures/Assessments
Review Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
ePROs (HRQoL Measures: EQ5D-3L, EORTC 
QLQ-C30, EORTC QLQ-CR29)d
X
X
X
X
X
X
X
X
Full Physical Examination
X
X
Directed Physical Examination
X
X
X
X
X
X
X
X
Height, Weight, and Vital Signs 
Xe
X
X
X
X
X
X
X
X
X
08GT0T


Product:  MK-3475 
63
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
Study Period:
Screening Phase
Treatment Cycles (3-Week Cycles)
End of 
Treatment
Post-treatment
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-upa
At time of 
discon
30 days 
post-
discon
Q9W
post-discon
Q9W
Scheduling Window (Days)b:
-42 to -29
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 7
± 7
± 7
12-Lead Electrocardiogram
X
ECOG Performance Status
Xf
X
X
X
X
X
X
X
X
X
Post-study Anticancer Therapy Status
X
X
Pembrolizumab (MK-3475) Administration 
Xb
X
X
X
X
X
X
X
LOCAL Laboratory Assessments
MSI/MMR Statusg
X
Pregnancy Test – Serum β-HCG
Xh
X
X
X
X
X
X
X
X
X
X
PT/INR and aPTT
Xf
CBC with Differentiali,j
Xf
X
X
X
X
X
X
X 
X
X
Chemistry Paneli,j
Xf
X
X
X
X
X
X
X 
X
X
Urinalysisi,k
Xf
X
X
X
X
X
X
T3 or FT3, FT4, TSHi.k
Xf
X
X
X
X 
X
X
Serum Tumor Marker (CEA)l
X
X
X
X
CENTRAL Laboratory Assessments
Blood for Genetics (DNA)m,n
X
Blood for Correlative Studies (DNA and RNA)n
X
X
X
X
Blood for Biomarker Studies (plasma and 
serum)o
X
Tumor Tissue Collection
Tumor Tissuep
X
08GT0T


Product:  MK-3475 
64
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
Study Period:
Screening Phase
Treatment Cycles (3-Week Cycles)
End of 
Treatment
Post-treatment
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-upa
At time of 
discon
30 days 
post-
discon
Q9W
post-discon
Q9W
Scheduling Window (Days)b:
-42 to -29
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 7
± 7
± 7
Efficacy Measurements
Tumor Imaging
X
Xq
Xr
Xr
a.
After the start of new anticancer therapy, contacts are made by telephone Q9W.
b.
Cycle 1 treatment must be given within 3 days of randomization (however, every effort should be made to start the first dose on day of randomization). The window for each 
visit is ± 3 days unless otherwise noted. For Imaging ONLY: the visit window is ± 7 days and should follow calendar days and not be adjusted for cycle delays.
c.
After documented disease progression, or the start of new anticancer treatment; contacts are approximately every 9 weeks by telephone. Updated survival status may be 
requested by the Sponsor at any time during the course of the study. Upon Sponsor notification, all subjects who do not/will not have a scheduled study visit or study contact 
during the Sponsor defined time period will be contacted for their survival status (excluding subjects who have a death event previously recorded).
d.
It is strongly recommended that electronic subject reported outcomes (ePROs) are administered prior to drug administration, adverse event evaluation and disease status 
notification starting with the EQ5D-3L, followed by EORTC QLQ-C30, and EORTC QLQ-CR29; an exception to this recommendation may occur at the treatment 
discontinuation visit where subjects may have already been notified of their disease status or an AE evaluation is known prior to them arriving to the clinic. All ePROs are to 
be performed at Cycle 1 (Week 0), Cycle 2 (Week 3), Cycle 3 (Week 6), Cycle 4 (Week 9), Cycle 5 (Week 12), Cycle 7 (Week 18), and then Q9W up to a year [Cycle 10 
(Week 27), Cycle 13 (Week 36), Cycle 16 (Week 45)] or End of Treatment, whichever comes first, and the 30-day post-treatment discontinuation Safety Follow-up Visit. 
e.
Height will be measured at Visit 1 only.
f.
ECOG Performance Status and Laboratory tests for screening are to be performed within 10 days prior to the first dose of study medication. If these laboratory tests are 
performed within 72 hours of the first dose of study medication, then they do not need to be repeated at Cycle 1.
g.
For subjects whose MSI/MMR status is unknown at the time of providing documented informed consent, the site should submit required samples to their local lab for 
MSI/MMR testing using an IHC or PCR-based assay prior to performing any other screening procedures. Subjects found not to be MSI-H or dMMR are deemed ineligible 
and should not continue with additional screening procedures (see Section 4.2.4.4).
h.
For women of reproductive potential, a serum pregnancy test for screening is to be performed within 10 days prior to the first dose of study medication. If the serum 
pregnancy test is performed within 72 hours of the first dose of study medication, then it does not need to be repeated at Cycle 1. Thereafter, a serum pregnancy test should be 
performed within 72 hours prior to each cycle of study medication and 30 days post treatment. 
i.
After Cycle 1, lab samples can be collected up to 72 hours prior to the scheduled time point. 
j.
To be performed every cycle through Cycle 6 and then every other cycle thereafter.
k.
To be performed every other cycle. 
l.
Serum tumor marker (CEA) to be collected Q9W (±3 days), beginning at Cycle 1. Collection follows calendar days; do not adjust for cycle delays.
m.
Details for the Planned Genetic Analysis Sample Collection can be found in Section 7.1.3.2.2. 
n.
Whole blood samples for correlative studies (DNA and RNA) should be collected pre-dose for each of the following:  Day 1, Cycle 1, Day 1, Cycle 2, Day 1, Cycle 3 and at 
treatment discontinuation. 
o.
Blood for biomarker studies (plasma and serum) should be collected pre-dose on Day 1, Cycle 1 only.
08GT0T


Product:  MK-3475 
65
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
Study Period:
Screening Phase
Treatment Cycles (3-Week Cycles)
End of 
Treatment
Post-treatment
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-upa
At time of 
discon
30 days 
post-
discon
Q9W
post-discon
Q9W
Scheduling Window (Days)b:
-42 to -29
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 7
± 7
± 7
p.
Submitting tumor tissue for exploratory analysis and future biomedical research (FBR) is optional and should be submitted only after the samples have been evaluated at the 
local site laboratory for MSI/MMR status.
q.
The first on-study imaging time point will be performed at 9 weeks (63 days ± 7 days) calculated from the date of randomization and will continue to be performed Q9W (63 
days ± 7 days), or earlier if clinically indicated. 
r.
For subjects who discontinue study medication without confirmed PD by the site per irRECIST: confirmatory tumor imaging should be performed at the time of treatment 
discontinuation unless previous tumor imaging was obtained within 4 weeks prior to the date of discontinuation; tumor imaging should be continued Q9W during the post-
treatment period until PD, initiation of a new anticancer therapy, withdrawal of consent, loss to follow-up, or death.
08GT0T


Product:  MK-3475 
66
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
Initial Treatment Phase: SOC Chemotherapy Arm
Study Period:
Screening Phase
Treatment Cycles (2-Week Cycles)
End of 
Treatment
Post-treatment
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-upa
At time of 
discon
30 days 
post-
discon
Q9W
post-
discon
Q9W
Scheduling Window (Days)b:
-42 to -29
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 7
± 7
± 7
Administrative Procedures
Informed Consent
X
Informed Consent for Future Biomedical 
Research (optional)
X
Inclusion/Exclusion Criteria
X
Subject Identification Card
X
Demographics and Medical History
X
Prior and Concomitant Medication Review
X
X
X
X
X
X
X
X
X
X
X
Survival Statusc
X
Clinical Procedures/Assessments
Review Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
ePROs (HRQoL Measures: EQ5D-3L, EORTC 
QLQ-C30, EORTC QLQ-CR29)d
X
X
X
X
X
X
X
Full Physical Examinatione
X
X
Directed Physical Examinatione
X
X
X
X
X
X
X
X
Height, Weight, and Vital Signs
Xf
X
X
X
X
X
X
X
X
X
12-Lead Electrocardiogram
X
ECOG Performance Status
Xg
X
X
X
X
X
X
X
X
X
08GT0T


Product:  MK-3475 
67
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
Study Period:
Screening Phase
Treatment Cycles (2-Week Cycles)
End of 
Treatment
Post-treatment
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-upa
At time of 
discon
30 days 
post-
discon
Q9W
post-
discon
Q9W
Scheduling Window (Days)b:
-42 to -29
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 7
± 7
± 7
Post-study Anticancer Therapy Status
X
X
Chemotherapy Administration 
Xb
X
X
X
X
X
X
X
LOCAL Laboratory Assessments
MSI/MMR Statush
X
Pregnancy Test – Serum β-HCG
Xi
X
X
X
X
X
X
X
X
X
X
PT/INR and aPTT
Xg
CBC with Differentialj,k
Xg
X
X
X
X
X
X
X
X
X
X
Chemistry Panelj,k
Xg
X
X
X
X
X
X
X
X
X
X
Urinalysisj,l
Xg
X
X
X
X
X
X
T3 or FT3, FT4, and TSHj,l
Xg
X
X
X
X
X
X
Serum Tumor Marker (CEA)m
X
X
X
X
CENTRAL Laboratory Assessments
Blood for Genetics (DNA)n
X
Blood for Correlative Studies (DNA and 
RNA)o
X
X
X
X
Blood for Biomarker Research (plasma and 
serum)p
X
Tumor Tissue Collection
Tumor Tissueq
X
08GT0T


Product:  MK-3475 
68
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
Study Period:
Screening Phase
Treatment Cycles (2-Week Cycles)
End of 
Treatment
Post-treatment
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-upa
At time of 
discon
30 days 
post-
discon
Q9W
post-
discon
Q9W
Scheduling Window (Days)b:
-42 to -29
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 7
± 7
± 7
Efficacy Measurements
Tumor Imaging
X
Xr
Xs
Xs
a.
After the start of new anticancer therapy contacts should be made by telephone Q9W.
b.
Cycle 1 treatment must be given within 3 days of randomization (however, every effort should be made to start the first treatment cycle on day of randomization). The 
window for each visit is ± 3 days unless otherwise noted. For Imaging ONLY: the visit window is ± 7 days and should follow calendar days and not be adjusted for cycle 
delays.
c.
After documented disease progression, or the start of new anticancer treatment; contacts are approximately every 9 weeks by telephone. Updated survival status may be 
requested by the Sponsor at any time during the course of the study. Upon Sponsor notification, all subjects who do not/will not have a scheduled study visit or study contact 
during the Sponsor defined time period will be contacted for their survival status (excluding subjects who have a death event previously recorded).
d.
It is strongly recommended that ePROs are administered prior to drug administration, adverse event evaluation and disease status notification starting with the EQ5D-3L, 
followed by EORTC QLQ-C30, and EORTC QLQ-CR29; an exception to this recommendation may occur at the treatment discontinuation visit where subjects may have 
already been notified of their disease status or an AE evaluation is known prior to them arriving to the clinic. All ePROs  are to be performed at Cycle 1 (Week 0), Cycle 2 
(Week 2), Cycle 4 (Week 6), in between Cycle 5 and Cycle 6 (Week 9), Cycle 7 (Week 12), Cycle 10 (Week 18) and then Q9W up to a year: [In between Cycle 14 and 15 
(Week 27), Cycle 19 (Week 36), in between Cycle 23 and 24 (Week 45)] or End of Treatment, whichever comes first, and the 30-day post-treatment discontinuation Safety 
Follow-up Visit. 
e.
UK Only:  For subjects assigned to FOLFOX based regimens only: full physical examination and directed physical examination will include neurologic and hearing 
examinations by the treating physician or designee.
f.
Height will be measured at Visit 1 only.
g.
ECOG Performance Status and Laboratory tests for screening are to be performed within 10 days prior to the first dose of study medication. If these laboratory tests are 
performed within 72 hours of the first dose of study medication, then they do not need to be repeated at Cycle 1.
h.
For subjects whose MSI/MMR status is unknown at the time of providing documented informed consent, the site should submit required samples to their local lab for 
MSI/MMR testing using an IHC or PCR-based assay prior to performing any other screening procedures. Subjects found not to be MSI-H or dMMR are deemed ineligible 
and should not continue with additional screening procedures (see Section 4.2.4.4).
i.
For women of reproductive potential, a serum pregnancy test for screening is to be performed within 10 days prior to the first dose of study medication. If the serum 
pregnancy test is performed within 72 hours of the first dose of study medication, then it does not need to be repeated at Cycle 1 Thereafter, a serum pregnancy test should be 
performed within 72 hours prior to each cycle of study medication and 30 days post treatment. 
j.
After Cycle 1, lab samples can be collected up to 72 hours prior to the scheduled time point. 
k.
To be performed every cycle.  
l.
To be performed every other cycle. 
m.
Serum tumor marker (CEA) to be collected Q8W (±3 days), beginning at Cycle 1. Collection follows calendar days; do not adjust for cycle delays.
n.
Details for the Planned Genetic Analysis Sample Collection can be found in Section 7.1.3.2.2. 
08GT0T


Product:  MK-3475 
69
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
Study Period:
Screening Phase
Treatment Cycles (2-Week Cycles)
End of 
Treatment
Post-treatment
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-upa
At time of 
discon
30 days 
post-
discon
Q9W
post-
discon
Q9W
Scheduling Window (Days)b:
-42 to -29
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 7
± 7
± 7
o.
Whole blood samples for correlative studies (DNA and RNA) should be collected pre-dose for each of the following:  Day 1, Cycle 1, Day 1, Cycle 2, Day 1, Cycle 3 and at 
treatment discontinuation. 
p.
Blood for biomarker studies (plasma and serum) should be collected pre-dose on Day 1, Cycle 1 only.
q.
Submitting tumor tissue for exploratory analysis and FBR is optional and should be submitted only after the samples have been evaluated at the local site laboratory for 
MSI/MMR status.
r.
The first on-study imaging time point will be performed at 9 weeks (63 days ± 7 days) calculated from the date of randomization and will continue to be performed Q9W (63 
days ± 7 days), or earlier if clinically indicated. 
s.
For subjects who discontinue study medication without confirmed PD by the site per RECIST 1.1: confirmatory tumor imaging should be performed at the time of treatment 
discontinuation unless previous tumor imaging was obtained within 4 weeks prior to the date of discontinuation; tumor imaging should be continued Q9W during the post-
treatment period until PD, initiation of a new anticancer therapy, withdrawal of consent, loss to follow-up, or death.
08GT0T


Product:  MK-3475 
70
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
Second Course Treatment Phase: Pembrolizumab (MK-3475) Arm and SOC Chemotherapy Arm following Crossover
Study Period:
Treatment Period (3-Week Cycles)
End of 
Treatment
Post-treatment
Treatment Cycle/Title:
1
2
3
4
5
6
7
8 and 
beyond
Discon
Safety 
Follow-up
Follow-Up 
Visits
Survival 
Follow-Upa
At time of 
discon
30 days 
post-
discon
Q9W
post-
discon
Q9W
Scheduling Window (Days)b
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 7
± 7
± 7
Administrative Procedures
Eligibility Criteria
X
Concomitant Medication Review
X
X
X
X
X
X
X
X
X
X
Survival Statusc
X
Clinical Procedures/Assessments
Review Adverse Events
X
X
X
X
X
X
X
X
X
X
X
Full Physical Examination
X
X
Directed Physical Examination
X
X
X
X
X
X
X
Weight, and Vital Signs 
X
X
X
X
X
X
X
X
X
ECOG Performance Status
X
X
X
X
X
X
X
X
X
Post-study anticancer Therapy Status
X
X
Pembrolizumab (MK-3475) Administration
X
X
X
X
X
X
X
X
LOCAL Laboratory Assessments
Pregnancy Test – Serum β-HCGd
X
X
X
X
X
X
X
X
X
X
PT/INR and aPTT
Xf
CBC with Differentiale,g
X f
X
X
X
X
X
X
X
X
Chemistry Panele,g
X f
X
X
X
X
X
X
X
X
Urinalysise,h
X f
X
X
X
X
X
08GT0T


Product:  MK-3475 
71
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
Study Period:
Treatment Period (3-Week Cycles)
End of 
Treatment
Post-treatment
Treatment Cycle/Title:
1
2
3
4
5
6
7
8 and 
beyond
Discon
Safety 
Follow-up
Follow-Up 
Visits
Survival 
Follow-Upa
At time of 
discon
30 days 
post-
discon
Q9W
post-
discon
Q9W
Scheduling Window (Days)b
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 7
± 7
± 7
T3 or FT3, FT4, and TSHe,h
X f
X
X
X
X
X
Serum Tumor Marker (CEA)i
X
X
X
Efficacy Measurements
Tumor Imaging
Xj
X
X
Xk
Xk
a.
After the start of new anticancer treatment or PD the subject should be contacted by telephone Q9W.
b.
The window for each visit is ± 3 days unless otherwise noted. For Imaging ONLY: the visit window is ± 7 days and should follow calendar days and not be adjusted for 
cycle delays.  
c.
After documented disease progression, or the start of new anticancer treatment; contacts are approximately every 9 weeks by telephone. Updated survival status may be 
requested by the Sponsor at any time during the course of the study. Upon Sponsor notification, all subjects who do not/will not have a scheduled study visit or study 
contact during the Sponsor defined time period will be contacted for their survival status (excluding subjects who have a death event previously recorded).
d.
For women of reproductive potential, a serum pregnancy test for screening is to be performed within 10 days prior to the first dose of study medication. If the serum 
pregnancy test is performed within 72 hours of the first dose of study medication, then it does not need to be repeated at Cycle 1. Thereafter, a serum pregnancy test should 
be performed within 72 hours prior to each cycle of retreatment with pembrolizumab (MK-3475) and 30 days post treatment. 
e.
After Cycle 1, lab samples can be collected up to 72 hours prior to the scheduled time point.  
f.
Laboratory tests for determining eligibility are to be performed within 10 days prior to the first retreatment dose of pembrolizumab (MK-3475). If these laboratory tests are 
performed within 72 hours of the first dose of study medication, then they do not need to be repeated at Cycle 1.
g.
Complete blood count (CBC) and Chemistry to be performed every cycle through Cycle 6 and then every other cycle thereafter. 
h.
To be performed every other cycle. 
i.
Serum tumor marker (CEA) to be collected Q9W (±3 days), beginning at Cycle 1. Collection follows calendar days; do not adjust for cycle delays.
j.
Tumor imaging should be performed within 28 days prior to restarting treatment with pembrolizumab (MK-3475) and continue to be performed Q9W (63 ± 7 days) 
calculated from the first dose of retreatment, or more frequently if clinically indicated. 
k.
For subjects who discontinue study medication without confirmed PD by the site per irRECIST: confirmatory tumor imaging should be performed at the time of treatment 
discontinuation unless previous tumor imaging was obtained within 4 weeks prior to the date of discontinuation; tumor imaging should be continued Q9W during the post-
treatment period until PD, initiation of a new anticancer therapy, withdrawal of consent, loss to follow-up, or death.
08GT0T


Product:  MK-3475 
72
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
Crossover Phase:  SOC Chemotherapy Arm
Crossover subjects from SOC chemotherapy must have confirmation of PD per RECIST 1.1 by blinded central imaging 
vendor and be qualified for Crossover Phase.
Study Period:
Treatment Period (3-Week Cycles)
End of 
Treatment
Post-treatment
Treatment Cycle/Title:
1
2
3
4
5
6
7
8 and 
beyond
Discon
Safety 
Follow-up
Follow-Up 
Visits
Survival 
Follow-
Upa
At time of 
discon
30 days 
post-
discon
Q9W 
post-
discon
Q9W
Scheduling Window (Days)b
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 7
± 7
± 7
Administrative Procedures
Eligibility Criteria
X
Concomitant Medication Review
X
X
X
X
X
X
X
X
X
X
Survival Statusc
X
Clinical Procedures/Assessments
Review Adverse Events
X
X
X
X
X
X
X
X
X
X
X
Full Physical Examination
X
X
Directed Physical Examination
X
X
X
X
X
X
X
Weight, and Vital Signs 
X
X
X
X
X
X
X
X
X
ECOG Performance Status
X
X
X
X
X
X
X
X
X
Post-study anticancer Therapy Status
X
X
Pembrolizumab (MK-3475) Administration 
X
X
X
X
X
X
X
X
LOCAL Laboratory Assessments
Pregnancy Test – Serum β-HCGd
X
X
X
X
X
X
X
X
X
X
PT/INR and aPTT
Xf
08GT0T


Product:  MK-3475 
73
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
Study Period:
Treatment Period (3-Week Cycles)
End of 
Treatment
Post-treatment
Treatment Cycle/Title:
1
2
3
4
5
6
7
8 and 
beyond
Discon
Safety 
Follow-up
Follow-Up 
Visits
Survival 
Follow-
Upa
At time of 
discon
30 days 
post-
discon
Q9W 
post-
discon
Q9W
Scheduling Window (Days)b
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 7
± 7
± 7
CBC with Differentiale,g
Xf
X
X
X
X
X
X
X
X
Chemistry Panele,g
Xf
X
X
X
X
X
X
X
X
Urinalysise,h
Xf
X
X
X
X
X
T3 or FT3, FT4, and TSHe,h
Xf
X
X
X
X
X
Serum Tumor Marker (CEA)i
X
X
X
Efficacy Measurements
Tumor Imaging
Xj
X
X
Xk
Xk
a.
After the start of new anticancer treatment or PD the subject should be contacted by telephone Q9W.
b.
The window for each visit is ± 3 days unless otherwise noted. For Imaging ONLY: the visit window is ± 7 days and should follow calendar days and not be adjusted for cycle 
delays.
c.
After documented disease progression, or the start of new anticancer treatment; contacts are approximately every 9 weeks by telephone. Updated survival status may be 
requested by the Sponsor at any time during the course of the study. Upon Sponsor notification, all subjects who do not/will not have a scheduled study visit or study contact 
during the Sponsor defined time period will be contacted for their survival status (excluding subjects who have a death event previously recorded).
d.
For women of reproductive potential, a serum pregnancy test for screening is to be performed within 10 days prior to the first dose of study medication. If the serum 
pregnancy test is performed within 72 hours of the first dose of study medication, then it does not need to be repeated at Cycle 1. Thereafter, a serum pregnancy test should be 
performed within 72 hours prior to each cycle of retreatment with pembrolizumab (MK-3475) and 30 days post treatment. 
e.
After Cycle 1, laboratory samples can be collected up to 72 hours prior to the scheduled time point.
f.
Laboratory tests for determining eligibility are to be performed within 10 days prior to the first retreatment dose of pembrolizumab (MK-3475). If these laboratory tests are 
performed within 72 hours of the first dose of study medication, then they do not need to be repeated at Cycle 1.
g.
Complete blood count (CBC) and Chemistry to be performed every cycle through Cycle 6 and then every other cycle thereafter. 
h.
To be performed every other cycle. 
i.
Serum tumor marker (CEA) to be collected Q9W (±3 days), beginning at Cycle 1. Collection follows calendar days; do not adjust for cycle delays.
j.
Tumor imaging should be performed within 28 days prior to restarting treatment with pembrolizumab (MK-3475) and continue to be performed Q9W (63 ± 7 days) calculated 
from the first dose of retreatment, or more frequently if clinically indicated. 
k.
For subjects who discontinue study medication without confirmed PD by the site per irRECIST: confirmatory tumor imaging should be performed at the time of treatment 
discontinuation unless previous tumor imaging was obtained within 4 weeks prior to the date of discontinuation; tumor imaging should be continued Q9W during the 
post-treatment period until PD, initiation of a new anticancer therapy, withdrawal of consent, loss to follow-up, or death.
08GT0T


Product:  MK-3475 
74
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
7.0 TRIAL PROCEDURES
Trial Procedures
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to 
perform these procedures at unscheduled time points if deemed clinically necessary by the 
investigator.
Furthermore, additional evaluations/testing may be deemed necessary by the investigator and 
or the Sponsor for reasons related to subject safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations 
may require that additional informed consent be obtained from the subject.  In these cases, 
such evaluations/testing will be performed in accordance with those regulations.
Administrative Procedures
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented informed consent from each potential subject (or their legally acceptable 
representative) prior to participating in this clinical trial or Future Biomedical Research. If 
there are changes to the subject’s status during the study (eg, health or age of majority 
requirements), the investigator or medically qualified designee must ensure the appropriate 
documented informed consent is in place.
7.1.1.1.1 General Informed Consent
Informed consent given by the subject or their legally acceptable representative must be 
documented on a consent form. The form must include the trial protocol number, trial 
protocol title, dated signature, and agreement of the participant (or his/her legally acceptable 
representative) and of the person conducting the consent discussion.
A copy of the signed and dated informed consent form should be given to the subject (or 
their legally acceptable representative) before participation in the trial.
The initial informed consent form, any subsequent revised informed consent form, and any 
written information provided to the subject must receive the IRB/IEC’s approval/favorable 
opinion in advance of use. The subject or his/her legally acceptable representative should be 
informed in a timely manner if new information becomes available that may be relevant to 
the subject’s willingness to continue participation in the trial. The communication of this 
information will be provided and documented via a revised consent form or addendum to the 
original consent form that captures the subject’s or the subject’s legally acceptable 
representative’s dated signature.
Specifics about the trial and the trial population are to be included in the trial informed 
consent form.
08GT0T


Product:  MK-3475 
75
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
Informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, and 
Sponsor requirements.
7.1.1.1.2 Consent and Collection of Specimens for Future Biomedical Research
The investigator or medically qualified designee will explain the Future Biomedical Research 
consent to the subject, or the subject’s legally acceptable representative, answer all of his/her 
questions, and obtain documented informed consent before performing any procedure related 
to Future Biomedical Research. A copy of the informed consent will be given to the subject 
before performing any procedure related to Future Biomedical Research.
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the study.
Subject Identification Card
All subjects will be given a Subject Identification Card identifying them as participants in a 
research trial. The card will contain trial site contact information (including direct telephone 
numbers) to be used in the event of an emergency. The investigator or qualified designee will 
provide the subject with a Subject Identification Card immediately after the subject provides 
documented informed consent. At the time of intervention randomization, site personnel will 
add the treatment/randomization number to the Subject Identification Card.
The subject identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about trial 
medication/vaccination in emergency situations where the investigator is not available.
Medical History
A medical history will be obtained by the investigator or qualified designee. Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
are considered to be clinically significant by the investigator. Disease details regarding the 
subject’s CRC will be recorded separately and not listed as medical history. 
Please note that if the subject has lost at least 15 lbs. (6.8 kg.) over the three months prior to 
screening, “weight loss” should be entered as an active condition on the Medical History. As 
well, any autoimmune disorders, regardless of onset date, should be recorded.
Disease Details
The investigator or qualified designee will obtain prior and current details regarding the 
subject’s CRC.
08GT0T


Product:  MK-3475 
76
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
Prior and Concomitant Medications Review
7.1.1.6.1 Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject 
within 28 days of first dose of study medication. Prior anticancer treatment for CRC be 
recorded separately and not listed as a prior medication. 
Prior Treatment Details for Colorectal Carcinoma
The investigator or qualified designee will review all prior anticancer treatments including
systemic treatments, radiation and surgeries.
7.1.1.6.2 Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the subject 
during the study from the date of first dose of study medication through the Safety Follow-up 
Visit. In addition, new medications started during the Second Course/Crossover Phase 
through the Second Course/Crossover Safety Follow-up Visit should be recorded. 
All medications related to reportable SAEs should be recorded as defined in Section 7.2.
Assignment of Screening Number
All consented subjects will be given a unique screening number that will be used to identify 
the subject for all procedures that occur prior to randomization or treatment allocation.  Each 
subject will be assigned only one screening number.  Screening numbers must not be re-used 
for different subjects.
Any subject who is screened multiple times will retain the original screening number 
assigned at the initial screening visit.
Specific details on the screening visit requirements (screening/rescreening) are provided in 
Section 7.1.6.1.
Assignment of Treatment/Randomization Number
All eligible subjects will be randomly allocated and will receive a treatment/randomization 
number.  The treatment/randomization number identifies the subject for all procedures 
occurring after treatment allocation/randomization.  Once a treatment/randomization number 
is assigned to a subject, it can never be re-assigned to another subject.
A single subject cannot be assigned more than 1 treatment/randomization number.
08GT0T


Product:  MK-3475 
77
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
Trial Compliance (Medication/Diet/Activity/Other)
Dosing interruptions are permitted with Sponsor consultation in the case of medical/surgical 
events or logistical reasons not related to study medication (eg, elective surgery [including 
surgery for curative intent], unrelated medical events, subject vacation, and/or holidays). 
Subjects should be placed back on study medication within 3 weeks of the scheduled 
interruption, unless otherwise discussed with the Sponsor. As such, there shall be a maximum 
of 6 weeks between doses of pembrolizumab and a maximum of 5 weeks between doses of 
SOC. Scheduled dosing interruption of longer than the aforementioned requires written 
Sponsor approval.
Administration of study medication will be monitored by the investigator and/or study staff, 
and/or qualified designee per institutional guidelines and procedures.
Clinical Procedures/Assessments
Adverse Event Monitoring
The investigator or qualified designee will assess each subject to evaluate for potential new 
or worsening AEs as specified in the Study Flow Chart and more frequently if clinically 
indicated. Adverse events will be graded and recorded throughout the study and during the 
follow-up period according to NCI CTCAE version 4.0 (see Section 12.6). Toxicities will be 
characterized in terms regarding seriousness, causality, toxicity grading, and action taken 
with regard to study medication.
Please refer to Section 7.2 for detailed information regarding the assessment and recording of 
AEs.  
Electronic Subject Reported Outcomes (ePROs)
The EuroQoL EQ5D-3L, EORTC QLQ-C30, and EORTC QLQ-CR29 questionnaires will be 
administered by trained study site personnel and completed electronically by subjects. It is 
strongly recommended that the electronic EORTC QLQ-C30, EORTC QLQ-CR29 and 
EuroQoL EQ5D-3L are completed by the subject prior to drug administration, adverse event 
evaluation and disease status notification; an exception to this recommendation may occur at 
the treatment discontinuation visit. ePROs will be administered in the following order: 
EuroQoL EQ5D-3L first, then EORTC QLQ-C30, and lastly the EORTC QLQ-CR29 at the 
time points specified in the Study Flow Chart.
Physical Exam
7.1.2.3.1 Full Physical Exam
The investigator or clinical designee will perform a complete physical exam during the 
screening period. Clinically significant abnormal findings should be recorded as medical 
history. Additional full physical exams should be performed as specified in the Study Flow 
Chart – Section 6.0. After the first dose of study medication new clinically significant 
abnormal findings should be recorded as AEs.
08GT0T


Product:  MK-3475 
78
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
7.1.2.3.2 Directed Physical Exam
For cycles that do not require a full physical exam per the Study Flow Chart – Section 6.0, 
the investigator or qualified designee will perform a directed physical exam as clinically 
indicated prior to dosing ±3 days of Day 1 of each treatment cycle. New clinically significant 
abnormal findings should be recorded as AEs.
Height, Weight, and Vital Signs
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of study medication, and at treatment discontinuation as 
specified in the Study Flow Chart – Section 6.0.  
Vital signs should include temperature, pulse, respiratory rate, blood pressure, and weight. 
Height will be measured at screening only.  
12-Lead Electrocardiogram
A standard 12-lead electrocardiogram (ECG) will be performed one time during screening 
using local standard procedures. Clinically significant abnormal findings should be recorded 
as medical history. Additional time points may be performed as clinically necessary.
Eastern Cooperative Oncology Group (ECOG) Performance Status
The investigator or qualified designee will assess ECOG Performance Status (see Section 
12.5) at screening, prior to dosing ±3 days of Day 1 of each treatment cycle, and at 
discontinuation of study medication as specified in the Study Flow Chart – Section 6.0.
Post-study Anticancer Therapy Status
The investigator or qualified designee will review all new anticancer therapy initiated after 
the last dose of study medication. If a subject initiates a new anticancer therapy within 
30 days after the last dose of study medication, the 30 day Safety Follow-up Visit must occur 
before the first dose of the new therapy.  
Once new anticancer therapy has been initiated the subject will move into survival follow-up.
Laboratory Procedures/Assessments
Details regarding specific laboratory procedures/assessments to be performed in this study
are provided below. The total amount of blood/tissue to be drawn/collected over the course 
of the study (from pre-study to post-study visits), including approximate blood/tissue 
volumes drawn/collected by visit and by sample type per subject can be found in the 
Procedures Manual.
Refer to the Study Flow Chart – Section 6.0 for the schedule of laboratory assessments.
08GT0T


Product:  MK-3475 
79
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
Local Laboratory Assessments
7.1.3.1.1 Hematology, Chemistry, Urinalysis, and Other Labs
All required laboratory tests are specified in Table 8.
Table 8
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
ALT
Glucose
Total triiodothyronine 
(T3) or Free T3 (FT3)c
Absolute neutrophil 
countd
AST
Blood
Free thyroxine (FT4)
Absolute lymphocyte 
countd
Bicarbonate or Carbon 
dioxidee
PT(INR)
Calcium
aPTT
Chloride
Blood for correlative 
studies
Creatinine
PK
Glucose
Anti-pembrolizumab 
(MK-3475) antibodies
Potassium
Blood for Genetics
Sodium
Blood for Biomarkers
Total bilirubin  
Direct bilirubin, if total 
bilirubin is elevated above 
the upper limit of normal
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 Central Laboratory
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 tests do not need to be performed.
f.
Blood Urea Nitrogen is preferred; if not available urea may be tested.
Laboratory tests for screening should be performed within 10 days prior to the first dose of 
study medication. Subjects eligible for retreatment with pembrolizumab (MK-3475) should 
have lab test performed within 10 days prior to the first dose of study medication in the 
Second Course Phase. After Cycle 1, in both the Initial Treatment Phase for pembrolizumab 
(MK-3475)
or SOC chemotherapy,
and the Second Course Phase/Crossover
with 
pembrolizumab (MK-3475) treatment, pre-dose laboratory safety tests can be conducted up 
to 72 hours prior to dosing. 
08GT0T


Product:  MK-3475 
80
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
Laboratory test results (with the exception of thyroid tests and CEA) must be reviewed by the 
investigator or qualified designee and found to be acceptable prior to administration of each 
dose of study medication. Unresolved abnormal labs that are drug-related AEs should be 
followed until resolution. Labs do not need to be repeated after the end of treatment if labs 
are within normal range.
7.1.3.1.2 Serum β-hCG
All women who are being considered for participation in the study, and who are not
surgically sterilized or postmenopausal, will be tested for pregnancy within 72 hours prior to 
each cycle of study medication and 30 days post treatment and must be excluded in the event 
of a positive or borderline-positive test result. Serum β-HCG test is required.
Central Laboratory Assessments
7.1.3.2.1 Pharmacokinetic Evaluations
The accumulation of robust PK and ADA data has allowed for the adequate characterization 
the clinical pharmacology of pembrolizumab across indications. Therefore, upon approval of 
Amendment 3, each site is to stop the collection of PK and ADA samples for all subjects.
Blood samples for PK and ADA collected prior to Amendment 3 may be stored only at this 
time. Analysis will be performed if required.
7.1.3.2.2 Planned Genetic Analysis Sample Collection
A sample should be drawn at the Cycle 1 visit for planned analysis of the association 
between genetic variants in DNA and drug response. If there is either a documented law or 
regulation prohibiting collection, or if the IRB/IEC does not approve the collection of the 
sample for these purposes, then this sample will not be collected at that site. If the sample is 
collected, leftover extracted DNA will be stored for future biomedical research if the subject 
provides documented informed consent for Future Biomedical Research. If the planned 
genetic analysis is not approved, but Future Biomedical Research is approved and consent is 
given, this sample will be collected for the purpose of Future Biomedical Research. 
7.1.3.2.3 Blood for Correlative and Biomarker Studies
Blood for correlative biomarker studies (RNA and DNA) should be collected pre-dose for 
each of the following: Day 1, Cycle 1, Day 1, Cycle 2, Day 1, Cycle 3 and at treatment 
discontinuation; blood for biomarker studies (plasma and serum) should be collected 
pre-dose on Day 1, Cycle 1 only. Detailed instructions for each sample are provided in the 
Procedures Manual.
If the sample is collected, leftover DNA, RNA, plasma and serum will be stored for future 
biomedical research if the subject provides documented informed consent for Future 
Biomedical Research.
08GT0T


Product:  MK-3475 
81
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
Tumor Tissue for Exploratory Analyses
Submitting tumor tissue is optional in this study. The Sponsor may use tumor tissue for 
exploratory analyses to identify factors important for pembrolizumab (MK-3475) therapy
(see Section 4.2.4.5). If the subject provides documented informed consent for Future 
Biomedical Research (FBR), any leftover tissue that would ordinarily be discarded at the end 
of the main study will be retained for FBR.
Future Biomedical Research Sample Collection
The following specimens are to be obtained as part of Future Biomedical Research:

(DNA) for future research.

Leftover tumor tissue

Leftover DNA, RNA, plasma and serum
Efficacy Measurements
Tumor Imaging and RECIST Assessment
The process for image collection and transmission to the central imaging vendor can be 
found in the Site Imaging Manual (SIM). Tumor imaging should be acquired by CT (strongly 
preferred). MRI should be used when CT is contraindicated or for imaging in the brain. The 
same imaging technique regarding modality and use of contrast should be used in a subject 
throughout the study to optimize the visualization of existing and new tumor burden.
Imaging should include the chest, abdomen, and pelvis.
Local site investigator/radiology assessment based on RECIST 1.1 will be used to determine 
subject eligibility. All scheduled images for all study subjects from the sites will be 
submitted to the central imaging vendor. In addition, if the site obtains additional 
unscheduled imaging (including other modalities) that is related to disease progression, 
response, or adverse events, all of these additional imaging must be submitted to the central 
imaging vendor.
The central imaging vendor will verify PD following local site investigator-assessed 1st
radiologic evidence of PD.  Expedited verification of radiologic PD by the central imaging 
vendor will be communicated to the study site and Sponsor (See Section 7.1.4.6).
Initial Tumor Imaging
Tumor imaging at screening must be performed within 28 days prior to the date of 
randomization. The site study team must review screening images to confirm the subject has 
measurable disease per RECIST 1.1. The screening images must be submitted to the central 
imaging vendor for retrospective confirmation of eligibility.
08GT0T


Product:  MK-3475 
82
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
Scans performed as part of routine clinical management are acceptable for use as screening 
tumor imaging if they are of diagnostic quality and performed within 28 days prior to the 
date of randomization and can be assessed by the central imaging vendor. 
Subjects with previously treated brain metastases may participate provided they have stable 
brain metastases, ie, without evidence of progression by imaging (confirmed by MRI if MRI 
was used at prior imaging, or confirmed by CT if CT was used at prior imaging for at least 
four weeks prior to the first dose of study medication; also, any neurologic symptoms must 
have returned to baseline, have no evidence of new or enlarging brain metastases, and have 
not used steroids for brain metastases for at least 28 days prior to study initiation as per local 
site assessment. This exception does not include carcinomatous meningitis, as subjects with 
carcinomatous meningitis are excluded regardless of clinical stability. 
On Study Tumor Imaging
During the Initial Treatment Phase, the first on-study imaging assessment will be performed 
at 9 weeks (63 days ±7 days) from the date of randomization. Subsequent tumor imaging will
be performed Q9W (63 days ±7 days) or more frequently if clinically indicated. Imaging 
timing will follow calendar days and should not be adjusted for delays in cycle starts or any 
dose interruptions. Subjects who undergo surgical resection with curative intent while on 
study should resume imaging postoperatively when clinically possible to maintain the Q9W
imaging schedule.
Imaging should continue to be performed until 1) radiologic disease progression per 
RECIST 1.1 (see Figure 8), 2) the start of new anticancer treatment, 3) withdrawal of 
consent, 4) death, or 5) notification by the Sponsor.
For all subjects, per RECIST 1.1, partial or complete response (PR or CR) should be 
confirmed by a repeat tumor imaging assessment. The tumor imaging for confirmation of 
response may be performed at the earliest 4 weeks after the first indication of response, or at 
the next scheduled scan (ie, 9 weeks later), whichever is clinically indicated. Subjects will 
then return to regular scheduled imaging Q9W, starting with the next scheduled imaging time
point. Subjects who obtain a confirmation scan do not need to undergo the next scheduled 
tumor imaging if it is <4 weeks later; tumor imaging may resume at the subsequent 
scheduled imaging time point.  
Per irRECIST (Section 7.1.4.6), disease progression on subjects treated with pembrolizumab 
should be confirmed locally by the site at least 4 weeks after central verification of site-
assessed first radiologic evidence of PD in clinically stable subjects. Subjects who have 
unconfirmed disease progression may continue on treatment at the discretion of the site 
investigator until progression is confirmed by the site provided they have met the conditions 
detailed in Section 7.1.4.6. Subjects who obtain a confirmation scan do not need to undergo 
the next scheduled tumor imaging if it is <4 weeks later; tumor imaging may resume at the 
subsequent scheduled imaging time point if clinically stable. Subjects with confirmed disease 
progression, as assessed by the site, will discontinue study medication. Exceptions are 
detailed in Section 7.1.4.6.
08GT0T


Product:  MK-3475 
83
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
For subjects who restart treatment in the Second Course Phase or subjects who crossover to 
pembrolizumab (MK-3475) from SOC arm, tumor imaging must be performed within 
28 days prior to treatment with pembrolizumab
(MK-3475). The first Second 
Course/Crossover Phase imaging assessment should be performed at 9 weeks (63 days 
±7 days) after the restart of treatment. Subsequent tumor imaging should be performed Q9W 
or more frequently if clinically indicated. If tumor imaging shows initial PD per RECIST 1.1, 
tumor assessment should be repeated ≥4 weeks later in order to confirm PD with the option 
of continuing treatment while awaiting radiologic confirmation of progression. Subjects who 
obtain a confirmation scan do not need to undergo scheduled tumor imaging if it is <4 weeks 
later and may wait until the next scheduled imaging time point if clinically stable.
Imaging should continue to be performed until disease progression, the start of a new 
anticancer treatment, withdrawal of consent, death, or notification by the Sponsor, whichever 
occurs first. Disease progression may be confirmed at least 4 weeks after the first tumor 
imaging indicating PD in clinically stable subjects. Additional irRECIST detail is described 
in Section 7.1.4.6.
All scheduled images for all study subjects from the sites will be submitted to the central 
imaging vendor. In addition, if the site obtains additional imaging, including other 
modalities, that are obtained at an unscheduled time point to determine if the subject has 
progressed as well as imaging obtained for other reasons but captures radiologic progression, 
all of these imaging scans must be sent to the central imaging vendor.
End of Treatment and Follow-up Tumor Imaging
In subjects who discontinue study medication, tumor imaging should be performed at the 
time of treatment discontinuation (±4 week window). If a previous scan was obtained within 
4 weeks prior to the date of discontinuation, then a scan at treatment discontinuation is not 
mandatory. In subjects who discontinue study medication due to documented disease 
progression (PD or irPD for subjects managed under irRECIST), this is the final required 
tumor imaging if the Investigator elects not to implement irRECIST.
In subjects who discontinue study medication without documented disease progression, every 
effort should be made to continue monitoring their disease status by tumor imaging using the 
same imaging schedule used while on treatment (Q9W) until the start of new anticancer 
treatment, disease progression, death, or the end of the study, whichever occurs first.
RECIST 1.1 Assessment of Disease
Evaluation of tumor response by RECIST 1.1 per the central imaging vendor is the basis for 
efficacy assessment in this study.
Figure 8 illustrates the imaging flow after 1st radiologic evidence of PD per RECIST 1.1.
08GT0T


Product:  MK-3475 
84
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
Immune-related RECIST (irRECIST) Assessment of Disease (for subjects on 
Pembrolizumab (MK-3475) ONLY)
irRECIST is RECIST 1.1 adapted as described below to account for the unique tumor 
response seen with immunotherapeutic drugs. irRECIST will be used by site 
investigator/local radiology review to assess tumor response and progression, and make 
treatment decisions while subjects are receiving pembrolizumab (MK-3475). Treatment 
efficacy based on irRECIST as assessed by central imaging vendor review will be evaluated 
retrospectively and is an exploratory objective for this study. See Table 9 for management of 
subjects per irRECIST.  
This clinical judgment decision by the site should be based on the subject’s overall clinical 
condition, including performance status, clinical symptoms, and laboratory data. Clinical 
stability is defined as the following: 
1. Absence of symptoms and signs indicating clinically significant progression of 
disease, including worsening of laboratory values
2. No decline in ECOG performance status 
3. Absence of rapid progression of disease 
4. Absence of progressive tumor at critical anatomical sites (eg, cord compression) 
requiring urgent alternative medical intervention  
In determining whether or not the tumor burden has increased or decreased per irRECIST, 
the local site investigator should consider all target and non-target lesions as well as any 
incremental new lesion(s). Confirmation of PD at repeat imaging is defined by occurrence of
ANY of the following conditions:

Tumor burden remains ≥20% and at least 5 mm absolute increase compared to nadir

Non-target disease resulting in initial PD is qualitatively worse

New lesion resulting in initial PD is qualitatively worse

Additional new lesion(s) since last evaluation

Additional new non-target progression since last evaluation
ALL of the following conditions must be met in order for PD NOT to be confirmed at repeat 
imaging: 

Tumor burden is <20% or <5 mm absolute increase compared to nadir

Non-target disease resulting in initial PD is stable or qualitatively improved

New lesion resulting in initial PD is stable or qualitatively improved 
08GT0T


Product:  MK-3475 
85
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential

No incremental new lesion(s) since last evaluation

No incremental new non-target progression since last evaluation
Additional details about irRECIST are referenced in the MSD TIP Sheet for RECIST 1.1 and 
irRECIST.
When feasible, subjects should not be discontinued until progression is confirmed by the 
local site investigator/radiology assessment.  
Table 9
Imaging and Treatment after First Radiologic Evidence of PD for Subjects 
Receiving Pembrolizumab (MK-3475) (management per irRECIST)
Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
1st radiologic 
evidence of PD 
by RECIST 1.1 
(1)
Repeat imaging at ≥
4 weeks at site to 
confirm PD
May continue study 
medication at the 
investigator’s 
discretion while 
awaiting 
confirmatory tumor 
imaging.
Repeat imaging at ≥
4 weeks to confirm 
PD per physician 
discretion only
Discontinue 
treatment
Repeat tumor 
imaging 
confirms PD 
by irRECIST 
at the local site
No additional 
imaging required
Discontinue 
treatment (2)
No additional 
imaging required
N/A
Repeat tumor 
imaging shows 
SD, PR or CR 
by irRECIST 
by the local 
site
Continue regularly 
scheduled imaging 
assessments
Continue study 
medication at the 
local site 
investigator’s 
discretion
Continue regularly 
scheduled imaging 
assessments
May restart study 
medication if
condition has 
improved and/or 
clinically stable per 
investigator’s 
discretion. Next 
tumor image should 
occur according to 
the regular imaging 
schedule outlined in 
the protocol
(1) PD must be verified by the central imaging vendor for subjects who experience 1st PD while receiving 
pembrolizumab (MK-3475) in the Initial Treatment Phase. Subjects who cross over from chemotherapy (control) 
arm, and who experience 1st PD on pembrolizumab (MK-3475) will have PD verified by the local site/investigator.
(2) If a subject has confirmed radiographic progression (ie, 2 scans at least 4 weeks apart demonstrating progressive 
disease) per irRECIST, but the subject is achieving a clinically meaningful benefit, an exception to continue treatment 
may be considered following consultation with the Sponsor. Follow-up scans will then be performed Q9W (63 ± 7 
days) or earlier as clinically indicated. (France only:  does not apply.) 
08GT0T


Product:  MK-3475 
86
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
Figure 8
Imaging and Treatment after First Radiologic Evidence of PD
Other Procedures
Withdrawal/Discontinuation
Subjects who discontinue/withdraw from treatment prior to completion of the treatment
should be encouraged to continue to be followed for all remaining study visits.
When a subject discontinues/withdraws from participation in the trial, all applicable activities 
scheduled for the final study visit should be performed at the time of discontinuation.  Any 
adverse events which are present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements outlined in Section 7.2 - Assessing and 
Recording Adverse Events.
08GT0T


Product:  MK-3475 
87
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
7.1.5.1.1 Withdrawal From Future Biomedical Research
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.  Subjects may withdraw consent at any time by 
contacting the principal investigator for the main trial.  If medical records for the main trial 
are still available, the investigator will contact the Sponsor using the designated mailbox 
(clinical.specimen.management@MSD.com), and a form will be provided by the Sponsor to 
obtain appropriate information to complete specimen withdrawal.  Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed.  A letter will 
be sent from the Sponsor to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for destruction or already performed prior to the 
request being received by the Sponsor will continue to be used as part of the overall research 
trial data and results.  No new analyses would be generated after the request is received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial records) or 
the specimens have been completely anonymized, there will no longer be a link between the 
subject’s personal information and their specimens.  In this situation, the request for 
specimen destruction cannot be processed.
Blinding/Unblinding
This is an open label trial; there is no blinding for this trial.
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 
reproducible.  Documentation of equipment calibration must be retained as source 
documentation at the trial site.
Critical Equipment for this trial includes:
•
Laboratory equipment – as required for inclusion labs and study assessments
•
Imaging equipment – as required for study objectives
See protocol-specified guidance in the Administrative Binder, Procedures Manual and Site 
Imaging Manual.
Visit Requirements
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.  Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures.
08GT0T


Product:  MK-3475 
88
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
Screening
Approximately 42 days prior to treatment randomization, potential subjects will be evaluated 
to determine that they fulfill the entry requirements as set forth in Section 5.1. Screening 
procedures may be repeated after consultation with the Sponsor.
Results of a test performed prior to the subject providing documented informed consent as 
part of routine clinical management are acceptable in lieu of a screening test if performed 
within the specified time frame. Once MSI/MMR status is determined and a subject is 
considered eligible, the remaining screening procedures are to be completed within 28 days 
prior to randomization except for the following:
•
Laboratory tests and ECOG performance status are to be performed within 10 days prior 
to treatment initiation.
•
For women of reproductive potential, a serum pregnancy test will be performed within 
72 hours prior to the first dose of study medication. 
Subjects may be rescreened after initially failing to meet the inclusion/exclusion criteria. 
Results from assessments performed during the initial screening period are acceptable in lieu 
of repeat screening test if performed within the specified time frame and the 
inclusion/exclusion criteria is met. Subjects may not rescreen more than 1 time without 
consulting with the Sponsor. Subjects who are rescreened will retain their original screening 
number. 
Treatment Period
Visit requirements are outlined in the Study Flow Chart (Section 6.0). Specific procedure-
related details are provided above in the Study Procedures (Section 7.1)
Second Course Phase for Subjects Receiving Pembrolizumab (MK-3475) in the 
Initial Treatment Phase or Crossover from SOC Treatment Phase
Subjects who stop pembrolizumab (MK-3475) with SD or better may be eligible for up to 
17 additional study medications (approximately 1 year) if they progress after stopping study 
medications. Retreatment with pembrolizumab (MK-3475) is termed the Second Course 
Phase and is only available if the subject meets the following conditions:

Either 

Stopped initial/crossover treatment with pembrolizumab (MK-3475) after 
attaining an investigator-determined confirmed CR according to RECIST 1.1
o
Was treated with at least 8 study medications (approximately 
6 months) with pembrolizumab (MK-3475) before discontinuing 
therapy
08GT0T


Product:  MK-3475 
89
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
o
Received at least 2 treatments with pembrolizumab (MK-3475)
beyond the date when the initial CR was declared
OR

Had SD, PR or CR and stopped pembrolizumab (MK-3475) after 35 study 
medications (approximately 2 years) for reasons other than disease 
progression or intolerability

AND

Experienced an investigator-determined radiographic disease progression 
(which must also be verified centrally) after stopping their initial/crossover
treatment with pembrolizumab (MK-3475). If a subject is unstable as a result 
of a new or progressing brain metastasis, the subject will not be eligible for 
the Second Course Treatment Phase, unless stability per exclusion criterion # 
6 is satisfied after the management of the new/progressing brain metastasis

Did not receive any anticancer treatment since the last dose of pembrolizumab
(MK-3475)

Has a performance status of 0 or 1 on the ECOG Performance Scale

Demonstrates adequate organ function as detailed in Table 4.

Female subject of childbearing potential should have a negative serum test 
within 72 hours prior to receiving retreatment with pembrolizumab
(MK-3475).

Female subject of childbearing potential should be willing to use 2 methods of 
birth control or be surgically sterile, or abstain from heterosexual activity for 
the course of the study through 120 days after the last dose of pembrolizumab
(MK-3475) (see Section 5.7.2). Subjects of childbearing potential are those 
who have not been surgically sterilized or have been free from menses for > 1 
year. 

Does not have a history or current evidence of any condition, therapy, or 
laboratory abnormality that might interfere with the subject’s participation for 
the full duration of the study or is not in the best interest of the subject to
participate, in the opinion of the treating investigator.
Subjects who enter the Second Course Phase will be retreated at the same dose frequency as 
when they last received pembrolizumab (MK-3475). Pembrolizumab (MK-3475) may be 
administered for up to an additional 17 study medications (approximately 1 year).
Visit requirements for the Second Course Phase are outlined in the Second Course Phase 
Study Flow Chart (Section 6.3).
08GT0T


Product:  MK-3475 
90
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
Crossover Phase for Subjects in the Chemotherapy Arm with Documented 
Disease Progression
Subjects on the SOC arm with documented disease progression following chemotherapy may 
be eligible to participate in the crossover arm of this study. Crossover subjects may be treated 
with up to 35 pembrolizumab (MK-3475) treatment cycles. Subjects who permanently 
discontinue chemotherapy due to an adverse event (see below for details) or withdrawal of
consent, or for any reason other than progressive disease, will not be eligible for crossover. 
Surgical subjects who progress post-operatively are eligible to receive pembrolizumab
(MK-3475) in the Crossover Phase with up to 35 administrations (approximately 2 years) of 
pembrolizumab (MK-3475).  
If SOC is delayed due to surgery or an AE resulting in >5 weeks between doses of SOC, and 
progression of disease occurs during the delay, the subject may qualify for crossover if he or 
she fulfill all criteria described below and after consultation with the Sponsor.  
Subjects on the SOC arm who have entered the Follow-up Phase (discontinued treatment due 
to a reason other than disease progression) are not allowed to move to the crossover phase, as 
they do not meet the criteria outlined above.
Crossover subjects may not initiate treatment with pembrolizumab (MK-3475) any earlier 
than 30 days after their last dose of chemotherapy (washout period) regardless of the time of 
progression. Subjects will need to complete the discontinuation visit. Of note, the 30 day 
Safety Follow-up Visit may occur on the same day as the first dose of pembrolizumab
(MK-3475) in the Crossover Phase. Subjects may not initiate therapy with pembrolizumab
(MK-3475) until PD has been verified by central imaging vendor and meeting eligibility 
criteria. 
Crossover is optional and is at the discretion of the investigator (with the Sponsor’s 
agreement). Imaging must be completed to establish a new baseline for the Crossover Phase. 
Subject must meet the following criteria for crossover:

Has progressive disease per RECIST 1.1 verified by central imaging vendor. If a
subject is unstable as a result of a new or progressing brain metastasis, the subject 
will not be eligible for crossover, unless stability per exclusion criterion # 6 is 
satisfied after the management of the new/progressing brain metastasis.

Did not receive any other anticancer treatment since the last dose of study 
chemotherapy

Chemotherapy and bevacizumab/cetuximab induced adverse events must have 
improved to CTCAE (version 4.0) ≤ Grade 1. Exceptions may be considered 
following Sponsor consultation.

Has a performance status of 0 or 1 on the ECOG Performance Scale
08GT0T


Product:  MK-3475 
91
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential

Demonstrates adequate organ function as detailed in Table 4.

Female subject of childbearing potential should have a negative serum test within 
72 hours prior to receiving treatment with pembrolizumab (MK-3475).

Female subject of childbearing potential should be willing to use 2 methods of birth 
control or be surgically sterile, or abstain from heterosexual activity for the course of 
the study through 120 days after the last dose of pembrolizumab (MK-3475) (see
Section 5.7.2) or through 180 days after the last dose of chemotherapy, whichever 
later. Subjects of childbearing potential are those who have not been surgically 
sterilized or have been free from menses for >1 year. 

Male subject should agree to use an adequate method of contraception starting with 
the first dose through 180 days after the last dose of chemotherapy.  

Does not have evidence of any condition, therapy, or laboratory abnormality that 
might interfere with the subject’s participation for the full duration of the study or is 
not in the best interest of the subject to participate, in the opinion of the treating 
investigator.

Has no major surgical procedure, open biopsy or significant traumatic injury within 
28 days prior to first dose of pembrolizumab (MK-3475).

For subjects who stopped Oxaliplatin to prevent neuropathy (see Section 5.2.1.2), if 
progression occurs after Oxaliplatin is restarted per Section 5.2.1.2, Dose 
Modification – SOC arm, crossover is allowed if the patient has no neuropathy or 
other treatment induced AE with grade >1.  If progression occurs during the 12 
cycles of 5FU/leucovorin without Oxaliplatin and the patient has no neuropathy or 
other treatment induced AE with grade >1, crossover is also allowed.  If Oxaliplatin 
is not restarted after 12 cycles of 5FU/leucovorin without evidence of neuropathy, 
and the subject has progression, crossover is not allowed.
Subjects who crossover and then achieve a CR per RECIST 1.1 have the option to hold 
pembrolizumab (MK-3475) at the discretion of the investigator. See Section 7.1.4.6 for 
management per irRECIST. Subjects who stop pembrolizumab (MK-3475) in the 
crossover phase with SD or better may be eligible for up to 17 additional study medications 
(approximately 1 year) in the Second Course Phase if they progress after stopping study 
medication.
Additional details are provided in Second Course Phase Section 7.1.6.3. 
Subjects who permanently discontinue the Crossover Phase will follow the same Survival 
Follow-up assessments outlined Section 7.1.6.5.3. Visit requirements for the Crossover Phase 
are outlined in the Crossover Phase Study Flow Chart (Section 6.4).
08GT0T


Product:  MK-3475 
92
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
Post Treatment Visits
7.1.6.5.1 Safety Follow-up Visits
The mandatory Safety Follow-up Visit should be conducted approximately 30 days after the 
last dose of study medication or before the initiation of a new anticancer treatment, 
whichever comes first.
Subjects who are eligible for retreatment/crossover
with 
pembrolizumab (MK-3475) may have up to two safety follow-up visits, one after the Initial 
Treatment Period and one after the Second Course Treatment/Crossover Phase.
7.1.6.5.2 Follow-up Visits
Subjects who discontinue study medication for reasons other than disease progression 
(including subjects who have received the maximum 35 pembrolizumab treatments) will 
move into the Follow-up Phase and should be assessed Q9W by radiologic imaging to 
monitor disease status. The Sponsor may request survival status to be assessed at additional 
time points during the course of the study. Every effort should be made to collect information 
regarding disease status until the start of new anticancer therapy, disease progression, death, 
end of study (or if the subject begins retreatment with pembrolizumab as detailed in 
Sections 7.1.6.3). Information regarding post-study anticancer treatment will be collected if 
new treatment is initiated.
Subjects who are eligible to receive retreatment with pembrolizumab (MK-3475) according 
to the criteria in Section 7.1.6.3 will move from the Follow-up Phase to the Second Course 
Phase when they experience centrally confirmed disease progression. Details are provided in 
the Trial Flow Chart (Section 6) for retreatment with pembrolizumab.
7.1.6.5.3 Survival Follow-up
Subjects, who experience confirmed disease progression or start a new anticancer therapy, 
will move into the Survival Follow-Up Phase and should be contacted by telephone Q9W to 
assess for survival status until death, withdrawal of consent, or the end of the study, 
whichever occurs first.
Survival Status
Details regarding Survival Follow-up are outlined in Section 7.1.6.5.3.  
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 
eDMC review, interim, and/or final analysis. Upon Sponsor notification, all subjects who do 
not/will not have a scheduled study visit or study contact during the Sponsor defined time 
period will be contacted for their survival status (excluding subjects that have a previously 
recorded death event in the collection tool).
08GT0T


Product:  MK-3475 
93
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
Assessing and Recording Adverse Events
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavourable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the 
use of the Sponsor’s product, is also an adverse event.
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  
Examples of this may include, but are not limited to, teething, typical crying in infants and 
children and onset of menses or menopause occurring at a physiologically appropriate time.
Sponsor's product includes any pharmaceutical product, biological product, device, 
diagnostic agent or protocol-specified procedure, whether investigational (including placebo 
or active comparator medication) or marketed, manufactured by, licensed by, provided by or 
distributed by the Sponsor for human use.
Adverse events may occur during clinical trials, or as prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal.
Progression of the cancer under study is not considered an adverse event.
All adverse events that occur after the subject provides documented informed consent but 
before treatment allocation/randomization must be reported by the investigator if they cause 
the subject to be excluded from the trial, or are the result of a protocol-specified intervention, 
including but not limited to washout or discontinuation of usual therapy, diet, placebo 
treatment or a procedure. From the time of treatment allocation/randomization through 30 
days following cessation of treatment, all adverse events must be reported by the 
investigator. Such events will be recorded at each examination on the Adverse Event case 
report forms/worksheets.  The reporting timeframe for adverse events meeting any serious 
criteria is described in section 7.2.3.1. The investigator will make every attempt to follow all 
subjects with non-serious adverse events for outcome.
Electronic reporting procedures can be found in the EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
Adverse events will not be collected for subjects during the pre-screening period (for 
determination of archival tissue status) as long as that subject has not undergone any 
protocol-specified procedure or intervention.  If the subject requires a blood draw, fresh 
tumor biopsy etc., the subject is first required to provide consent to the main study and AEs 
will be captured according to guidelines for standard AE reporting.
08GT0T


Product:  MK-3475 
94
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor
In this study, an overdose is any dose higher than ≥1000 mg (5 times the protocol defined 
dose) of pembrolizumab (MK-3475). No specific information is available on the treatment of 
overdose of pembrolizumab (MK-3475). In the event of overdose, study medication should 
be discontinued and the subject should be observed closely for signs of toxicity. Appropriate 
supportive treatment should be provided if clinically indicated.
If an adverse event(s) is associated with (“results from”) the overdose of Sponsor's product or 
vaccine, the adverse event(s) is reported as a serious adverse event, even if no other 
seriousness criteria are met.
If a dose of Sponsor's product or vaccine meeting the protocol definition of overdose is taken 
without any associated clinical symptoms or abnormal laboratory results, the overdose is 
reported as a non-serious Event of Clinical Interest (ECI), using the terminology “accidental 
or intentional overdose without adverse effect.”
All reports of overdose with and without an adverse event must be reported by the 
investigator within 24 hours to the Sponsor either by electronic media or paper. Electronic 
reporting procedures can be found in the EDC data entry guidelines. Paper reporting 
procedures can be found in the Investigator Trial File Binder (or equivalent).
Reporting of Pregnancy and Lactation to the Sponsor
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them) that occurs during the trial.
Pregnancies and lactations that occur after the subject provides documented informed 
consent but before treatment allocation/randomization must be reported by the investigator if 
they cause the subject to be excluded from the trial, or are the result of a protocol-specified 
intervention, including but not limited to washout or discontinuation of usual therapy, diet, 
placebo treatment or a procedure. Pregnancies and lactations that occur from the time of 
treatment allocation/randomization through 120 days following cessation of Sponsor’s 
product, or 30 days following cessation of treatment if the subject initiates new anticancer 
therapy, whichever is earlier, must be reported by the investigator.  All reported pregnancies  
must be followed to the completion/termination of the pregnancy. Pregnancy outcomes of 
spontaneous abortion, missed abortion, benign hydatidiform mole, blighted ovum, fetal 
death, intrauterine death, miscarriage and stillbirth must be reported as serious events 
(Important Medical Events). If the pregnancy continues to term, the outcome (health of 
infant) must also be reported.
Such events must be reported within 24 hours to the Sponsor either by electronic media or 
paper. Electronic reporting procedures can be found in the EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
08GT0T


Product:  MK-3475 
95
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
Immediate Reporting of Adverse Events to the Sponsor
Serious Adverse Events
A serious adverse event is any adverse event occurring at any dose or during any use of 
Sponsor's product that:
●
Results in death;
●
Is life threatening;
●
Results in persistent or significant disability/incapacity;
●
Results in or prolongs an existing inpatient hospitalization;
●
Is a congenital anomaly/birth defect;
●
Is an other important medical event.
Note: In addition to the above criteria, adverse events meeting either of the below criteria, 
although not serious per ICH definition, are reportable to the Sponsor in the same timeframe 
as SAEs to meet certain local requirements. Therefore, these events are considered serious by 
the Sponsor for collection purposes.
●
Is a new cancer (that is not a condition of the study);
●
Is associated with an overdose.
Refer to Table 10 for additional details regarding each of the above criteria.
For the time period beginning when the subject provides documented informed consent until 
treatment allocation/randomization, any serious adverse event, or follow up to a serious 
adverse event, including death due to any cause other than progression of the cancer under 
study (reference Section 7.2.3.3 for additional details), that occurs to any subject must be 
reported within 24 hours to the Sponsor if it causes the subject to be excluded from the trial, 
or is the result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 90 days 
following cessation of treatment, or 30 days following cessation of treatment if the subject 
initiates new anticancer therapy, whichever is earlier, any serious adverse event, or follow up 
to a serious adverse event, including death due to any cause other than progression of the 
cancer under study (reference Section 7.2.3.3 for additional details), whether or not related to 
the Sponsor's product, must be reported within 24 hours to the Sponsor either by electronic 
media or paper. Electronic reporting procedures can be found in the EDC data entry 
guidelines. Paper reporting procedures can be found in the Investigator Trial File Binder (or 
equivalent).
08GT0T


Product:  MK-3475 
96
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to the Sponsor's product that is brought to the attention of the 
investigator at any time following consent through the end of the specified safety follow-up 
period specified in the paragraph above, or at any time outside of the time period specified in 
the previous paragraph also must be reported immediately to the Sponsor.  
All subjects with serious adverse events must be followed up for outcome.
Events of Clinical Interest
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported to the Sponsor.
For the time period beginning when the subject provides documented informed consent until 
treatment allocation/randomization, any ECI, or follow up to an ECI, that occurs to any 
subject must be reported within 24 hours to the Sponsor if it causes the subject to be 
excluded from the trial, or is the result of a protocol-specified intervention, including but not 
limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure.
For the time period beginning at treatment allocation/randomization through 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 
guidelines.  Paper reporting procedures can be found in the Investigator Trial File Binder (or 
equivalent).
Events of clinical interest for this trial include:

an overdose of Sponsor's product, as defined in Section 7.2.1 - Definition of an 
Overdose for This Protocol and Reporting of Overdose to the Sponsor, that is not 
associated with clinical symptoms or abnormal laboratory results. 

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).
08GT0T


Product:  MK-3475 
97
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
Protocol-Specific Exceptions to Serious Adverse Event Reporting
Efficacy endpoints as outlined in this section will not be reported to the Sponsor as described 
in Section 7.2.3.
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study.
The Sponsor will monitor unblinded aggregated efficacy endpoint events and safety data to 
ensure the safety of the subjects in the study. Any suspected endpoint which upon review is 
not progression of the cancer under study will be forwarded to Global Safety as an SAE 
within 24 hours of determination that the event is not progression of the cancer under study.
Evaluating Adverse Events
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version v4.0. Any adverse event 
which changes CTCAE grade over the course of a given episode will have each change of 
grade recorded on the adverse event case report forms/worksheets.
All adverse events regardless of CTCAE grade must also be evaluated for seriousness.
For studies in which multiple agents are administered as part of a combination regimen, the 
investigator may attribute each adverse event causality to the combination regimen or to a 
single agent of the combination.  In general, causality attribution should be assigned to the 
combination regimen (i.e., to all agents in the regimen). However, causality attribution may 
be assigned to a single agent if in the investigator’s opinion, there is sufficient data to support 
full attribution of the adverse experience to the single agent.
08GT0T


Product:  MK-3475 
98
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
Table 10
Evaluating Adverse Events
An investigator who is a qualified physician, will evaluate all adverse events as to:
V4.0 CTCAE 
Grading
Grade 1
Mild; asymptomatic or mid 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 or hospitalization indicated; 
disabling; limiting self-care ADL.
Grade 4
Life threatening consequences; urgent intervention indicated.
Grade 5
Death related to AE
Seriousness
A serious adverse event is any adverse event occurring at any dose or during any use of Sponsor’s product that:
†Results in death; or
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include an 
adverse event that, had it occurred in a more severe form, might have caused death.); or
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation. (Note: Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not a serious adverse event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of an MSD product and is documented in 
the patient’s medical history.); or
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or
Is a new cancer (that is not a condition of the study) (although not serious per ICH definition, is reportable to the Sponsor within 24 hours to meet certain local 
requirements); or
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event for collection purposes. An 
overdose that is not associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 hours.
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes 
listed previously (designated above by a †).
Duration
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units
Action taken 
Did the adverse event cause the Sponsor’s product to be discontinued?
Relationship to 
Sponsor’s 
Product
Did the Sponsor’s product cause the adverse event? The determination of the likelihood that the Sponsor’s product caused the adverse event will be provided by an 
investigator who is a qualified physician. The investigator’s signed/dated initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed document must be retained for the required regulatory time frame. The 
criteria below are intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the adverse event 
based upon the available information.
The following components are to be used to assess the relationship between the Sponsor’s product and the AE; the greater the correlation with the components 
and their respective elements (in number and/or intensity), the more likely the Sponsor’s product caused the adverse event (AE):
Exposure
Is there evidence that the subject was actually exposed to the Sponsor’s product such as: reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen?
Time Course
Did 
the 
AE 
follow 
in 
a 
reasonable 
temporal 
sequence 
from 
administration 
of 
the 
Sponsor’s 
product? 
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)?
Likely Cause
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental factors
08GT0T


Product:  MK-3475 
99
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
Relationship
The following components are to be used to assess the relationship between the test drug and the AE: (continued)
to Sponsor's 
Product
(continued) 
Dechallenge
Was the Sponsor’s product discontinued or dose/exposure/frequency reduced?
If yes, did the AE resolve or improve?
If yes, this is a positive dechallenge. If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite continuation of 
the Sponsor’s product; or (3) the trial is a single-dose drug trial); or (4) Sponsor’s product(s) is/are only used one time.)
Rechallenge
Was the subject re-exposed to the Sponsor’s product in this study?
If yes, did the AE recur or worsen?
If yes, this is a positive rechallenge. If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose drug trial); or 
(3) Sponsor’s product(s) is/are used only one time).
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN 
CAUSED BY THE SPONSOR'S PRODUCT, OR IF REEXPOSURE TO THE SPONSOR'S PRODUCT POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR 
CLINICAL DIRECTOR AS PER DOSE MODIFICATION GUIDELINES IN THE PROTOCOL.
Consistency 
with Trial 
Treatment 
Profile
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the Sponsor’s product or drug class pharmacology 
or toxicology?
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements.
Record one of the following
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a Sponsor’s product relationship).
Yes, there is a reasonable 
possibility of Sponsor's product 
relationship.
There is evidence of exposure to the Sponsor's product.  The temporal sequence of the AE onset relative to the administration of the Sponsor's 
product is reasonable.  The AE is more likely explained by the Sponsor's product than by another cause.
No, there is not a reasonable 
possibility of Sponsor's product 
relationship
Subject did not receive the Sponsor's product OR temporal sequence of the AE onset relative to administration of the Sponsor's product is not 
reasonable OR the AE is more likely explained by another cause than the Sponsor’s product.  (Also entered for a subject with overdose without an 
associated AE.)
08GT0T


Product:  MK-3475 
100
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
Sponsor Responsibility for Reporting Adverse Events
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations, i.e., per ICH Topic E6 (R1) 
Guidelines for Good Clinical Practice.
Data Monitoring Committee
To supplement the routine trial monitoring outlined in this protocol, an external Data 
Monitoring Committee (DMC) will monitor the interim data from this trial.  The voting 
members of the committee are external to the Sponsor.  The members of the DMC must not 
be involved with the trial in any other way (e.g., they cannot be trial investigators) and must 
have no competing interests that could affect their roles with respect to the trial. 
The DMC will make recommendations to the Executive Oversight Committee (EOC)
regarding steps to ensure both subject safety and the continued ethical integrity of the trial.  
Also, the DMC will review interim trial results, consider the overall risk and benefit to trial 
participants (see Section 8.7 - Interim Analyses) and recommend to the EOC if the trial 
should continue in accordance with the protocol.
Specific details regarding composition, responsibilities, and governance, including the roles 
and responsibilities of the various members and the sponsor protocol team; meeting 
facilitation; the trial governance structure; and requirements for and proper documentation of 
DMC reports, minutes, and recommendations will be described in a separate charter that is 
reviewed and approved by the DMC.  The DMC will monitor the trial at an appropriate 
frequency, as described in the detailed DMC charter.  The DMC will also make 
recommendations to the sponsor protocol team regarding steps to ensure both subject safety 
and the continued ethical integrity of the trial.
8.0 STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study. If, after the 
study has begun, changes are made to the primary and/or secondary hypotheses, or the 
statistical methods related to those hypotheses, then the protocol will be amended (consistent 
with ICH Guideline E-9). Changes to exploratory or other non-confirmatory analyses made 
after the protocol has been finalized, but prior to the conduct of any analysis, will be 
documented in a supplemental statistical analysis plan (sSAP) and referenced in the Clinical 
Study Report (CSR) for the study. There will be a separate PK analysis plan, if required (see 
Section 7.1.3.2.1), as well as a biomarker analysis plan. Post hoc exploratory analyses will be 
clearly identified in the CSR. The PRO analysis plan will also be included in the sSAP.
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Sections 8.2 through 8.12.
08GT0T


Product:  MK-3475 
101
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
Study Design Overview
A Phase III Study of Pembrolizumab (MK-3475) vs. Chemotherapy in 
Microsatellite Instability-High (MSI-H) or Mismatch Repair Deficient 
(dMMR) Stage IV Colorectal Carcinoma (KEYNOTE-177)
Treatment Assignment
Approximately 300 subjects will be randomized in a 1:1 ratio to receive 
pembrolizumab (MK-3475) or standard of care (SOC). This is an open-
label study. 
Analysis Populations
Efficacy: Intention-to-Treat (ITT)
Safety: All Subjects as Treated (ASaT)
Primary Endpoints
1.
Progression-free Survival (PFS) per RECIST 1.1 by central imaging 
vendor
2.
Overall Survival (OS)  
Secondary Endpoint
Overall Response Rate (ORR)  
Statistical Methods for Key 
Efficacy Analyses
The primary hypotheses will be evaluated by comparing pembrolizumab
(MK-3475) to SOC on PFS and OS using a Log-rank test. Estimation of 
the hazard ratio will be done using a Cox regression model. Event rates 
over time will be estimated within each treatment group using the Kaplan-
Meier method.
Statistical Methods for Key 
Safety Analyses
The analysis of safety results will follow a tiered approach. The tiers differ 
with respect to the analyses that will be performed. “Tier 1” safety 
endpoints will be subject to inferential testing for statistical significance 
with p-values and 95% confidence intervals provided for between-group 
comparisons. Other safety parameters will be considered Tier 2 or Tier 3.
Tier 2 parameters will be assessed via point estimates with 95% confidence 
intervals
for between-group comparisons; only point estimates by 
treatment group are provided for Tier 3 safety parameters. There are no 
Tier 1 events in this study. The between-treatment difference will be 
analyzed using the Miettinen and Nurminen method.
In the primary safety comparison between pembrolizumab (MK-3475) and 
SOC, subjects who crossover to pembrolizumab (MK-3475) are censored 
at time of crossover (ie,
AEs
occurring during
treatment with 
pembrolizumab (MK-3475) are excluded for control-arm subjects). An 
exploratory safety analysis will be conducted for the crossover population 
including all safety events starting from the date of randomization.
Interim Analysis
Two interim analyses will be performed. Results will be reviewed by an 
external DMC. Details are provided in Section 8.7.
IA1: to be performed after 1) approximately 162 PFS events have 
occurred; and 2) 6 months after last subject randomized 
Primary purpose: interim PFS and interim OS analysis
IA2: to be performed after approximately 209 PFS events have occurred or 
24 months after last subject randomized, whichever occurs first
Primary purpose: final PFS and interim OS analysis
Multiplicity
The overall type-I error over the primary hypotheses (related to PFS and 
OS) and the secondary hypothesis (related to ORR) is strongly controlled 
at 2.5% (one-sided), with initially 1.25% allocated to the PFS hypothesis, 
1.25% to the OS hypothesis, and 0% to the ORR hypothesis.
By using the graphical approach of Maurer and Bretz [39], if one primary
hypothesis is rejected, the alpha will be shifted to the other hypotheses
using the weights specified in Section 8.8.
08GT0T


Product:  MK-3475 
102
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
Sample Size and Power 
The planned sample size is approximately 300 subjects. 
The final analysis will be performed after approximately 190 OS events 
have occurred or 12 months after Interim Analysis 2, whichever occurs 
first (see Section 8.9).
For PFS, the study
has around 98%
power to demonstrate that 
pembrolizumab (MK-3475) is superior to SOC at a one-sided 1.25% alpha-
level, if the underlying hazard ratio of PFS is 0.55.
For OS, the study has 85% power to demonstrate that pembrolizumab
(MK-3475) is superior to SOC at a one-sided 1.25% alpha-level, if the 
underlying hazard ratio of OS is 0.62. However, due to the anticipated high 
crossover rate, the actual power could be substantially lower.
Responsibility for Analyses/In-House Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
The Sponsor will generate the randomized allocation schedule(s) for study medication
assignment for this protocol, and the randomization will be implemented in IVRS. Although 
the study is open label, analyses or summaries generated by randomized treatment 
assignment, and/or actual treatment received will be limited and documented. In addition, the 
independent radiologist(s) will perform the central imaging review without knowledge of 
treatment group assignment.
The eDMC will serve as the primary reviewer of the treatment-level results and will make 
recommendations for discontinuation of the study or modification to an executive oversight 
committee of the SPONSOR. Depending on the recommendation of the eDMC, the Sponsor 
may prepare a regulatory submission. If the eDMC recommends modifications to the design 
of the protocol or discontinuation of the study, this executive oversight committee may be 
unblinded to results at the treatment-level in order to act on these recommendations. 
Additional logistical details, revisions to the above plan and data monitoring guidance will be 
provided in the eDMC Charter.
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.0.
08GT0T


Product:  MK-3475 
103
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
Analysis Endpoints
Efficacy Endpoints
Primary

Progression-free survival (PFS) – RECIST 1.1 assessed by central imaging vendor
Progression-free-survival (PFS) is defined as the time from randomization to the first 
documented disease progression per RECIST 1.1 based on blinded central imaging vendor 
review or death due to any cause, whichever occurs first. See Section 8.6.1 for definition of 
censoring.

Overall Survival
Overall Survival (OS) is defined as the time from randomization to death due to any cause. 
Subjects without documented death at the time of analysis will be censored at the date of 
last known contact.
Secondary

Overall Response Rate (ORR) – RECIST 1.1 assessed by central imaging vendor 
Overall response rate is defined as the proportion of the subjects in the analysis population 
who have a CR or PR.
Exploratory 

Progression-free survival 2 (PFS2)
Progression-free survival 2 (PFS2) is defined as the time from randomization to disease
progression on the next line of therapy, or death from any cause, whichever first.

Progression-free survival (PFS) – irRECIST assessed by central imaging vendor 
Progression-free-survival (PFS) is defined as the time from randomization to the first 
confirmed disease progression or death due to any cause, whichever occurs first.

Duration of Overall Response (DOR) – RECIST 1.1 by central imaging vendor
For subjects who demonstrated CR or PR, response duration is defined as the time from the 
date of first response (CR or PR) until the date of first documented disease progression or 
death.

Surgical conversion rate
The surgical conversion rate is the rate of subjects who become eligible and undergo 
resection with curative intent as a result of study therapy.
08GT0T


Product:  MK-3475 
104
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
Safety Endpoints
Safety measurements are described in Section 7.
Analysis Populations
Efficacy Analysis Populations
The Intention-to-Treat (ITT) population will serve as the population for primary efficacy 
analysis. All randomized subjects will be included in this population. Subjects will be 
included in the treatment group to which they are randomized. ITT population consists of all 
randomized subjects whether or not treatment was administered. Any subject who receives a 
treatment randomization number will be considered to have been randomized.
Details on the approach to handling missing data are provided in Section 8.6 Statistical 
Methods.
Safety Analysis Populations
The All Subjects as Treated (ASaT) population will be used for the analysis of safety data in 
this study. The ASaT population consists of all randomized subjects who received at least 
one dose of study medication. Subjects will be included in the treatment group corresponding 
to the study medication they actually received for the analysis of safety data using the ASaT 
population. For most subjects this will be the treatment group to which they are randomized. 
Subjects who take incorrect study medication for the entire treatment period will be included 
in the treatment group corresponding to the study medication actually received. Any subject 
who receives the incorrect study medication for one cycle but receives the correct treatment 
for all other cycles will be analyzed according to the correct treatment group and a narrative 
will be provided for any events that occur during the cycle for which the subject is 
incorrectly dosed. 
At least one laboratory or vital sign measurement obtained subsequent to at least one dose of 
study medication is required for inclusion in the analysis of each specific parameter. To 
assess change from baseline, a baseline measurement is also required.
Statistical Methods
Statistical Methods for Efficacy Analyses
This section describes the statistical methods that address the primary and secondary 
objectives. Methods related to exploratory objectives will be described in the supplemental 
SAP.
Efficacy results that will be deemed to be statistically significant after consideration of the 
Type I error control strategy are described in Section 8.8, Multiplicity. 
08GT0T


Product:  MK-3475 
105
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
Progression-Free Survival
The non-parametric Kaplan-Meier method will be used to estimate the PFS curve in each 
treatment group. The treatment difference in PFS will be assessed by the log-rank test and the 
p-value will be provided. A Cox proportional hazard model with Efron's method of tie 
handling will be used to assess the magnitude of the treatment difference (ie, hazard ratio) 
between the treatment arms. The hazard ratio and its 95% confidence interval from the Cox 
model with Efron's method of tie handling and with a single treatment covariate will be 
reported. 
Since disease progression is assessed periodically, PD can occur any time in the time interval 
between the last assessment where PD was not documented and the assessment when PD is 
documented. For the primary analysis, for the subjects who have PD, the true date of disease 
progression will be approximated by the date of the first assessment at which PD is 
objectively documented per RECIST 1.1 by central imaging vendor, regardless of 
discontinuation of study drug. Death is always considered as a confirmed PD event. 
Sensitivity analyses will be performed for comparison of PFS based on investigator’s 
assessment.
In order to evaluate the robustness of the PFS endpoint per RECIST 1.1 by central imaging 
vendor, we will perform several sensitivity analyses with a different set of censoring rules. 
The first sensitivity analysis is the same as the primary analysis except that it censors at the 
last disease assessment without PD when PD or death is documented after more than one 
missed disease assessment. The second sensitivity analysis is the same as the primary 
analysis except that it considers discontinuation of treatment or initiation of an anticancer 
treatment subsequent to discontinuation of study-specified treatments, whichever occurs
later, to be a PD event for subjects without documented PD or death. The censoring rules for 
primary and sensitivity analyses are summarized in Table 11. Surgical subjects (ie, those who 
have surgery with curative intent) will be censored at the surgical date in the PFS analysis. In 
order to show the benefit of surgery, we may also perform additional PFS sensitivity 
analysis: for the surgical subjects, a PFS using time from randomization to the disease 
recurrence after the surgery.
08GT0T


Product:  MK-3475 
106
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
Table 11
Censoring rules for Primary and Sensitivity Analyses of PFS
Situation
Primary Analysis
Sensitivity
Analysis 1
Sensitivity
Analysis 2
No PD and no death; new 
anticancer treatment is 
not initiated
Censored at last disease 
assessment 
Censored at last disease 
assessment 
Censored at last disease 
assessment if still on 
study medication; 
progressed at treatment 
discontinuation otherwise
No PD and no death; new 
anticancer treatment is 
initiated
Censored at last disease 
assessment before new 
anticancer treatment
Censored at last disease 
assessment before new 
anticancer treatment
Progressed at date of new 
anticancer treatment
No PD and no death; ≥2 
consecutive missed 
disease assessments
Censored at last disease 
assessment
Censored at last disease 
assessment prior to ≥2 
consecutive missed visits
Censored at last disease 
assessment
PD or death documented 
after ≤1 missed disease 
assessment
Progressed at date of 
documented PD or death
Progressed at date of 
documented PD or death
Progressed at date of 
documented PD or death
PD or death documented 
at any time after ≥2 
consecutive missed 
disease assessments
Progressed at date of 
documented PD or death
Censored at last disease 
assessment prior to the 
≥2 consecutive missed 
disease assessment
Progressed at date of 
documented PD or death
Note: Surgical subjects will be censored at the surgical date in the PFS primary, sensitivity 1 and 2 analyses.
The proportional hazards assumption on PFS will be examined using both graphical and 
analytical methods if warranted. The log[-log] of the survival function vs. time for PFS will 
be plotted for the comparison between pembrolizumab (MK-3475) and the SOC arm. If the 
curves are not parallel, indicating that hazards are not proportional, supportive analyses may
be conducted to account for the possible non-proportional hazards effect associated with 
immunotherapies (eg, using Restricted Mean Survival Time (RMST) method, parametric 
method etc.).
Further details of sensitivity analyses will be described in the supplemental SAP.
Overall Survival (OS)
The non-parametric Kaplan-Meier method will be used to estimate the survival curves. The 
treatment difference in survival will be assessed by the log-rank test. A Cox proportional 
hazard model with Efron's method of tie handling will be used to assess the magnitude of the 
treatment difference (ie, the hazard ratio). The hazard ratio and its 95% confidence interval 
from the Cox model with a single treatment covariate will be reported. 
Since subjects in the SOC arm are allowed to switch to the pembrolizumab (MK-3475)
treatment after progressive disease, adjustment for the effect of crossover on OS will be 
performed as a sensitivity analysis based on recognized methods, eg, the Rank Preserving 
Structural Failure Time (RPSFT) model proposed by Robins and Tsiatis [40], two-stage 
model, etc., based on an examination of the appropriateness of the data to the assumptions 
required by the methods. An additional OS sensitivity analysis will be performed with 
survival dates censored at the start of crossover treatment or the start of first subsequent 
immune checkpoint inhibitor treatment, whichever occurs first.
08GT0T


Product:  MK-3475 
107
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
Further details of sensitivity analyses will be described in the supplemental SAP.
Overall Response Rate (ORR)
The Miettinen and Nurminen method will be used for comparison of the ORR between the 
treatment arms. The point estimate, 95% Confidence Interval for the difference in response 
rate between the pembrolizumab arm and the control arm will be provided. Subjects without 
response data will be counted as non-responders. Table 12 summarizes the primary analysis 
approach for primary and secondary efficacy endpoints. Sensitivity analysis methods are 
described above for each endpoint.
The strategy to address multiplicity issues with regard to multiple efficacy endpoints, and 
interim analyses is described in Section 8.7 Interim Analyses and in Section 8.8 Multiplicity.
Table 12
Analysis Strategy for Key Efficacy Endpoints
Endpoint/Variable
(Description, Time 
Point) 
Statistical Method†
Analysis Population
Missing Data Approach
Primary Endpoints
PFS per RECIST 1.1 by 
central imaging vendor
Test: Log-rank test 
Estimation: Cox model 
with Efron’s tie handling 
method
ITT
Primary censoring 
rule 
Sensitivity analysis 1
Sensitivity analysis 2
(More details are in
Table 11)
OS 
Test: Log-rank test 
Estimation: Cox model 
with Efron’s tie handling 
method 
ITT 
Censored at the date of 
last known contact
Secondary Endpoint
ORR per RECIST 1.1 by 
central imaging vendor
Test: Miettinen and 
Nurminen method
ITT
Subjects with missing 
data are considered as 
non-responders.
† Statistical models are described in further detail in the text.  
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
adverse experiences (AEs), laboratory tests, vital signs, etc.
Adverse Events
Adverse events (AEs) will be coded using the standard MedDRA and grouped system organ 
class. AEs will be graded by the investigator according to the CTCAE version 4.0.
Tiered Approach
The analysis of safety results will follow a tiered approach (Table 13). The tiers differ with 
respect to the analyses that will be performed. “Tier 1” safety endpoints that will be subject 
08GT0T


Product:  MK-3475 
108
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
to inferential testing for statistical significance with p-values and 95% confidence intervals 
provided for between-group comparisons. For this protocol, there are no Tier 1 events. Other 
safety parameters will be considered Tier 2 or Tier 3. Tier 2 parameters will be assessed via 
point estimates with 95% confidence intervals provided for between-group comparisons; 
only point estimates by treatment group are provided for Tier 3 safety parameters. 
Adverse experiences (specific terms as well as system organ class terms) that are not pre-
specified as Tier-1 endpoints will be classified as belonging to "Tier 2" or "Tier 3", based on 
the number of events observed. Membership in Tier 2 requires that at least 4 subjects in any 
treatment group exhibit the event; all other adverse experiences and predefined limits of 
change will belong to Tier 3.
The threshold of at least 4 events was chosen because the 95% confidence interval for the 
between-group difference in percent incidence will always include zero when treatment 
groups of equal size each have less than 4 events and thus would add little to the 
interpretation of potentially meaningful differences. Because many 95% confidence intervals 
may be provided without adjustment for multiplicity, the confidence intervals should be 
regarded as a helpful descriptive measure to be used in review, not a formal method for 
assessing the statistical significance of the between-group differences in adverse experiences 
and predefined limits of change.
Continuous measures such as changes from baseline in laboratory, vital signs, that are not 
pre-specified as Tier-1 endpoints will be considered Tier 3 safety parameters. Summary 
statistics for baseline, on-treatment, and change from baseline values will be provided by 
treatment group in table format.
Based on the mechanism of action of pembrolizumab and safety data observed in historic 
pembrolizumab studies to date, there are no events of interest that warrant classification as 
Tier I events for this protocol. In addition, the broad clinical and laboratory AE categories 
consisting of the percentage of subjects with any AE, any drug-related AE, any Grade 3-5 
AE, any serious AE, any AE which is both drug-related and Grade 3-5, any AE which is both 
serious and drug-related, dose modification due to AE, and who discontinued due to an AE, 
and death will be considered Tier 2 endpoints. 95% confidence intervals (Tier 2) will be 
provided for between-treatment differences in the percentage of subjects with events; these 
analyses will be performed using the Miettinen and Nurminen method (1985), an 
unconditional, asymptotic method.
In the primary safety comparison between pembrolizumab (MK-3475) and SOC, subjects 
who crossover to pembrolizumab (MK-3475) are censored at time of crossover (ie, AEs
occurring during treatment with pembrolizumab (MK-3475) are excluded for control-arm 
subjects). An exploratory safety analysis will be conducted for the crossover population 
including all safety events starting from the date of randomization.
08GT0T


Product:  MK-3475 
109
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
Table 13
Analysis Strategy for Safety Parameters
Safety 
Tier
Safety Endpoint
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 2
Any AE
X
X
Any Serious AE 
X
X
Any Grade 3-5 AE
X
X
Any Drug-Related AE
X
X
Any Serious and Drug-Related AE
X
X
Any Grade 3-5 and Drug-Related AE
X
X 
Dose Modification due to AE
X
X
Discontinuation due to AE
X
X
Death
X
X
Specific AEs, SOCs, or PDLCs (incidence ≥4 of subjects 
in one of the treatment groups)
X
X
Tier 3
Specific AEs, SOCs or PDLCs (incidence <4 of subjects 
in all of the treatment groups)
X
Change from Baseline Results (Labs, ECGs, Vital Signs)
X
Summaries of Demographic and Baseline Characteristics
The comparability of the treatment groups for each relevant characteristic will be assessed by 
the use of tables and/or graphs. No statistical hypothesis tests will be performed on these 
characteristics. The number and percentage of subjects screened, randomized, the primary 
reasons for screening failure, and the primary reason for discontinuation will be displayed. 
Demographic variables (eg, age), baseline characteristics, primary and secondary diagnoses, 
and prior and concomitant therapies will be summarized by treatment either by descriptive 
statistics or categorical tables.
Interim Analyses
The study has 2 planned interim analyses. Results will be reviewed by an eDMC. 
For the PFS and OS hypotheses, Lan-DeMets O'Brien-Fleming alpha spending function will 
be used to construct group sequential boundaries to control the Type-I error. For PFS 
analysis, the extended graphical method (Anderson et al, unpublished data, 2018) is used. 
This method spends alpha as a function of the minimum of the actual event information 
fraction and the expected event information fraction. Interim analyses timing, criteria and 
decision guidance are in Table 14. The actual boundaries will be adjusted using the Lan-
DeMets O’Brien-Fleming spending function with spending time determined by the minimum 
of the actual information fraction and the expected information fraction. For OS analysis, the 
actual boundaries will be determined based upon the number of events observed at the time 
of the interim efficacy analyses and the planned final number of events for the specified 
analyses, using the alpha spending function.
08GT0T


Product:  MK-3475 
110
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
Table 14 summarizes the timing, sample size, and decision guidance (p-value and boundary)
for the interim and final efficacy analyses. 
Table 14
Timing, Sample Size, and Decision Guidance
Analysis
Criteria for Conduct of 
Analysis
Endpoint
p-value†
Approximate 
Efficacy Boundary 
(HR)†
Interim Analysis 1:
Interim PFS and 
interim OS analysis
To
be 
performed 
after 
1) 
approximately 162 PFS events 
have occurred; and 2) 6 months 
after last subject randomized.
Expected OS events: ~95
PFS
0.0046
0.66
OS
0.0004
0.50
Interim Analysis 2:
Final PFS and 
interim OS analysis
To
be 
performed 
after 
approximately 209 PFS events 
have occurred or 24 months after 
last 
subject 
randomized, 
whichever occurs first. Expected 
OS events:~135
PFS
0.0111
0.73
OS
0.0029
0.62
Final Analysis: 
Final OS analysis
To
be 
performed 
after 
approximately 190 OS events 
have occurred or 12 months after 
Interim Analysis 2, whichever 
occurs first.
OS
0.0115
0.72
†The “p value” and “Approximate Efficacy Boundary (HR)” for efficacy assume no re-distribution of initially 
assigned type I error.
Multiplicity
The overall type I error over the primary endpoints (PFS and OS) and the secondary endpoint 
(ORR) is strongly controlled at 2.5% (one-sided), with initially 1.25% allocated to the PFS 
hypothesis, 1.25% to the OS hypothesis, and 0% to the ORR hypothesis. An extension of the 
graphical method of Maurer and Bretz [39] is used to strongly control the overall Type I error 
rate for testing of multiple endpoints at the 2.5% 1-sided level (Anderson et al, unpublished 
data, 2018). Figure 9 shows the initial 1-sided α-allocation for each hypothesis in the ellipse 
representing the hypotheses. The weights for reallocation from each hypothesis to the others 
are represented in the boxes on the lines connecting hypotheses. The transfer weights of 0.01 
from OS and PFS to ORR essentially imply that if null hypotheses for both OS and PFS are 
rejected that an ORR benefit may be tested at the 2.5% 1-sided level; if only 1 of OS or PFS 
null hypotheses are rejected, then ORR would be tested at the 0.0125% 1-sided level.
See Figure 9 for the multiplicity strategy diagram of the study.
08GT0T


Product:  MK-3475 
111
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
Figure 9
Multiplicity Strategy
Sample Size and Power Calculations
The primary objective of this study is to evaluate the efficacy of Pembrolizumab (MK-3475)
compared to the standard of care with respect to PFS and OS for subjects with Microsatellite 
Instability-High or Mismatch Repair Deficient Stage IV Colorectal Carcinoma.
Approximately 300 subjects will be enrolled.
PFS analysis: The final PFS analysis will be performed at the time of Interim Analysis 2 
when approximately 209 PFS events have occurred or 24 months after last subject 
randomized, whichever occurs first. With 209 PFS events, the study has ~98% power for 
PFS to detect a hazard ratio (pembrolizumab [MK-3475] vs. SOC) of 0.55 at the 1.25% (one-
sided) significance level. If fewer than 209 events are observed 24 months after last subject 
randomized, the power will be lower; for example, if 192 events are observed, then the study 
has 97% power for PFS.
The sample size calculations are based on the following assumptions: 1) PFS follows an 
exponential distribution with a median of 10 months in the SOC arm; 2) an enrollment period 
of 30 months from first subject randomized and a minimum of 13 months follow-up after 
enrollment completion; and 3) a yearly dropout rate of 5%.
OS analysis: The final OS analysis will be performed after approximately 190 OS events 
have occurred or 12 months after Interim Analysis 2, whichever occurs first. With 190 OS 
events, the study has ~85% power for OS to detect a hazard ratio (pembrolizumab 
[MK-3475] vs. SOC) of 0.62 at the 1.25% (one-sided) significance level. If fewer than 190 
events are observed 12 months after Interim Analysis 2, the power will be lower; for 
example, if 170 events are observed, then the study has 80% power for OS. However, due to 
the anticipated high crossover rate, the actual power could be substantially lower.
08GT0T


Product:  MK-3475 
112
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
ORR analysis: ORR is a secondary endpoint. The ORR analysis will be conducted when 
either PFS or OS null hypothesis is rejected. The study has 92% power to demonstrate the 
superiority of Pembrolizumab (MK-3475) over SOC at one-sided 2.5% α-level, if the 
underlying treatment difference in ORR is 19%, assuming a 50% response rate in the SOC 
arm.
Subgroup Analyses and Effect of Baseline Factors
To determine whether the treatment effect is consistent across various subgroups, the 
between-group treatment effect (with a nominal 95% CI) for the 2 primary endpoints will be 
estimated and plotted within each category of the following classification variables: 

Age category (≤70 vs. >70 years)

Geographic region (Asia vs. Western Europe/North America vs. Rest of World)

Hepatic or pulmonary metastases vs other metastases

Recurrent vs newly diagnosed stage IV CRC

BRAF wild-type vs. BRAF V600E

Site of primary tumor (right vs. left)

Surgical vs non-surgical subjects, where surgical subjects are those who have surgery 
with curative intent
Compliance (Medication Adherence)
Drug accountability data for study medication will be collected during the study. 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
08GT0T


Product:  MK-3475 
113
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
9.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES
Investigational Product
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations.
Clinical Supplies will be provided by the Sponsor as summarized in Table 15.
Clinical supplies will be packaged to support enrollment and replacement subjects as 
required.  When a replacement subject is required, the Sponsor or designee needs to be 
contacted prior to dosing the replacement supplies.
Table 15
Product Descriptions
Product Name & Potency
Dosage 
Form
Source / Additional Information
Pembrolizumab, (MK-3475) 25 
mg/mL, 4 mL
Injection
Provided centrally by the SPONSOR
Oxaliplatin, 5 mg/mL
Injection
Provided centrally by the Sponsor or locally by 
the study site, subsidiary, or designee
Fluorouracil, 50 mg/mL
Injection
Provided centrally by the Sponsor or locally by 
the study site, subsidiary, or designee
Calcium leucovorin, 10 mg/mL
Injection
Provided centrally by the Sponsor or locally by 
the study site, subsidiary, or designee
Irinotecan, 20 mg/mL
Injection
Provided centrally by the Sponsor or locally by 
the study site, subsidiary, or designee
Bevacizumab, 25 mg/mL
Injection
Provided centrally by the Sponsor or locally by 
the study site, subsidiary, or designee
Cetuximab, 5 mg/mL
Injection
Provided centrally by the Sponsor or locally by 
the study site, subsidiary, or designee
All other supplies not indicated in Table 15 above will be provided centrally by the Sponsor 
or locally by the trial site, subsidiary or designee, depending on local country operational or 
regulatory requirements.
For any commercially available product that is provided by the trial site, subsidiary or 
designee every attempt will be made to source these supplies from a single lot/batch number. 
The trial site is responsible to record the lot number, manufacturer and expiry date for any 
locally purchased product as per local guidelines unless otherwise instructed by the Sponsor.
08GT0T


Product:  MK-3475 
114
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
Packaging and Labeling Information
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
Subjects will receive open label vials for every 3-week dosing for MK-3475 and every 
2 weeks for the standard of care drugs. The standard of care supplies may or may not be 
kitted, depending on the commercial presentation.
Clinical Supplies Disclosure
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded. Treatment (name, strength or potency) is included in the label text; 
random code/disclosure envelopes or lists are not provided.
Storage and Handling Requirements
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.  
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site.
Clinical supplies may not be used for any purpose other than that stated in the protocol.
Discard/Destruction/Returns and Reconciliation
The investigator is responsible for keeping accurate records of the clinical supplies received 
from the Sponsor or designee, the amount dispensed to and returned by the subjects and the 
amount remaining at the conclusion of the trial. For all trial sites, the local country Sponsor 
personnel or designee will provide appropriate documentation that must be completed for 
drug accountability and return, 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.
Standard Policies
Trial 
site 
personnel 
will 
have 
access 
to 
a 
central 
electronic 
treatment 
allocation/randomization system (IVRS/IWRS system) to allocate subjects, to assign 
treatment to subjects and to manage the distribution of clinical supplies. Each person 
accessing the IVRS system must be assigned an individual unique PIN.  They must use only 
their assigned PIN to access the system, and they must not share their assigned PIN with 
anyone.
08GT0T


Product:  MK-3475 
115
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
10.0 ADMINISTRATIVE AND REGULATORY DETAILS
Confidentiality
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the institutional review board, ethics review committee (IRB/ERC) or similar 
or expert committee; affiliated institution and employees, only under an appropriate 
understanding of confidentiality with such board or committee, affiliated institution and 
employees.  Data generated by this trial will be considered confidential by the investigator, 
except to the extent that it is included in a publication as provided in the Publications section 
of this protocol.
Confidentiality of Subject Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/ERC, or regulatory authority representatives may consult and/or copy trial documents in 
order to verify worksheet/case report form data.  By signing the consent form, the subject 
agrees to this process.  If trial documents will be photocopied during the process of verifying 
worksheet/case report form information, the subject will be identified by unique code only; 
full names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all subject data used and disclosed in 
connection with this trial in accordance with all applicable privacy laws, rules and 
regulations.
Confidentiality of Investigator Information
By signing this protocol, the investigator recognizes that certain personal identifying 
information with respect to the investigator, and all subinvestigators and trial site personnel, 
may be used and disclosed for trial management purposes, as part of a regulatory 
submissions, and as required by law.  This information may include:
1. name, address, telephone number and e-mail address;
2. hospital or clinic address and telephone number;
3. curriculum vitae or other summary of qualifications and credentials; and
4. other professional documentation.
Consistent with the purposes described above, this information may be transmitted to the 
Sponsor, and subsidiaries, affiliates and agents of the Sponsor, in your country and other 
countries, including countries that do not have laws protecting such information.  
Additionally, the investigator’s name and business contact information may be included 
when reporting certain serious adverse events to regulatory authorities or to other 
08GT0T


Product:  MK-3475 
116
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
investigators.  By signing this protocol, the investigator expressly consents to these uses and 
disclosures.
If this is a multicenter trial, in order to facilitate contact between investigators, the Sponsor 
may share an investigator’s name and contact information with other participating 
investigators upon request.
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC member that 
reviews and approves this trial.  The Sponsor is also required to document that each IRB/IEC 
meets regulatory and ICH GCP requirements by requesting and maintaining records of the 
names and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
Compliance with Financial Disclosure Requirements
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54).  It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
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.
Compliance with Law, Audit and Debarment
By signing this protocol, the investigator agrees to conduct the trial in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of Good 
Clinical Practice (e.g., International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice: 
Consolidated Guideline and other generally accepted standards of good clinical practice); and 
all applicable federal, state and local laws, rules and regulations relating to the conduct of the 
clinical trial.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in Section 12.1 -
Code of Conduct for Clinical Trials.
08GT0T


Product:  MK-3475 
117
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
The investigator also agrees to allow monitoring, audits, IRB/ERC review and regulatory 
authority inspection of trial-related documents and procedures and provide for direct access 
to all trial-related source data and documents.
The investigator agrees not to seek reimbursement from subjects, their insurance providers or 
from government programs for procedures included as part of the trial reimbursed to the 
investigator by the Sponsor.
The investigator shall prepare and maintain complete and accurate trial documentation in 
compliance with Good Clinical Practice standards and applicable federal, state and local 
laws, rules and regulations; and, for each subject participating in the trial, provide all data, 
and, upon completion or termination of the clinical trial, submit any other reports to the 
Sponsor as required by this protocol or as otherwise required pursuant to any agreement with 
the Sponsor.
Trial documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the trial site upon request for inspection, 
copying, review and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities.  The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor as a result of an audit to cure deficiencies in the trial documentation 
and worksheets/case report forms.
The investigator must maintain copies of all documentation and records relating to the 
conduct of the trial in compliance with all applicable legal and regulatory requirements.  This 
documentation includes, but is not limited to, the protocol, worksheets/case report forms, 
advertising for subject participation, adverse event reports, subject source data, 
correspondence with regulatory authorities and IRBs/ERCs, consent forms, investigator’s 
curricula vitae, monitor visit logs, laboratory reference ranges, laboratory certification or 
quality control procedures and laboratory director curriculum vitae.  By signing this protocol, 
the investigator agrees that documentation shall be retained until at least 2 years after the last 
approval of a marketing application in an ICH region or until there are no pending or 
contemplated marketing applications in an ICH region or until at least 2 years have elapsed 
since the formal discontinuation of clinical development of the investigational product.  
Because the clinical development and marketing application process is variable, it is 
anticipated that the retention period can be up to 15 years or longer after protocol database 
lock. The Sponsor will determine the minimum retention period and notify the investigator 
when documents may be destroyed.  The Sponsor will determine the minimum retention 
period and upon request, will provide guidance to the investigator when documents no longer 
need to be retained.  The sponsor also recognizes that documents may need to be retained for 
a longer period if required by local regulatory requirements. All trial documents shall be 
made available if required by relevant regulatory authorities. The investigator must consult 
with and obtain written approval by the Sponsor prior to destroying trial and/or subject files.  
ICH Good Clinical Practice guidelines recommend that the investigator inform the subject’s 
primary physician about the subject’s participation in the trial if the subject has a primary 
physician and if the subject agrees to the primary physician being informed.
08GT0T


Product:  MK-3475 
118
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this trial.
Persons debarred from conducting or working on clinical trials by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s trials.  The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the trial is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will 
promptly notify that trial site’s IRB/IEC.
According to European legislation, a Sponsor must designate an overall coordinating 
investigator for a multi-center trial (including multinational).  When more than one trial site 
is open in an EU country, MSD, as the Sponsor, will designate, per country, a national 
principal coordinator (Protocol CI), responsible for coordinating the work of the principal 
investigators at the different trial sites in that Member State, according to national 
regulations.  For a single-center trial, the Protocol CI is the principal investigator.  In 
addition, the Sponsor must designate a principal or coordinating investigator to review the 
trial report that summarizes the trial results and confirm that, to the best of his/her 
knowledge, the report accurately describes the conduct and results of the trial [Clinical Study 
Report (CSR) CI].  The Sponsor may consider one or more factors in the selection of the 
individual to serve as the Protocol CI and or CSR CI (e.g., availability of the CI during the 
anticipated review process, thorough understanding of clinical trial methods, appropriate 
enrollment of subject cohort, timely achievement of trial milestones).  The Protocol CI must 
be a participating trial investigator.
Compliance with Trial Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements 
for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov.  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 FDAMA/FDAAA mandated trials. 
Information posted will allow subjects to identify potentially appropriate trials for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate trial locations and trial site contact information.
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAMA/FDAAA are that of the Sponsor and agrees not to submit any information about this 
trial or its results to the Clinical Trials Data Bank.
Quality Management System
By signing this protocol, the Sponsor agrees to be responsible for implementing and 
maintaining a quality management system with written development procedures and 
08GT0T


Product:  MK-3475 
119
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
functional area standard operating procedures (SOPs) to ensure that trials are conducted and 
data are generated, documented, and reported in compliance with the protocol, accepted 
standards of Good Clinical Practice, and all applicable federal, state, and local laws, rules and 
regulations relating to the conduct of the clinical trial.
Data Management
The investigator or qualified designee is responsible for recording and verifying the accuracy 
of subject data.  By signing this protocol, the investigator acknowledges that his/her 
electronic signature is the legally binding equivalent of a written signature.  By entering 
his/her electronic signature, the investigator confirms that all recorded data have been 
verified as accurate.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
Publications
This trial is intended for publication, even if terminated prematurely. Publication may include 
any or all of the following: posting of a synopsis online, abstract and/or presentation at a 
scientific conference, or publication of a full manuscript.  The Sponsor will work with the 
authors to submit a manuscript describing trial results within 12 months after the last data 
become available, which may take up to several months after the last subject visit in some 
cases such as vaccine trials.  However, manuscript submission timelines may be extended on 
OTC trials.  For trials intended for pediatric-related regulatory filings, the investigator agrees 
to delay publication of the trial results until the Sponsor notifies the investigator that all 
relevant regulatory authority decisions on the trial drug have been made with regard to 
pediatric-related regulatory filings. MSD will post a synopsis of trial results for approved 
products on www.clinicaltrials.gov by 12 months after the last subject's last visit for the 
primary outcome, 12 months after the decision to discontinue development, or product 
marketing (dispensed, administered, delivered or promoted), whichever is later.
These timelines may be extended for products that are not yet marketed, if additional time is 
needed for analysis, to protect intellectual property, or to comply with confidentiality 
agreements with other parties.  Authors of the primary results manuscript will be provided 
the complete results from the Clinical Study Report, subject to the confidentiality agreement. 
When a manuscript is submitted to a biomedical journal, the Sponsor's policy is to also 
include the protocol and statistical analysis plan to facilitate the peer and editorial review of 
the manuscript.  If the manuscript is subsequently accepted for publication, the Sponsor will 
allow the journal, if it so desires, to post on its website the key sections of the protocol that 
are relevant to evaluating the trial, specifically those sections describing the trial objectives 
and hypotheses, the subject inclusion and exclusion criteria, the trial design and procedures, 
the efficacy and safety measures, the statistical analysis plan, and any amendments relating to 
those sections.  The Sponsor reserves the right to redact proprietary information.
For multicenter trials, subsequent to the multicenter publication (or after public disclosure of 
the results online at www.clinicaltrials.gov if a multicenter manuscript is not planned), an 
08GT0T


Product:  MK-3475 
120
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
investigator and his/her colleagues may publish their data independently.  In most cases, 
publication of individual trial site data does not add value to complete multicenter results, 
due to statistical concerns.  In rare cases, publication of single trial site data prior to the main 
paper may be of value.  Limitations of single trial site observations in a multicenter trial 
should always be described in such a manuscript.
Authorship credit should be based on 1) substantial contributions to conception and design, 
or acquisition of data, or analysis and interpretation of data; 2) drafting the article or revising 
it critically for important intellectual content; and 3) final approval of the version to be 
published. Authors must meet conditions 1, 2 and 3.  Significant contributions to trial 
execution may also be taken into account to determine authorship, provided that 
contributions have also been made to all three of the preceding authorship criteria.  Although 
publication planning may begin before conducting the trial, final decisions on authorship and 
the order of authors’ names will be made based on participation and actual contributions to 
the trial and writing, as discussed above. The first author is responsible for defending the 
integrity of the data, method(s) of data analysis and the scientific content of the manuscript.
The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or 
presentations regarding this trial 45 days prior to submission for publication/presentation. 
Any information identified by the Sponsor as confidential must be deleted prior to 
submission; this confidentiality does not include efficacy and safety results. Sponsor review 
can be expedited to meet publication timelines.
11.0 LIST OF REFERENCES
[1]
Llosa NJ, Cruise M, Tam A, Wicks EC, Hechenbleikner EM, Taube JM, et al. The 
vigorous immune microenvironment of microsatellite instable colon cancer is 
balanced by multiple counter-inhibitory checkpoints. Cancer Discov. 2015 
Jan;5(1):43-51.
[2]
Gubin MM, Zhang X, Schuster H, Caron E, Ward JP, Noguchi T, et al. Checkpoint 
blockade cancer immunotherapy targets tumour-specific mutant antigens. Nature. 
2014 Nov 27;515(7528):577-81.
[3]
Lipson EJ, Sharfman WH, Drake CG, Wollner I, Taube JM, Anders RA, et al. 
Durable cancer regression off-treatment and effective reinduction therapy with an 
anti-PD-1 antibody.  Clin Cancer Res 2012;19(2):462-8.
[4]
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.
[5]
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.
08GT0T


Product:  MK-3475 
121
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
[6]
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.
[7]
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.
[8]
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.
[9]
Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Annu Rev 
Immunol 2005;23:515-48.
[10]
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.
[11]
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;22(2):229-37.
[12]
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.
[13]
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.
[14]
Goldberg RM, Sargent DJ, Morton RF, Green E, Sanoff HK, McLeod H, et al. 
NCCTG Study N9741: leveraging learning from an NCI Cooperative Group phase III 
trial. Oncologist. 2009 Oct;14(10):970-8.
[15]
Saltz LB, Clarke S, Diaz-Rubio E, Scheithauer W, Figer A, Wong R, et al. 
Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line 
therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 
2008 Apr 20;26(12):2013-9. Erratum in: J Clin Oncol. 2008 Jun;26(18):3110. J Clin 
Oncol. 2009 Feb 1;27(4):653.
08GT0T


Product:  MK-3475 
122
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
[16]
Van Cutsem E, Kohne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, et al. 
Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N 
Engl J Med. 2009 Apr 2;360(14):1408-17.
[17]
Bokemeyer C, Bondarenko I, Hartmann JT, de Braud F, Schuch G, Zubel A, et al. 
Efficacy according to biomarker status of cetuximab plus FOLFOX-4 as first-line 
treatment for metastatic colorectal cancer: the OPUS study. Ann Oncol. 2011 
Jul;22(7):1535-46.
[18]
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.
[19]
American Cancer Society. Colorectal cancer facts & figures 2014-2016 [Internet]. 
Atlanta: 
American 
Cancer 
Society; 
2014. 
Available 
from: 
http://www.cancer.org/acs/groups/content/documents/document/acspc-042280.pdf.
[20]
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015 
Jan;65(1):5-29.
[21]
Surveillance Research Program, NCI. SEER Stat fact sheets: Colon and rectum 
cancer 
[Internet]. 
Bethesda: 
NCI; 
2015. 
Available 
from: 
http://seer.cancer.gov/statfacts/html/colorect.html.
[22]
Surveillance, Epidemiology, and End Results Program. Cancer of the colon and 
rectum (invasive) [Internet]. Bethesda (MD): National Cancer Institute; 2015. 
Available 
from: 
http://seer.cancer.gov/archive/csr/1975_2011/browse_csr.php?sectionSEL=6&pageS
EL=sect_06_table.01.html.
[23]
Stadler ZK. Diagnosis and management of DNA mismatch repair-deficient colorectal 
cancer. Hematol Oncol Clin North Am. 2015 Feb;29(1):29-41.
[24]
Kim GP, Colangelo LH, Wieand HS, Paik S, Kirsch IR, Wolmark N, et al. 
Prognostic and predictive roles of high-degree microsatellite instability in colon
cancer: a National Cancer Institute-National Surgical Adjuvant Breast and Bowel 
Project Collaborative Study. J Clin Oncol. 2007 Mar 1;25(7):767-72.
[25]
Phipps AI, Limburg PJ, Baron JA, Burnett-Hartman AN, Weisenberger DJ, Laird 
PW, et al. Association between molecular subtypes of colorectal cancer and patient 
survival. Gastroenterology. 2015 Jan;148(1):77-87.
[26]
Benson AB 3rd, Venook AP, Bekaii-Saab T, Chan E, Chen YJ, Cooper HS, et al. 
Colon cancer, version 3.2014. J Natl Compr Canc Netw. 2014 Jul;12(7):1028-59.
08GT0T


Product:  MK-3475 
123
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
[27]
Zhang X, Li J. Era of universal testing of microsatellite instability in colorectal 
cancer. World J Gastrointest Oncol. 2013 Feb 15;5(2):12-9.
[28]
Smyrk TC, Watson P, Kaul K, Lynch HT. Tumor-infiltrating lymphocytes are a 
marker for microsatellite instability in colorectal carcinoma. Cancer. 2001 Jun 
15;91(12):2417-22.
[29]
Xiao Y, Freeman GJ. The microsatellite instable subset of colorectal cancer is a 
particularly good candidate for checkpoint blockade immunotherapy. Cancer Discov. 
2015 Jan;5(1):16-8.
[30]
Roth AD, Tejpar S, Delorenzi M, Yan P, Fiocca R, Klingbiel D, et al. Prognostic role 
of KRAS and BRAF in stage II and III resected colon cancer: results of the 
translational study on the PETACC-3, EORTC 40993, SAKK 60-00 trial. J Clin 
Oncol. 2010 Jan 20;28(3):466-74.
[31]
Koopman M, Kortman GA, Mekenkamp L, Ligtenberg MJ, Hoogerbrugge N, 
Antonini NF, et al. Deficient mismatch repair system in patients with sporadic 
advanced colorectal cancer. Br J Cancer. 2009 Jan 27;100(2):266-73.
[32]
Venderbosch S, Nagtegaal ID, Maughan TS, Smith CG, Cheadle JP, Fisher D, et al. 
Mismatch repair status and BRAF mutation status in metastatic colorectal cancer 
patients: a pooled analysis of the CAIRO, CAIRO2, COIN, and FOCUS studies. Clin 
Cancer Res. 2014 Oct 15;20(20):5322-30.
[33]
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 Jun 
25;372(26):2509-20.
[34]
Nishino M, Giobbie-Hurder A, Gargano M, Suda M, Ramaiya NH, Hodi FS. 
Developing a common language for tumor response to immunotherapy: immune-
related response criteria using unidimensional measurements. Clin Cancer Res. 2013 
Jul 15;19(14):3936-43.
[35]
Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, et al. The 
European Organization for Research and Treatment of Cancer QLQ-C30: a quality-
of-life instrument for use in international clinical trials in oncology. J Natl Cancer 
Inst 1993;85(5):365-76.
[36]
Balmana J, Castells A, Cervantes A. Familial colorectal cancer risk: ESMO Clinical 
Practice Guidelines. Ann Oncol. 2010 May;21 Suppl 5:v78-81.
[37]
Stoffel EM, Mangu PB, Gruber SB, Hamilton SR, Kalady MF, Lau MW, et al. 
Hereditary colorectal cancer syndromes: American Society of Clinical Oncology 
Clinical Practice Guideline endorsement of the familial risk-colorectal cancer: 
European Society for Medical Oncology Clinical Practice Guidelines. J Clin Oncol. 
2015 Jan 10;33(2):209-17.
08GT0T


Product:  MK-3475 
124
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
[38]
Tournigand C, Cervantes A, Figer A, Lledo G, Flesch M, Buyse M, et al. 
OPTIMOX1: a randomized study of FOLFOX4 or FOLFOX7 with oxaliplatin in a 
stop-and-Go fashion in advanced colorectal cancer--a GERCOR study. J Clin Oncol. 
2006 Jan 20;24(3):394-400.
[39]
Maurer W and Bretz F. Multiple testing in group sequential trials using graphical 
approaches. Stat Biopharm Res 2013;5(4):311-20.
[40]
Robins JM, Tsiatis AA. Correcting for non-compliance in randomized trials using 
rank preserving structural failure time models. Commun Stat-Theor M 
1991;20(8):2609-31.
08GT0T


Product:  MK-3475 
125
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
12.0 APPENDICES
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.
08GT0T


Product:  MK-3475 
126
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
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.
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.
08GT0T


Product:  MK-3475 
127
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
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.
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.
08GT0T


Product:  MK-3475 
128
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
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 collected in this trial as outlined in Section 7.1.3.3 – Future Biomedical 
Research Sample Collection will be used to study various causes for how subjects may 
respond to a drug/vaccine.  Future biomedical research specimen(s) will be stored to 
provide a resource for future trials conducted by the Sponsor focused on the study of 
biomarkers responsible for how a drug/vaccine enters and is removed by the body, how a 
drug/vaccine works, other pathways a drug/vaccine may interact with, or other aspects of 
disease. The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need.  All specimens will be used by the Sponsor or those working for 
or with the Sponsor.
3. Summary of Procedures for Future Biomedical Research
a.
Subjects for Enrollment
All subjects enrolled in the clinical trial will be considered for enrollment in 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 subjects or legal guardians, at a trial 
visit by the investigator or his or her designate.  Informed consent for Future 
08GT0T


Product:  MK-3475 
129
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
Biomedical Research should be presented to the subjects on Visit 1.  If delayed, 
present consent at next possible Subject Visit. Informed consent must be obtained 
prior to collection of all Future Biomedical Research specimens.  Consent forms 
signed by the subject will be kept at the clinical trial site under secure storage for 
regulatory reasons.  
A template of each trial site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository. Each consent will be assessed for appropriate 
specimen permissions.  
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of patient 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 Collections
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 subject is having blood drawn for other trial purposes.
4. Confidential Subject Information for Future Biomedical Research 
In order to optimize the research that can be conducted with Future Biomedical Research 
specimens, it is critical to link subject' clinical information with future test results. In fact 
little or no research can be conducted without connecting the clinical trial data to the 
specimen. The clinical data allow specific analyses to be conducted. Knowing subject 
characteristics like gender, age, medical history and treatment outcomes are critical to 
understanding clinical context of analytical results.
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 for transfer to the storage facility.  This first code is a random number which 
does not contain any personally identifying information embedded within it. The link (or 
key) between subject identifiers and this first unique code will be held at the trial site.  No 
personal identifiers will appear on the specimen tube.  
5. Biorepository Specimen Usage
Specimens obtained for the MSD Biorepository 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 (e.g., a university investigator) 
designated by the Sponsor. The investigator conducting the analysis will follow the 
08GT0T


Product:  MK-3475 
130
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
Sponsor’s privacy and confidentiality requirements. Any contracted third party analyses 
will conform to the specific scope of analysis outlined in future biomedical research 
protocol 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 
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   Subjects may withdraw consent at any time by 
contacting the principal investigator for the main trial. If medical records for the main 
trial are still available, the investigator will contact the Sponsor using the designated 
mailbox (clinical.specimen.management@MSD.com) and a form will be provided to 
obtain appropriate information to complete specimen withdrawal. Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed. 
Documentation will be sent to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for destruction or already performed prior to 
the request being received by the Sponsor will continue to be used as part of the overall 
research trial data and results. No new analyses would be generated after the request is 
received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the subject’s personal information and their specimens. In this situation, the 
request for specimen destruction can not be processed. 
7. Retention of Specimens 
Future Biomedical Research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from 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 
08GT0T


Product:  MK-3475 
131
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards (e.g., ISO17799) to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Subjects
No information obtained from exploratory laboratory studies will be reported to the 
subject, family, or physicians. Principle reasons not to inform or return results to the 
subject include: Lack of relevance to subject health, limitations of predictive capability, 
and concerns regarding misinterpretation.
If any exploratory results are definitively associated with clinical significance for subjects 
while the clinical trial is still ongoing, investigators will be contacted with information. 
After the clinical trial has completed, if any exploratory results are definitively associated 
with clinical significance, the Sponsor will endeavor to make such results available 
through appropriate mechanisms (e.g., scientific publications and/or presentations). 
Subjects 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 subjects 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 subject have been minimized. No additional 
risks to the subject 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 subject data 
privacy concerns.  Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality.  In this highly unlikely situation there is risk that the 
information, like all medical information, may be misused.
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
08GT0T


Product:  MK-3475 
132
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
Understanding the Intent, Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff
08GT0T


Product:  MK-3475 
133
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
08GT0T


Product:  MK-3475 
134
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
08GT0T


Product:  MK-3475 
135
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
08GT0T


Product:  MK-3475 
136
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
08GT0T


Product:  MK-3475 
137
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
08GT0T


Product:  MK-3475 
138
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
08GT0T


Product:  MK-3475 
139
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
08GT0T


Product:  MK-3475 
140
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
08GT0T


Product:  MK-3475 
141
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
08GT0T


Product:  MK-3475 
142
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
08GT0T


Product:  MK-3475 
143
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
RECIST 1.1* will be used in this study for assessment of tumor response. After initial 
disease progression, tumor response assessment will be per irRECIST for subjects on the 
pembrolizumab (MK-3475) arm (see Section 7.1.4.6).
While either CT or MRI may be utilized, as per RECIST 1.1, CT is the preferred imaging 
technique in this study.
* As published in the European Journal of Cancer 
08GT0T


Product:  MK-3475 
144
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
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 (e.g., 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, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, 
T.E., McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative 
Oncology Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, 
Robert Comis M.D., Group Chair.
08GT0T


Product:  MK-3475 
145
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
Common Terminology Criteria for Adverse Events v4.0
The descriptions and grading scales found in the revised NCI CTCAE version 4.0 will be 
utilized for adverse event reporting. (http://ctep.cancer.gov/reporting/ctc.html).
08GT0T


Product:  MK-3475 
146
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
List of Abbreviations
Abbreviation/Term
Definition
1L
First Line
5-FU
5-fluorouracil
ADA
Anti-Drug Antibodies
ADL
Activities of Daily Living
AE
Adverse Event
ALT
Alanine Aminotransferase
ANC
Absolute Neutrophil Count
API
Asian/Pacific Islander
aPTT
Activated Partial Thromboplastin Time
ASaT
All Subjects as Treated
ASCO
American Society of Clinical Oncology
AST
Aspartate Aminotransferase
β-HCG
Beta Human Chorionic Gonadotropin
CBC
Complete Blood Count
CEA
Carcinoembryonic Antigen
CI
Confidence Interval
CIV
Central Imaging Vendor
CL
Clearance
Cmax
Maximum Concentration
CNS
Central Nervous System
COVID-19
Coronavirus disease caused by severe acute respiratory 
syndrome coronavirus 2
CR
Complete Response
CRC
Colorectal Carcinoma or Colorectal Cancer
CRF
Case Report Form
CSR
Clinical Study Report
CT
Computed Tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTFG
Clinical Study Facilitation Group
CTL
Cytotoxic T-Cell
CTLA-4
Cytotoxic T-Lymphocyte-Associated Antigen-4
Ctrough
Minimum Concentration
DKA
Metabolic Acidosis
DMC
Data Monitoring Committee
dMMR
Mismatch Repair Deficient
DNA
Deoxyribonucleic acid
DOR
Duration of Response
DPD 
Dihydropyrimidine Dehydrogenase
ECG
Electrocardiogram
ECI
Event of Clinical Interest
ECOG
Eastern Cooperative Oncology Group
EDC
Electronic Data Capture 
eDMC
external Data Monitoring Committee
EGFR
Epidermal Growth Factor Receptor
EOC
Executive Oversight Committee
EORTC
European Organization for Research and Treatment of Cancer
EPO
Erythropoietin
ePRO
Electronic Subject Reported Outcomes
ER
Emergency Room
ERC
Ethics Review Committee
08GT0T


Product:  MK-3475 
147
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
Abbreviation/Term
Definition
ESMO
European Society for Medical Oncology
EU
European Union
FBR
Future Biomedical Research
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FDAMA
Food and Drug Administration Modernization Act
FSH
Follicle-stimulating hormone
FT3
Free Total Triiodothyronine
FT4
Free Thyroxine
GCP
Good Clinical Practice
GFR
Glomerular Filtration Rate
GI
Gastrointestinal
HBsAg
Hepatitis B surface Antigen
HCV
Hepatitis C Virus
HIV
Human Immunodeficiency Virus
HR
Hazard Ratio
HRQoL
Health-related Quality of Life
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonization
IDO
Indoleamine 2,3-Dioxygenase
IFNγ
Interferon Gamma
IgG4
Immunoglobulin G4
IHC
Immunohistochemistry
INR
International Normalized Ratio
IRB
Institutional Review Board
irRECIST
Immune-related RECIST 
irRC
Immune-Related Response Criteria
ITT
Intention-To-Treat
IUD
Intrauterine Device
IUS
Intrauterine Hormone-Releasing System
IV
Intravenous
IVRS
Interactive Voice Response System
IWRS
Integrated Web Response System
JSCCR
Japanese Society for Cancer of the Colon and Rectum
Kg
Kilogram
LAG-3
Lymphocyte-Activation Gene 3
LDH
Lactate Dehydrogenase
mAb
Monoclonal Antibody
mcL
Microliters
Mg
Milligram
Mg/kg
Milligram per Kilogram
MHC
Major Histocompatibility Complex
mL
milliliter
MRI
Magnetic Resonance Imaging
mRNA
Messenger RNA
MSI
Microsatellite Instability
MSI-H
Microsatellite Instability-High
MSS
Microsatellite-Stable
MTD
Maximum Tolerated Dose
N/A
Not Applicable
NCCN
National Comprehensive Cancer Network
08GT0T


Product:  MK-3475 
148
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
Abbreviation/Term
Definition
NCI
National Cancer Institute
NSAID
Non-Steroidal Anti-inflammatory Drug
NSCLC
Non-Small Cell Lung Cancer
ORR
Overall Response Rate
OS
Overall Survival
OTC
Over-the-Counter
PBPK
Physiologically Based Pharmacokinetic
PCR
Polymerase Chain Reaction
PD
Progressive Disease
PD-1
Programmed Death 1 
PD-L1
Programmed Death Ligand 1
PD-L2
Programmed Death Ligand 2
PFS
Progression-Free Survival
PIN
Personal Identification Number
PK
Pharmacokinetic
PR
Partial Response
PRO
Subject Reported Outcomes
PS
Performance Status
PT
Prothrombin Time
PTT
Partial Prothrombin Time
QALY
Quality Adjusted Life Years
QoL
Quality-of-Life
Q2W
Every 2 Weeks
Q3W
Every 3 Weeks
Q9W
Every 9 Weeks
RECIST
Response Evaluation Criteria in Solid Tumors
RMST
Restricted Mean Survival Time
RNA
Ribonucleic Acid
RPSFT
Rank Preserving Structural Failure Time
SAE
Serious Adverse Events
SAP
Statistical Analysis Plan
SD
Stable Disease
SEER
Surveillance, Epidemiology, and End Results
SGOT
Serum Glutamic Oxaloacetic Transaminase
SGPT
Serum Glutamic Pyruvic Transaminase
SIM
Site Imaging Manual
SLD
Sum of Longest Diameters
SOC
Standard of Care
SOP
Standard Operating Procedures
sSAP
Supplemental Statistical Analysis Plan
T1DM
Type 1 Diabetes Mellitus
T3
Total Triiodothyronine
TMDD
Target Mediated Drug Disposition
TSH
Thyroid Stimulating Hormone
TTP
Time to Progression
UK
United Kingdom
ULN
Upper Limit of Normal
US
United States
V
Volume of Distribution
VEGF
Vascular Endothelial Growth Factor
WBC
White Blood Cell
08GT0T


Product:  MK-3475 
149
Protocol/Amendment No.: 177-07
MK-3475-177-07 Final Protocol
12-Oct-2022
Confidential
13.0 SIGNATURES
Sponsor's Representative
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
Investigator
I agree to conduct this clinical trial in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol (including other manuals and documents 
referenced from this protocol).  I agree to conduct the trial in accordance with generally 
accepted standards of Good Clinical Practice.  I also agree to report all information or data in 
accordance with the protocol and, in particular, I agree to report any serious adverse events 
as defined in Section 7.2 – Assessing and Recording Adverse Events.  I also agree to handle 
all clinical supplies provided by the Sponsor and collect and handle all clinical specimens in 
accordance with the protocol.  I understand that information that identifies me will be used 
and disclosed as described in the protocol, and that such information may be transferred to 
countries that do not have laws protecting such information.  Since the information in this 
protocol and the referenced Investigator’s Brochure is confidential, I understand that its 
disclosure to any third parties, other than those involved in approval, supervision, or conduct 
of the trial is prohibited.  I will ensure that the necessary precautions are taken to protect such 
information from loss, inadvertent disclosure or access by third parties.
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
08GT0T