A Phase II Study of Pembrolizumab (MK-3475) as Monotherapy in Subjects With Previously Treated Locally Advanced Unresectable or Metastatic (Stage IV) Mismatched Repair Deficient or Microsatellite Instability-High Colorectal Carcinoma (KEYNOTE-164)
Phase: PHASE2
Conditions: Colorectal Carcinoma
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
NCT02460198
13-Nov-2019
Document Date: 
A Phase II Study of Pembrolizumab (MK-3475) as 
Monotherapy in Subjects with Previously Treated Locally 
Advanced Unresectable or Metastatic (Stage IV) Mismatched 
Repair Deficient or Microsatellite Instability-High Colorectal 
Carcinoma (KEYNOTE-164)

Product:  MK-3475 
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THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., 
WHITEHOUSE STATION, NJ, U.S.A.
SPONSOR:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. 
(hereafter referred to as the Sponsor or Merck)
One Merck Drive
P.O. Box 100
Whitehouse Station, New Jersey, 08889-0100, U.S.A.
Protocol-specific Sponsor Contact information can be found in the Investigator Trial File 
Binder (or equivalent).
TITLE:
A Phase II Study of Pembrolizumab (MK-3475) as Monotherapy in Subjects with Previously 
Treated Locally Advanced Unresectable or Metastatic (Stage IV) Mismatched Repair 
Deficient or Microsatellite Instability-High Colorectal Carcinoma (KEYNOTE-164)
IND NUMBER:  123,482
EudraCT NUMBER:  2015-001852-32 
 
 
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TABLE OF CONTENTS
DOCUMENT HISTORY ..................................................................................................... 11
SUMMARY OF CHANGES................................................................................................ 13
TRIAL SUMMARY.................................................................................................. 16
TRIAL DESIGN........................................................................................................ 17
Trial Design ........................................................................................................... 17
Trial Diagram........................................................................................................ 18
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 19
Primary Objective(s) & Hypothesis(es).............................................................. 19
Secondary Objective(s) & Hypothesis(es)........................................................... 20
Other Tertiary and Exploratory Objectives ...................................................... 20
BACKGROUND & RATIONALE.......................................................................... 20
Background ........................................................................................................... 20
Pharmaceutical and Therapeutic Background .................................................... 21
Pre-clinical and Clinical Trials ........................................................................... 21
4.1.2.1
Preclinical Studies........................................................................................ 21
4.1.2.2
Ongoing Clinical Trials................................................................................ 22
Rationale................................................................................................................ 22
Rationale for the Trial and Selected Subject Population .................................... 22
Rationale for Dose Selection/Regimen............................................................... 24
4.2.2.1
Rationale for Fixed Dose Pembrolizumab................................................... 24
Rationale for Endpoints ...................................................................................... 25
4.2.3.1
Efficacy Endpoints....................................................................................... 25
Primary Endpoint.................................................................................. 25
Secondary Endpoints ............................................................................ 25
Tertiary and Exploratory Endpoints ..................................................... 25
Immune-related RECIST................................................................ 25
4.2.3.2
Safety Endpoints.......................................................................................... 27
4.2.3.3
Biomarkers................................................................................................... 27
MSI Status Testing................................................................................ 27
 
 
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Planned Exploratory Biomarker Research............................................ 27
4.2.3.4
Future Biomedical Research........................................................................ 29
Benefit/Risk ........................................................................................................... 29
METHODOLOGY ................................................................................................... 29
Entry Criteria........................................................................................................ 29
Subject Inclusion Criteria.................................................................................... 29
Subject Exclusion Criteria .................................................................................. 31
Trial Treatment(s) ................................................................................................ 33
Dose Selection/Modification .............................................................................. 34
5.2.1.1
Dose Selection (Preparation) ....................................................................... 34
5.2.1.2
Dose Modification and Toxicity Management Guidelines
for 
Pembrolizumab............................................................................................ 34
Timing of Dose Administration.......................................................................... 39
Trial Blinding/Masking....................................................................................... 40
Randomization or Treatment Allocation............................................................ 40
Stratification.......................................................................................................... 40
Concomitant Medications/Vaccinations (Acceptable and Prohibited)............ 40
Acceptable Concomitant Medications ................................................................ 40
Prohibited Concomitant Medications.................................................................. 41
Rescue Medications & Supportive Care............................................................. 42
Supportive Care Guidelines for Pembrolizumab ................................................ 42
Diet/Activity/Other Considerations..................................................................... 42
Diet...................................................................................................................... 42
Contraception...................................................................................................... 42
Use in Pregnancy ................................................................................................ 45
Use in Nursing Women....................................................................................... 45
Subject Withdrawal/Discontinuation Criteria................................................... 45
Discontinuation of Study Therapy after Complete Response............................. 46
Subject Replacement Strategy............................................................................. 47
Beginning and End of the Trial ........................................................................... 47
Clinical Criteria for Early Trial Termination ................................................... 47
TRIAL FLOW CHART ........................................................................................... 48
 
 
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Flow Chart for Initial Treatment Phase with Pembrolizumab ........................ 48
Flow Chart for Second Course Phase with Pembrolizumab (Retreatment) ... 51
TRIAL PROCEDURES ........................................................................................... 53
Trial Procedures ................................................................................................... 53
Administrative Procedures.................................................................................. 53
7.1.1.1
Informed Consent......................................................................................... 53
General Informed Consent.................................................................... 53
Consent and Collection of Specimens for Future Biomedical 
Research................................................................................................ 54
7.1.1.2
Inclusion/Exclusion Criteria ........................................................................ 54
7.1.1.3
Subject Identification Card .......................................................................... 54
7.1.1.4
Medical History ........................................................................................... 54
7.1.1.5
Disease Details............................................................................................. 54
7.1.1.6
Prior and Concomitant Medications Review............................................... 54
Prior Medications.................................................................................. 54
Prior Treatment Details for Colorectal Carcinoma ........................ 55
Concomitant Medications..................................................................... 55
7.1.1.7
Assignment of Screening Number............................................................... 55
7.1.1.8
Assignment of Treatment/Randomization Number..................................... 55
7.1.1.9
Trial Compliance (Medication/Diet/Activity/Other) ................................... 55
Clinical Procedures/Assessments........................................................................ 56
7.1.2.1
Adverse Event Monitoring........................................................................... 56
7.1.2.2
Physical Exam.............................................................................................. 56
Full Physical Exam ............................................................................... 56
Directed Physical Exam........................................................................ 56
7.1.2.3
Height, Weight, and Vital Signs .................................................................. 56
7.1.2.4
12-Lead Electrocardiogram ......................................................................... 57
7.1.2.5
Eastern Cooperative Oncology Group Performance Status......................... 57
7.1.2.6
Post-study Anti-Cancer Therapy Status....................................................... 57
Laboratory Procedures/Assessments .................................................................. 57
7.1.3.1
Local Laboratory Assessments .................................................................... 58
Serum/Urine β-hCG.............................................................................. 59
 
 
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7.1.3.2
Central Laboratory Assessments.................................................................. 59
Pharmacokinetic/Pharmacodynamic Evaluations................................. 59
Planned Genetic Analysis Sample Collection ...................................... 59
Plasma Sample for Circulating Tumor DNA Study ............................. 59
Blood Collections for Correlative Studies............................................ 60
Tumor Tissue Collection ...................................................................... 60
7.1.3.3
Future Biomedical Research Sample Collection ......................................... 60
Efficacy Measurements....................................................................................... 60
7.1.4.1
Tumor Imaging and RECIST Assessment................................................... 60
Initial Tumor Imaging........................................................................... 61
Tumor Imaging During Trial ................................................................ 61
End of Treatment and Follow-up Tumor Imaging................................ 62
Second Course Phase Tumor Imaging.................................................. 62
RECIST 1.1 Assessment of Disease..................................................... 63
Immune-related RECIST (irRECIST)............................................ 63
Other Procedures................................................................................................. 64
7.1.5.1
Withdrawal/Discontinuation........................................................................ 64
Withdrawal From Future Biomedical Research ................................... 65
7.1.5.2
Blinding/Unblinding .................................................................................... 65
7.1.5.3
Calibration of Equipment............................................................................. 65
Visit Requirements.............................................................................................. 65
7.1.6.1
Screening...................................................................................................... 66
7.1.6.2
Treatment Period.......................................................................................... 66
Second Course Phase (Retreatment)..................................................... 66
7.1.6.3
Post-Treatment Visits................................................................................... 68
Safety Follow-up Visits ........................................................................ 68
Follow-up Visits ................................................................................... 68
Survival Follow-up ............................................................................... 68
7.1.6.4
Survival Status ............................................................................................. 68
Assessing and Recording Adverse Events .......................................................... 69
Definition of an Overdose for This Protocol and Reporting of Overdose to 
the Sponsor.......................................................................................................... 69
 
 
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Reporting of Pregnancy and Lactation to the Sponsor ....................................... 70
Immediate Reporting of Adverse Events to the Sponsor.................................... 70
7.2.3.1
Serious Adverse Events ............................................................................... 70
7.2.3.2
Events of Clinical Interest............................................................................ 71
7.2.3.3
Protocol-Specific Exceptions to Serious Adverse Event Reporting............ 72
Evaluating Adverse Events................................................................................. 73
Sponsor Responsibility for Reporting Adverse Events ...................................... 76
STATISTICAL ANALYSIS PLAN ........................................................................ 76
Statistical Analysis Plan Summary ..................................................................... 76
Responsibility for Analyses/In-House Blinding ................................................. 78
Hypotheses/Estimation ......................................................................................... 78
Analysis Endpoints ............................................................................................... 78
Efficacy Endpoints.............................................................................................. 78
8.4.1.1
Primary Efficacy Endpoint .......................................................................... 78
8.4.1.2
Secondary Efficacy Endpoints..................................................................... 78
Safety Endpoints ................................................................................................. 79
Analysis Populations............................................................................................. 79
Efficacy Analysis Populations ............................................................................ 79
Safety Analysis Populations ............................................................................... 79
Statistical Methods................................................................................................ 80
Statistical Methods for Efficacy Analyses .......................................................... 80
Statistical Methods for Safety Analyses ............................................................. 81
Summaries of Baseline Characteristics, Demographics, and Other Analyses.... 81
Interim Analyses ................................................................................................... 82
Multiplicity ............................................................................................................ 82
Sample Size and Power Calculations .................................................................. 82
Subgroup Analyses and Effect of Baseline Factors ........................................... 84
Compliance (Medication Adherence).................................................................. 84
Extent of Exposure................................................................................................ 84
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 84
Investigational Product ........................................................................................ 84
 
 
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Packaging and Labeling Information ................................................................. 85
Clinical Supplies Disclosure................................................................................. 85
Storage and Handling Requirements.................................................................. 85
Discard/Destruction/Returns and Reconciliation .............................................. 85
Standard Policies................................................................................................... 86
ADMINISTRATIVE AND REGULATORY DETAILS....................................... 86
Confidentiality....................................................................................................... 86
Confidentiality of Data ....................................................................................... 86
Confidentiality of Subject Records..................................................................... 86
Confidentiality of Investigator Information........................................................ 86
Confidentiality of IRB/IEC Information............................................................. 87
Compliance with Financial Disclosure Requirements....................................... 87
Compliance with Law, Audit and Debarment ................................................... 88
Compliance with Trial Registration and Results Posting Requirements ........ 89
Quality Management System............................................................................... 90
Data Management................................................................................................. 90
Publications ........................................................................................................... 90
LIST OF REFERENCES......................................................................................... 92
APPENDICES........................................................................................................... 96
Merck Code of Conduct for Clinical Trials........................................................ 96
Collection and Management of Specimens for Future Biomedical 
Research................................................................................................................. 98
Understanding the
Intent, Scope and Public Health Benefits of 
Exploratory Biomarker Research: A Guide for IRBs/IECs and 
Investigational Site Staff .................................................................................... 102
Response Evaluation Criteria in Solid Tumors ............................................... 113
ECOG Performance Status................................................................................ 114
Common Terminology Criteria for Adverse Events v4.0 ............................... 115
List of Abbreviations .......................................................................................... 116
Country-specific Requirements......................................................................... 119
France-specific Requirements........................................................................... 119
SIGNATURES......................................................................................................... 120
Sponsor's Representative ................................................................................... 120
 
 
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Investigator.......................................................................................................... 120
 
 
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LIST OF TABLES
Table 1
Adequate Organ Function Lab Values.................................................................... 31
Table 2
Trial Treatment ....................................................................................................... 33
Table 3
Dose Modification and Toxicity Management Guidelines for Immune-related 
AEs Associated with Pembrolizumab.................................................................... 35
Table 4
Pembrolizumab Infusion Reaction Dose modification and Treatment 
Guidelines............................................................................................................... 38
Table 5
Laboratory Assessments ......................................................................................... 58
Table 6
Imaging and Treatment After First Radiologic Evidence of PD ............................ 63
Table 7
Evaluating Adverse Events..................................................................................... 74
Table 8
Key Elements of the Statistical Analysis Plan........................................................ 77
Table 9
Censoring Rules for DOR....................................................................................... 80
Table 10 Analysis Strategy for Efficacy Variables ............................................................... 81
Table 11 Two-sided 95% Confidence Interval of ORR with 60 Subjects ............................ 83
Table 12 Two-sided 95% Confidence Interval of ORR with 60 Subjects ............................ 83
Table 13 Clinical Supplies..................................................................................................... 85
 
 
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LIST OF FIGURES
Figure 1
Trial Diagram...................................................................................................... 19
 
 
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 08
13-NOV-2019
To allow participants access to an extension study.
Amendment 07
03-JAN-2018
Alignment of dose modification language with the most 
current label and safety information for pembrolizumab.
Amendment 06
13-OCT-2017
Following FDA approval of pembrolizumab in MMR 
deficient or MSI-H mCRC, addition of 3 cohorts to continue 
to study safety and efficacy of immunotherapies for the 
MSI-H mCRC population.  The study will now add 
pembrolizumab in combination with anti- Lymphocyte-
activation gene 3 (LAG-3), MK-4280.
Amendment 05/ France-specific 
amendment
06-MAR-2017
Alignment with France-specific template requirements
Amendment 04
04-JAN-2017
To allow additional follow-up analysis to be performed that
would provide improved data maturity and to change the 
timing of Cohort A interim analysis due to rapid enrolled.
 
 
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Document
Date of Issue
Overall Rationale
Amendment 03
24-MAR-2016
Addition of a second cohort (Cohort B) of 60 subjects to 
evaluate pembrolizumab 200 mg Q3W in subjects with 
colorectal cancer (CRC) who have undergone 1 line of 
systemic treatment (fluoropyrimidine + oxaliplatin or 
fluoropyrimidine 
+ 
irinotecan 
+/-
anti-VEGF/EGFR 
monoclonal antibody).  The first cohort will be designated 
Cohort A.
Amendment 02
19-OCT-2015
To further clarify prior treatments a subject should have 
received in order to be eligible for participation in the study.
Amendment 01
08-JUL-2015
To reflect routine clinical practice and allow enrollment 
flexibility when defining previous treatments.
Original Protocol
21-MAY-2015
Not Applicable
 
 
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SUMMARY OF CHANGES
PRIMARY REASON(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title(s)
Description of Change (s)
Rationale
1.0
2.2
5.10
Trial Summary: Duration 
of participation
Trial Diagram
Beginning and End of the 
Trial
Addition of text to allow enrollment in an
extension study to continue protocol-
defined assessments and treatment.
To allow participants access to 
an extension study.
ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
1.0
2.1
5.8
Trial Summary: Duration of 
participation
Trial Design
Subject 
Withdrawal/Discontinuation 
Criteria
Replace withdraw in the 
discontinuation criteria 
"investigator’s decision to 
withdraw the subject” with 
discontinue.
Alignment with program 
standards
 
 
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Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
Throughout
Multiple Sections
Changed timing of imaging 
schedule from Q9W to “The 
first on-study imaging will be 
performed at 9 weeks (63 days 
± 7 days) from date of 
allocation.  Subsequent 
imaging will be performed 
every 9 weeks (Q9W; 63 days 
± 7 days) for the first 
12 months, then every 
12 weeks (Q12W; 84 days, ± 
7 days) thereafter, or more 
frequently if clinically 
indicated.
Changed timing of post-
treatment follow-up and 
survival follow-up visits from 
every 9 weeks to every 
12 weeks.
Reduce subject burden and 
alignment with extension study
5.5.2
Prohibited Concomitant 
Medications
Bullet for Systemic 
glucocorticoids revised
Clarity and to alignment with 
program standards - AEs with 
immunological etiology are no 
longer routinely collected as 
ECIs
 
 
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Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
5.8 
Subject 
Withdrawal/Discontinuation 
Criteria
Deletion of: noncompliance 
with trial treatment or 
procedure requirements.
Alignment with program 
standards
7.1.6.3.1
Safety Follow-up
Deletion of text defining the 
time windows for collection of 
AEs/SAEs information.
The deleted text introduces a 
conflict in the reporting of 
AEs/SAEs for pembrolizumab 
requested by Merck Global 
Safety.
7.2.3.2
Events of Clinical Interest
Deletion of timings for 
collection of ECI.
Deletion of reference to irAE
Remove repetition and 
alignment with program 
standards - AEs with 
immunological etiology are no 
longer routinely collected as 
ECIs
Throughout
N/A
Minor editorial changes
Correction of 
typographical/formatting errors 
and consistency. 
 
 
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TRIAL SUMMARY
Abbreviated Title
A Phase II Study of Pembrolizumab in Previously Treated Subjects with 
Mismatched 
Repair
Deficient 
or 
Microsatellite
Instability-High
Colorectal Carcinoma
Trial Phase
Phase II
Clinical Indication
Locally Advanced Unresectable or Metastatic (Stage IV) Mismatched 
Repair
Deficient or Microsatellite
Instability -
High
Colorectal 
Carcinoma 
Trial Type
Interventional
Type of control
No treatment control
Route of administration
Intravenous (IV)
Trial Blinding
Unblinded Open-label
Treatment Groups
Pembrolizumab (MK-3475) 200 mg IV every 3 weeks (Q3W)
Number of trial subjects
Approximately 120 subjects will be enrolled.
Estimated duration of trial
The Sponsor estimates that the trial will require approximately 24
months from the time the first subject signs the informed consent until 
the last subject’s last study-related phone call or visit.
Duration of Participation
Each subject will participate in the trial from the time the subject signs 
the Informed Consent Form (ICF) through the final contact.  After a 
screening phase of up to 28 days, eligible subjects will receive 
pembrolizumab beginning on Day 1 of each 3-week dosing cycle.  
Treatment with pembrolizumab will continue until progressive disease 
(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 trial treatment or procedure requirements, 
subject 
receives 
35 
treatments
(approximately
2 
years)
of 
pembrolizumab, or administrative reasons requiring cessation of 
treatment. Subjects who stop pembrolizumab as a result of obtaining a 
confirmed complete response (CR) or those subjects who stop after 
receiving 35 trial treatments may be eligible, at the discretion of the 
investigator, for an additional 17 trial treatments (approximately 1 year) 
after experiencing PD if they meet the criteria for re-treatment; this will 
be designated as the Second Course Treatment Phase.
Subjects who 
discontinue for reasons other than PD will have post-treatment follow-up 
for disease status until PD, initiating a non-study cancer treatment, 
withdrawing consent, or becoming lost to follow-up. All subjects will be 
followed for overall survival (OS) until death, withdrawal of consent, or 
the end of the study.
After the end of treatment, each subject will be followed for 30 days for 
AE monitoring. Serious adverse events (SAE) and events of clinical 
interest (ECI) 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.  
Once the participant has achieved the study objective or the study has 
ended, the participant is discontinued from this study and may be 
enrolled in an extension study to continue protocol-defined assessments 
and treatment.
 
 
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A list of abbreviations used in this document can be found in Section 12.7.
TRIAL DESIGN
Trial Design
This is a single arm, multi-cohort, open-label, multi-site trial of pembrolizumab in previously 
treated subjects who have locally advanced unresectable or metastatic (Stage IV) 
Mismatched Repair (MMR) Deficient or Microsatellite- Instability (MSI) high 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 4.2.3.3 for further 
details).  Subjects will be required to have at least one measurable lesion by Response 
Evaluation Criteria in Solid Tumors (RECIST 1.1) for response assessment and had to have 
been previously treated with standard therapies, which must include fluoropyrimidine, 
oxaliplatin, and irinotecan (for Cohort A), and at least one line of systemic standard of care 
therapy: fluoropyrimidine + oxaliplatin or fluoropyrimidine + irinotecan +/- anti-vascular 
endothelial growth factor (VEGF)/ epidermal growth factor regulator (EGFR) monoclonal 
antibody (for Cohort B).
Subjects who have withdrawn from standard treatment due to 
unacceptable toxicity warranting discontinuation of that treatment and precluding retreatment 
with the same agent before progression of disease will also be eligible. Regimens given with 
adjuvant intent will be counted as treatment for metastatic disease if the patient’s disease had 
progressed within 6 months following treatment.  Tumor tissue samples, while optional in 
Cohort A, will be obtained from all subjects enrolled into Cohort B. Blood will be collected 
for biomarker studies; plasma for circulating tumor DNA will be collected for Cohort B only.  
The enrollment of subjects and the data analysis will be performed separately for each 
Cohort.
Approximately 60 subjects will be enrolled in Cohort A and approximately 60 subjects will 
be enrolled in Cohort B to receive single agent pembrolizumab 200 mg IV Q3W. 
The primary objective of this trial is to determine the objective response rate (ORR) of 
pembrolizumab given as monotherapy. Beginning with screening, all imaging assessments
will be submitted for central imaging vendor review and will be evaluated using RECIST 1.1 
for determining eligibility and assessment of response. The first on-study imaging will be 
performed at 9 weeks (63 days ± 7 days) from date of allocation.  Subsequent imaging will 
be performed every 9 weeks (Q9W; 63 days ± 7 days) for the first 12 months, then every 12 
weeks (Q12W; 84 days, ± 7 days) thereafter, or more frequently if clinically indicated.
RECIST 1.1 will be used by the site for treatment decisions until first radiologic evidence of 
PD. Following the first evidence of radiologic PD, treatment decisions may be made by the 
adaption of RECIST 1.1 as described in Section 7.1.4.1.5.1 termed immune-related RECIST 
(irRECIST) to accommodate for the tumor response patterns seen with pembrolizumab 
treatment (e.g., tumor flare). For a clinically stable subject with first radiologic evidence of 
PD it is at the discretion of the site investigator to continue treating the subject with 
pembrolizumab until PD is confirmed at least 4 weeks from the date of the first tumor 
imaging suggesting PD.  If radiologic PD is confirmed by the subsequent tumor imaging the 
 
 
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subject should be discontinued from treatment unless, in the opinion of the investigator, the 
subject is achieving a clinically meaningful benefit; an exception to continue treatment may 
be considered following consultation with the Sponsor.
Subjects will continue to be treated with pembrolizumab until PD, unacceptable 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 trial treatment or procedure requirements, administrative reasons, or the 
subject has received 35 trial treatments (approx. 2 years) with pembrolizumab. Subjects who 
discontinue treatment for reasons other than PD will have post-treatment follow-up visits for 
disease status until PD, initiating a non-study cancer treatment, withdrawing consent, or 
becoming lost to follow-up.  All subjects will be followed for OS until death, withdrawal of 
consent or the end of the study, whichever comes first.
Subjects who attain confirmed CR (assessed by the site) by 2 tumor imaging assessments at 
least 4 weeks apart and who have received at least 8 treatments (approximately 6 months) 
with pembrolizumab may discontinue treatment at the discretion of the investigator after 
receiving at least 2 treatments beyond the initial determination of a CR. Subjects who stop 
pembrolizumab after receiving 35 trial treatments for reasons other than PD or intolerability
or who stopped after attaining a CR may be eligible for retreatment with up to an additional 
17 treatments (approx. 1 year) after they have experienced radiographic PD. The decision to 
retreat will be at the discretion of the investigator only if no other cancer treatment was 
administered since the last dose of pembrolizumab, the subject still meets the parameters 
listed in the retreatment criteria (Section 7.1.6.2.1), and the trial remains open. 
Adverse events will be monitored throughout the trial 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).  After the end of treatment, each 
subject will be followed for 30 days for AE monitoring. SAEs and ECIs 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.  
There is one interim analysis planned in this study for Cohort A and no interim analyses 
planned for Cohort B. See Section 8.7 for details about the timing and purpose of the interim 
analysis. Enrollment will not be paused when interim analysis is conducted. Results will be 
reviewed by study team.
This study will be conducted in conformance with Good Clinical Practices.
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.
Trial Diagram
The trial design is depicted in Figure 1 below.
 
 
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Figure 1
Trial Diagram
OBJECTIVE(S) & HYPOTHESIS(ES)
Primary Objective(s) & Hypothesis(es)
(1)
Objective (Cohort A): To evaluate the ORR per RECIST 1.1 assessed by central 
imaging vendor of the 200 mg Q3W dose of pembrolizumab in subjects with locally 
advanced unresectable or metastatic MMR deficient or MSI high CRC and who have been 
previously treated with standard of care therapies, which must include fluoropyrimidine, 
oxaliplatin, and irinotecan.
Hypotheses:  The ORR based on RECIST 1.1 assessed by central imaging vendor in 
subjects with locally advanced unresectable or metastatic MMR deficient or MSI high
CRC is greater than 15%.
(2)
Objective (Cohort B): To estimate the ORR per RECIST 1.1 assessed by central 
imaging vendor of the 200 mg Q3W dose of pembrolizumab in subjects with locally 
advanced unresectable or metastatic MMR deficient or MSI high CRC and who have been 
previously treated with at least one line of
systemic standard of care therapy
 
 
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(fluoropyrimidine + oxaliplatin or fluoropyrimidine + irinotecan +/- anti-VEGF/EGFR 
monoclonal antibody).
Secondary Objective(s) & Hypothesis(es)
In both Cohort A and Cohort B separately: 
(1) Objective:  To determine safety and tolerability of pembrolizumab.
(2) Objective:  To evaluate Duration of Response (DOR), Disease Control Rate (DCR) and 
Progression-free Survival (PFS) per RECIST 1.1 assessed by central imaging vendor and 
Overall Survival (OS).
Other Tertiary and Exploratory Objectives 
For Cohorts A and B separately:
(1) Objective:  To evaluate ORR, DOR, DCR and PFS per RECIST 1.1 assessed by 
investigator.
(2) Objective:  To evaluate ORR, DOR, DCR and PFS per irRECIST 1.1 assessed by central 
imaging vendor.
(3) Objective: To identify molecular (genomic, metabolic, and/or proteomic) biomarkers 
that may be indicative of clinical response/resistance, safety, pharmacodynamic activity, 
and/or the mechanism of action of pembrolizumab.  
BACKGROUND & RATIONALE
Background
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background 
information on MK-3475.
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4)  mAb with high 
specificity of binding to the programmed cell death 1 (PD-1) receptor, thus inhibiting its 
interaction with programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 
2 (PD-L2).  Based on preclinical in vitro data, pembrolizumab has high affinity and potent 
receptor blocking activity for PD-1.  Pembrolizumab has an acceptable preclinical safety 
profile and is in clinical development as an intravenous (IV) immunotherapy for advanced 
malignancies.  Keytruda™ (pembrolizumab) is indicated for the treatment of patients across 
a number of indications.  For more details on specific indications refer to the pembrolizumab 
IB.
 
 
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Pharmaceutical and Therapeutic Background
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades [1].  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies [2] [3] [4] [5] [6].  In particular, the presence of CD8+ T-cells and the 
ratio of CD8+ effector T-cells / FoxP3+ regulatory T-cells seems to correlate with improved 
prognosis and long-term survival in many solid malignancies, such as ovarian, colorectal, 
and pancreatic cancer; hepatocellular carcinoma; malignant melanoma; and renal cell 
carcinoma.  Tumor-infiltrating lymphocytes can be expanded ex vivo and reinfused, inducing 
durable objective tumor responses in cancers such as melanoma [7] [8].
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control.  The normal function of PD-1, expressed on the cell surface of activated T-
cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions.  PD-1 (encoded by the gene Pdcd1) is an Ig 
superfamily member related to cluster of differentiation 28 (CD28) and cytotoxic T-
lymphocyte-associated protein 4 (CTLA-4) that has been shown to negatively regulate 
antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PD L2) [9] [10].
The structure of murine PD-1 has been resolved [11].  PD-1 and family members are type I 
transmembrane glycoproteins containing an Ig variable-type (IgV-type) domain responsible 
for ligand binding and a cytoplasmic tail which is responsible for the binding of signaling 
molecules.  The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an 
immunoreceptor tyrosine-based inhibition motif and an immunoreceptor tyrosine-based 
switch motif.  Following T-cell stimulation, PD 1 recruits the tyrosine phosphatases SHP-1 
and SHP-2 to the immunoreceptor tyrosine-based switch motif within its cytoplasmic tail, 
leading to the dephosphorylation of effector molecules such as CD3 zeta (CD3ζ), protein 
kinase C-theta (PKCθ) and zeta-chain associated protein kinase (ZAP70), which are involved 
in the CD3 T-cell signaling cascade [9] [12] [13] [14]. The mechanism by which PD-1 down 
modulates T-cell responses is similar to, but distinct from that of CTLA-4, because both 
molecules regulate an overlapping set of signaling proteins [15] [16].
Because of higher mutational load (and thus potentially more neo-antigens) than MSS 
tumors, MSI high colorectal tumors have vigorous immune microenvironment. Although 
there have been inconsistent observations about the expression of PD-L1 in MSI high 
colorectal cancer [17] [18]. MSI high colorectal cancer has been considered as a good 
candidate for immune checkpoint inhibitors including anti PD-1/ PD-L1 antibodies [18] [19].
Pre-clinical and Clinical Trials
4.1.2.1
Preclinical Studies
Therapeutic studies in mouse models have shown that administration of antibodies blocking 
PD-1/PD-L1 interaction enhances infiltration of tumor-specific CD8+ T-cells and leads 
ultimately to tumor rejection, either as a mono-therapy or in combination with other 
 
 
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treatment modalities.  Anti-mouse PD-1 or anti-mouse PD-L1 antibodies have demonstrated 
anti-tumor responses as a mono-therapy in models of squamous cell carcinoma, pancreatic 
carcinoma, MEL and colorectal carcinoma.  Blockade of the PD-1 pathway effectively 
promoted CD8+ T-cell infiltration into the tumor and the presence of IFN-γ, granzyme B and 
perforin, indicating that the mechanism of action involved local infiltration and activation of 
effector T-cell function in vivo [7] [8] [20] [21] [22] [23]. Experiments have confirmed the in 
vivo efficacy of PD-1 blockade as a mono-therapy as well as in combination with 
chemotherapy in syngeneic mouse tumor models (see the Investigator’s Brochure [IB]).
4.1.2.2
Ongoing Clinical Trials
Clinical trials have demonstrated pembrolizumab monotherapy efficacy in subjects with
many different indications including advanced melanoma, non-small cell lung cancer
(NSCLC), head and neck cancer, bladder cancer, Hodgkin’s lymphoma, triple-negative 
breast cancer, gastric adenocarcinoma, and MSI-H cancers.
Ongoing clinical trials of pembrolizumab 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.
Rationale
Rationale for the Trial and Selected Subject Population
Colorectal cancer is a heterogeneous disease arising through different pathways including the 
chromosomal instability (CIN) pathway, the MSI pathway, and CpG island methylator 
phenotype (CIMP) [24]. MSI CRC comprises approximately 15% of sporadic CRC and 5% 
of Stage IV CRC, whereas microsatellite stable (MSS) CRC comprises the remainder [19]
[25]. MSI status plays a role as a predictive factor of chemosensitivity [26] and MSI status 
test is recommended in both National Comprehensive Cancer Network (NCCN) and 
European Society for Medical Oncology (ESMO) guidelines [27] [28]. The lack of efficacy 
with standard 5-fluorouracil (5-FU) based adjuvant chemotherapies in MSI high CRC have 
been reported [26] [29].
In stage III MSI high CRC, irinotecan-containing regimen 
demonstrated improved outcomes compared to 5-FU/leucovorin alone [30]. However, the 
prognosis of MSI high Stage IV patients was worse than MSS patients with the irinotecan-
containing regimens [31].
In early stage CRC, favorable prognosis with MSI high patients has been reported [26] [29].
The survival benefit of MSI high CRC has been explained with prognostic effect of tumor-
infiltrating T-cell subsets (CD3+, CD8+, CD45RO+ and FOXP3+) [32].  The strong 
association between MSI status and CD45RO+-cell density supports stimulated host immune 
response in MSI high CRC, which may offer one explanation for favorable prognosis and 
attenuated response to cytotoxic chemotherapy [32].
A recent study reported that once there is a recurrence the prognostic advantage is lost as the 
median OS after recurrence in stage II disease is 1.6 versus 2.2 years (MSI high vs MSS, 
 
 
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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 high vs. MSS, respectively; HR 1.00, 95% 
CI, 0.85-1.17; p > 0.99) [33]. The same group reported that there is actually a disadvantage 
in having deficient mismatch repair (dMMR) status.  Five percent of the primary tumors of 
3063 patients, pooled from four phase III first-line studies in metastatic CRC (mCRC), were 
found to be dMMR.  The median PFS and OS were significantly worse for patients with MSI 
high 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) [24].
The prognosis of patients with metastatic CRC who have progressed on all standard therapies 
is very poor.  Despite a minimal improvement in PFS and OS, regorafenib was recently 
approved for the treatment in this patient population [34]. Progression-free survival and OS 
for patients treated with regorafenib versus placebo was 1.9 vs. 1.7 months (HR 0.49, 95% CI 
0.4-0.58; p < 0.0001) and OS was 6.4 versus 5.0 months (HR 0.77, 95% CI 0.64-0.94; one-
sided p = 0.0052), respectively.  Novel and effective therapies that are capable of producing 
durable responses are desperately needed in this patient population [34].
There have been several reports about increased tumor-specific neo-antigens in MSI high 
CRC [18] [35], suggesting potential benefit from immunotherapy. However, there have been 
inconsistent observations about the expression of PD-L1 in MSI high CRC [17] [18].
Pembrolizumab monotherapy in MSI high and MSS CRC patients was evaluated in KN016 
study. The data for KN016, in an article by Le et al., was presented at the American Society 
of Clinical Oncology (ASCO) 2015 conference held on 30-May-2015 [36]. The trial accrued 
11 MSI high and 21 MSS CRC patients. All CRC patients received >2 prior chemotherapy 
regimens (median=4) except for one MMR-proficient patient who had received one 
chemotherapeutic and one (non-PD1-based) immunotherapeutic regimens. 
The patients 
received pembrolizumab 10mg/kg every 2 weeks. Radiologic assessments were made using 
RECIST 1.1 and immune-related response criteria (irRC) at 12 weeks and then every 8 
weeks. There were no treatment-related serious adverse events. Treatment-related adverse 
events are listed in the article for KN016. A total of 4/10 (40%) MSI high CRC patients 
achieved a confirmed RECIST 1.1 partial response (PR), whereas there were no MSS CRC 
patients achieved PR with pembrolizumab monotherapy. In the patients with MSI high 
colorectal cancer, median PFS and median OS were not reached. In contrast, the patients 
with MSS cancers achieved a PFS of only 2.2 months (95% CI, 1.4 to 2.8) and median OS of 
5.0 months (95% CI, 3.0 to not estimable). 
At the annual Society of Immunotherapy of Cancer meeting, Le et al. updated results for this 
cohort; as of September 2015, the ORR for patients with MMR-deficient colorectal cancer 
(N=20) was 55% with a DCR of 90%. Responses were durable with the median PFS and OS 
not reached as of October 2015, with a median follow up time of 37 weeks (range, 11 to
93 weeks).  The results of KN016 suggest that MSI status predicts clinical benefit of immune 
checkpoint blockade with pembrolizumab, and patients with MSI-H CRC may experience 
durable benefit from the treatment.  The recent update from KN-016, especially demonstrates 
the durability of responses, and strongly indicates that pembrolizumab might offer clinical 
benefits to patients in an earlier treatment line setting (i.e. patients who were previously 
 
 
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treated with one line of standard of care therapy).
As such, Cohort B of this study is 
designed to evaluate the anticancer activity of pembrolizumab in a population of subjects 
who have undergone less prior treatment than those in Cohort A.
Rationale for Dose Selection/Regimen
4.2.2.1
Rationale for Fixed Dose Pembrolizumab
The planned dose of pembrolizumab for this trial 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 eight randomized studies demonstrating flat dose- and exposure-
efficacy relationships from 2 mg/kg Q3W to 10 mg/kg every two weeks (Q2W), 
•
Clinical data showing meaningful improvement in benefit-risk including overall 
survival at 200 mg Q3W across multiple indications, and
•
Pharmacology data showing full target saturation in both systemic circulation 
(inferred from pharmacokinetic [PK] data) and tumor (inferred from physiologically 
based pharmacokinetic [PBPK] analysis) at 200 mg Q3W
Among the eight 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 Q2W (KN001 B2, KN001 D, KN002, KN010 and KN021), and 
three 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. These findings are consistent with the mechanism of action of pembrolizumab, 
which acts by interaction with immune cells, and not via direct binding to cancer cells.
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W. First, PK 
data in KN001 evaluating target-mediated drug disposition (TMDD) conclusively 
demonstrated saturation of PD-1 in systemic circulation at doses much lower than 200 mg 
Q3W. 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-dosing 
 
 
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provides similar control of PK variability as weight-based dosing, with considerable overlap 
in the distribution of exposures from the 200 mg Q3W fixed dose and 2 mg/kg Q3W dose. 
Supported by these PK characteristics and given that fixed-dose has advantages of reduced 
dosing complexity and reduced potential of dosing errors, the 200 mg Q3W fixed-dose was 
selected for evaluation across all pembrolizumab protocols.
Rationale for Endpoints
4.2.3.1
Efficacy Endpoints
Primary Endpoint
The primary efficacy objective of this study is to evaluate the anti-tumor activity of 
pembrolizumab in subjects with locally advanced unresectable or metastatic (Stage IV) 
MMR deficient or MSI-high CRC.
Objective response rate (ORR) will be used as the 
primary endpoint per RECIST 1.1 assessed by the central imaging vendor.
Secondary Endpoints
The secondary efficacy objectives of this study are to evaluate DOR, DCR, and PFS per 
RECIST 1.1 as assessed by the central imaging vendor, and OS in subjects with locally 
advanced unresectable or metastatic (Stage IV) MMR deficient or MSI-high CRC. 
Tertiary and Exploratory Endpoints
The exploratory efficacy objectives of this study are to evaluate ORR, DOR, and PFS per 
RECIST 1.1 as assessed by the investigator; and to evaluate the ORR, DOR, DCR, and PFS 
per irRECIST as assessed by the central imaging vendor in subjects with locally advanced 
unresectable or metastatic (Stage IV) MMR deficient or MSI-high CRC.
Immune-related RECIST 
RECIST 1.1 will be adapted to account for the unique tumor response characteristics seen 
with treatment of pembrolizumab. Immunotherapeutic agents such as pembrolizumab may 
produce antitumor effects by potentiating endogenous cancer-specific immune responses.  
The response patterns seen with such an approach may extend beyond the typical time course 
of responses seen with cytotoxic agents, and can manifest a clinical response after an initial 
increase in tumor burden or even the appearance of new lesions. RECIST may not provide 
an accurate response assessment of immunotherapeutic agents such as pembrolizumab. 
Immune-related RECIST (irRECIST) is RECIST 1.1 adapted as described below to account 
for the unique tumor response seen with immunotherapeutics. Following site identification 
of PD, irRECIST will be used by site investigators to assess tumor response and progression, 
and make treatment decisions. 
If radiologic imaging by the site identifies PD by RECIST 1.1, subject management and 
tumor assessment will shift to irRECIST.  Imaging should be repeated ≥4 weeks later in 
 
 
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order to confirm PD with the option of continuing treatment per below while awaiting 
radiologic confirmation of progression.  
If repeat imaging shows <20% increase in tumor burden compared to nadir, stable or 
improved previous new lesion (if identified as cause for initial PD), and stable/improved non-
target disease (if identified as cause for initial PD), PD is not confirmed.  Treatment may 
continue and subsequently follow regular imaging schedule.  
If repeat imaging confirms PD (irPD) due to any of the scenarios listed below, subjects will 
be discontinued from study therapy (exception noted in Section 7.1.4.1.5.1).  
In determining whether or not the tumor burden has increased or decreased, site study team 
should consider all target lesions as well as non-target lesions.
Scenarios where PD is confirmed at repeat imaging:

Tumor burden remains ≥20% and at least 5 mm absolute increase compared to nadir

Non-target disease resulting in initial PD is worse (qualitative)

New lesion resulting in initial PD is worse (qualitative)

Additional new lesion(s) since last evaluation

Additional new non-target progression since last evaluation
In subjects who have initial evidence of radiological PD by the site, it is at the discretion of 
the site investigator whether to continue a subject on study treatment until repeat imaging is 
obtained (irRECIST subject management).  This clinical judgment decision should be based 
on the subject’s overall clinical condition, including performance status, clinical symptoms, 
and laboratory data.  Subjects may receive study treatment while waiting for confirmation of 
PD if they are clinically stable as defined by the following criteria:

Absence of symptoms and signs indicating clinically significant progression of disease, 
including worsening of laboratory values

No decline in ECOG performance status

Absence of rapid progression of disease

Absence of progressive tumor at critical anatomical sites (e.g., cord compression) 
requiring urgent alternative medical intervention
When feasible, subjects should not be discontinued until progression is confirmed.  This 
allowance to continue treatment despite initial radiologic progression takes into account the 
observation that some subjects can have a transient tumor flare in the first few months after 
the start of immunotherapy, but with subsequent disease response.  Subjects that are deemed 
clinically unstable are not required to have repeat imaging for confirmation of PD. 
 
 
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4.2.3.2
Safety Endpoints
The safety objective of this trial is to characterize the safety and tolerability of 
pembrolizumab in subjects with MMR deficient or MSI-high CRC.  The primary safety 
analysis will be based on subjects who experienced toxicities as defined by CTCAE, v4.0 
(Section 12.6). The attribution to drug, time-of-onset, duration of the event, its resolution, 
and any concomitant medications administered will be recorded.  AEs will be analyzed 
including but not limited to all AEs, SAEs, fatal AEs, and laboratory changes.  Furthermore, 
specific immune-related adverse events (irAEs) will be collected and designated as immune-
related events of clinical interest (ECIs) as described in Section 7.2.3.2.
4.2.3.3
Biomarkers
MSI Status Testing
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 ASCO guidelines [27] [28] [37]. MMR- or MSI status 
is, respectively, determined by examining either CRC tumor 1) protein expression by 
immunohistochemistry of 4 MMR enzymes (MLH1/MSH2/MSH6/PMS2) or 2) 3-5 tumor 
microsatellite loci using PCR-based assay.
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 mismatch repair 
proteins expression is detected by IHC.
Planned Exploratory Biomarker Research
Cancer immunotherapies represent an important and novel class of antitumor agents.  
However, the mechanism of action of these exciting new therapies is not completely 
understood and much remains to be learned regarding how best to leverage these new drugs 
in treating patients.  Thus, to aid future patients, it is important to investigate the 
determinants of response or resistance to cancer immunotherapy, as well as determinants of 
AEs in the course of our clinical trials.  These efforts will identify novel predictive/PD 
biomarkers and generate information that will better guide single-agent and combination
therapy with immuno-oncology drugs.  To identify novel biomarkers, biospecimens (ie, 
blood components, tumor material) will be collected to support analyses of cellular 
components (eg, protein, DNA, ribonucleic acid [RNA], metabolites) and other circulating 
molecules.  Investigations may include but are not limited to:
Germline (blood) genetic analyses (eg, single-nucleotide polymorphism [SNP] analyses, 
whole exome sequencing, whole genome sequencing)
This research will evaluate whether genetic variation within a clinical trial population 
correlates with response to the treatment(s) under evaluation.  If genetic variation is found to 
predict efficacy or AEs, the data might inform optimal use of therapies in the patient 
 
 
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population.  Furthermore, it is important to evaluate germline DNA variation across the 
genome in order to interpret tumor-specific DNA mutations.    
Genetic (DNA) analyses from tumor
The application of new technologies, such as next generation sequencing, has provided 
scientists the opportunity to identify tumor-specific DNA changes (ie, mutations, methylation 
status, microsatellite instability). Key molecular changes of interest to immune-oncology 
drug development include the mutational burden of tumors and the clonality of T-cells in the 
tumor microenvironment. Increased mutational burden (sometimes referred to as a ‘hyper-
mutated’ state) may generate neo-antigen presentation in the tumor microenvironment. To 
conduct this type of research, it is important to identify tumor-specific mutations that occur 
across all genes in the tumor genome. Thus, genome-wide approaches may be used for this 
effort. Note that in order to understand tumor-specific mutations; it is necessary to compare 
the tumor genome with the germline genome. 
Tumor and blood RNA analyses
Both genome-wide and targeted messenger RNA (mRNA) expression profiling and 
sequencing in tumor tissue and in blood may be performed to define gene signatures that 
correlate to clinical response to treatment with pembrolizumab or other immunotherapies. 
Pembrolizumab induces a response in tumors that likely reflects an inflamed/immune 
phenotype. 
Specific immune-related gene sets (ie, those capturing interferon-gamma 
transcriptional pathways) may be evaluated and new signatures may be identified. Individual 
genes related to the immune system may also be evaluated (eg, IL-10). MicroRNA profiling 
may also be pursued.
Proteomics and IHC using blood or tumor
Tumor and blood samples from this trial may undergo proteomic analyses (eg, PD-L1 IHC). 
PD-L1 protein level in tumor sections, assessed by IHC, has been shown to correlate with 
response to pembrolizumab in patients with NSCLC, and an in vitro diagnostic (IVD) device 
has been developed for use with pembrolizumab in NSCLC. Preliminary data indicates that 
this association may also be true in additional cancer types (ie, triple negative breast cancer, 
head and neck, and gastric). Additional tumor or blood-derived proteins may also correlate 
with response to immunotherapeutics. 
Therefore, tumor tissue may be subjected to 
proteomic analyses using a variety of platforms that could include but are not limited to 
immunoassays and liquid chromatography/mass spectrometry. This approach could identify 
novel protein biomarkers that could aid in patient selection for pembrolizumab therapies.
Other blood-derived biomarkers
In addition to expression on the tumor tissue, PD-L1 and other tumor derived proteins can be 
shed from tumor and released into the blood.  Assays such as enzyme-linked immunosorbent 
assay (ELISA) measure such proteins in serum.  Correlation of expression with response to 
pembrolizumab therapy may identify new approaches for predictive biomarkers in blood, 
 
 
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representing a major advance from today’s reliance on assessing tumor biomarkers.  This 
research would serve to develop such assays for future clinical use.
4.2.3.4
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 sub-trial are presented in Section 12.2 - Collection and 
Management of Specimens for Future Biomedical Research.  Additional informational 
material for institutional review boards/ethics committees (IRBs/ERCs) and investigational
site staff is provided in Section 12.3.
Benefit/Risk
Subjects in clinical trials generally cannot expect to receive direct benefit from treatment
during participation, as clinical trials are designed to provide information about the safety 
and effectiveness of an investigational medicine.
Additional details regarding specific benefits and risks for subjects participating in this 
clinical trial may be found in the accompanying Investigators Brochure (IB) and Informed 
Consent documents.
METHODOLOGY
Entry Criteria
Subject Inclusion Criteria
In order to be eligible for participation in this trial, the subject must:
1. Be willing and able to provide written informed consent for the trial. The subject may 
also provide consent for Future Biomedical Research. 
However, the subject may 
participate in the main trial without participating in Future Biomedical Research.
2. Be male or female subjects who are ≥18 years of age on the day of signing the informed 
consent.
 
 
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3. Locally confirmed MMR deficient or MSI-h CRC (refer to Section 4.2.3.3.1 for details).
4. Have a histologically proven locally advanced unresectable or metastatic (Stage IV)
CRC.  
5. Have been previously treated with standard therapies, which must include, for Cohort A, 
fluoropyrimidine, oxaliplatin, and irinotecan, and for Cohort B, at least one line of 
systemic standard of care therapy: fluoropyrimidine + oxaliplatin or fluoropyrimidine + 
irinotecan +/- anti-VEGF/EGFR monoclonal antibody.

Subjects who have withdrawn from standard treatment due to unacceptable 
toxicity warranting discontinuation of that treatment and precluding 
retreatment with the same agent before progression of disease will also be 
eligible. 

Regimens given with adjuvant intent will be counted as treatment for 
metastatic disease if the patient’s disease had progressed within 6 month 
following treatment.
6. Have an ECOG performance status of 0 or 1.
7. Have a life expectancy of greater than 3 months.
8. Provide an archival or newly obtained tumor tissue sample (Cohort B) (refer to 
Section 7.1.3.2.5).  
9. Have at least one measurable lesion by RECIST 1.1 as determined by central review for 
response assessment.
Note:  The same imaging modality, acquisition and technical parameters should be used 
throughout the study unless clinically contraindicated (please refer to the Site Imaging 
Manual)
10. Female subjects of childbearing potential should have a negative urine or serum 
pregnancy test within 72 hours prior to receiving the first dose of study medication.  If 
the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will 
be required. 
11. Female subjects of childbearing potential (Section 5.7.2) must be willing to use an 
adequate method of contraception as outlined in Section 5.7.2 – Contraception, for the 
course of the study through 120 days after the last dose of study medication.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception 
for the subject.
12. Male subjects of childbearing potential (Section 5.7.2) must agree to use an adequate 
method of contraception as outlined in Section 5.7.2 – Contraception, starting with the 
first dose of study therapy through 120 days after the last dose of study therapy.
 
 
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Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception 
for the subject.
13. Demonstrated adequate organ function as defined in Table 1. All screening labs should be 
performed within 10 days of treatment initiation.
Table 1
Adequate Organ Function Lab Values
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
≥1,500/mcL
Platelets
≥100,000/mcL
Hemoglobin
≥9 g/dL or ≥5.6 mmol/L without transfusion or EPO 
dependency within 7 days.
Renal
Creatinine OR
Measured or calculateda creatinine clearance
(GFR can also be used in place of creatinine or 
CrCl)
≤1.5 X upper limit of normal (ULN) OR
≥60 mL/min for subject with creatinine levels >1.5 X 
institutional ULN
Hepatic
Total bilirubin
≤ 1.5 X ULN OR
Direct bilirubin ≤ ULN for subjects with total bilirubin levels 
>1.5 ULN
AST (SGOT) and ALT (SGPT)
≤ 2.5 X ULN OR
≤ 5 X ULN for subjects with liver metastases
Albumin
>2.5 g/dL
Coagulation
International Normalized Ratio (INR) or 
Prothrombin Time (PT)
≤1.5 X ULN unless subject is receiving anticoagulant therapy
as long as PT or PTT is within therapeutic range of intended use 
of anticoagulants
Activated Partial Thromboplastin Time (aPTT)
≤1.5 X 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.
Subjects who did not meet entry criteria for enrollment in Cohort A may be rescreened for 
Cohort B only after consultation with the SPONSOR.
Subject Exclusion Criteria
The subject must be excluded from participating in the trial if the subject:
1. Is currently participating in another study and receiving trial treatment, has participated in 
a study of an investigational agent and received trial treatment within 4 weeks of the first 
dose of treatment in this study, or used an investigational device within 4 weeks of the 
first dose of treatment in this study.
 
 
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Note: Subjects who have entered the follow-up phase of an investigational study may 
participate as long as it has been 4 weeks since the last dose of the previous 
investigational agent or device.
2. Has an active autoimmune disease that has required systemic treatment in past 2 years 
(i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). 
Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic 
treatment. 
3. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any 
other form of immunosuppressive therapy within 7 days prior to the first dose of trial 
treatment.  
4. 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 
[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] for at 
least four weeks prior to the first dose of trial treatment; 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 7 days prior to trial treatment. 
This exception does not include carcinomatous meningitis, as subjects with 
carcinomatous meningitis are excluded regardless of clinical stability. 
5. Has had prior monoclonal antibody (mAb), chemotherapy, targeted small molecule 
therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not 
recovered (i.e., ≤Grade 1 or at baseline) from adverse events due to a previously
administered agent.
Note:  Subjects with ≤Grade 2 neuropathy or ≤Grade 2 alopecia are an exception to this 
criterion and may qualify for the study
Note:  If subject received major surgery, they must have recovered adequately from the 
toxicity and/or complications from the intervention prior to starting therapy.
6. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. 
7. Has a known additional malignancy that is progressing or requires active treatment.  
Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the 
skin that has undergone potentially curative therapy or in situ cervical cancer.
8. Has received a live vaccine within 30 days of planned start of study therapy.
Note:  The killed virus vaccines used for seasonal influenza vaccines for injection are 
allowed; however intranasal influenza vaccines (e.g., FluMist®) are live attenuated 
vaccines, and are not allowed.
 
 
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9. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the subject’s participation for 
the full duration of the trial, or is not in the best interest of the subject to participate, in 
the opinion of the treating investigator.
10. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
11. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected).
12. Has known history of, or any evidence of interstitial lung disease or active, non-
infectious pneumonitis. 
13. Has an active infection requiring systemic therapy.
14. Has known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the trial.
15. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the screening visit through 120 days after the 
last dose of trial treatment.  
Trial Treatment(s)
The treatment to be used in this trial is outlined below in Table 2.
Table 2
Trial Treatment
Study 
Treatment
Dose/
Potency
Dose 
Frequency
Route of 
Administration
Regimen
Use
Pembrolizumab 
(MK-3475)
200 mg
Q3W
IV Infusion
Day 1 of each 
21-day cycle
experimental
All products indicated in Table 2 will be provided centrally by the Sponsor or locally by the 
trial site, subsidiary or designee, depending on local country operational or regulatory 
requirements.
Trial treatment for Cycle 1 should begin within 3 days of allocation.  However, every effort 
should be made to begin trial treatment on the day of allocation.
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.
 
 
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Dose Selection/Modification
5.2.1.1
Dose Selection (Preparation)
The rationale for selection of the dose to be used in this trial is provided in Section 4.0
Background & Rationale.  Details on preparation and administration of pembrolizumab are 
provided in the Pharmacy Manual
5.2.1.2
Dose Modification and Toxicity Management Guidelines for Pembrolizumab
Dose modification and toxicity management for immune-related AEs associated with 
pembrolizumab
AEs associated with pembrolizumab exposure may represent an immunologic etiology. 
These immune-related AEs (irAEs) may occur shortly after the first dose or several months 
after the last dose of pembrolizumab treatment and may affect more than one body system 
simultaneously. Therefore, early recognition and initiation of treatment is critical to reduce 
complications.  Based on existing clinical trial data, most irAEs were reversible and could be 
managed with interruptions of pembrolizumab, administration of corticosteroids and/or other 
supportive care. For suspected irAEs, ensure adequate evaluation to confirm etiology or 
exclude other causes. Additional procedures or tests such as bronchoscopy, endoscopy, skin 
biopsy may be included as part of the evaluation. Based on the severity of irAEs, withhold or 
permanently discontinue pembrolizumab and administer corticosteroids. Dose modification 
and toxicity management guidelines for irAEs associated with pembrolizumab are provided 
in Table 3. 
 
 
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Table 3
Dose Modification and Toxicity Management Guidelines for Immune-related AEs Associated with Pembrolizumab
General instructions:
1.
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks.
2.
For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and 
corticosteroid has been tapered. Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last dose or 
corticosteroids cannot be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks. 
3.
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive treatment 
should be initiated if irAEs cannot be controlled by corticosteroids.
Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with 
corticosteroid and/or other 
therapies 
Monitor and follow-up 
Pneumonitis 
Grade 2
Withhold 
Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper

Monitor subjects for signs and symptoms of 
pneumonitis

Evaluate subjects with suspected 
pneumonitis with radiographic imaging and 
initiate corticosteroid treatment

Add prophylactic antibiotics for 
opportunistic infections
Grade 3 or 4, or 
recurrent Grade 2
Permanently 
discontinue
Diarrhea / Colitis 
Grade 2 or 3
Withhold

Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper

Monitor subjects 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).

Subjects with ≥ Grade 2 diarrhea suspecting 
colitis should consider GI consultation and 
performing endoscopy to rule out colitis. 

Subjects with diarrhea/colitis should be 
advised to drink liberal quantities of clear 
fluids.  If sufficient oral fluid intake is not 
feasible, fluid and electrolytes should be 
substituted via IV infusion.
Grade 4
Permanently 
discontinue
 
 
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Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with 
corticosteroid and/or other 
therapies 
Monitor and follow-up 
AST / ALT 
elevation or 
Increased 
bilirubin
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
Type 1 diabetes 
mellitus (T1DM) 
or 
Hyperglycemia
Newly onset 
T1DM or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -cell 
failure
Withhold

Initiate insulin replacement 
therapy for subjects with T1DM 

Administer anti-hyperglycemic in 
subjects with hyperglycemia 

Monitor subjects 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 
discontinue1
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 
discontinue1
Hypothyroidism
Grade 2-4
Continue 

Initiate thyroid replacement 
hormones (eg, levothyroxine or 
liothyroine) 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
 
 
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Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with 
corticosteroid and/or other 
therapies 
Monitor and follow-up 
Myocarditis
Grade 1 or 2
Withhold

Based on severity of AE 
administer corticosteroids

Ensure adequate evaluation to confirm 
etiology and/or exclude other causes
Grade 3 or 4
Permanently 
discontinue
All other 
immune-related 
AEs
Intolerable/ 
persistent Grade 2
Withhold

Based on type and severity of AE 
administer corticosteroids 

Ensure adequate evaluation to confirm 
etiology and/or exclude other causes
Grade 3
Withhold or 
discontinue based 
on the type of 
event.  Events that 
require 
discontinuation 
include and not 
limited to:  
Guillain-Barre 
Syndrome, 
encephalitis
Grade 4 or 
recurrent Grade 3 
Permanently 
discontinue
1.
Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.  
NOTE: 
For subjects with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may be resumed when 
AE resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM).  
 
 
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Dose modification and toxicity management of infusion-reactions related to 
pembrolizumab
Pembrolizumab may cause severe or life-threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion. 
Dose modification and toxicity management guidelines on pembrolizumab associated 
infusion reaction are provided in Table 4. 
Table 4
Pembrolizumab Infusion Reaction Dose modification and Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at 
Subsequent Dosing
Grade 1
Mild reaction; infusion 
interruption not 
indicated; intervention 
not indicated
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator.
None
Grade 2
Requires therapy or 
infusion interruption but 
responds promptly to 
symptomatic treatment 
(e.g., antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated 
for ≤24 hr
Stop Infusion.
Additional appropriate medical therapy may 
include but is not limited to:
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator.
If symptoms resolve within 1 hour of stopping 
drug infusion, the infusion may be restarted at 
50% of the original infusion rate (e.g. from 100 
mL/hr to 50 mL/hr).  Otherwise dosing will be 
held until symptoms resolve and the subject 
should be premedicated for the next scheduled 
dose.
Subjects who develop Grade 2 toxicity despite 
adequate premedication should be permanently 
discontinued from further study drug treatment
Subject may be premedicated 
1.5h (± 30 minutes) prior to 
infusion of pembrolizumab
with:
Diphenhydramine 50 mg po 
(or equivalent dose of 
antihistamine).
Acetaminophen 500-1000 mg 
po (or equivalent dose of 
analgesic).
 
 
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NCI CTCAE Grade
Treatment
Premedication at 
Subsequent Dosing
Grades 3 or 4
Grade 3:
Prolonged (i.e., not 
rapidly responsive to 
symptomatic medication 
and/or brief interruption 
of infusion); recurrence 
of symptoms following 
initial improvement; 
hospitalization indicated 
for other clinical 
sequelae (e.g., renal 
impairment, pulmonary 
infiltrates)
Grade 4:
Life-threatening; 
pressor or ventilatory 
support indicated
Stop Infusion.
Additional appropriate medical therapy may 
include but is not limited to:
Epinephrine**
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
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 drug treatment.
No subsequent dosing
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during 
the period of drug administration.
For further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) at 
http://ctep.cancer.gov
Other allowed dose interruption for pembrolizumab 
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as
medical / surgical events or logistical reasons not related to study therapy. Subjects should be 
placed back on study therapy within 3 weeks of the scheduled interruption, unless otherwise 
discussed with the Sponsor. The reason for interruption should be documented in the
subject’s study record.
Timing of Dose Administration
Cycle 1 Day 1 treatment with pembrolizumab should begin on the day of allocation, but no 
later than 3 days from the date the subject is allocated to study treatment. However, every 
effort should be made to begin trial treatment on the day of allocation.
For all additional cycles of pembrolizumab, treatment may be administered up to 3 days 
before or 3 days after the scheduled Day 1 of each cycle due to administrative reasons per the 
investigator’s judgment.  
All study treatments will begin on Day 1 of each cycle after all pre-dose study procedures 
and assessments have been completed as detailed on the Trial Flow Chart – Section 6.0
Pembrolizumab will be administered as a 30 minute IV infusion every 3 weeks.  Sites should 
make every effort to target infusion timing to be as close to 30 minutes as possible.  
 
 
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However, given the variability of infusion pumps from site to site, a window of -5 minutes 
and +10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min).
The Pharmacy Manual contains specific instructions for the preparation of the 
pembrolizumab infusion fluid and administration of infusion solution.
All trial treatments will be administered on an outpatient basis.
Trial Blinding/Masking
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered.
Randomization or Treatment Allocation
Assignment of the treatment/allocation number will occur centrally using an interactive voice 
response system/integrated web response system (IVRS/IWRS). All enrolled subjects will be 
allocated to receive pembrolizumab 200 mg IV Q3W as monotherapy in an unblinded 
fashion.
Stratification
No stratification based on age, sex or other characteristics will be used in this trial.
Concomitant Medications/Vaccinations (Acceptable and 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 may 
be required.  The investigator should discuss any questions regarding this with the Sponsor 
Clinical Director.  The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the subject's primary physician.  However, the decision to continue the 
subject on trial therapy or vaccination schedule requires the mutual agreement of the 
investigator, the Sponsor and the subject.
Acceptable Concomitant Medications
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.  All concomitant medication will be recorded on the case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications 
and fluids.  If changes occur during the trial period, documentation of drug dosage, 
frequency, route, and date may also be included on the CRF.
Palliative and supportive care is permitted during the course of the trial for underlying 
medical conditions and management of symptoms. Surgery for tumor control or symptom 
management is not permitted during the study. Palliative radiotherapy is permitted to a 
 
 
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single lesion if considered medically necessary by the treating physician as long as the lesion 
is NOT a RECIST 1.1 defined target lesion and is NOT administered for tumor control. Trial 
therapy should be held during the course of palliative radiotherapy and should be resumed no 
earlier than the next scheduled administration of trial therapy. The specifics of the radiation 
treatment, including the location, will be recorded.
All concomitant medications received within 28 days prior to the first dose of trial treatment 
and up to 30 days after the last dose of trial treatment should be recorded.  All concomitant 
medications received within 28 days prior to the first dose of retreatment should also be 
recorded. Concomitant medications administered more than 30 days after the last dose of trial 
treatment should be recorded for SAEs and ECIs as defined in Section 7.2
Prohibited Concomitant Medications
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-complete response relapse) of this trial:

Antineoplastic systemic chemotherapy or biological therapy

Immunotherapy not specified in this protocol

Chemotherapy not specified in this protocol

Investigational agents other than pembrolizumab

Radiation therapy
Note: Palliative radiation therapy to a symptomatic solitary non-target lesion or to 
the brain may be allowed after consultation with the Sponsor.

Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited to, 
the following: measles, mumps, rubella, chickenpox, yellow fever, rabies, BCG, 
and typhoid (oral) vaccines. The killed virus vaccines used for seasonal influenza 
vaccines for injection are allowed. However, intranasal influenza vaccines (e.g. 
FluMist®) are live attenuated vaccines, and are not allowed.

Systemic glucocorticoids for any purpose other than to modulate symptoms from 
an AE of suspected immunologic etiology.  The use of physiologic doses of 
corticosteroids may be approved after consultation with the Sponsor.
o
Note: Inhaled steroids are allowed for the management of asthma
o
Note: Use of prophylactic corticosteroids to avoid allergic reactions (e.g., 
to IV contrast dye) is permitted.
Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be discontinued from study 
treatment. Subjects may receive other medications or treatments that the investigator deems 
to be medically necessary.
 
 
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The Exclusion Criteria describe other medications that are prohibited in this trial.
There are no prohibited therapies during the Post-Treatment Follow-up Phase.
Rescue Medications & Supportive Care
Supportive Care Guidelines for Pembrolizumab
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of adverse 
events with potential immunologic etiology are outlined along with the dose modification 
guidelines in Section 5.2.1.2, Table 3. 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. 
Note: if after the evaluation the event is determined not to be related to pembrolizumab, the 
investigator does not need to follow the treatment guidance. Refer to Table 3 in Section 
5.2.1.2 for guidelines regarding dose modification and supportive care.
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event.
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 may have adverse effects on a fetus in utero.  Furthermore, it is not known if 
pembrolizumab has transient adverse effects on the composition of sperm.  
For this trial, 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 are either: 
(1) postmenopausal (defined as at least 12 months with no menses without an alternative 
medical cause; in women < 45 years of age a high follicle stimulating hormone (FSH) 
 
 
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level in the postmenopausal range may be used to confirm a post-menopausal state in 
women not using hormonal contraception or hormonal replacement therapy. In the 
absence of 12 months of amenorrhea, a single FSH measurement is insufficient.); 
OR 
(2) have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or 
bilateral tubal ligation/occlusion, at least 6 weeks prior to screening; 
OR 
(3) has a congenital or acquired condition that prevents childbearing.
Female and male subjects of reproductive potential must agree to avoid becoming pregnant 
or impregnating a partner, respectively, while receiving study drug and for 120 days after the 
last dose of study drug by complying with one of the following:  
(1) practice abstinence† from heterosexual activity; 
OR 
(2) use (or have their partner use) acceptable contraception during heterosexual activity. 
Acceptable methods of contraception are‡:
Single method (one 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 two 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
†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 lifestyle and 
if considered acceptable by local regulatory agencies and ERCs/IRBs.  Periodic abstinence 
 
 
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(e.g., calendar, ovulation, sympto-thermal, post-ovulation methods, etc.) and withdrawal are 
not acceptable methods of contraception. 
‡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 trial therapy.  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.
For countries or sites that follow the Clinical Trial Facilitation Group (CTFG) 
guidance, please use the following:
Pembrolizumab 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:
o Oral
o Intravaginal
o Transdermal

Progestogen-only hormonal contraception associated with inhibition of ovulation:
o Oral
o Injectable
o Implantable

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)

Bilateral tubal occlusion

Vasectomised partner

Sexual abstinence
 
 
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Subjects should start using birth control from study Visit 1 throughout the study period up to
180 days after the last dose of study therapy.
Use in Pregnancy
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, the 
subject will immediately be removed from the study.  The site will contact the subject at least 
monthly and document the subject’s status until the pregnancy has been completed or 
terminated.  The outcome of the pregnancy will be reported to the Sponsor without delay and 
within 24 hours if the outcome is a serious adverse experience (e.g., death, abortion, 
congenital anomaly, or other disabling or life-threatening complication to the mother or 
newborn).  The study investigator will make every effort to obtain permission to follow the 
outcome of the pregnancy and report the condition of the fetus or newborn to the Sponsor.   
If a male subject impregnates his female partner, the study personnel at the site must be 
informed immediately and the pregnancy 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 is excreted in human milk.  Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the 
nursing infant, subjects who are breast-feeding are not eligible for enrollment.
Subject Withdrawal/Discontinuation Criteria
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.
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.
 
 
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A subject must be discontinued from treatment but 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 (irPD) as outlined in Section 7.1.4.1 (exception if 
Sponsor approves treatment continuation)

Unacceptable adverse experiences as described in Section 7.2

Any progression or recurrence of any malignancy, or any occurrence of another 
malignancy that requires active treatment

Recurrent Grade 2 pneumonitis

Intercurrent illness that prevents further administration of treatment

Investigator’s decision to discontinue the subject

The subject has a confirmed positive serum pregnancy test

Administrative reasons

Completed 35 treatments with pembrolizumab
o
Note: 35 treatments (approx. 2 years) are calculated from the first dose. Subjects 
who stop pembrolizumab after receiving 35 treatments may be eligible for 
retreatment if they progress after stopping study treatment provided they meet the 
requirements detailed in Section 7.1.6.2.1.  Subjects may be retreated in the 
Second Course Phase with up to 17 (approx. 1 year) additional trial treatments.
The End of Treatment and Follow-up Visit procedures are listed in Section 7.1.6.3 and the
Trial Flow Chart and Section 6.0. After the end of treatment, each subject will be followed 
for a minimum of 30 days for AE monitoring (SAEs and ECIs will be collected for up to 
90 days after the end of treatment as described in Section 7.2.3.1). Subjects who discontinue 
for reasons other than PD will have post-treatment follow-up for disease status until PD, 
initiating a non-study cancer treatment, withdrawing consent or becoming lost to follow-up. 
After documented PD each subject will be followed for OS until death, withdrawal of 
consent, or the end of the study, whichever occurs first.
Discontinuation of Study Therapy after Complete Response 
Discontinuation of treatment may be considered for subjects who have attained a confirmed 
CR (assessed by the site) that have received at least 8 trial treatments (approx. 6 months) of 
pembrolizumab and had at least 2 treatments with pembrolizumab beyond the date when the 
 
 
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initial CR was declared.  Subjects who stop then experience radiographic disease progression 
may be eligible for up to 17 additional treatments (approx. 1 year) with pembrolizumab in the 
Second Course Phase at the discretion of the investigator if:
•
No cancer treatment was administered since the last dose of pembrolizumab
•
The subject meets the parameters listed in the Inclusion/Exclusion criteria
•
The trial is ongoing
Subjects will resume therapy at the same dose and schedule at the time of initial 
discontinuation. Additional details are provided in Section 7.1.6.2.1. Response or progression 
in this Second Course Phase will not count towards the primary endpoint in this trial.
Subject Replacement Strategy
A subject who discontinues from the trial will not be replaced.
Beginning and End of the Trial
The overall trial ends when fewer than 25% of subjects are evaluable for OS or all subjects 
have discontinued trial treatment (including retreatment), whichever occurs earlier.
Upon study completion, participants are discontinued and may be enrolled in a 
pembrolizumab extension study.
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, Good Clinical 
Practice (GCP) and/or other applicable regulatory requirements, procedure-related problems, 
or the number of discontinuations for administrative reasons is too high.
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.
 
 
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TRIAL FLOW CHART
Flow Chart for Initial Treatment Phase with Pembrolizumab
Trial Period:
Screening 
Phase
Treatment Cycles
End of 
Treatment
Post-treatment
Treatment Cycle/Title:
Screening 
(Visit 1)
1
2
3
4
5
6
7
8 to 35
Discon
Safety Follow-
up
Follow-up 
Visits
Survival 
Follow-upa
At Time of 
Discon
30 Days from 
Last Dose
Every 12
Weeksn
Every 12
Weeks
Scheduling Window (Days)b
-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
Clinical Procedures/Assessments
Review Adverse Events
X
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
X
Height, Weight, and Vital Signs 
(T,P,RR,BP)c
X
X
X
X
X
X
X
X
X
X
12-Lead Electrocardiogram
X
ECOG Performance Status
Xe
X
X
X
X
X
X
X
X
X
Post-study Anticancer Therapy Status
X
X
X
Survival Statusa
X
Trial Treatment Administration
Pembrolizumab Administration
Xb
X
X
X
X
X
X
X
LOCAL Laboratory Assessments
Pregnancy Test - Urine or Serum -
hCG
Xd
X
X
X
X
X
X
X
X
X
PT/INR and aPTT
Xe
CBC with Differentialf
Xe
X
X
X
X
X
Xf
X
X
Chemistry Panelf
Xe
X
X
X
X
X
Xf
X
X
Urinalysis 
Xe
T3 (or FT3), FT4, and TSHf
X
X
X
X
Xf
X
X
 
 
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Trial Period:
Screening 
Phase
Treatment Cycles
End of 
Treatment
Post-treatment
Treatment Cycle/Title:
Screening 
(Visit 1)
1
2
3
4
5
6
7
8 to 35
Discon
Safety Follow-
up
Follow-up 
Visits
Survival 
Follow-upa
At Time of 
Discon
30 Days from 
Last Dose
Every 12
Weeksn
Every 12
Weeks
Serum Tumor Markersg
Xe
X
X
X
X
X
X
X
X
X
CENTRAL Laboratory Assessments
Blood for Geneticsh
X
Plasma for circulating tumor DNA 
(Cohort B only)(optional)
X
X
X
Correlative Blood Samples (DNA and 
RNA)i
X
X
X
X
Tumor Tissue Collection
Archival or Newly Obtained Tumor 
Tissuem
Xm
X
Efficacy Measurements
Tumor Imaging k
Xj
Xk
Xl
X
 
 
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a. Subjects that experience site assessed PD or start a new anti-cancer therapy should be followed approximately Q12W to assess for survival status. 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 that have a death event previously recorded).
b. Cycle 1 treatment must be given within 3 days of allocation. The window for each visit is ± 3 days unless otherwise noted.  
c. Height will be measured at Visit 1 only.
d. For women of reproductive potential, a serum or urine pregnancy test should be performed within 72 hours prior to each dose of trial treatment and 30 days post last dose of study 
treatment.  
e. ECOG Performance Status and Laboratory tests for screening are to be performed within 10 days prior to the first dose of trial treatment.
f.
After Cycle 1, lab samples can be collected up to 72 hours prior to the scheduled time point. Thyroid function tests to be performed every other cycle. CBC and Chemistry to be 
performed every cycle through Cycle 6 and then every other cycle thereafter.
g. Serum tumor markers (CEA) should be collected at screening (baseline) and every Cycle until treatment discontinuation; may be collected up to 72 hours prior to the scheduled 
time point.
h. Sample should be drawn for planned genetic analysis of DNA and drug response unless there is either a documented law or regulation prohibiting collection, or unless the 
IRB/IEC does not approve of the collection of the sample for these purposes. Leftover extracted DNA will be stored for future biomedical research if the subject signs the ICF for 
FBR. Details for collection can be found in Section 7.1.3.2 Central Laboratory Assessments. 
i.
Whole blood samples for correlative studies should be collected pre-dose on Day 1 of Cycle 1, Cycle 2, and Cycle 3, and again at treatment discontinuation.
j.
Screening tumor imaging will be performed within 28 days prior to allocation. Confirmation of measurable disease by the central imaging vendor is required prior to subject 
allocation. 
k. The first on-study imaging time point will be performed 9 weeks (63 days ± 7 days) from date of allocation. Subsequent imaging will be performed Q9W (63 days ± 7 days) for 
the first 12 months, then Q12W (84 days, ± 7 days) thereafter, or more frequently if clinically indicated. Imaging timing should be calculated from the date of allocation, should 
follow calendar days, and should not be adjusted for delays in cycle starts.
l.
In subjects who discontinue study therapy without confirmed PD by the site per irRECIST, tumor imaging should be performed at the time of treatment discontinuation (± 4 
weeks). If previous tumor imaging was obtained within 4 weeks prior to the date of discontinuation, then additional tumor imaging at treatment discontinuation is not required.
m. Submitting tumor tissue for exploratory analysis is optional for Cohort A, but required for Cohort B, and should be submitted only after the samples have been evaluated at the 
local site laboratory for MSI/MMR status.  Note: In subjects for whom newly obtained samples cannot be obtained (e.g., inaccessible and/or patient safety concern) and for whom 
no archived tissue is available, eligibility must be discussed with the Sponsor prior to enrollment.  Leftover tumor tissue will be stored for future biomedical research for subjects 
who sign the Future Biomedical Research (FBR) consent. A tumor biopsy at treatment discontinuation is highly encouraged for all subjects in Cohort B, but not mandatory.
n. The Follow-up Visits should occur approximately Q12W (after treatment discontinuation) to review AEs and post-treatment anti-cancer therapy status. However, to minimize 
subject burden, if the time window for this visit does not align with the timing for the continued tumor imaging (also occurring Q12W), the first Follow-up Visit may be performed 
earlier than scheduled to align these two visits. The imaging schedule should not be adjusted. All subsequent Follow -up Visits should occur Q12W as scheduled.
 
 
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Flow Chart for Second Course Phase with Pembrolizumab (Retreatment)
Trial Period:
Treatment Cycles
End of 
Treatment
Post-treatment
Treatment Cycle/Title:
1
2
3
4
5
6
7
8 to 17
Discon
Safety Follow-
up
Follow Up 
Visits
Survival Follow-
Upa
At Time of 
Discon
30 Days from 
Last Dose
Every 12
Weeks h
Every 12     
Weeks
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
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 (T,P,RR,BP)
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
X
Survival Statusa
X
Trial Treatment Administration
Pembrolizumab
X
X
X
X
X
X
X
X
LOCAL Laboratory Assessments
Pregnancy Test – Urine or Serum -hCGc
X
X
X
X
X
X
X
X
X
X
PT/INR and aPTT
Xd
CBC with Differentiale
Xd
X
X
X
X
X
X
X
X
Chemistry Panele
Xd
X
X
X
X
X
X
X
X
Urinalysis
Xd
T3, FT4, and TSH e
X
X
X
X
Xe
X
X
Efficacy Measurements
Tumor Imaging
Xf
Xf
Xg
X
 
 
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a. After the start of new anti-cancer treatment or PD the subject should be followed approximately Q12W to assess for survival status. 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 that have a death event previously recorded).
b. In general, the window for each visit is ± 3 days unless otherwise noted.  
c. For women of reproductive potential, a urine or serum pregnancy test should be performed within 72 hours prior to each dose of study treatments and 30 days post last dose of 
study treatment.
d. Laboratory tests for determining eligibility are to be performed within 10 days prior to the first retreatment dose of pembrolizumab  
e. After Cycle 1, lab samples can be collected up to 72 hours prior to the scheduled time point.  Thyroid function tests to be performed every other cycle. CBC and Chemistry, to be 
performed every cycle through Cycle 6 and then every other cycle thereafter. 
f. Tumor imaging should be performed within 28 days prior to restarting treatment with pembrolizumab and continue to be performed every 12 weeks (84 ± 7 days) after the first 
dose of retreatment, or more frequently if clinically indicated. 
g. Tumor imaging should be performed at the time of treatment discontinuation (i.e., date of discontinuation ± 4-week window).  If previous tumor imaging was obtained within 4 
weeks prior to the date of discontinuation, then additional tumor imaging at treatment discontinuation isn’t mandatory.
h. The Follow-up Visits should occur approximately Q12W (after treatment discontinuation and completion of 17 cycles) to review AEs and post-treatment anti-cancer therapy status. 
However, to minimize subject burden, if the time window for this visit does not align with the timing for the continued tumor imaging (also occurring Q12W), the first Follow -up 
Visit may be performed earlier than scheduled to align these two visits. The imaging schedule should not be adjusted. All subsequent Follow -up Visits should occur Q12W as 
scheduled.
 
 
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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
7.1.1.1
Informed Consent
The investigator or qualified designee must obtain documented consent from each potential 
subject or each subject’s legally acceptable representative prior to participating in a clinical 
trial or Future Biomedical Research.
General Informed Consent
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion. 
A copy of the signed and dated consent form should be given to the subject before 
participation in the trial.
The initial informed consent form, any subsequent revised written informed consent form 
and any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The subject or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the trial.  The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the subject’s dated signature or 
by the subject’s legally acceptable representative’s dated signature.
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.  
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements.
 
 
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Consent and Collection of Specimens for Future Biomedical Research
The investigator or qualified designee will explain the Future Biomedical Research consent 
to the subject, answer all of his/her questions, and obtain written informed consent before 
performing any procedure related to the Future Biomedical Research sub-trial.  A copy of the 
informed consent will be given to the subject.
7.1.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.
7.1.1.3
Subject Identification Card
All subjects will be given a Subject Identification Card identifying them as participants in a 
research trial.  The card will contain trial site contact information (including direct telephone 
numbers) to be utilized in the event of an emergency.  The investigator or qualified designee 
will provide the subject with a Subject Identification Card immediately after the subject 
provides written informed consent.
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.
7.1.1.4
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.
7.1.1.5
Disease Details
The investigator or qualified designee will obtain prior and current details regarding the 
subject’s colorectal carcinoma.
7.1.1.6
Prior and Concomitant Medications Review
Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject 
within 28 days of first dose of trial treatment.  
 
 
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Prior anti-cancer treatment for colorectal carcinoma will 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 anti-cancer treatments including 
systemic treatments, radiation and surgeries. 
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the subject
during the trial from the time of signing the informed consent form until the Safety 
Follow-up Visit. In addition, new medications started within 28 days prior to the first dose of 
the Second Course Phase through the Second Course Safety Follow-up Visit should be 
recorded. 
All medications related to reportable SAEs and ECIs should be recorded as defined in 
Section 7.2
7.1.1.7
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.
7.1.1.8
Assignment of Treatment/Randomization Number
All eligible subjects will be allocated, by non-random assignment, and will receive an 
allocation number.  The allocation number identifies the subject for all procedures occurring 
after treatment allocation.  Once an allocation number is assigned to a subject, it can never be 
re-assigned to another subject.
A single subject cannot be assigned more than 1 allocation number.
7.1.1.9
Trial Compliance (Medication/Diet/Activity/Other)
Interruptions from the protocol specified treatment for greater than 12 weeks between 
pembrolizumab doses for non-drug-related or administrative reasons require consultation 
between the investigator and the Sponsor and written documentation of the collaborative 
decision on subject management.
 
 
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The total volume of pembrolizumab infused will be compared to the total volume prepared to 
determine compliance with each dose of pembrolizumab administered.  The instructions for 
preparing and administering pembrolizumab are provided in the Pharmacy Manual.  
Administration of trial medication will be witnessed by the investigator and/or trial staff.
Clinical Procedures/Assessments
7.1.2.1
Adverse Event Monitoring
The investigator or qualified designee will assess each subject to evaluate for potential new 
or worsening AEs as specified in the Trial Flow Chart and more frequently if clinically 
indicated.  Adverse events will be graded and recorded throughout the trial 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 trial treatment.  
All AEs of unknown etiology associated with pembrolizumab exposure should be evaluated 
to determine if it is possibly an ECI of a potentially immunologic etiology (termed immune-
related adverse events, or irAEs); see Section 5.2.1 regarding the identification, evaluation 
and management of potential irAEs.  
Please refer to Section 7.2 for detailed information regarding the assessment and recording of 
AEs.  
7.1.2.2
Physical Exam
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 Trial Flow 
Chart-Section 6.0.  After the first dose of trial treatment new clinically significant abnormal 
findings should be recorded as AEs.
Directed Physical Exam
For cycles that do not require a full physical exam per the Trial Flow Chart-Section 6.0, the 
investigator or qualified designee will perform a directed physical exam as clinically 
indicated prior to dosing on Day 1 of each treatment cycle.  New clinically significant 
abnormal findings should be recorded as AEs.
7.1.2.3
Height, Weight, and Vital Signs
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment, and at treatment discontinuation as specified in 
the Trial Flow Chart- Section 6.0.  
 
 
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Vital signs should include temperature, pulse, respiratory rate, blood pressure, height, and 
weight.    
7.1.2.4
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.
7.1.2.5
Eastern Cooperative Oncology Group Performance Status
The investigator or qualified designee will assess Eastern Cooperative Oncology Group 
(ECOG) PS (see Section 12.5) at screening, prior to dosing on Day 1 of each treatment cycle,
and at discontinuation of trial treatment as specified in the Trial Flow Chart – Section 6.0.
7.1.2.6
Post-study Anti-Cancer Therapy Status
The investigator or qualified designee will review all new anti-cancer therapy initiated after 
the last dose of trial treatment.  If a subject initiates a new anti-cancer therapy within 30 days 
after the last dose of trial treatment, the 30-day Safety Follow-up Visit must occur before the 
first dose of the new therapy.  
Once new anti-cancer 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 trial are 
provided below. The total amount of blood/tissue to be drawn/collected over the course of 
the trial (from pre-trial to post-trial visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per subject can be found in the Procedures 
Manual.
Refer to the Trial Flow Chart – Section 6.0 for the schedule of laboratory assessments.
 
 
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7.1.3.1
Local Laboratory Assessments
Table 5
Laboratory Assessments
Hematology
Chemistry
Urinalysis
Other
Hematocrit
Albumin
Specific gravity
TSH
Hemoglobin
Alkaline phosphatase
Microscopic exam, 
if abnormal results 
are noted
Pregnancy testa
Platelet count
Lactate dehydrogenase 
(LDH)
Urine pregnancy 
testa
Tumor markers 
(CEA)
Red blood count
Alanine aminotransferase 
(ALT)
Protein
Total 
triiodothyronine (T3) 
or Free T3d
White blood cell 
count (total and 
differential)e
Aspartate aminotransferase 
(AST)
Glucose
Free thyroxine (FT4)
Absolute 
neutrophil countf
Bicarbonate or Carbon 
dioxidec
Blood
PT(INR)
Absolute 
lymphocyte countf
Calcium
aPTT
Chloride
Creatinine
Glucose
Potassium
Sodium
Total bilirubin  
Direct bilirubin, if total 
bilirubin is elevated above 
the upper limit of normal
Total protein
Blood urea nitrogen/Ureab
a. Perform on women of childbearing potential only.  Serum pregnancy test is preferred but urine test can be 
considered if serum not appropriate. 
b.Blood Urea Nitrogen is preferred; if not available urea may be tested.
c. If these tests are not done as part of standard of care in your region, then these tests do not need to be 
performed.
d.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 
procedure manual. 
e. Report % or absolute results per standard of practice. Report the results in the same manner throughout the 
study.
f. Results should be calculated per local standard of practice.
Laboratory tests for screening should be performed within 10 days prior to the first dose of 
trial treatment.  Subjects eligible for retreatment with pembrolizumab should have lab test 
 
 
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performed within 10 days prior to the first dose of trial treatment in the Second Course 
Phase. After Cycle 1, in both the Initial Treatment Phase and the Second Course Phase, pre-
dose laboratory safety tests can be conducted up to 72 hours prior to dosing. 
Laboratory test results must be reviewed by the investigator or qualified designee and found 
to be acceptable prior to administration of each dose of trial treatment.  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.
Serum/Urine β-hCG
All women who are being considered for participation in the trial, and who are not surgically
sterilized or postmenopausal, must be tested for pregnancy within 72 hours of each cycle of
trial treatment and 30 days post the last dose of study treatment. If a urine test is positive or 
not evaluable a serum test will be required. Subjects must be excluded/discontinued from the 
study in the event of a positive or borderline-positive test result.
The results of the pregnancy testing will not be recorded.
7.1.3.2
Central Laboratory Assessments
Sample collection timing, storage and shipment instructions for the Central Laboratory 
Assessments will be provided in the procedure manual.
Pharmacokinetic/Pharmacodynamic 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 7 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 7 may be stored. Analysis 
will be performed only if required.
Planned Genetic Analysis Sample Collection
Whole blood should be drawn prior to treatment 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 FBR if the subject signs 
the FBR consent. If the planned genetic analysis is not approved, but FBR is approved and 
consent is given, this sample will be collected for the purpose of FBR.
Plasma Sample for Circulating Tumor DNA Study
A plasma sample will be collected prior to treatment at the Cycle 1, Cycle 3, and 
discontinuation visits for planned analysis of circulating tumor DNA.
 
 
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Blood Collections for Correlative Studies
Additional biomarker research to identify factors important for pembrolizumab therapy will
also be pursued.  Analysis will include, but may not be limited to, the subset of tests 
mentioned in Section 4.2.3.3.2. 
If the subject signs the FBR consent, leftover DNA and RNA that would ordinarily be 
discarded at the end of the main study will be retained for FBR.
Tumor Tissue Collection 
Submitting tumor tissue is optional for Cohort A, but required for Cohort B of this study. 
Newly obtained tissue (≤60 days prior to first dose of study treatment) from primary tumor is 
encouraged if it is accessible and not a contraindication due to subject safety concerns;
otherwise, archival tumor tissue from primary tumor is accepted.  Tumor tissue obtained by 
fine needle aspiration will be inadequate and not acceptable.
A tumor biopsy at treatment discontinuation is highly encouraged for all subjects in 
Cohort B.  The Sponsor may use tumor tissue that is submitted for exploratory analyses to 
identify factors important for pembrolizumab therapy (see Section 4.2.3.3.2). Analyses will
include, but may not be limited to, the subset of tests mentioned in Section 4.2.3.3.2.
If the subject signs the FBR consent, any leftover tissue that would ordinarily be discarded at 
the end of the main study will be retained for FBR. 
7.1.3.3
Future Biomedical Research Sample Collection
The following specimens are to be obtained as part of FBR:
Leftover DNA for future research
Leftover archival or newly obtained tumor tissue
Leftover RNA testing
Efficacy Measurements
7.1.4.1
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 performed by CT 
(preferred).  Magnetic resonance imaging (MRI) should only be used when CT is 
contraindicated or for imaging in the brain, but the same imaging technique should be used in 
a subject throughout the trial.  CT imaging is the more commonly used modality and is 
preferred for the majority of subjects.  An MRI can be utilized if clinically appropriate.  
Imaging should include the chest, abdomen, and pelvis at baseline and all subsequent follow 
up time points; additional details are in the Site Imaging Manual (SIM).
 
 
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Confirmation of measurable disease based on RECIST 1.1 will be completed by the central 
imaging vendor prior to subject allocation.
All tumor imaging including scheduled and 
unscheduled images should be submitted to the central imaging vendor for evaluation and 
should be submitted in a timely fashion.
Initial Tumor Imaging
Initial tumor imaging at screening must be performed within 28 days prior to the date of 
allocation.  The site study team must review screening images to confirm the subject has 
measurable disease per RECIST 1.1. The screening images must be submitted immediately 
to the central imaging vendor for confirmation of measurable disease per RECIST 1.1.
Tumor imaging performed as part of routine clinical management are acceptable for use as 
initial tumor imaging if they are of diagnostic quality, include all anatomy as described in the 
SIM, and performed within 28 days prior to the date of allocation.
Tumor Imaging During Trial
The first on study imaging assessment should be performed at 9 weeks (63 days ±7 days) 
from the date of allocation. Subsequent tumor imaging should be performed Q9W (63 days 
±7 days) for the first year, and then Q12W (84 days ±7 days) thereafter, or more frequently 
if clinically indicated until PD. Imaging should not be delayed for delays in cycle starts or 
extension of pembrolizumab cycle intervals.  
Per RECIST 1.1, partial or complete response should be confirmed by a repeat tumor 
imaging assessment not less than 4 weeks from the date the response was first documented.  
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 tumor imaging (i.e. 9 weeks for
the first year, or 12 weeks thereafter), whichever is clinically indicated.  Subjects will then 
return to regular scheduled imaging Q9W in the first year, Q12W thereafter, starting with the 
next scheduled imaging time point. Subjects who obtain a confirmation imaging assessment 
do not need to undergo scheduled tumor imaging if it is <4 weeks later and may wait until the 
next scheduled imaging time point.
Per irRECIST (Section 4.2.3.1.3.1), if radiologic imaging identifies PD, 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 
confirmation tumor imaging 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 by RECIST 1.1 (unless 
the site investigator chooses to manage the patient by irRECIST which would then be irPD), 
the start of new anti-cancer 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 disease in clinically stable subjects.
 
 
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If the subject is clinically stable as per Section 4.2.3.1.3.1, it is the discretion of the PI to 
continue to treat and image the subject at least 4 weeks after the first tumor imaging 
indicating PD by RECIST 1.1 by the site.  irRECIST would then be followed by the study 
site to determine if the follow-up tumor imaging confirms PD (irPD).  Subjects who have 
unconfirmed PD may continue on treatment and follow the regular imaging schedule 
intervals until subsequent PD (irPD) is confirmed by the site per irRECIST provided they 
have met the conditions detailed in Section 4.2.3.1.3.1.
End of Treatment and Follow-up Tumor Imaging 
In subjects who discontinue trial treatment, 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 isn’t 
mandatory.
In subjects who discontinue trial treatment due to documented disease 
progression (PD or irPD for subjects managed under irRECIST), this is the final required 
tumor imaging.
In subjects who discontinue trial treatment without documented disease progression, every 
effort should be made to continue monitoring their disease status by radiologic imaging using 
the same imaging schedule of Q9W for the first year, Q12W thereafter to monitor disease 
status until the start of new anti-cancer treatment, disease progression, death, or the end of 
the study, whichever occurs first.
Second Course Phase Tumor Imaging
A scan must be performed within 28 days prior to restarting treatment with pembrolizumab.  
Imaging should be submitted to the central imaging vendor for retrospective analysis.
The first on study imaging assessment should be performed at 12 weeks (84 days ±7 days) 
after the restart of treatment. Subsequent tumor imaging should be performed Q12W 
(84 days ±7 days) or more frequently if clinically indicated.
Imaging should continue to be performed until disease progression, the start of new anti-
cancer treatment, withdrawal of consent, death, or notification by the Sponsor, whichever 
occurs first.  
The Follow-up Visits should occur approximately every 12 weeks (after treatment 
discontinuation or completion of 17 cycles) to review AEs and post-treatment anti-cancer 
therapy status. However, to minimize subject burden, if the time window for this visit does 
not align with the timing for the continued tumor imaging (also occurring every Q12W), the 
first Follow -up Visit may be performed earlier than scheduled to align these two visits. The 
imaging schedule should not be adjusted. All subsequent Follow -up Visits should occur 
every Q12W weeks as scheduled.
In subjects who discontinue trial treatment, tumor imaging should be performed at the time 
of treatment discontinuation (±4-week window).  If a previous scan was obtained within 4 
 
 
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weeks prior to the date of discontinuation, then a scan at treatment discontinuation isn’t 
mandatory.
All tumor imaging (scheduled and unscheduled) should be submitted to the central imaging 
vendor.
RECIST 1.1 Assessment of Disease
RECIST 1.1 will be applied by the central imaging vendor as the primary measure for 
assessment of tumor response, date of disease progression, and as a basis for all protocol 
guidelines related to disease status (e.g., discontinuation of study therapy). 
During the follow-up period, imaging will be repeated every Q9W (63 ±7 days) for the first 
year, and Q12W (84 ± 7 days) thereafter from the date of allocation until PD. See the Trial 
Flow Charts - Section 6.0 and Section 7.1.6.3.2 for information about the Follow-up Visits.
Immune-related RECIST (irRECIST)
As noted above, if the site has identified PD by RECIST 1.1, subject management can shift to 
irRECIST if clinically stable and the study site may elect to continue treatment, repeat 
imaging ≥4 weeks later and assess tumor response or confirmed progression per irRECIST 
(see Section 4.2.3.1.3.1 and Table 6). 
Table 6
Imaging and Treatment After First Radiologic Evidence of PD
Clinically Stable
Clinically Unstable
Tumor Imaging
Treatment
Tumor Imaging
Treatment
1st radiologic 
evidence of PD
Repeat tumor 
imaging at > 4 
weeks at site to 
confirm PD
May continue study 
treatment at the local 
site investigator’s 
discretion while 
awaiting confirmatory 
tumor imaging by site
Repeat tumor imaging 
at > 4 weeks to 
confirm PD per 
physician discretion 
only
Discontinue treatment
Repeat tumor 
imaging confirms 
PD
No additional 
tumor imaging 
required*
Discontinue 
treatment**
No additional tumor 
imaging required
N/A
Repeat tumor 
imaging shows 
SD, PR or CR
Continue regularly 
scheduled tumor 
imaging 
assessments
Continue study 
treatment at the local 
site investigator’s 
discretion
Continue regularly 
scheduled tumor 
imaging assessments
May restart study 
treatment if condition 
has improved and/or 
clinically stable per 
local site investigator’s 
discretion

In determining whether or not the tumor burden has increased or decreased, local 
study site investigators should consider all target lesions as well as non-target lesions 
as per irRECIST.  Subjects that are deemed clinically unstable are not required to 
have repeat tumor imaging for confirmation.  
 
 
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
For a clinically stable subject with first radiologic evidence of PD (i.e., unconfirmed 
progression of disease), it is at the discretion of the site investigator to continue 
treating the subject with the assigned treatment per protocol until progression of 
disease is confirmed at least 28 days from the date of the tumor imaging first 
suggesting PD. If radiologic progression is confirmed by subsequent tumor imaging
(irPD) then the subject will be discontinued from trial treatment.  If radiologic 
progression is not confirmed, then the subject should resume or continue trial 
treatment and have their next tumor imaging according to the protocol schedule of 
Q9W (63 days ± 7 days) for the first year, and then Q12W thereafter.  

*NOTE: If a subject has confirmed radiographic progression (i.e. 2 tumor 
imaging assessments at least 4 weeks apart demonstrating PD per irRECIST, but 
the subject is achieving a clinically meaningful benefit, an exception to continue 
treatment may be considered following consultation with the Sponsor.
If 
treatment is continued beyond confirmed radiographic progression, tumor 
imaging assessments should continue to be performed Q9W for the first year, and 
then Q12W thereafter, and be submitted to the central imaging vendor.

**NOTE:  In subjects who discontinue study therapy without documented disease 
progression, every effort should be made to continue monitoring their disease 
status by tumor imaging Q9W (63 days ± 7 days) for the first year, and then 
Q12W
thereafter, until;
the start of new anti-cancer treatment,
disease 
progression, death, or the end of the study, whichever occurs first.
irRECIST data will be collected in the clinical database.
Other Procedures
7.1.5.1
Withdrawal/Discontinuation
Subjects who discontinue/withdraw from treatment prior to completion of the treatment 
regimen should be encouraged to continue to be followed for all remaining study visits.
When a subject discontinues/withdraws from participation in the trial, all applicable activities 
scheduled for the end of treatment 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. Subjects who attain a CR or complete 35 trial treatments 
(approximately 2 years) may discontinue treatment with the option of restarting treatment if 
they meet the criteria specified in Section 7.1.6.2.1. After discontinuing treatment following 
assessment of a CR or the 35 trial treatments, subjects should return to the site for a Safety 
Follow-up Visit (Section 7.1.6.3.1) and then proceed to the Follow-up Period of the study 
(Section 7.1.6.3.2).
 
 
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Withdrawal From Future Biomedical Research
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   Subjects may withdraw consent at any time by 
contacting the principal investigator for the main trial.  If medical records for the main trial 
are still available, the investigator will contact the Sponsor using the designated mailbox 
(clinical.specimen.management@merck.com), and a form will be provided by the Sponsor to 
obtain appropriate information to complete specimen withdrawal.  Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed.  A letter will 
be sent from the Sponsor to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for destruction or already performed prior to the 
request being received by the Sponsor will continue to be used as part of the overall research 
trial data and results.   No new analyses would be generated after the request is received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial records) or 
the specimens have been completely anonymized, there will no longer be a link between the 
subject’s personal information and their specimens.  In this situation, the request for 
specimen destruction cannot be processed.
7.1.5.2
Blinding/Unblinding
This is an open label trial; there is no blinding for this trial.
7.1.5.3
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical trial that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or 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.
Equipment requiring calibration for this trial includes:
•
Laboratory equipment – as required for inclusion labs and trial 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.
 
 
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7.1.6.1
Screening
Approximately 28 days prior to treatment allocation, potential subjects will be evaluated to 
determine that they fulfill the entry requirements as set forth in Section 5.0.  Screening 
procedures may be repeated.
Results of a test performed prior to the subject signing consent as part of routine clinical 
management are acceptable in lieu of a screening test if performed within the specified time 
frame.  Screening procedures are to be completed within 28 days prior to the first dose of 
trial treatment except for the following:
•
Laboratory tests and ECOG PS are to be performed within 10 days prior to the first dose 
of trial treatment.
•
For women of reproductive potential, a serum pregnancy test will be performed within 
72 hours prior to the first dose of trial treatment. A urine test may be considered if serum 
test is not appropriate.
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 who are rescreened will retain their original 
screening number.
7.1.6.2
Treatment Period
Visit requirements are outlined in the Trial Flow Chart (Section 6.0).  Specific procedure-
related details are provided above in the Trial Procedures (Section 7.0)
Second Course Phase (Retreatment)
Subjects who stop pembrolizumab with stable disease (SD) or better may be eligible for up to 
17 additional trial treatments (approximately 1 year) if they progress after stopping study 
treatments.  Retreatment with pembrolizumab is termed the Second Course Phase and is only 
available if the trial remains open and the subject meets the following conditions:

Either 
o
Stopped initial treatment with pembrolizumab after attaining an investigator-
determined confirmed CR according to RECIST 1.1

Was treated with at least 8 trial treatments (approximately 6 months) with 
pembrolizumab before discontinuing therapy

Received at least two treatments with pembrolizumab beyond the date when 
the initial CR was declared
 
 
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OR
o
Had SD, PR or CR and stopped pembrolizumab after 35 trial treatments 
(approximately 2 years)
for reasons other than disease progression or 
intolerability

AND
o
Experienced an investigator-determined radiographic disease progression after 
stopping their initial treatment with pembrolizumab.
o
Did not receive any anti-cancer treatment since the last dose of pembrolizumab.
o
Has a performance status of 0 or 1 on the ECOG Performance Scale.
o
Demonstrates adequate organ function as detailed in Section Table 1.
o
Female subject of childbearing potential should have a negative serum or urine 
pregnancy test within 72 hours prior to receiving retreatment with study 
medication.  
o
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 study medication 
(Reference Section 5.7.2).  Subjects of child bearing potential are those who have 
not been surgically sterilized or have been free from menses for > 1 year. 
o
Male subject should agree to use an adequate method of contraception starting 
with the first dose of study therapy through 120 days after the last dose of study 
therapy.  
o
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 trial 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.  Pembrolizumab will be administered for up to an 
additional 17 trial treatments (approximately 1 year).
Visit requirements for the second course phase are outlined in the Second Course Phase Trial 
Flow Chart (Section 6.2).
 
 
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7.1.6.3
Post-Treatment Visits
Safety Follow-up Visits
The mandatory Safety Follow-up Visit should be conducted approximately 30 days after the 
last dose of trial treatment or before the initiation of a new anti-cancer treatment, whichever 
comes first.  
Subjects who are eligible for retreatment with pembrolizumab may have up to two safety 
follow-up visits, one after the Initial Treatment Period and one after the Second Course 
Treatment Phase.
Follow-up Visits
Subjects who discontinue trial treatment for reasons other than disease progression will move 
into the Follow-up Phase and should be assessed Q9W (63 days ± 7 days) for the first year, 
and then Q12W (84 days ±7 days) thereafter, from the date of allocation by radiologic 
imaging to monitor disease status. Every effort should be made to collect information 
regarding disease status until the start of a new anti-cancer therapy, disease progression,
death, the end of the study, or if the subject begins retreatment with study treatment. 
Information regarding post-study anti-cancer treatment will be collected if new treatment is 
initiated.  
Subjects who are eligible to receive retreatment with pembrolizumab according to the criteria 
in Section 7.1.6.2.1 will move from the Follow-up Phase to the Second Course Phase when 
they experience disease progression. 
Survival Follow-up
Subjects, who experience confirmed disease progression (by site assessment) or start a new 
anti-cancer therapy, will move into the Survival Follow-Up phase and should be contacted by 
telephone approximately Q12W to assess for survival status until death, withdrawal of 
consent, or the end of the study, whichever occurs first.
7.1.6.4
Survival Status
To ensure current and complete survival data is available at the time of database locks, 
updated survival status may be requested during the course of the study by the Sponsor. For 
example, updated survival status may be requested prior to but not limited to an external Data 
Monitoring Committee (eDMC) review, interim and/or final analysis.
Upon Sponsor 
notification, all participants who do not/will not have a scheduled study visit or study contact 
during the sponsor defined time period will be contacted for their survival status (excluding 
participants that have a previously recorded death event in the collection tool).
 
 
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Assessing and Recording Adverse Events
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavourable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the 
use of the Sponsor’s product, is also an adverse event.
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  
Examples of this may include, but are not limited to, teething, typical crying in infants and 
children and onset of menses or menopause occurring at a physiologically appropriate time.
Sponsor's product includes any pharmaceutical product, biological product, device, 
diagnostic agent or protocol-specified procedure, whether investigational (including placebo 
or active comparator medication) or marketed, manufactured by, licensed by, provided by or 
distributed by the Sponsor for human use.
Adverse events may occur during clinical trials, or as prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal.
Progression of the cancer under study is not considered an adverse event.
All adverse events that occur after the consent form is signed but before 
randomization/treatment allocation 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 randomization/treatment allocation 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).
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor
In this trial, an overdose is any dose higher than ≥1000 mg (5 times the protocol defined 
dose) of pembrolizumab. No specific information is available on the treatment of over dose
of pembrolizumab.  In the event of overdose, study treatment should be discontinued and the 
 
 
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subject should be observed closely for signs of toxicity.  Appropriate supportive treatment 
should be provided if clinically indicated.
If an adverse event(s) is associated with (“results from”) the overdose of Sponsor's product or 
vaccine, the adverse event(s) is reported as a serious adverse event, even if no other 
seriousness criteria are met.
If a dose of Sponsor's product or vaccine meeting the protocol definition of overdose is taken 
without any associated clinical symptoms or abnormal laboratory results, the overdose is 
reported as a non-serious Event of Clinical Interest (ECI), using the terminology “accidental 
or intentional overdose without adverse effect.”
All reports of overdose with and without an adverse event must be reported by the 
investigator within 24 hours to the Sponsor either by electronic media or paper. Electronic 
reporting procedures can be found in the EDC data entry guidelines. Paper reporting 
procedures can be found in the Investigator Trial File Binder (or equivalent).
Reporting of Pregnancy and Lactation to the Sponsor
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them) that occurs during the trial.
Pregnancies and lactations that occur after the consent form is signed but before 
randomization/treatment allocation 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 
randomization/treatment allocation 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).
Immediate Reporting of Adverse Events to the Sponsor
7.2.3.1
Serious Adverse Events
A serious adverse event is any adverse event occurring at any dose or during any use of 
Sponsor's product that:
 
 
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●
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 7 for additional details regarding each of the above criteria.
For the time period beginning when the consent form is signed until randomization/treatment 
allocation, 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 randomization/treatment allocation through 90 days 
following cessation of treatment, or 30 days following cessation of treatment if the subject 
initiates new anticancer therapy, whichever is earlier, any serious adverse event, or follow up 
to a serious adverse event, including death due to any cause other than progression of the 
cancer under study (reference Section 7.2.3.3 for additional details), whether or not related to 
the Sponsor's product, must be reported within 24 hours to the Sponsor either by electronic 
media or paper. Electronic reporting procedures can be found in the EDC data entry 
guidelines. Paper reporting procedures can be found in the Investigator Trial File Binder (or 
equivalent).
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to the Sponsor's product that is brought to the attention of the 
investigator 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.
7.2.3.2
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.
 
 
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For the time period beginning when the consent form is signed until randomization/treatment 
allocation, 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 randomization/treatment allocation through 90 days 
following cessation of treatment, or 30 days following cessation of treatment if the subject 
initiates new anticancer therapy, whichever is earlier, any ECI, or follow up to an ECI, 
whether or not related to the Sponsor’s product, must be reported within 24 hours to the 
Sponsor, either by electronic media or paper.  Electronic reporting procedures can be found 
in the EDC data entry guidelines.  Paper reporting procedures can be found in the 
Investigator Trial File Binder (or equivalent).
Events of clinical interest for this trial include:
1. an overdose of Sponsor's product, as defined in Section 7.2.1 - Definition of an Overdose 
for This Protocol and Reporting of Overdose to the Sponsor, that is not associated with 
clinical symptoms or abnormal laboratory results. 
2. an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less 
than 2X the upper limit of normal, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.*
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology. The trial site guidance for assessment 
and follow up of these criteria can be found in the Investigator Trial File Binder (or 
equivalent).
7.2.3.3
Protocol-Specific Exceptions to Serious Adverse Event Reporting
Efficacy endpoints as outlined in this section will not be reported to the Sponsor as described 
in Section 7.2.3. - Immediate Reporting of Adverse Events to the Sponsor.
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study.
The Sponsor will monitor safety data to ensure the safety of the subjects in the trial. Any 
suspected endpoint which upon review is not progression of the cancer under study will be 
forwarded to global safety as a SAE within 24 hours of determination that the event is not 
progression of the cancer under study.
 
 
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Evaluating Adverse Events
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 4.0. Any adverse event 
which changes CTCAE grade over the course of a given episode will have each change of 
grade recorded on the adverse event case report forms/worksheets.
All adverse events regardless of CTCAE grade must also be evaluated for seriousness.
 
 
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Table 7
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 a Merck product and is documented in 
the patient’s medical history.); or
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or
Is a new cancer (that is not a condition of the study) (although not serious per ICH definition, is reportable to the Sponsor within 24 hours to meet certain local 
requirements); or
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event for collection purposes. An 
overdose that is not associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 hours.
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes 
listed previously (designated above by a †).
Duration
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units
Action taken 
Did the adverse event cause the Sponsor’s product to be discontinued?
Relationship to 
Sponsor’s 
Product
Did the Sponsor’s product cause the adverse event? The determination of the likelihood that the Sponsor’s product caused the adverse event will be provided by an 
investigator who is a qualified physician. The investigator’s signed/dated initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed document must be retained for the required regulatory time frame. The 
criteria below are intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the adverse event 
based upon the available information.
The following components are to be used to assess the relationship between the Sponsor’s product and the AE; the greater the correlation with the components 
and their respective elements (in number and/or intensity), the more likely the Sponsor’s product caused the adverse event (AE):
Exposure
Is there evidence that the subject was actually exposed to the Sponsor’s product such as: reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen?
Time Course
Did the AE follow in a reasonable temporal sequence from administration of the Sponsor’s product?
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)?
Likely Cause
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental factors
 
 
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Relationship
The following components are to be used to assess the relationship between the test drug and the AE: (continued)
to Sponsor's 
Product
(continued) 
Dechallenge
Was the Sponsor’s product discontinued or dose/exposure/frequency reduced?
If yes, did the AE resolve or improve?
If yes, this is a positive dechallenge. If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite continuation of 
the Sponsor’s product; or (3) the trial is a single-dose drug trial); or (4) Sponsor’s product(s) is/are only used one time.)
Rechallenge
Was the subject re-exposed to the Sponsor’s product in this study?
If yes, did the AE recur or worsen?
If yes, this is a positive rechallenge. If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose drug trial); or 
(3) Sponsor’s product(s) is/are used only one time).
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN 
CAUSED BY THE SPONSOR'S PRODUCT, OR IF REEXPOSURE TO THE SPONSOR'S PRODUCT POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR 
CLINICAL DIRECTOR AS PER DOSE MODIFICATION GUIDELINES IN THE PROTOCOL.
Consistency 
with Trial 
Treatment 
Profile
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the Sponsor’s product or drug class pharmacology 
or toxicology?
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements.
Record one of the following
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a Sponsor’s product relationship).
Yes, there is a reasonable 
possibility of Sponsor's product 
relationship.
There is evidence of exposure to the Sponsor's product.  The temporal sequence of the AE onset relative to the administration of the Sponsor's 
product is reasonable.  The AE is more likely explained by the Sponsor's product than by another cause.
No, there is not a reasonable 
possibility of Sponsor's product 
relationship
Subject did not receive the Sponsor's product OR temporal sequence of the AE onset relative to administration of the Sponsor's product is not 
reasonable OR the AE is more likely explained by another cause than the Sponsor’s product.  (Also entered for a subject with overdose without an 
associated AE.)
 
 
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Sponsor Responsibility for Reporting Adverse Events
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations, i.e., per ICH Topic E6 (R1) 
Guidelines for Good Clinical Practice.
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study.  If, after 
the study has begun, but prior to any final database lock, changes made to primary and/or key 
secondary hypotheses, or the statistical methods related to those hypotheses, then the 
protocol will be amended (consistent with ICH Guideline E-9).  Changes to exploratory or 
other non-confirmatory analyses made after the protocol has been finalized, but prior to final 
database lock, will be documented in a supplemental SAP (sSAP) and referenced in the 
Clinical Study Report (CSR) for the study. Post hoc exploratory analyses will be clearly 
identified in the CSR.  
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized in Table 8. The comprehensive 
plan is provided in Sections 8.2 through 8.12. The analyses described in section 8 will be 
applied to Cohort A and Cohort B separately.
 
 
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Table 8
Key Elements of the Statistical Analysis Plan
Study Design Overview
A Phase II Study of Pembrolizumab in Previously Treated Subjects 
with Mismatched Repair Deficient or Microsatellite-High Colorectal 
Carcinoma
Treatment Assignment
This is an open-label study. 
Analysis Populations
All Subjects as Treated (ASaT)
Primary Endpoint(s)
ORR based on RECIST 1.1 assessed by central imaging vendor
Statistical Methods for Key 
Efficacy Analyses
The analyses described in this section will be applied separately for 
Cohort A and Cohort B.
Cohort A: The primary hypothesis will be evaluated by testing the 
centrally reviewed RECIST 1.1 ORR greater than 15% using Exact 
method based on binomial distribution.
Cohort B: 95% CI for ORR will be calculated using Exact method 
based on binomial distribution.
Statistical Methods for Key 
Safety Analyses
Count and percentage of AE will be provided. 
Interim Analyses
For Cohort A, an interim analysis is planned. The interim analysis is 
summarized below; details are provided in Section 8.7.

Interim Analysis
o
Timing: To be performed when the first 40 subjects 
have been followed up for at least 18 weeks
o
Purpose: Efficacy analysis for primary endpoint ORR

Final Analysis
o
Timing: To be performed when all patients have been 
followed up for at least 6 months. If data is not 
mature, additional analysis will be performed when 
all patients have had longer follow-up time or have 
discontinued study therapy.  In that case, the 
originally planned final analysis will be considered 
supportive.
There is no interim analysis planned for Cohort B.
Multiplicity
Cohort A and Cohort B will be evaluated independently.  
No multiplicity adjustment in each cohort.
Sample Size and Power 
The overall sample size is approximately 120.
Cohort A: The planned sample size is 60 subjects. 
For the ORR per RECIST 1.1 assessed by central imaging vendor, the 
trial has 93% power to demonstrate that ORR of pembrolizumab is 
better than 15% at an overall one-sided 2.5% alpha level, if the 
underlying centrally reviewed RECIST 1.1 ORR of pembrolizumab is 
35%.
Cohort B: The planned sample size is 60 subjects.
 
 
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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.
This trial is being conducted as an open-label study, i.e., subjects, investigators, and 
SPONSOR personnel will be aware of subject treatment assignments after each subject is 
enrolled and treatment is assigned.
The Clinical Biostatistics department will generate the allocation schedule.
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.0.
Analysis Endpoints
Efficacy Endpoints
8.4.1.1
Primary Efficacy Endpoint

Objective response rate (ORR) - RECIST 1.1 assessed by central imaging vendor
Objective response rate is defined as the proportion of the subjects in the analysis population 
who have a complete response (CR) or partial response (PR). Responses are based upon 
blinded central imaging vendor per RECIST 1.1.
8.4.1.2
Secondary Efficacy Endpoints

Disease Control Rate (DCR) - RECIST 1.1 assessed by central imaging vendor
Disease control rate (DCR) is defined as the percentage of subjects who have achieved 
confirmed CR or PR or have demonstrated SD for at least 24 weeks prior to any evidence of 
progression.

Duration of Response (DOR) - RECIST 1.1 assessed by central imaging vendor
For subjects who demonstrate CR or PR, duration of response is defined as the time from 
first documented evidence of CR or PR until disease progression or death due to any cause, 
whichever occurs first. 

Progression-free Survival (PFS) - RECIST 1.1 assessed by central imaging vendor
PFS is defined as the time from first day of study treatment to the first documented disease 
progression or death due to any cause, whichever occurs first.
 
 
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
Overall survival (OS)
OS is defined as the time from first day of study treatment to death due to any cause. 
Subjects without documented death at the time of analysis will be censored at the date of the 
last follow-up.
Safety Endpoints
The primary safety objective of this trial is to characterize the safety and tolerability of 
pembrolizumab in subjects with MMR deficient or MSI-high CRC.  The primary safety 
analysis will be based on subjects who experienced toxicities as defined by CTCAE, Version 
4.0 criteria (Appendix 12.6). The attribution to drug, time-of-onset, duration of the event, its 
resolution, and any concomitant medications administered will be recorded.  AEs will be 
analyzed including but not limited to all AEs, SAEs, fatal AEs, and laboratory changes.  
Furthermore, specific immune-related adverse events (irAEs) will be collected and 
designated as immune-related events of clinical interest (ECIs) as described in Section 
7.2.3.2
Analysis Populations
Efficacy Analysis Populations
The All Subjects as Treated (ASaT) population will be used for the analysis of ORR, DCR, 
PFS, and OS. The ASaT population consists of all subjects who received at least one dose of 
study treatment.
The analysis population for DOR consists of responders.
Details on the approach to handling missing data are provided in Section 8.6 Statistical 
Methods.
Safety Analysis Populations
The ASaT population will be used for the analysis of safety data in this study.  The ASaT 
population consists of all allocated subjects who received at least one dose of study 
treatment. 
At least one laboratory or vital sign measurement obtained subsequent to at least one dose of 
study treatment is required for inclusion in the analysis of each specific parameter.  To assess 
change from baseline, a baseline measurement is also required.
Details on the approach to handling missing data for safety analyses are provided in Section 
8.6 Statistical Methods.
 
 
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Statistical Methods
Statistical Methods for Efficacy Analyses
This section describes the statistical methods that address the primary and secondary 
objectives. Efficacy for each cohort will be analyzed separately.  
The primary efficacy endpoint is ORR per RECIST 1.1 assessed by central imaging vendor.
In Cohort A, the point estimate, 95% confidence interval, and p-value for testing the response 
rate is greater than 15% will be provided using exact binomial method proposed by Clopper 
and Pearson (1934) [38]. In Cohort B, the point estimate and 95% confidence interval will be 
provided using exact binomial method proposed by Clopper and Pearson (1934) [38]. 
Subjects in the primary analysis population (ASaT) without ORR data will be counted as 
non-responder.
For DCR, the point estimate, 95% confidence interval will be provided using exact binomial 
method proposed by Clopper and Pearson (1934) [38].  Subjects in the analysis population 
(ASaT) with missing DCR are considered as disease not under control.
For DOR, Kaplan-Meier (KM) curves and median estimates from the KM curves will be 
provided as appropriate. 
Censoring rules for DOR are summarized in Table 9.
Table 9
Censoring Rules for DOR
Situation
Date of Progression or 
Censoring
Outcome
Neither progression nor death, 
no 
new 
anti-cancer 
therapy 
initiated
Last adequate disease assessment
Censor
(non-event)
Neither progression nor death, 
new anti-cancer therapy initiated
Last adequate disease assessment 
before new anti-cancer therapy 
initiated
Censor
(non-event)
Death or progression after ≥2 
consecutive
missed 
adequate 
disease assessments
Last adequate disease assessment 
prior to ≥2 missed adequate 
disease assessments
Censor
(non-event)
Death or progression after ≤1 
missed 
adequate 
disease 
assessments
PD or death
End of response
(Event)
Subjects are considered to have an ongoing response if censored, alive, have not progressed, have not 
started a new anti-cancer therapy and have not been determined to be lost to follow-up.
For PFS and OS endpoints, Kaplan-Meier (KM) curves and median estimates from the KM 
curves will be provided as appropriate. 
 
 
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The efficacy analysis is summarized in Table 10. The efficacy analyses will be applied to 
Cohort A and Cohort B separately.
Table 10
Analysis Strategy for Efficacy Variables
Endpoint/Variable
(Description, Time Point)
Statistical Method
Analysis 
Population
Missing Data 
Approach
Primary Endpoint and Hypothesis 
ORR (Cohort A)

RECIST 1.1, Central assessment
Hypotheses: ORR per RECIST 1.1 by central 
imaging vendor is greater than assumed 
historical control (15%).
Exact method 
based on binomial
distribution
ASaT in 
Cohort A
Subjects with 
missing data are 
considered non-
responders
ORR (Cohort B)

RECIST 1.1, Central assessment
ASaT in 
Cohort B
Secondary Endpoints
DCR

RECIST 1.1, Central assessment
Exact method 
based on binomial
distribution
ASaT in 
below 
populations:
Cohort A
Cohort B
Subjects with 
missing data are 
considered as
disease not under
control
DOR

RECIST 1.1, Central assessment
Summary statistics 
using Kaplan-
Meier method
All 
responders
in below 
populations:
Cohort A
Cohort B
Non-responders 
are excluded from 
analysis
PFS

RECIST 1.1, Central assessment
Summary statistics 
using Kaplan-
Meier method
ASaT in 
below 
populations:
Cohort A
Cohort B
Censored at last 
assessment
OS
Summary statistics 
using Kaplan-
Meier method
ASaT in 
below 
populations:
Cohort A
Cohort B
Censored at last 
known alive date
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including
adverse experiences (AEs), laboratory tests, and vital signs for each cohort separately. Count 
and percentage of AE will be provided.
Summaries of Baseline Characteristics, Demographics, and Other Analyses
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 (e.g., age, gender), baseline characteristics, primary and secondary diagnoses, and 
 
 
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prior and concomitant therapies will be summarized either by descriptive statistics or 
categorical tables for all enrolled subjects.
Interim Analyses
For Cohort A, there is one interim analysis planned in this study.
There is no interim 
analysis planned for Cohort B. In Cohort A, final analysis is to be performed 6 months after 
the last subject is enrolled. Subjects will continue to be followed until overall trial ends. If 
data is not mature at the pre-planned final analysis after all subjects have been followed up 
for 6 months or have discontinued study therapy, additional analyses will be performed after 
all patients have had longer follow-up time or have discontinued study therapy. 
The 
originally planned final analysis will then be considered as a supportive analysis.
There is one planned interim analysis in Cohort A. The purpose of the interim analysis is 
efficacy analysis for primary endpoint ORR in Cohort A. It was originally planned to be 
performed 18 weeks after the 40th subject enrolled. However, due to the rapid enrollment of 
the remaining subjects in Cohort A, it was decided to be conducted after all 61 subjects
enrolled in Cohort A had been followed up for at least 18 weeks.  With this change, the group 
sequential approach based on the first 40 subjects as originally planned is no longer 
applicable.
Multiplicity
Cohort A and Cohort B will be evaluated independently.  No multiplicity adjustment in each 
cohort.
Sample Size and Power Calculations
Efficacy and safety for each cohort will be analyzed separately.
In this study, approximately 60 subjects for each cohort will be enrolled.
Cohort A
With a sample size of 60, the study has 93% power to reject the null hypothesis of 
ORR=15% with a one-sided type I error rate of 2.5% if the true ORR is 35%. The historical
response rate is less than 5% in CORRECT study [39].
At alpha level of 2.5% using exact method based on binomial distribution, the boundary to 
demonstrate statistical success corresponds to an approximate observed ORR ≥26.7% (16/60)
at α = 2.5% (one-sided).
Table 11 shows the two-sided 95% confidence interval of ORR with 60 subjects for different 
observed response rates.
 
 
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Table 11
Two-sided 95% Confidence Interval of ORR with 60 Subjects
Number of Observed 
Responders
ORR Estimates
95% CI of ORR (%)
15
25%
(14.7, 37.9)
16
26.7%
(16.1, 39.7)
17
28.3%
(17.5, 41.4)
18
30%
(18.8, 43.2)
Cohort B
The historical response rate is about 20% [40] [41] [42] for subjects with locally advanced 
unresectable or metastatic MMR deficient or MSI high CRC and have been previously 
treated with at least one line of systemic standard of care therapy.
With a sample size of 60, if there are at least 19 responders observed, the lower bound of the 
95% confidence interval for ORR will be above 20%. 
Table 12 shows the two-sided 95% confidence interval of ORR with 60 subjects for different 
observed response rates.
Table 12
Two-sided 95% Confidence Interval of ORR with 60 Subjects
Number of Observed 
Responders
ORR Estimates
95% CI of ORR (%)
18
30%
(18.8, 43.2)
19
31.7%
(20.3, 45.0)
20
33.3%
(21.7, 46.7)
21
35%
(23.1, 48.4)
 
 
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Subgroup Analyses and Effect of Baseline Factors
The estimate of the treatment effect for the primary endpoint will be estimated and plotted 
within each category of the following classification variables: 

Age category (≤65 vs. >65 years)

Sex (Female vs. Male)

Race (white vs. non-white)
The consistency of the treatment effect will be assessed descriptively via summary statistics 
by category for the classification variables listed above. 
Compliance (Medication Adherence)
Drug accountability data for pembrolizumab will be collected during the study. Any 
deviation from protocol-directed administration will be reported.
Extent of Exposure
Extent of Exposure for a subject is defined as number of cycles in which the subject receives 
the study medication infusion. Summary statistics will be provided on Extent of Exposure 
for ASaT population.
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 13.
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.
 
 
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Table 13
Clinical Supplies
Product Name & Potency
Dosage Form
MK-3475, 25 mg/mL 4 mL
Injection
All other supplies not indicated in Table 13 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.
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.  No kitting is required.
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 
 
 
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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.
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, 
 
 
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may be used and disclosed for trial management purposes, as part of a regulatory 
submissions, and as required by law.  This information may include:
1. name, address, telephone number and e-mail address;
2. hospital or clinic address and telephone number;
3. curriculum vitae or other summary of qualifications and credentials; and
4. other professional documentation.
Consistent with the purposes described above, this information may be transmitted to the 
Sponsor, and subsidiaries, affiliates and agents of the Sponsor, in your country and other 
countries, including countries that do not have laws protecting such information.  
Additionally, the investigator’s name and business contact information may be included 
when reporting certain serious adverse events to regulatory authorities or to other 
investigators.  By signing this protocol, the investigator expressly consents to these uses and 
disclosures.
If this is a multicenter trial, in order to facilitate contact between investigators, the Sponsor 
may share an investigator’s name and contact information with other participating 
investigators upon request.
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC member that 
reviews and approves this trial.  The Sponsor is also required to document that each IRB/IEC 
meets regulatory and ICH GCP requirements by requesting and maintaining records of the 
names and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
Compliance with Financial Disclosure Requirements
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54).  It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
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.
 
 
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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 Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice: 
Consolidated Guideline and other generally accepted standards of good clinical practice); and 
all applicable federal, state and local laws, rules and regulations relating to the conduct of the 
clinical trial.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by Merck, is provided in Section 12.1-
Merck Code of Conduct for Clinical Trials.
The investigator also agrees to allow monitoring, audits, IRB/ERC review and regulatory 
authority inspection of trial-related documents and procedures and provide for direct access 
to all trial-related source data and documents.
The investigator agrees not to seek reimbursement from subjects, their insurance providers or 
from government programs for procedures included as part of the trial reimbursed to the 
investigator by the Sponsor.
The investigator shall prepare and maintain complete and accurate trial documentation in 
compliance with Good Clinical Practice standards and applicable federal, state and local 
laws, rules and regulations; and, for each subject participating in the trial, provide all data, 
and, upon completion or termination of the clinical trial, submit any other reports to the 
Sponsor as required by this protocol or as otherwise required pursuant to any agreement with 
the Sponsor.
Trial documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the trial site upon request for inspection, 
copying, review and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities.  The investigator agrees to promptly take any reasonable steps that are 
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 
 
 
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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.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this trial.
Persons debarred from conducting or working on clinical trials by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s trials.  The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the trial is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will 
promptly notify that trial site’s IRB/IEC.
According to European legislation, a Sponsor must designate an overall coordinating 
investigator for a multi-center trial (including multinational).  When more than one trial site 
is open in an EU country, Merck, as the Sponsor, will designate, per country, a national 
principal coordinator (Protocol CI), responsible for coordinating the work of the principal 
investigators at the different trial sites in that Member State, according to national 
regulations.  For a single-center trial, the Protocol CI is the principal investigator.  In 
addition, the Sponsor must designate a principal or coordinating investigator to review the 
trial report that summarizes the trial results and confirm that, to the best of his/her 
knowledge, the report accurately describes the conduct and results of the trial [Clinical Study 
Report (CSR) CI].  The Sponsor may consider one or more factors in the selection of the 
individual to serve as the Protocol CI and or CSR CI (e.g., availability of the CI during the 
anticipated review process, thorough understanding of clinical trial methods, appropriate 
enrollment of subject cohort, timely achievement of trial milestones).  The Protocol CI must 
be a participating trial investigator.
Compliance with Trial Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Amendments Act (FDAAA) of 2007 
and the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, the Sponsor 
 
 
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of the trial is solely responsible for determining whether the trial and its results are subject to 
the 
requirements 
for 
submission 
to 
http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries.  Merck, as Sponsor of this trial, will 
review this protocol and submit the information necessary to fulfill these requirements. 
Merck entries are not limited to FDAAA or the EMA clinical trial directive mandated trials.  
Information posted will allow subjects to identify potentially appropriate trials for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate trial locations and trial site contact information.  
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this trial or its results to those 
registries.
Quality Management System
By signing this protocol, the Sponsor agrees to be responsible for implementing and 
maintaining a quality management system with written development procedures and 
functional area standard operating procedures (SOPs) to ensure that trials are conducted and 
data are generated, documented, and reported in compliance with the protocol, accepted 
standards of Good Clinical Practice, and all applicable federal, state, and local laws, rules and 
regulations relating to the conduct of the clinical trial.
Data Management
The investigator or qualified designee is responsible for recording and verifying the accuracy 
of subject data.  By signing this protocol, the investigator acknowledges that his/her 
electronic signature is the legally binding equivalent of a written signature.  By entering 
his/her electronic signature, the investigator confirms that all recorded data have been 
verified as accurate.
Detailed information regarding Data Management procedures for this protocol will be 
provided 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. Merck will post a synopsis of trial results for approved 
 
 
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products on www.clinicaltrials.gov by 12 months after the last subject's last visit for the 
primary outcome, 12 months after the decision to discontinue development, or product 
marketing (dispensed, administered, delivered or promoted), whichever is later.
These timelines may be extended for products that are not yet marketed, if additional time is 
needed for analysis, to protect intellectual property, or to comply with confidentiality 
agreements with other parties.  Authors of the primary results manuscript will be provided 
the complete results from the Clinical Study Report, subject to the confidentiality agreement. 
When a manuscript is submitted to a biomedical journal, the Sponsor's policy is to also 
include the protocol and statistical analysis plan to facilitate the peer and editorial review of 
the manuscript.  If the manuscript is subsequently accepted for publication, the Sponsor will 
allow the journal, if it so desires, to post on its website the key sections of the protocol that 
are relevant to evaluating the trial, specifically those sections describing the trial objectives 
and hypotheses, the subject inclusion and exclusion criteria, the trial design and procedures, 
the efficacy and safety measures, the statistical analysis plan, and any amendments relating to 
those sections.  The Sponsor reserves the right to redact proprietary information.
For multicenter trials, subsequent to the multicenter publication (or after public disclosure of 
the results online at www.clinicaltrials.gov if a multicenter manuscript is not planned), an 
investigator and his/her colleagues may publish their data independently.  In most cases, 
publication of individual trial site data does not add value to complete multicenter results, 
due to statistical concerns.  In rare cases, publication of single trial site data prior to the main 
paper may be of value.  Limitations of single trial site observations in a multicenter trial 
should always be described in such a manuscript.
Authorship credit should be based on 1) substantial contributions to conception and design, 
or acquisition of data, or analysis and interpretation of data; 2) drafting the article or revising 
it critically for important intellectual content; and 3) final approval of the version to be
published. Authors must meet conditions 1, 2 and 3.  Significant contributions to trial 
execution may also be taken into account to determine authorship, provided that 
contributions have also been made to all three of the preceding authorship criteria.  Although 
publication planning may begin before conducting the trial, final decisions on authorship and 
the order of authors’ names will be made based on participation and actual contributions to 
the trial and writing, as discussed above. The first author is responsible for defending the 
integrity of the data, method(s) of data analysis and the scientific content of the manuscript.
The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or 
presentations regarding this trial 45 days prior to submission for publication/presentation. 
Any information identified by the Sponsor as confidential must be deleted prior to 
submission; this confidentiality does not include efficacy and safety results. Sponsor review 
can be expedited to meet publication timelines.
 
 
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Sargent DJ, Shi Q, Yothers G, Tejpar S, Bertagnolli MM, Thibodeau SN, et al. 
Prognostic impact of deficient mismatch repair (dMMR) in 7,803 stage II/III 
colon cancer (CC) patients (pts): A pooled individual pt data analysis of 17 
adjuvant trials in the ACCENT database [abstract]. Abstracts of the 50th annual 
Meeting of American Society of Clinical Oncology; 2014 May 30 - Jun 3; 
Illinois(United States); ASCO; 2014. p. 2.
 
 
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[34]
Grothey A, Van Cutsem E, Sobrero A, Siena S, Falcone A, Ychou M, et al. 
Regorafenib monotherapy for previously treated metastatic colorectal cancer 
(CORRECT): an international, multicentre, randomised, placebo-controlled, 
phase 3 trial. Lancet. 2013 Jan 26;381(9863):303-12.
[35]
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.
[36]
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.
[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.
[38]
Clopper CJ, Pearson ES. The use of confidence or fiducial limits illustrated in the 
case of binomial. Biometrika 1934;26(4):404-13.
[39]
Wilke H, Muro K, Van Cutsem E, Oh SC, Bodoky G, Shimada Y, et al. 
Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with 
previously 
treated 
advanced 
gastric 
or 
gastro-oesophageal 
junction 
adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet 
Oncol. 2014 Oct;15(11):1224-35.
[40]
Tournigand C, AndréT, Achille E, Lledo G, Flesh M, Mery-Mignard D, et al. 
FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal 
cancer: A randomized GERCOR study. J Clin Oncol 2004;22(2):229-37.
[41]
Sobrero AF, Maurel J, Fehrenbacher L, Scheithauer W, Abubakr YA, Lutz MP, 
et al. EPIC: Phase III trial of cetuximab plus irinotecan after fluoropyrimidine 
and oxaliplatin failure in patients with metastatic colorectal cancer. J Clin Oncol 
2008;26(14):2311-9.
[42]
Tournigand C, Andre T, Achille E, Lledo G, Flesh M, Mery-Mignard D, et al. 
FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal 
cancer: a randomized GERCOR study. J Clin Oncol. 2004 Jan 15;22(2):229-37.
[43]
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. 
New response evaluation criteria in solid tumours: revised RECIST guideline 
(version 1.1). Eur J Cancer 2009;45(2):228-47.
 
 
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APPENDICES
Merck Code of Conduct for Clinical Trials
Merck*
Code of Conduct for Clinical Trials
I.
Introduction
A. Purpose
Merck, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing and reporting these trials in 
compliance with the highest ethical and scientific standards. Protection of subject safety is the overriding concern in 
the design of clinical trials. In all cases, Merck clinical trials will be conducted in compliance with local and/or 
national regulations and in accordance with the ethical principles that have their origin in the Declaration of Helsinki. 
B. Scope
Such standards shall be endorsed for all clinical interventional investigations sponsored by Merck irrespective of the 
party (parties) employed for their execution (e.g., contract research organizations, collaborative research efforts). This 
Code is not intended to apply to trials which are observational in nature, or which are retrospective. Further, this Code 
does not apply to investigator-initiated trials which are not under the control of Merck.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of Merck or comparator products.  Alternatively, Merck may 
conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to determine 
subject preferences, etc.  
The design (i.e., subject population, duration, statistical power) must be adequate to address the specific purpose 
of the trial.  Research subjects must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
Merck selects investigative sites based on medical expertise, access to appropriate subjects, adequacy of facilities 
and staff, previous performance in Merck trials, as well as budgetary considerations.  Prior to trial initiation, sites 
are evaluated by Merck personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Trial sites are monitored to assess compliance with the trial protocol and general principles of Good Clinical 
Practice.  Merck reviews clinical data for accuracy, completeness and consistency. Data are verified versus source 
documentation according to standard operating procedures.  Per Merck policies and procedures, if fraud, 
misconduct or serious GCP-non-Compliance are suspected, the issues are promptly investigated. When necessary, 
the clinical site will be closed, the responsible regulatory authorities and ethics review committees notified and 
data disclosed accordingly. 
B. Publication and Authorship
To the extent scientifically appropriate, Merck seeks to publish the results of trials it conducts.  Some early phase or 
pilot trials are intended to be hypothesis-generating rather than hypothesis testing.  In such cases, publication of 
results may not be appropriate since the trial may be underpowered and the analyses complicated by statistical issues 
of multiplicity.
Merck’s policy on authorship is consistent with the requirements outlined in the ICH-Good Clinical Practice 
guidelines. In summary, authorship should reflect significant contribution to the design and conduct of the trial, 
performance or interpretation of the analysis, and/or writing of the manuscript.  All named authors must be able to 
defend the trial results and conclusions.  Merck funding of a trial will be acknowledged in publications. 
 
 
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III. Subject Protection
A. IRB/ERC review
All clinical trials will be reviewed and approved by an independent IRB/ERC before being initiated at each site.  
Significant changes or revisions to the protocol will be approved by the IRB/ERC prior to implementation, except that 
changes required urgently to protect subject safety and well-being may be enacted in anticipation of IRB/ERC 
approval. For each site, the IRB/ERC and Merck will approve the subject informed consent form. 
B. Safety
The guiding principle in decision-making in clinical trials is that subject welfare is of primary importance.  Potential 
subjects will be informed of the risks and benefits of, as well as alternatives to, trial participation. At a minimum, trial 
designs will take into account the local standard of care.  Subjects are never denied access to appropriate medical care 
based on participation in a Merck clinical trial. 
All participation in Merck clinical trials is voluntary.  Subjects are enrolled only after providing informed consent for 
participation.  Subjects may withdraw from a Merck trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
Merck is committed to safeguarding subject confidentiality, to the greatest extent possible.  Unless required by law, 
only the investigator, sponsor (or representative) and/or regulatory authorities will have access to confidential medical 
records that might identify the research subject by name.  
D. Genomic Research
Genomic Research will only be conducted in accordance with informed consent and/or as specifically authorized by 
an Ethics Committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive.  It is Merck’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of Merck trials.   Merck does not pay incentives to 
enroll subjects in its trials.  However, when enrollment is particularly challenging, additional payments may be made 
to compensate for the time spent in extra recruiting efforts.
Merck does not pay for subject referrals.  However, Merck may compensate referring physicians for time spent on 
chart review to identify potentially eligible subjects.
B. Clinical Research Funding 
Informed consent forms will disclose that the trial is sponsored by Merck, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial.  However, the local IRB/ERC may wish to alter 
the wording of the disclosure statement to be consistent with financial practices at that institution.  As noted above, 
publications resulting from Merck trials will indicate Merck as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices including, in the U.S., those established by the American Medical 
Association (AMA). 
V. Investigator Commitment
Investigators will be expected to review Merck’s Code of Conduct as an appendix to the trial protocol, and in signing 
the protocol, agree to support these ethical and scientific standards.
* In this document, "Merck" refers to Merck Sharp & Dohme Corp. and Schering Corporation, each of which is a 
subsidiary of Merck & Co., Inc.  Merck is known as MSD outside of the United States and Canada.  As warranted by 
context, Merck also includes affiliates and subsidiaries of Merck & Co., Inc."
 
 
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Collection and Management of Specimens for Future Biomedical Research
1. Definitions
a.
Biomarker:  A biological molecule found in blood, other body fluids, or tissues that is 
a sign of a normal or abnormal process or of a condition or disease.  A biomarker may 
be used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics:  The investigation of variations of DNA and RNA characteristics 
as related to drug/vaccine response.2
c.
Pharmacogenetics:  A subset of pharmacogenomics, pharmacogenetics is the 
influence of variations in DNA sequence on drug/vaccine response.2
d. DNA:  Deoxyribonucleic acid.
e.
RNA:  Ribonucleic acid.
2. Scope of Future Biomedical Research
The 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 the 
Future Biomedical Research sub-trial.
b. Informed Consent
Informed consent for specimens (i.e., DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all subjects or legal guardians, at a trial 
visit by the investigator or his or her designate.  Informed consent for Future 
Biomedical Research should be presented to the subjects on Visit 1.  If delayed, 
present consent at next possible Subject Visit. Informed consent must be obtained 
prior to collection of all Future Biomedical Research specimens.  Consent forms 
signed by the subject will be kept at the clinical trial site under secure storage for 
regulatory reasons.  
 
 
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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 Merck 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 
Sponsor’s privacy and confidentiality requirements. Any contracted third party analyses 
will conform to the specific scope of analysis outlined in this sub-trial. Future Biomedical 
Research specimens remaining with the third party after 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 
 
 
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trial are still available, the investigator will contact the Sponsor using the designated 
mailbox (clinical.specimen.management@merck.com) and a form will be provided 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 
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 
 
 
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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 (i.e., 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@merck.com.
13. References
1. National Cancer Institute: http://www.cancer.gov/dictionary/?searchTxt=biomarker
2. International Conference on Harmonisation: DEFINITIONS FOR GENOMIC 
BIOMARKERS, PHARMACOGENOMICS, PHARMACOGENETICS, GENOMIC 
DATA 
AND 
SAMPLE 
CODING 
CATEGORIES 
-
E15; 
http://www.ich.org/LOB/media/MEDIA3383.pdf
 
 
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Understanding the Intent, Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff
 
 
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Response Evaluation Criteria in Solid Tumors 
RECIST 1.1* will be used in this study for assessment of tumor response. 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 [43].
 
 
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ECOG Performance Status
The ECOG PS, developed by the ECOG, Robert L. Comis, MD, Group Chair, will be used.
Oken M, Creech R, Tormey D, et al. Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol. 1982;5:649-655.
http://ecog-acrin.org/resources/ecog-performance-status
 
 
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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).
 
 
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List of Abbreviations
Abbreviation/Term
Definition
1L
First Line
5-FU
5-fluorouracil
AE
Adverse Event
ADA
Anti-Drug Antibodies
ALT
Alanine Aminotransferase
ANC
Absolute Neutrophil Count
aPTT
Activated Partial Thromboplastin Time
ASaT
All Subjects as Treated
ASCO
American Society of Clinical Oncology
AST
Aspartate Aminotransferase
AUC
Area Under the Curve
BCG
Bacillus Calmette-Guerin
ß-hCG
Beta Human Chorionic Gonadotropin
CBC
Complete Blood Count
CI
Confidence Interval
CIMP
CPG Island Methylator Phenotype
CIN
Chromosomal Instability
CNS
Central Nervous System
CR
Complete Response
CRC
Colorectal Carcinoma
CrCl
Calculated Creatinine Clearance
CRF
Case Report Form
CSR
Clinical Study Report
CT
Computed Tomography
CTCAE
Common Toxicity Criteria for Adverse Events
CTLA-4
Cytotoxic T-Lymphocyte-Associated Antigen-4
DCR
Disease Control Rate
dMMR
Mismatch Repair Deficient
DNA
Deoxyribonucleic acid
DOR
Duration of Response
ECI
Events of Clinical Interest
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
eDMC
External Data Monitoring Committee
EGFR
Epidermal Growth Factor Regulator
ELISA
Enzyme-linked Immunosorbent assay
ERC
Ethics Review Committee
ESMO
European Society for Medical Oncology
FBR
Future Biomedical Research
FDA
Food and Drug Administration
 
 
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Abbreviation/Term
Definition
FDAAA
Food and Drug Administration Amendments Act
FIH
First in Human
FSH
Follicle Stimulating Hormone
GCP
Good Clinical Practice
GFR
Glomerular Filtration Rate
HBsAg
Hepatitis B surface Antigen
HCV
Hepatitis C Virus
HIV
Human Immunodeficiency Virus
HR
Hazard Ratio
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
Ig
Immunoglobulin
IgV
Immunoglobulin Variable-Type
IHC
Immunohistochemistry
INR
International Normalized Ratio
irAEs
Immune-related Adverse Events
irRECIST
Immune related RECIST (Modification of RECIST 1.1)
irRC
Immune realted Response Criteria
IRB
Institutional Review Board
ITIM
Immunoreceptor Tyrosine-based Inhibition Motif
ITSM
Immunoreceptor Tyrosine-based Switch Motif
IUD
Intrauterine Device
IUS
Intrauterine Hormone-releasing System
IV
Intravenous
IVRS
Interactive Voice Response System
IWRS
Integrated Web Response System
KM
Kaplan-Meier
kg
Kilogram
LDH
Lactate Dehydrogenase
mAb
Monoclonal Antibody
mCRC
Metastatic Colorectal Carcinoma
mcL
Microliters
mg
Milligram
mg/kg
Milligram per Kilogram
mL
milliliter
MMR
Mismatched Repair
MRI
Magnetic Resonance Imaging
mRNA
Messenger Ribonucleic Acid
MSD
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., 
Inc.
MSI-H
Microsatellite Instability High
NA or N/A
Not Applicable
 
 
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Abbreviation/Term
Definition
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NSAID
Non-Steroidal Anti-inflammatory Drug
NSCLC
Non-Small Cell Lung Cancer
ORR
Objective Response Rate
OS
Overall Survival
OTC
Over-the-counter
PD
Progressive Disease
PD-1
Programmed cell death 1
PD-2
Programmed cell death 2
PFS
Progression Free Survival
PIN
Personal Identification Number
PK
Pharmacokinetic
PKCθ
Protein Kinase C-theta
PR
Partial Response
PT
Prothrombin Time
PS
Performance Status
Q3W
Every 3 Weeks
Q9W
Every 9 Weeks
Q12W
Every 12 Weeks
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
Ribonucleic Acid
RR
Response Rate
SAE
Serious Adverse Events
SAP
Statistical Analysis Plan
SGOT
Serum Glutamic Oxaloacetic Transaminase
SGPT
Serum Glutamic Pyruvic Transaminase
SIM
Site Imaging Manual
SOP
Standard Operating Procedures
sSAP
Supplemental Statistical Analysis Plan
Tregs
Regulatory T cells
TSH
Thyroid Stimulating Hormone
ULN
Upper Limit of Normal
VEGF
Vascular Endothelial Growth Factor
ZAP70
Zeta-Chain Associated Protein Kinase
 
 
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Country-specific Requirements
France-specific Requirements
France has country-specific requirements for the protocol which are summarized below:
Section 5.1.1 – Subject Inclusion Criteria
Subjects participating in the study in France may not be enrolled into Cohort B. They must 
meet the criteria for Cohort A only for enrollment.
 
 
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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 7.0 – 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
 
 
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Supplemental Statistical Analysis Plan (sSAP)
1. INTRODUCTION
This supplemental SAP (sSAP) is a companion document to the protocol. In addition
to the information presented in the protocol SAP which provides the principal
features of confirmatory analyses for this trial, this supplemental SAP provides
additional statistical analysis details/data derivations and documents modifications or
additions to the analysis plan that are not “principal” in nature and result from
information that was not available at the time of protocol finalization. 
2. SUMMARY OF CHANGES
A second cohort of 60 subjects was added to evaluate pembrolizumab 200 mg 3QW
in subjects with colorectal cancer (CRC) who have undergone 1 line of systemic
treatment (fluoropyrimidine + oxaliplatin or fluoropyrimidine + irinotecan +/- anti-
VEGF/EGFR monoclonal antibody).  The first cohort will be designated Cohort A,
the second, Cohort B.
Details and clarifications for Cohort A and B are given in the following sections:
Analysis summary, details and sample size calculation for Cohort B  (Section 3.1,
3.6.1, 3.6.2, 3.8, 3.9), Secondary Efficacy Endpoints (Sections 3.4.1), definition of
duration of response and censoring rules (Sections 3.6.1), Interim analysis (Section
3.7). 
3. ANALYTICAL AND METHODOLOGICAL DETAILS
3.1 Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized in Table 1. The
comprehensive plan is provided in Sections 3.2 through 3.12. The analyses described
in section 3will be applied to Cohort A and Cohort B separately.
 
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Table 1  Key Elements of the Statistical Analysis Plan
Study Design Overview 
A  Phase II Study of Pembrolizumab in Previously Treated Subjects
with Mismatched Repair Deficient or Microsatellite-High Colorectal
Carcinoma
Treatment Assignment 
This is an open-label study.
Analysis Populations
All Subjects as Treated (ASaT)
Primary Endpoint(s)
ORR based on RECIST 1.1 assessed by central imaging vendor
Statistical Methods for
Key Efficacy Analyses
The analyses described in this section will be applied separately for
Cohort A and Cohort B.
Cohort A: The primary hypothesis will be evaluated by testing the
centrally reviewed RECIST 1.1 ORR greater than 15%using Exact
method based on binomial distribution.
Cohort B: 95% CI for ORR will be calculated using Exact method
based on binomial distribution.
Statistical Methods for
Key Safety Analyses
Count and percentage of AE will be provided.
Interim Analyses
For Cohort A, an  interim analysis is planned in this study. The
interim analysis is summarized below; Details are provided in
Section 3.7.
 
Interim Analysis
o 
o 
Purpose: Efficacy analysis for primary endpoint
ORR
 
Final Analysis
o 
 
There is no interim analysis planned for Cohort B.
Multiplicity
For Cohort A, the overall type I error is controlled at 2.5% (one-
sided) by group sequential approach for interim analysis and final
analysis. For Cohort B, no multiplicity adjustment will be applied.
Sample Size and Power 
The overall sample size is approximately 120.
Cohort A: The planned sample size is 60 subjects.
For the ORR per RECIST 1.1 assessed by central imaging vendor,
the trial has 93%power to demonstrate that ORR of pembrolizumab
is better than 15%at an overall one-sided 2.5% alpha-level, if the
underlying centrally reviewed RECIST 1.1 ORR of pembrolizumab
is 35%.
Cohort B: The planned sample size is 60 subjects.
 
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3.2 
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.
This trial is being conducted as an open-label study, i.e., subjects, investigators, and
SPONSOR personnel will be aware of subject treatment assignments after each
subject is enrolled and treatment is assigned.
The Clinical Biostatistics department will generate the allocation schedule.
3.3 Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Protocol Section 3.0.
3.4 Analysis Endpoints
3.4.1 Efficacy Endpoints
3.4.1.1 Primary Efficacy Endpoint
 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 complete response (CR) or partial response (PR). Responses
are based upon blinded central imaging vendor per RECIST 1.1.
3.4.1.2 Secondary Efficacy Endpoints
 Disease Control Rate (DCR) - RECIST 1.1 assessed by central imaging vendor
Disease control rate (DCR) is defined as the percentage of subjects who have
achieved confirmed CR or PR or have demonstrated SD for at least 24 weeks prior to
any evidence of progression.
 Duration of Response (DOR) - RECIST 1.1 assessed 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 disease progression or
death.
 Progression-free Survival (PFS) - RECIST 1.1 assessed by central imaging
vendor
PFS is defined as the time from first day of study treatment to the first documented
disease progression or death due to any cause, whichever occurs first.
 
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
Overall survival (OS)
OS is defined as the time from first day of study treatment to death due to any cause.
Subjects without documented death at the time of the final analysis will be censored
at the date of the last follow-up.
3.4.2 Safety Endpoints
The primary safety objective of this trial is to characterize the safety and tolerability
of pembrolizumab in subjects MMR deficient or MSI-high CRC.  The primary safety
analysis will be based on subjects who experienced toxicities as defined by CTCAE,
Version 4.0 criteria (Protocol Appendix 12.6). The attribution to drug, time-of-onset,
duration of the event, its resolution, and any concomitant medications administered
will be recorded.  AEs will be analyzed including but not limited to all AEs, SAEs,
fatal AEs, and laboratory changes.  Furthermore, specific immune-related adverse
events (irAEs) will be collected and designated as immune-related events of clinical
interest (ECIs) as described in Protocol Section 7.2.3.2.
3.5 Analysis Populations
3.5.1 Efficacy Analysis Populations
The All Subjects as Treated (ASaT) population will be used for the analysis of ORR,
DCR, PFS, and OS. The ASaT population consists of all subjects who received at
least one dose of study treatment.
The analysis population for DOR consists of responders.
Details on the approach to handling missing data are provided in Protocol Section 8.6
Statistical Methods.
3.5.2 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 allocated subjects who
received at least one dose of study treatment.
At least one laboratory or vital sign measurement obtained subsequent to at least one
dose of study treatment is required for inclusion in the analysis of each specific
parameter.  To assess change from baseline, a baseline measurement is also required.
Details on the approach to handling missing data for safety analyses are provided in
Protocol Section 8.6 Statistical Methods.
 
 
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3.6   Statistical Methods
3.6.1 Statistical Methods for Efficacy Analyses
This section describes the statistical methods that address the primary and secondary
objectives.
The primary efficacy endpoint is ORR per RECIST 1.1 assessed by central imaging
vendor. In Cohort A, the point estimate, 95% confidence interval, and p-value for
testing the response rate is greater than 15% will be provided using exact binomial
method proposed by Clopper and Pearson (1934) [1]. In Cohort B, the point estimate
and 95% confidence interval will be provided using exact binomial method proposed
by Clopper and Pearson  (1934) [1]. Subjects in the primary analysis population
(ASaT) without ORR data will be counted as non-responder.
For DCR, the point estimate, 95% confidence interval will be provided using exact
binomial method proposed by Clopper and Pearson (1934) [1].Subjects in the analysis
population (ASaT) with missing DCR are considered as disease not under control.
For DOR, Kaplan-Meier (KM) curves and median estimates from the KM curves will
be provided as appropriate.
Censoring rules for DOR are summarized in Table 2.
 
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For PFS and OS endpoints, Kaplan-Meier (KM) curves and median estimates from
the KM curves will be provided as appropriate.
The efficacy analysis is summarized in Table 3 . The efficacy analyses will be applied
to Cohort A and Cohort B separately.
 
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3.6.2 Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters
including adverse experiences (AEs), laboratory tests, and vital signs. Count and
percentage of AE will be provided.
3.6.3 Summaries of Baseline Characteristics, Demographics, and Other Analyses
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 (e.g., age, gender), baseline characteristics, primary and
 
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secondary diagnoses, and prior and concomitant therapies will be summarized either
by descriptive statistics or categorical tables for all enrolled subjects.
3.7 
Interim Analyses
For Cohort A, there is one interim analysis planned in this study. There is no interim
analysis planned for Cohort B. In each cohort separately, final analysis is to be
performed 6 months after the last subject is enrolled. Subjects will continue to be
followed after the final analysis until overall trial ends. The purpose of the interim
analysis is efficacy  analysis for primary endpoint ORR  
 Results will be
reviewed by study team.
The O`Brien-Fleming alpha spending function will be used to control the Type-I error
rate. 
3.8 
Multiplicity
For Cohort A, the overall type I error is controlled at 2.5% (one-sided) by group
sequential approach for interim analysis and final analysis. Refer to Section 3.7 for
group sequential approach.
For Cohort B, no multiplicity adjustment will be applied.
 
 
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3.9 
Sample Size and Power Calculations
Efficacy and safety for each cohort will be analyzed separately.
In this study, approximately 60 subjects for each cohort will be enrolled.
Cohort A
With a sample size of 60, the study has 93% power to reject the null hypothesis of
ORR=15% with a one-sided type I error rate of 2.5% if the true ORR is 35%. The
historical response rate is less than 5% in CORRECT study [2].
 
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3.10 Subgroup Analyses and Effect of Baseline Factors
The estimate of the treatment effect for the primary endpoint will be estimated and
plotted within each category of the following classification variables:
 Age category (≤65 vs. >65 years)
 Sex (Female vs. Male)
 Race (white vs. non-white)
The consistency of the treatment effect will be assessed descriptively via summary
statistics by category for the classification variables listed above.
3.11 Compliance (Medication Adherence)
Drug accountability data for MK-3475 will be collected during the study. Any
deviation from protocol-directed administration will be reported.
3.12 Extent of Exposure
Extent of Exposure for a subject is defined as number of cycles in which the subject
receives the study medication infusion. Summary statistics will be provided on
Extent of Exposure for ASaT population.
 
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4.
REFERENCES
[1] 
Clopper CJ, Pearson ES. The use of confidence or fiducial limits illustrated in
the case of binomial. Biometrika 1934;26(4):404-13.
[2] 
Wilke H, Muro K, Van Cutsem E, Oh SC, Bodoky G, Shimada Y, et al.
Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with
previously treated advanced gastric or gastro-oesophageal junction
adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial.
Lancet Oncol. 2014 Oct;15(11):1224-35.
[3] 
Tournigand C, AndréT, Achille E, Lledo G, Flesh M, Mery-Mignard D, et al.
FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced
colorectal cancer: A randomized GERCOR study. J Clin Oncol
2004;22(2):229-37.
[4] 
Sobrero AF, Maurel J, Fehrenbacher L, Scheithauer W, Abubakr YA, Lutz
MP, et al. EPIC: Phase III trial of cetuximab plus irinotecan after
fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal
cancer. J Clin Oncol 2008;26(14):2311-9.
 
 
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