Clinical trial NCT02335411
Conditions: Gastric Adenocarcinoma Gastroesophageal Junction Adenocarcinoma
Keywords: Gastric cancer Gastroesophageal junction cancer Programmed Cell Death-1 (PD1, PD-1) Programmed Death-Ligand 1 (PDL1, PD-L1)
Sponsor: Merck Sharp & Dohme LLC
Start date: 2015-02-03; Completion date: 2021-07-23
Enrollment: 318 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a study of pembrolizumab (MK-3475) for advanced gastric or gastroesophageal junction adenocarcinoma; pembrolizumab will be given as monotherapy to participants who have had previous treatment or who are treatment-naïve; pembrolizumab will also be evaluated as combination therapy with cisplatin and 5-Fluorouracil (5-FU) or (Japan only) capecitabine in treatment-naïve participants. The primary study hypothesis is that pembrolizumab will provide a clinically meaningful Overall Response Rate (ORR).

Detailed description:
This study will have 3 cohorts. In Cohort 1, participants who have received at least two prior therapies for their advanced disease will receive monotherapy with pembrolizumab. In Cohort 2, participants who have not received any previous therapy for their disease will receive pembrolizumab in combination with cisplatin and 5-FU or (Japan only) capecitabine. In Cohort 3, participants who have not received any previous therapy and who have programmed death ligand 1 (PD-L1)-positive tumors will receive pembrolizumab monotherapy.

Arms: arm 1: Participants receive pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle (Q3W) arm 2: Participants receive pembrolizumab 200 mg IV each 3-week cycle (Q3W) + cisplatin 80 mg/m\^2 IV Q3W for up to 6 cycles + 5-FU 800 mg/m\^2 IV on Days 1-5 every 3 weeks or (Japan only) capecitabine 1000 mg/m\^2 orally, twice per day (BID) on Days 1-14 of each 3-week cycle arm 3: Programmed death-ligand 1 (PD-L1) positive participants receive pembrolizumab 200 mg IV on Day 1 of each 3-week cycle (Q3W)
Interventions: intervention 1: pembrolizumab intervention 2: cisplatin intervention 3: 5-FU intervention 4: capecitabine
Intervention descriptions: intervention 1: IV infusion intervention 2: IV infusion intervention 3: IV infusion intervention 4: oral tablets

Protocol documents:
Prot_SAP_000.pdf: 
Official Protocol Title: 
NCT number: 
Document Date: 
A Phase II Clinical Trial of Pembrolizumab as Monotherapy and 
in Combination with Cisplatin+5-Fluorouracil in Subjects with 
Recurrent or Metastatic Gastric or Gastroesophageal Junction 
Adenocarcinoma (KEYNOTE-059).
01-May-2020
NCT02335411


Product:  MK-3475 
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Protocol/Amendment No.: 059-12 
MK-3475-059-12 Final Protocol
01-May-2020
Confidential
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., 
WHITEHOUSE STATION, NJ, U.S.A.
SPONSOR:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. 
(hereafter referred to as the Sponsor or Merck)
One Merck Drive
P.O. Box 100
Whitehouse Station, NJ 08889-0100, U.S.A.
Protocol-specific Sponsor Contact information can be found in the Investigator Trial File
Binder (or equivalent).
TITLE:
A Phase II Clinical Trial of Pembrolizumab as Monotherapy and in Combination with 
Cisplatin+5-Fluorouracil 
in 
Subjects 
with 
Recurrent 
or 
Metastatic 
Gastric 
or 
Gastroesophageal Junction Adenocarcinoma (KEYNOTE-059). 
IND NUMBER:  123,482
EudraCT NUMBER:  2014-003574-16
 
 
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TABLE OF CONTENTS
DOCUMENT HISTORY ..................................................................................................... 11
SUMMARY OF CHANGES................................................................................................ 14
1.0
TRIAL SUMMARY.................................................................................................. 21
2.0
TRIAL DESIGN........................................................................................................ 22
2.1
Trial Design ........................................................................................................... 22
2.2
Trial Diagram........................................................................................................ 24
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 27
3.1
Primary Objective(s) & Hypothesis(es).............................................................. 27
3.2
Secondary Objective(s) & Hypothesis(es)........................................................... 28
3.3
Exploratory Objectives......................................................................................... 28
4.0
BACKGROUND & RATIONALE.......................................................................... 29
4.1
Background ........................................................................................................... 29
Pharmaceutical and Therapeutic Background .................................................... 29
Pre-clinical and Clinical Trials ........................................................................... 30
Ongoing Clinical Trials....................................................................................... 30
4.2
Rationale................................................................................................................ 31
Rationale for the Trial and Selected Subject Population .................................... 31
Cohort 1:  3L and Later Subjects................................................................. 31
Cohort 2:  1L Subjects Receiving Combination Treatment......................... 32
Cohort 3:  1L Subjects Receiving Pembrolizumab Monotherapy ............... 33
Rationale for Dose Selection/Regimen/Modification......................................... 33
Rationale for Pembrolizumab 200 mg Q3W Dosing................................... 33
Rationale for Endpoints ...................................................................................... 34
Efficacy Endpoints....................................................................................... 34
Safety Endpoints.......................................................................................... 35
Exploratory Endpoints ................................................................................. 35
4.2.3.3.1
Planned Exploratory Biomarker Research............................................ 35
Future Biomedical Research........................................................................ 36
4.3
Benefit/Risk ........................................................................................................... 37
5.0
METHODOLOGY ................................................................................................... 37
 
 
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5.1
Entry Criteria........................................................................................................ 37
Diagnosis/Condition for Entry into the Trial...................................................... 37
Subject Inclusion Criteria.................................................................................... 37
Subject Exclusion Criteria .................................................................................. 40
5.2
Trial Treatment(s) ................................................................................................ 42
Dose Selection/Modification .............................................................................. 43
Dose Selection (Preparation) ....................................................................... 43
Dose Modification (Escalation/Titration/Other).......................................... 43
5.2.1.2.1
Definition of Dose Limiting Toxicity................................................... 43
5.2.1.2.2
Guidelines for Dose Modification Due to Adverse Events .................. 44
5.2.1.2.3
Dose Modification for Pembrolizumab ................................................ 45
5.2.1.2.4
Dose Modification and Toxicity Management of Infusion 
Reactions Related to Pembrolizumab................................................... 49
5.2.1.2.5
Dose Modifications for Cisplatin.......................................................... 50
5.2.1.2.6
Dose Modifications for 5-FU/Capecitabine......................................... 52
Timing of Dose Administration.......................................................................... 53
Pembrolizumab ............................................................................................ 53
Cisplatin (Cohort 2 only) ............................................................................. 53
5-Fluorouracil (Cohort 2 only)..................................................................... 54
Capecitabine (Cohort 2 only)....................................................................... 54
Trial Blinding/Masking....................................................................................... 54
5.3
Randomization or Treatment Allocation............................................................ 54
5.4
Stratification.......................................................................................................... 54
5.5
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 54
Acceptable Concomitant Medications ................................................................ 55
Prohibited Concomitant Medication................................................................... 55
5.6
Rescue Medications & Supportive Care............................................................. 56
Supportive Care Guidelines for Pembrolizumab ................................................ 56
Supportive Care Guidelines for Chemotherapy Agents...................................... 56
5.7
Diet/Activity/Other Considerations..................................................................... 57
Diet...................................................................................................................... 57
Contraception...................................................................................................... 57
 
 
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Use in Pregnancy ................................................................................................ 57
Use in Nursing Women....................................................................................... 58
Pembrolizumab ............................................................................................ 58
Cisplatin....................................................................................................... 58
5-Fluorouracil .............................................................................................. 58
Capecitabine (Japan).................................................................................... 58
Photosensitivity................................................................................................... 58
5.8
Subject Withdrawal/Discontinuation Criteria................................................... 58
Discontinuation of Study Treatment after CR .................................................... 60
5.9
Subject Replacement Strategy............................................................................. 60
5.10
Beginning and End of the Trial ........................................................................... 60
5.11
Clinical Criteria for Early Trial Termination ................................................... 60
6.0
TRIAL FLOW CHART ........................................................................................... 61
6.1
Initial Treatment Phase........................................................................................ 61
6.2
Second Course Phase (Retreatment)................................................................... 64
7.0
TRIAL PROCEDURES ........................................................................................... 66
7.1
Trial Procedures ................................................................................................... 66
Administrative Procedures.................................................................................. 66
Informed Consent......................................................................................... 66
7.1.1.1.1
General Informed Consent.................................................................... 66
7.1.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research................................................................................................ 67
Inclusion/Exclusion Criteria ........................................................................ 67
Subject Identification Card .......................................................................... 67
Medical History ........................................................................................... 67
7.1.1.4.1
Disease Details...................................................................................... 67
Prior and Concomitant Medications Review............................................... 67
7.1.1.5.1
Prior Medications.................................................................................. 67
7.1.1.5.1.1
Prior Treatment Details for Gastric or Gastroesophageal 
Junction Adenocarcinoma........................................................................68
7.1.1.5.2
Concomitant Medications..................................................................... 68
7.1.1.5.2.1
Subsequent Anti-cancer Therapy Status .........................................68
 
 
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Assignment of Screening Number............................................................... 68
Assignment of Randomization Number....................................................... 68
Trial Compliance (Medication/Diet/Activity/Other)................................... 69
Clinical Procedures/Assessments........................................................................ 69
Adverse Event (AE) Monitoring.................................................................. 69
Physical Exam.............................................................................................. 69
7.1.2.2.1
Full Physical Exam ............................................................................... 69
7.1.2.2.2
Directed Physical Exam........................................................................ 69
Vital Signs.................................................................................................... 70
12-Lead Electrocardiogram ......................................................................... 70
Eastern Cooperative Oncology Group (ECOG) Performance Status .......... 70
Pharmacokinetic/Pharmacodynamic Evaluations........................................ 70
7.1.2.6.1
Blood Collection for Serum Pembrolizumab (MK-3475) .................... 70
7.1.2.6.2
Blood Collection for Anti-Pembrolizumab (MK-3475)....................... 70
Tumor Imaging and Assessment of Disease................................................ 70
7.1.2.7.1
Baseline Tumor Imaging ...................................................................... 71
7.1.2.7.2
Tumor Imaging During Trial ................................................................ 71
7.1.2.7.3
Second Course (Retreatment) Tumor Imaging..................................... 72
7.1.2.7.4
Assessment of Disease – RECIST 1.1 and irRECIST.......................... 72
7.1.2.7.4.1
Application of irRECIST ................................................................73
Tumor Tissue Collection.............................................................................. 74
Blood Collections – Genetics, Proteomics and Transcriptional Analyses... 75
Laboratory Procedures/Assessments .................................................................. 75
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) .. 75
Future Biomedical Research........................................................................ 77
Other Procedures................................................................................................. 78
Withdrawal/Discontinuation........................................................................ 78
7.1.4.1.1
Withdrawal From Future Biomedical Research ................................... 78
Blinding/Unblinding .................................................................................... 78
Calibration of Equipment............................................................................. 79
Visit Requirements.............................................................................................. 79
Screening...................................................................................................... 79
 
 
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Treatment Cycles ......................................................................................... 79
Discontinuation Visit ................................................................................... 80
Post-Treatment............................................................................................. 80
7.1.5.4.1
Safety Follow-up................................................................................... 80
7.1.5.4.2
Follow-up Visits ................................................................................... 80
7.1.5.4.3
Survival Follow-up ............................................................................... 80
Second Course Phase (Retreatment Period) ................................................ 81
Survival Status ............................................................................................. 82
7.2
Assessing and Recording Adverse Events .......................................................... 82
Definition of an Overdose for This Protocol and Reporting of Overdose to 
the Sponsor.......................................................................................................... 83
Reporting of Pregnancy and Lactation to the Sponsor ....................................... 84
Immediate Reporting of Adverse Events to the Sponsor.................................... 84
Serious Adverse Events ............................................................................... 84
Events of Clinical Interest............................................................................ 85
Protocol-Specific Exceptions to Serious Adverse Event Reporting............ 86
Evaluating Adverse Events................................................................................. 86
Sponsor Responsibility for Reporting Adverse Events ...................................... 89
7.3
TRIAL GOVERNANCE AND OVERSIGHT................................................... 89
Executive Oversight Committee......................................................................... 89
Data Monitoring Committee............................................................................... 89
Scientific Advisory Committee........................................................................... 89
8.0
STATISTICAL ANALYSIS PLAN ........................................................................ 89
8.1
Statistical Analysis Plan Summary ..................................................................... 90
8.2
Responsibility for Analyses/In-House Blinding ................................................. 91
8.3
Hypotheses/Estimation ......................................................................................... 91
8.4
Analysis Endpoints ............................................................................................... 91
Efficacy Endpoints.............................................................................................. 91
Safety Endpoints ................................................................................................. 92
8.5
Analysis Populations............................................................................................. 92
Efficacy Analysis Populations ............................................................................ 92
Safety Analysis Populations ............................................................................... 92
 
 
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8.6
Statistical Methods................................................................................................ 92
Statistical Methods for Efficacy Analyses.......................................................... 92
Statistical Methods for Safety Analyses ............................................................. 94
Summaries of Baseline Characteristics, and Demographics............................... 95
8.7
Interim Analyses ................................................................................................... 95
8.8
Multiplicity ............................................................................................................ 96
8.9
Sample Size and Power Calculations .................................................................. 96
8.10
Subgroup Analyses and Effect of Baseline Factors ........................................... 98
8.11
Compliance (Medication Adherence).................................................................. 98
8.12
Extent of Exposure................................................................................................ 98
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 98
9.1
Investigational Product ........................................................................................ 98
9.2
Packaging and Labeling Information ................................................................. 99
9.3
Clinical Supplies Disclosure................................................................................. 99
9.4
Storage and Handling Requirements.................................................................. 99
9.5
Discard/Destruction/Returns and Reconciliation ............................................ 100
9.6
Standard Policies................................................................................................. 100
10.0
ADMINISTRATIVE AND REGULATORY DETAILS..................................... 100
10.1
Confidentiality..................................................................................................... 100
Confidentiality of Data ..................................................................................... 100
Confidentiality of Subject Records................................................................... 100
Confidentiality of Investigator Information...................................................... 101
Confidentiality of IRB/IEC Information........................................................... 101
10.2
Compliance with Financial Disclosure Requirements..................................... 101
10.3
Compliance with Law, Audit and Debarment ................................................. 102
10.4
Compliance with Trial Registration and Results Posting Requirements ...... 104
10.5
Quality Management System............................................................................. 104
10.6
Data Management............................................................................................... 104
10.7
Publications ......................................................................................................... 104
11.0
LIST OF REFERENCES....................................................................................... 106
12.0
APPENDICES......................................................................................................... 109
 
 
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12.1
Merck Code of Conduct for Clinical Trials...................................................... 109
12.2
Collection and Management of Specimens for Future Biomedical 
Research............................................................................................................... 111
12.3
Understanding the Intent, Scope and Public Health Benefits of 
Exploratory Biomarker Research: A Guide for IRBs/IECs and 
Investigational Site Staff .................................................................................... 117
12.4
ECOG Performance Status................................................................................ 128
12.5
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 .. 129
12.6
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for 
Evaluating Response in Solid Tumors .............................................................. 130
12.7
Dose Modification Table (based on modified Toxicity Profile Interval 
[33]) ...................................................................................................................... 131
12.8
List of Abbreviations .......................................................................................... 132
13.0
SIGNATURES......................................................................................................... 135
13.1
Sponsor's Representative ................................................................................... 135
13.2
Investigator.......................................................................................................... 135
 
 
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LIST OF TABLES
Table 1
Adequate Organ Function Laboratory Values ...................................................... 40
Table 2
Trial Treatments.................................................................................................... 43
Table 3
Dose Modifications for Trial Medication ............................................................. 45
Table 4
Dose Modification and Toxicity Management Guidelines for Immune-related 
AEs Associated with Pembrolizumab................................................................... 46
Table 5
Pembrolizumab Infusion Reaction Dose Modification and Treatment 
Guidelines ............................................................................................................. 49
Table 6
Dose Modification Guidelines for Cisplatin Drug-Related Adverse Events........ 51
Table 7
Dose Modification Guidelines for 5-FU/Capecitabine Drug-Related Adverse 
Events.................................................................................................................... 52
Table 8
Imaging and Treatment after 1st Radiologic Evidence of PD............................... 74
Table 9
Laboratory Tests ................................................................................................... 76
Table 10
Evaluating Adverse Events................................................................................... 87
Table 11
Censoring Rules for DOR..................................................................................... 93
Table 12
Summary of Analysis Strategy for Efficacy Endpoints........................................ 94
Table 13
Summary of Interim Analysis Strategy................................................................. 96
Table 14
Two-sided 95% CI of ORR with 210 Subjects..................................................... 97
Table 15
Two-sided 95% CI of ORR with 120 PD-L1 Positive Subjects........................... 97
Table 16
Two-sided 95% CI of ORR with 80 Subjects Meeting Revised Eligibility 
Criteria .................................................................................................................. 97
Table 17
Two-sided 95% CI of AE incidence rate with 18 Subjects .................................. 98
Table 18
Product Descriptions............................................................................................. 99
 
 
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LIST OF FIGURES
Figure 1
Cohort 1 –3L+ Monotherapy................................................................................ 25
Figure 2
Cohort 2 –1L Combination Treatment.................................................................. 26
Figure 3
Cohort 3 –1L Monotherapy .................................................................................. 27
 
 
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 12
01-MAY-2020
Addition of language allowing for participants to 
rollover to an extension study. Removal of cohort 4 
from Amendment 11 which was never implemented 
at sites
Amendment 11/ US-specific amendment
29-MAR-2019
Addition of new cohort 4 to be treated with 
mFOLFOX-6, Q2W + pembrolizumab 400 mg,
Q6W as first-line treatment. Amendment 11 was 
never implemented at sites.
Amendment 10
01-NOV-2017
Update pembrolizumab dose modification guidance 
upon health authority request and insertion of 
provision to allow more frequent survival 
monitoring.
Amendment 09
15-DEC-2016
Addition of requirement to discontinue treatment 
upon recurrent Grade 2 pneumonitis to align with the 
overall pembrolizumab program.
Amendment 08/ Japan-specific amendment
02-DEC-2016
Addition of requirement to discontinue treatment 
upon recurrent Grade 2 pneumonitis to align with the 
overall pembrolizumab program.
 
 
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Document
Date of Issue
Overall Rationale
Amendment 07
04-NOV-2015
Update the sample size in Cohort 1 to adjust the 
enrollment for subjects meeting the revised 
eligibility criteria. PD-L1 negative subjects in 
Cohort 1 have passed the futility analysis.
Removal of statistical hypothesis for the Cohort 1 
primary efficacy objective since the objective of the 
study is estimation and the success of the study is 
determined by clinically meaningful ORR and 
durability of the response.
Inclusion criteria updated as by the external 
Scientific Advisory Committee to ensure entry of 
subjects with the ability to participate for the full 
duration of the trial.
Amendment 06/ UK-specific amendment
16-JUL-2015
Addition of option for use of capecitabine instead of 
5-FU (Cohort 2) in Japan only, as per health 
authority request. Removed the collection of the 
MDSC assay and QoL assessments (EORTC QLQ-
C30, EORTC QLQ-ST022) from the protocol.
Amendment 05/ UK-specific amendment
30-JUN-2015
Clarify abstinence language as required by the 
regulatory agency in the UK.
Amendment 04
21-MAY-2015
Addition of option for use of capecitabine instead of 
5-FU (Cohort 2) in Japan only, as per health 
authority request. Removed the collection of the 
MDSC assay and QoL assessments (EORTC QLQ-
C30, EORTC QLQ-ST022) from the protocol.
 
 
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Document
Date of Issue
Overall Rationale
Amendment 03
10-APR-2015
Removed the collection of the MDSC assay and 
QoL assessments (EORTC QLQ-C30, EORTC 
QLQ-ST022) from the protocol.
Amendment 02
16-DEC-2014
Clarifications inserted to further define what is 
considered safely accessible tumor for the purposes 
of this study.
Amendment 01
14-NOV-2014
Correction of error to wording of exclusion criteria 
#2 that affects the interpretation of the criterion and 
would impact enrollment.
Original Protocol
07-NOV-2014
Not Applicable
 
 
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SUMMARY OF CHANGES
PRIMARY REASON(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title(s)
Description of Change (s)
Rationale
1.0
Trial Summary/Duration of Participation
Added extension study 
language
To include extension study
2.2
Trial Diagram
Added: Pembrolizumab 
Extension Study
5.10
Beginning and End of the Trial
Added: Upon study 
completion, participants are 
discontinued and may be
enrolled in a pembrolizumab 
extension study
Cover Page
Removal of US-specific 
amendment text
To reflect Cohort 4 removal, 
which was originally specific
to the US
Cover Page 
1.0
2.1
2.2
3.1
3.2
3.3
4.2.1
4.2.1.4
Title 
Trial Summary
Trial Design
Trial Diagram
Primary Objective(s) & Hypothesis(es)
Secondary Objective(s) & Hypothesis(es)
Exploratory Objective(s) & Hypothesis(es)
Rationale for the Trial and Selected Subject 
Population
Cohort 4: 1L Subjects Receiving 
Combination Treatment with mFOLFOX 6 
regimen)
Removal of Cohort 4 and 
associated rationales, 
treatment regimen, 
objectives, and dose 
modification/supportive care 
details.
To reflect Cohort 4 removal. 
Amendment 11 that included 
a new Cohort 4 was never 
implemented at sites.
 
 
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Section Number (s)
Section Title(s)
Description of Change (s)
Rationale
4.2.2.2
4.2.3.2
5.2
5.2.1.1.1
5.2.1.2.2
5.2.1.2.7
5.2.2
5.6.2
5.7.1
5.7.2
5.7.4
5.8
6.3 
6.4 
7.1.2.6 
7.1.2.7.1
7.1.2.7.2
7.1.3.1
7.1.4.1
7.1.5.4.2
7.1.5.5
Rationale for Pembrolizumab 400 mg Q6W 
dosing for Cohort 4  
Safety Endpoints
Trial Treatments
Cohort  4:  Dose Selection Using a Modified 
Toxicity Probability Interval Design
Dose Modification 
(Escalation/Titration/Other)
Dosing Modification for Oxaliplatin 
Timing of Dose Administration
Supportive Care Guidelines for 
Chemotherapy Agents
Diet
Contraception
Use in Nursing Women
Subject Withdrawal/Discontinuation Criteria
Study flow chart: Initial Treatment Phase-
Cohort 4 only (mFOLFOX-6)
Second Course Phase (Retreatment)-Cohort 
4 only (mFOLFOX-6)
Pharmacokinetic/Pharmacodynamic 
Evaluations
Baseline Tumor Imaging
Tumor Imaging During Trial
Laboratory Safety Evaluations (Hematology, 
Chemistry and Urinalysis)
Withdrawal/Discontinuation
Follow-up Visits
Second Course Phase (Retreatment Period)
 
 
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Section Number (s)
Section Title(s)
Description of Change (s)
Rationale
7.2.1
8.1
8.4.2
8.6.1
8.6.2
8.7
8.9
9.1
9.2
Definition of an Overdose for This Protocol 
and Reporting of Overdose to the Sponsor
Statistical Analysis Plan Summary
Safety Endpoints
Statistical Methods for Efficacy Analyses
Statistical Methods for Safety Analyses
Interim Analyses
Sample size and Power Calculations
Investigational Product 
Packaging and Labelling Information
ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
1.0
2.1
Trial Summary: Number of trial subjects
Trial Design
Updated from 335 to 253
subjects
To reflect Cohort 4 removal 
1.0
Trial Summary: Estimated duration of trial
Updated from 72 months to 
36 months
To reflect Cohort 4 removal
1.0
2.1
Trial Summary: Duration of participation
Trial Design
Initial treatment period: 
removed Cohort 4 treatment 
regimen
To reflect Cohort 4 removal
2.1
Trial Design
Removed Cohort 4 imaging 
information
To reflect Cohort 4 removal
 
 
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Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
4.2.3.4
Future Biomedical Research
Statement updated to: The 
details of this Future 
Biomedical Research sub 
trial are presented in Section 
12.2
Due to EU CTR changes that 
will require FBR results to be 
reported if FBR is indicated 
as a sub-study to the clinical 
protocol
5.1.2
Subject Inclusion Criteria
Criteria #14: Table 1 –
Adequate organ Function Lab 
values – Creatinine row –
removed oxaliplatin label 
information
To reflect Cohort 4 removal
5.1.3
Subject Exclusion Criteria
Removed in Criteria #12 –
“oxaliplatin, leucovorin; 
Criteria #20 through #24 
were removed
To reflect Cohort 4 removal
5.5.2
Prohibited Concomitant Medication
Removed list of concomitant 
medications to be used with 
caution associated with 
mFOLFOX-6 regimen
To reflect Cohort 4 removal
5.8.1
Discontinuation of Study Treatment after CR
Removed language that 
subjects can discontinue after 
4 administrations and at least 
1 treatment with 
pembrolizumab
To reflect Cohort 4 removal
 
 
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Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
5.9
Subjects Replacement Strategy
Removed language about 
DLT evaluation in Cohort 4
Requirements for DLT 
evaluation is no longer 
needed due to Cohort 4 
removal
6.2
Second Course Phase (Retreatment with 
Pembrolizumab)
Footnote e: Added “See 
Section 7.1.2.7.3.”
To clarify tumor imaging 
procedures during Second 
Course Phase
7.1.1.1.2
Consent and Collection of Specimen for 
Future Biomedical Research
State updated to: The 
investigator or qualified 
designee will explain the 
Future Biomedical Research
consent to the participant, 
answer all of his/her 
questions, and obtain written 
informed consent before 
performing any procedure 
related to the Future 
Biomedical Research sub-
trial.  A copy of the informed 
consent will be given to the 
participant.
Due to EU CTR changes that 
will require FBR results to be 
reported if FBR is indicated 
as a sub-study to the clinical 
protocol
7.1.1.8
Trial Compliance 
(Medication/Diet/Activity/Other)
Changed the word 
“witnessed” to “monitored”
To appropriately describe the 
work being done by the 
investigator and/or trial staff.
 
 
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Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
7.1.2.7.3 (Added)
Second Course (Retreatment) Tumor 
Imaging
Added Section and text
describing Second Course 
Tumor imaging including 
timing and activities
To clarify tumor imaging 
procedures during Second 
Course Phase
7.1.2.7.4
Assessment of Disease
Originally Section 7.1.2.7.3 
but moved to 7.1.2.7.4. 
Therefore, all references to 
Assessment of Disease was 
updated to 7.1.2.7.4
Due to the addition of Second 
Course (Retreatment) Tumor 
Imaging (Section 7.1.2.7.3), 
Assessment of Disease was 
moved to Section 7.1.2.7.4.
11.0
List of References
Removed 4 references that 
were specific to Cohort 4
To reflect Cohort 4 removal
12.2
Collection and Management of Specimens 
for Future Biomedical Research
Updated content under:
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.
Due to EU CTR changes that 
will require FBR results to be 
reported if FBR is indicated 
as a sub-study to the clinical 
protocol
 
 
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Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
12.2
Collection and Management of Specimens 
for Future Biomedical Research
Updated content under
5. Biorepository Specimen 
Usage
Any contracted third-party 
analyses will conform to the 
specific scope of analysis 
outlined in future 
biomedical research 
protocol and consent this 
sub-trial.  
Future Biomedical Research 
specimens remaining with the 
third party after the specific 
analysis is performed will be
reported to the sponsor.
Due to EU CTR changes that 
will require FBR results to be 
reported if FBR is indicated 
as a sub-study to the clinical 
protocol
12.8
List of Abbreviations
Removed abbreviations 
specific to Cohort 4
To reflect Cohort 4 removal
Throughout
Throughout
Text referencing Cohort 4 
and “Cohorts 1 to 3” 
removed
To reflect Cohort 4 removal; 
protocol is no longer 
delineating between Cohort 4 
and Cohorts 1 to 3
 
 
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1.0 TRIAL SUMMARY
Abbreviated Title
A Phase II Clinical Trial of Pembrolizumab as Monotherapy and in 
Combination with Cisplatin+5-Fluorouracil in Subjects with Recurrent or 
Metastatic 
Gastric 
or 
Gastroesophageal 
Junction 
Adenocarcinoma 
(KEYNOTE-059). 
Trial Phase
II
Clinical Indication
Gastric or Gastroesophageal Junction Adenocarcinoma
Trial Type
Interventional
Type of control
No Treatment Control
Route of administration
Intravenous
Trial Blinding
Unblinded Open-label
Treatment Groups
Cohort 1: Pembrolizumab 200 mg Q3W as monotherapy in 3L+ subjects
Cohort 2: Pembrolizumab 200 mg Q3W in combination with cisplatin + 5-
FU in 1L subjects.  Sites in Japan will also administer pembrolizumab in 
combination with cisplatin and capecitabine as combination therapy.
Cohort 3: Pembrolizumab 200 mg Q3W as monotherapy in PD-L1 positive
1L subjects
Number of trial subjects
Approximately 253 subjects will be enrolled.
Estimated duration of trial
The sponsor estimates that the trial will require approximately 36 months
from the time the first subject signs the informed consent until the last 
subject’s last visit.
Duration of Participation
Each subject will participate in the trial from the time the subject signs the 
Informed Consent Form (ICF) through the final contact.  After a screening 
period of up to 28 days, eligible subjects will be assigned by non-random 
assignment to one of 3 cohorts and receive treatment with pembrolizumab 
alone or in combination with cisplatin + 5-FU or, in Japan, cisplatin + 
capecitabine.
Treatment Period: 
Duration of treatment is approximately 2 years (35 administrations of study 
treatment); the duration of each treatment cycle is 3 weeks.  The first dose of 
study treatment will be on Day 1 of Cycle 1.
Subjects in Cohort 2 will 
receive pembrolizumab 200 mg every 3 weeks (Q3W) with cisplatin + 5 FU,
or, in Japan, cisplatin + capecitabine.  Treatment with cisplatin will end after 
6 cycles and treatment with 5-FU or, for Japan, capecitabine may continue 
for the duration of the treatment period. Subjects in Cohorts 1 and 3 will 
receive pembrolizumab 200 mg Q3W as a single agent.
Treatment in all cohorts will continue until documented confirmed disease 
progression, unacceptable adverse event(s) (AE), intercurrent illness that 
prevents further administration of treatment, investigator’s decision to 
discontinue the subject, subject withdraws consent, pregnancy of the subject, 
completion of approximately 2 years of treatment (35 administrations) with 
study medication or achievement of a complete response, or administrative 
reasons requiring cessation of treatment. 
 
 
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Safety Follow-up: After the end of treatment, a safety follow-up visit for all 
subjects to monitor for adverse events will be conducted at 30 days after last 
dose of study treatment or before the initiation of a new anti-cancer 
treatment, whichever is earlier. Serious adverse events and events of clinical 
interest 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 occurs first.  
Follow up: Subjects who discontinue study treatment for reasons other than 
disease progression 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
Second Course Phase: Subjects who discontinue study treatment with 
pembrolizumab 
monotherapy 
or 
combination 
treatment 
after 
35 
administrations of pembrolizumab (~2 years of treatment) for reasons other 
than disease progression or intolerability, or who discontinue after attaining 
a complete response may be eligible at the investigator’s discretion for up to 
1 year of retreatment with pembrolizumab only if they have experienced 
radiographic disease progression after stopping study treatment; this 
retreatment phase will be available to eligible subjects if the study remains 
open.
Survival Follow-up: All subjects will be contacted by telephone for overall 
survival until death, withdrawal of consent, or the end of the study.
Once the participant has achieved the study objective or the study has ended, 
the participant is discontinued from the study and may be enrolled in an 
extension study (NCT03486873) to continue protocol-defined assessments 
and treatment.
Randomization Ratio
N/A
A list of abbreviations used in this document can be found in Appendix 12.8.
2.0 TRIAL DESIGN
2.1
Trial Design
This is a non-randomized, multi-site, open-label trial of pembrolizumab in subjects with 
gastric or gastroesophageal junction adenocarcinoma.  Approximately 253 subjects may be
enrolled across 3 cohorts to examine the safety and efficacy of pembrolizumab as 
monotherapy or in combination with chemotherapy regimen:  
Cohort 1: subjects who have progressed on at least 2 prior systemic treatments for advanced 
disease (3L+ subjects) will receive pembrolizumab as monotherapy
Cohort 2: subjects who have not previously received systemic therapy for advanced disease 
(1L subjects) will receive pembrolizumab in combination with cisplatin and 5-fluorouracil 
(5-FU).  Sites in Japan will also administer pembrolizumab in combination with cisplatin and
capecitabine.
 
 
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Cohort 3: Programmed death-ligand 1 (PD-L1) positive subjects who have not previously 
received systemic therapy for advanced disease (1L subjects) will receive pembrolizumab as 
monotherapy.
All study subjects will continue to be evaluated every 6 to 9 weeks with radiologic imaging 
to assess response. Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 response 
rate as assessed by the central imaging vendor will be used as the primary efficacy endpoint.  
Standard RECIST 1.1 will be used by the investigator for treatment decisions until disease 
progression (PD) is determined by the investigator. The investigator will have an option of 
continuing study treatment until investigator determines radiographic confirmation of PD. 
After the initial radiographic disease progression by RECIST 1.1, clinical management of the 
subject will be made using an adaptation of RECIST 1.1, termed immune-related RECIST 
(irRECIST) to accommodate for possible tumor flare, which may be observed with 
immunotherapies such as pembrolizumab.  Refer to Section 7.1.2.7.4.1 for details.
Adverse events will be monitored throughout the trial and graded in severity according to the 
guidelines outlined in the NCI Common Terminology Criteria for Adverse Events (CTCAE) 
version 4.0 (see Appendix 12.5).  
Study treatment may continue until documented disease progression by irRECIST, 
unacceptable AEs, intercurrent illness that prevents further administration of treatment, 
investigator’s decision to discontinue the subject, subject withdraws consent, pregnancy of 
the subject, completion of 35 administrations (~approximately 2 years) of pembrolizumab
treatment, or administrative reasons requiring the cessation of treatment. Subjects who attain 
an investigator-confirmed complete response (CR) may consider stopping trial treatment 
after receiving at least 8 administrations of pembrolizumab and have received at least 
2 treatments with pembrolizumab beyond the date when the initial CR was declared. Subjects 
who discontinue after completing 35 administrations (~2 years) of pembrolizumab treatment 
for reasons other than disease progression or intolerability or who discontinue after attaining 
a CR may be eligible for up to 1 year of retreatment after they have experienced radiographic 
disease progression.  The decision to retreat will be at the discretion of the investigator only 
if no cancer treatment was administered since the last dose of pembrolizumab, the subject 
still meets the safety parameters listed in the Inclusion/Exclusion criteria, and the trial 
remains open (refer to Section 7.1.5.5 for further details).
After the end of treatment, each subject will be followed for 30 days for AE monitoring.  
Serious adverse events (SAEs) and Events of Clinical Interest (ECI) 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.  Subjects who discontinue treatment for reasons 
other than disease progression will have post-treatment follow-up for disease status until 
disease progression, initiating a non-study cancer treatment, withdrawing consent, or 
becoming lost to follow-up.  All subjects will be contacted by telephone for overall survival 
until death, withdrawal of consent or the end of the study, whichever comes first.
The primary objectives of the trial are to determine the safety, tolerability, and objective
response rate (ORR) of pembrolizumab (200 mg fixed dose Q3W) given as first and third 
 
 
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line monotherapy to subjects with gastric or gastroesophageal junction adenocarcinoma; to 
determine the safety and tolerability of pembrolizumab (200 mg Q3W) administered in 
combination with cisplatin and 5-FU, or cisplatin and capecitabine as first line (1L) therapy 
in subjects with gastric or gastroesophageal junction adenocarcinoma.  Secondary objectives 
include progression-free survival (PFS), overall survival (OS), disease control rate (DCR), 
and duration of response (DOR) in all subjects and those with PD-L1 positive tumors.  
Exploratory objectives are planned to assess the relationship between candidate 
efficacy/resistance biomarkers and anti-tumor activity of pembrolizumab and clinical utility 
of PD-L1 assessments in newly-obtained tissue vs. archived tissue.    
All subjects in all cohorts will be required to provide adequate tumor tissue for evaluation of 
PD-L1 expression and, based on the adequacy of the tissue sample quality for assessment of 
PD-L1 status, will receive notification of eligibility prior to non-random allocation. Subjects 
in Cohort 1 will initially be enrolled regardless of the PD-L1 expression status of their tumor 
tissue; however, after the 40th subject is enrolled, enrollment will be based on PD-L1 status.  
Cohort 2 will enroll without regard to the PD-L1 expression status.  Subjects in Cohort 3 
must express PD-L1.  Additional details about the subject population are provided below in 
Section 2.2.  Subjects receiving pembrolizumab as 1L therapy will be required to be 
HER2/neu negative.
If a newly-obtained tissue sample is submitted for a subject, an archived tissue sample is also 
requested (where available) at screening to support evaluation of the clinical utility of PD-L1 
assessment in newly-obtained vs. archived tissue samples.  An optional newly-obtained
tissue sample (if applicable) is also requested at any time point during the study, (preference 
as close as possible to dosing after 9 weeks of study treatment).  A biopsy is also requested at 
the time of discontinuation for PD but will not be required.  
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.
2.2
Trial Diagram
The trial design for each cohort is depicted in schematics below.
The study will begin by enrolling subjects in Cohorts 1 and 2 concurrently.  Enrollment into 
Cohort 3 is contingent on the availability of the PD-L1 assay.  Enrollment by cohort, 
region/country and for the study overall will be tracked via the IXR system. Should 
enrollment into a particular cohort or for a region or country reach maximum capacity, 
subjects already in the screening period will be allowed to continue participation and will 
receive study treatment if eligible.
Cohort 1 subjects will receive pembrolizumab as 3L+ monotherapy (Figure 1).
 
 
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Figure 1
Cohort 1 –3L+ Monotherapy
a.
Subjects may be either PD-L1 positive or negative.
b. If the response rate in PD-L1 negative subjects (from the first ~40 subjects enrolled) does not meet futility criterion, 
subjects that are PD-L1 negative may continue to be enrolled.
Enrollment of Cohort 1 will initially be open to all subjects regardless of PD-L1 status until 
the first 40 subjects are allocated to treatment (it is estimated that at this time approximately 
25 PD-L1 negative subjects will be enrolled).  Following enrollment of the 40th subject,
enrollment will be based on PD-L1 status and PD-L1 status must be known prior to 
allocation to treatment.  At this time, allocation of PD-L1 negative subjects to treatment will 
be stopped and an interim analysis will be conducted to determine if PD-L1 negative subjects 
show a clinically meaningful response to pembrolizumab.  Allocation of PD-L1 positive 
subjects to treatment will continue.
As of Oct 19, 2015, an interim analysis has been performed and the external DMC has 
reviewed the data. The futility criterion was not met (Please see section 8.7 for the futility 
rule) and the DMC recommended that enrollment of PD-L1 negative subjects can be resumed. 
The enrollment for all subjects will stop when at least 80 all-comer (PD-L1 positive or 
negative) subjects meeting the revised eligibility criteria are enrolled.  According to the 
enrollment rate projection, a total of approximately 130 subjects will be enrolled before the 
revised eligibility criteria are implemented. It is estimated that the overall sample size for 
Cohort 1 is approximately 210. 
 
 
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Cohort 2 subjects (1L) will receive pembrolizumab in combination with cisplatin and 5-FU.  
Sites in Japan will also administer pembrolizumab in combination with cisplatin and
capecitabine (Figure 2).
Figure 2
Cohort 2 –1L Combination Treatment
Approximately 18 subjects, regardless of PD-L1 status, will be enrolled in Cohort 2 and 
receive pembrolizumab as 1L therapy in combination with cisplatin+5-FU
or 
cisplatin+capecitabine (Figure 2). A total of 6 subjects in Japan will be administered 
capecitabine instead of 5-FU. Approximately 12 subjects in Cohort 2 will be enrolled by sites 
in Asia. Approximately 6 subjects will be enrolled by sites outside of Asia. Every effort will 
be made to adhere to the regional or country subject allocation identified here. 
Cohort 3 subjects will receive pembrolizumab as 1L monotherapy (Figure 3).
 
 
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Figure 3
Cohort 3 –1L Monotherapy
Approximately 25 PD-L1 positive subjects will be enrolled in Cohort 3 and receive 
pembrolizumab as 1L monotherapy (Figure 3).  Enrollment into Cohort 3 is contingent on the 
availability of the PD-L1 assay.
3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
3.1
Primary Objective(s) & Hypothesis(es)
Cohort 1: For subjects with recurrent and/or metastatic gastric or gastroesophageal 
adenocarcinoma who have progressed on at least 2 prior systemic treatments for advanced 
disease (3L+ subjects).
Cohort 2: For subjects with recurrent and/or metastatic gastric or gastroesophageal 
adenocarcinoma who have not previously received systemic therapy for advanced disease 
(1L subjects).
Cohort 3:
PD-L1 positive subjects with recurrent and/or metastatic gastric or 
gastroesophageal adenocarcinoma who have not previously received systemic therapy for 
advanced disease (1L subjects).
 
 
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
Objective (within each Cohort 1, 2 and 3):  To determine the safety and tolerability of 
pembrolizumab administered at 200 mg Q3W dosing as monotherapy and in combination 
with cisplatin and 5-FU or cisplatin and capecitabine.

Objective (Cohort 1):  To estimate the Objective Response Rate (ORR) per RECIST 1.1 
assessed by central imaging vendor in all subjects and in PD-L1 positive subjects.

Objective (Cohort 3): To estimate the ORR per RECIST 1.1 assessed by central imaging 
vendor review.  
3.2
Secondary Objective(s) & Hypothesis(es)

Objective (Cohort 1): To estimate the Duration of Response (DOR) per RECIST 1.1 
by central imaging vendor in all subjects and in PD-L1 positive subjects.  Supportive 
analyses for this objective and the primary objective include irRECIST by central 
imaging vendor evaluation of ORR and DOR in all subjects and in PD-L1 positive 
subjects as well as RECIST 1.1 and irRECIST by central imaging vendor evaluation 
of DCR, PFS and OS in all subjects and in PD-L1 positive subjects.

Objective (Cohort 2):  To estimate antitumor activity of pembrolizumab in 
combination with cisplatin and 5-FU or cisplatin and capecitabine for all subjects and 
in PD-L1 positive subjects, determined by ORR using RECIST 1.1 by central 
imaging vendor.  Supportive analyses for this objective include irRECIST by central 
imaging vendor evaluation of ORR in all subjects and in PD-L1 positive subjects as 
well as RECIST 1.1 and irRECIST by central imaging vendor evaluation of DOR, 
DCR, PFS and OS in all subjects and in PD-L1 positive subjects.

Objective (Cohort 3):  To estimate the Duration of Response (DOR) per RECIST 
1.1 by central imaging vendor in PD-L1 positive subjects.  Supportive analyses for 
this objective and the primary objective include irRECIST by central imaging vendor 
evaluation of ORR and DOR in PD-L1 positive subjects as well as RECIST 1.1 and 
irRECIST by central imaging vendor evaluation of DCR, PFS and OS in PD-L1 
positive subjects.

Objective (all Cohorts): To evaluate the relationship between PD-L1 status and 
efficacy endpoints in subjects receiving pembrolizumab (as monotherapy or in 
combination with chemotherapy) with recurrent and/or metastatic gastric or 
gastroesophageal junction adenocarcinoma.
3.3
Exploratory Objectives

Objective (all Cohorts): To investigate the relationship between pembrolizumab
treatment and biomarkers predicting response (e.g., genetic variation, serum sPDL1) 
utilizing newly-obtained or archival FFPE tumor tissue and/or blood (including whole 
blood, serum and plasma).  

Objective (all Cohorts):  To compare performance of PD-L1 assessment in newly-
obtained vs. archived tissue samples.  
 
 
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4.0 BACKGROUND & RATIONALE
4.1
Background
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background 
information on MK-3475.
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 tumors.
The programmed death-1 (PD-1) receptor-ligand interaction is a major pathway hijacked by 
tumors to suppress immune control.  The normal function of PD-1, expressed on the cell 
surface of activated T-cells under healthy conditions, is to down-modulate unwanted or 
excessive immune responses, including autoimmune reactions.  PD-1 (encoded by the gene 
Pdcd1) is an Ig superfamily member related to CD28 and CTLA-4 which has been shown to 
negatively regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or 
PD-L2) [7, 8].  The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an 
immunoreceptor tyrosine-based inhibition motif (ITIM) and an immunoreceptor tyrosine-
based switch motif (ITSM).  Following T-cell stimulation, PD-1 recruits the tyrosine 
phosphatases SHP-1 and SHP-2 to the ITSM motif within its cytoplasmic tail, leading to the 
dephosphorylation of effector molecules such as CD3ζ, PKCθ, and ZAP70 which are 
involved in the CD3 T-cell signaling cascade [7, 9, 10, 11].  The mechanism by which PD-1 
down modulates T-cell responses is similar to, but distinct from that of CTLA-4 as both 
molecules regulate an overlapping set of signaling proteins [12, 13].  PD-1 was shown to be 
expressed on activated lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, 
T regs and Natural Killer cells [14, 15].  Expression has also been shown during thymic 
development on CD4-CD8- (double negative) T-cells as well as subsets of macrophages and 
dendritic cells [16].  The ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed 
or can be induced in a variety of cell types, including non-hematopoietic tissues as well as in 
various tumors [17, 18, 19, 12].  Both ligands are type I transmembrane receptors containing 
both IgV- and IgC-like domains in the extracellular region and contain short cytoplasmic 
regions with no known signaling motifs.  Binding of either PD-1 ligand to PD-1 inhibits T-
cell activation triggered through the T-cell receptor.  PD-L1 is expressed at low levels on 
various non-hematopoietic tissues, most notably on vascular endothelium, whereas PD-L2 
protein is only detectably expressed on antigen-presenting cells found in lymphoid tissue or 
chronic inflammatory environments.  PD-L2 is thought to control immune T-cell activation 
in lymphoid organs, whereas PD-L1 serves to dampen unwarranted T-cell function in 
peripheral tissues [12].  Although healthy organs express little (if any) PD-L1, a variety of 
cancers were demonstrated to express abundant levels of this T-cell inhibitor.  PD-1 has been 
suggested to regulate tumor-specific T-cell expansion in patients with melanoma [20]. In 
 
 
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gastric cancer PD-L1 and PD-L2 overexpression have recently been associated with EBV-
positive tumors [21].  This suggests that the PD-1/PD-L1 pathway plays a critical role in 
tumor immune evasion and can be an attractive target for therapeutic intervention.
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of 
the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its 
ligands, PD-L1 and PD-L2.  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 Investigator’s Brochure.
Pre-clinical and Clinical Trials
Therapeutic studies in mouse models have shown that administration of antibodies blocking 
PD-1/PD-L1 interaction enhances infiltration of tumor-specific CD8+ T-cells and leads 
ultimately to tumor rejection, either as a mono-therapy or in combination with other 
treatment modalities.  Anti-mouse PD-1 or anti-mouse PD-L1 antibodies have demonstrated 
anti-tumor responses as a mono-therapy in models of squamous cell carcinoma, pancreatic 
carcinoma, melanoma and colorectal carcinoma.  Blockade of the PD-1 pathway effectively 
promoted CD8+ T-cell infiltration into the tumor and the presence of IFN-, granzyme B and 
perforin, indicating that the mechanism of action involved local infiltration and activation of 
effector T-cell function in vivo [22, 23, 24, 25, 26, 27].  Experiments have confirmed the in 
vivo efficacy of PD-1 blockade as a mono-therapy as well as in combination with 
chemotherapy in syngeneic mouse tumor models (see the IB).
Clinical trials have demonstrated efficacy in multiple solid tumor indications and 
hematologic malignancies.  Refer to pembrolizumab IB for study details.
Ongoing Clinical Trials
Ongoing clinical trials are being conducted in advanced melanoma, NSCLC, a number of 
advanced solid tumor indications and hematologic malignancies.  For study details please 
refer to the IB.
Preliminary interim data are available from a cohort of gastric adenocarcinoma patients 
studied in trial KN012 [28].  KEYNOTE-012 trial is a multi-cohort Phase 1b study of which 
one cohort enrolled subjects with recurrent or metastatic gastric or GEJ adenocarcinoma that 
expressed PD-L1 (≥1% by immunohistochemistry).  This cohort enrolled 39 subjects 
(19 from Asia and 20 outside Asia), 67% of whom had received 2 or more prior 
chemotherapy lines. The primary efficacy endpoint was objective response rate (ORR). 
Despite the heavily pre-treated patient population, Pembrolizumab monotherapy 
demonstrated an interim ORR of 33% by RECIST v.1.1 per investigator review (95% 
confidence interval [CI] 19.1%, 50.2%; all partial responses). The interim disease control rate 
(DCR) was 41% (95% CI 25.6%, 57.9%).  ORR was similar in patients from Asia and 
outside of Asia, while the DCR was numerically higher in Asia.  Responses were observed 
across all lines of treatment.  It should be noted that in the non-Asia group, patients had less 
 
 
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prior therapy relative to the Asian patients, and that ORR in later line patients (≥3L) was 
higher in the Asian group (1 PR/7 patients in the non-Asia group, 4 PR/13 patients in the 
Asia group).  As of the data cut-off date of 14-NOV-2014, the median duration of response 
was 24 weeks (6 months).  Based on preliminary data, there appears to be a correlation 
between response and degree of PD-L1 positivity.  
In these gastric cancer patients in KN012, single-agent pembrolizumab at 10 mg/kg Q2W 
was generally well tolerated, with the type, severity, and frequency of adverse events similar 
to that observed in other indications (see the IB for information about adverse events in other 
indications).  There was 1 death reported in the gastric cancer cohort.  This patient had
adverse events of tracheomalacia (Grade 3) and hypoxia (Grade 5).  The investigator 
considered the Grade 5 hypoxia to be related to study treatment.
4.2
Rationale
Rationale for the Trial and Selected Subject Population
KEYNOTE 059 (KN059) is a Phase II, 3-cohort, single arm, open-label trial of 
pembrolizumab alone or in combination with 5-FU (or capecitabine) and cisplatin in subjects 
with advanced gastric or gastroesophageal junction adenocarcinoma (note that term gastric 
cancer in this protocol will refer to both gastric adenocarcinoma as well as gastroesophageal 
junction adenocarcinoma).  It will be conducted as 3 separate cohorts: a cohort of subjects 
who have progressed on at least 2 prior systemic treatments for advanced disease (3L+ 
subjects), and 2 cohorts of subjects who have not previously received systemic therapy for 
advanced disease (1L subjects) - one of which consist of subjects receiving pembrolizumab 
in combination with different chemotherapy regimens and one will consist of subjects 
receiving pembrolizumab monotherapy.
The PD-L1 IHC assay planned for use in this trial will be a clinical assay with the potential to 
be further developed and registered.  In KN012 a PD-L1 prototype IHC assay was used that 
is different than the assay planned for KN059.  The definition of PD-L1 IHC positive in 
KN012 is ≥1% tumor cell staining or stromal staining.  The definition of PD-L1 positive in 
this trial, KN059, will be generally equivalent to the definition used in KN012 [28]; the 
actual percent positive staining required may be different with the updated assay currently 
being developed for use in the trial.  
Cohort 1:  3L and Later Subjects
Treatment options are limited for 3L+ gastric cancer subjects, especially in western countries, 
with no approved or recommended treatments.  In East Asian countries, single agent 
chemotherapy (taxane or irinotecan) is commonly used.  There is minimal data on the 
response to treatment in 3L or later.  One study conducted at a single site in Korea reported a 
response rate of 3.8% in 2L or later patients receiving weekly paclitaxel [29].  Overall 
survival was generally similar between the 2L and 3L+, while PFS was worse in the later line 
(3L+) patients, with a median PFS of 1.7 months.  However, these had poorer performance 
scores (ECOG 2-3) relative to that planned in this study.  A low ORR was also observed in 
 
 
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the REGARD study in which 2L patients were randomized to either ramucirumab or best 
supportive care [30].  In contrast to the previous study, patients in REGARD had better 
performance scores (ECOG 0 or 1) yet the ORR was still 3% in both treatment groups.  
Based on the improved overall survival observed in the ramucirumab group, ramucirumab as 
a single agent was approved in the United States for treatment of 2L gastric cancer.  
The gastric cancer proof-of-concept from KN012 data was obtained in PD-L1 positive 
subjects only; no data is currently available regarding the performance of pembrolizumab in 
PD-L1 negative subjects.  Therefore, the primary efficacy hypothesis for this cohort will be 
in the PD-L1 positive population.  However, due to the limited treatment opinions currently 
available, late line PD-L1 negative subjects may benefit from pembrolizumab.  The 
performance of pembrolizumab in these subjects will be explored in approximately 25 PD-L1 
negative subjects and a futility analysis will be conducted based on ORR at 9 weeks, with a 
futility criterion of the upper bound of the 95% confidence interval for ORR <20%.  Should 
the efficacy of pembrolizumab be non-futile in this subgroup, then enrollment of PD-L1 
negative subjects will continue and an assessment of all-comers with regard to PD-L1 will be 
performed at the end of the study.  
This will be operationalized by enrolling up to ~40 all-comer subjects, as the PD-L1 IHC 
assay will not be available for subject selection at the initiation of the trial (it will be 
available approximately 3 months after study initiation).  Assuming a 40% PD-L1 positive 
rate based on the data from KN012, this will give approximately 25 PD-L1 negative subjects. 
At this point the PD-L1 subject selection assay is expected to be available, and enrollment of 
PD-L1 negative subjects will stop until after the futility assessment in the subjects 
determined to be PD-L1 negative from these initial ~40 all-comers.  
As of 19-OCT-2015, the interim analysis has been performed and the external DMC has 
reviewed the data.  The futility criterion was not met (please see Section 8.7 for the futility 
rule) and the DMC recommended that enrollment of PD-L1 negative subjects can be resumed. 
The enrollment for all subjects will stop when at least 80 all-comer (PD-L1 positive or 
negative) subjects meeting the revised eligibility criteria are enrolled.  According to the 
enrollment rate projection, a total of approximately 130 subjects will be enrolled before the 
revised eligibility criteria are implemented.  It is estimated that the overall sample size for 
Cohort 1 is approximately 210.
Cohort 2:  1L Subjects Receiving Combination Treatment
Based on the results of KN012, pembrolizumab is expected to have meaningful activity in 
both early and late lines of therapy.  Current 1L treatments for metastatic gastric cancer 
consist of combination chemotherapy, most often consisting of a doublet containing a 
platinum agent and a fluoropyrimidine agent.  Western patients in good condition may 
receive a triple combination in which an agent from a third class (e.g., taxane or 
anthracycline) is added.  Response rates of combination chemotherapies in these patients are
generally in the 40% range.  It is possible that maximal treatment benefit can be obtained by 
adding pembrolizumab to doublet chemotherapy in 1L subjects.  Cohort 2 of this study is 
designed to assess the safety and tolerability of this combination regimen, with cisplatin and 
 
 
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5-FU as the doublet chemotherapy regimen.  Sites in Japan will also administer
pembrolizumab in combination with cisplatin and capecitabine as the doublet regimen.  This 
assessment will support the use of these regimens in future global clinical trials.  Based on 
safety and tolerability, the doses of the chemotherapies may be reduced for individual 
subjects or an entire cohort.  This information will inform dose selection for future 
combination trials.
The subject population for this cohort will be all-comers with respect to the PD-L1 selection 
assay.  It is possible that PD-L1 negative subjects could benefit from addition of 
pembrolizumab to chemotherapy, and the primary safety objective is not expected to be 
impacted by PD-L1 status.  In addition, an all-comer population will necessitate a shorter 
enrollment time and therefore earlier availability of the key safety data to support future 
trials.
Cohort 3: 1L Subjects Receiving Pembrolizumab Monotherapy
The final cohort in this study will be PD-L1 positive 1L gastric cancer subjects who will 
receive pembrolizumab monotherapy.  The objective of this cohort is to provide further data 
assessing the performance of pembrolizumab monotherapy in this population to support 
future trials of single-agent pembrolizumab in early-line patients.  In KN012, the current 
ORR in subjects who were treatment naïve or have had one prior line of therapy, there are 3 
partial responders in 9 subjects (with 3 additional subjects having stable disease).  Cohort 3 
of this study will provide data in an additional 25 subjects to better understand efficacy.  
PD-L1 positive only subjects will be enrolled in this cohort, since there are no current data in 
PD-L1 negative subjects and these subjects may be less likely to benefit from 
pembrolizumab monotherapy. Since the ORR of standard treatments for these subjects is in 
the range of 40%-50%, this efficacy objective is to show an ORR >35%, which would 
suggest that pembrolizumab may be similar to, or better than, standard of care, and support 
future trials with a monotherapy regimen in these subjects (e.g., pembrolizumab could have a 
similar ORR but long duration of response which could translate into a superior survival 
benefit).
Rationale for Dose Selection/Regimen/Modification
Rationale for Pembrolizumab 200 mg Q3W Dosing
The planned dose of pembrolizumab for Cohorts 1, 2 and 3 of 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 8 randomized studies demonstrating flat dose- and exposure-
efficacy relationships from 2 mg/kg Q3W to 10 mg/kg every 2 weeks (Q2W)
•
Clinical data showing meaningful improvement in benefit-risk including overall 
survival at 200 mg Q3W across multiple indications
 
 
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•
Pharmacology data showing full target saturation in both systemic circulation 
(inferred from PK data) and tumor (inferred from physiologically based 
pharmacokinetic [PBPK] analysis) at 200 mg Q3W
Among the 8 randomized dose-comparison studies, a total of 2262 subjects were enrolled 
with melanoma and NSCLC, covering different disease settings (treatment-naïve, previously 
treated, PD-L1 enriched and all-comers) and different treatment settings (monotherapy and in 
combination with chemotherapy). Five studies compared 2 mg/kg Q3W vs. 10 mg/kg Q3W 
(KN001 B2, KN001 D, KN002, KN010, and KN021), and 3 studies compared 10 mg/kg 
Q3W vs. 10 mg/kg Q2W (KN001 B3, KN001 F2, and KN006). All of these studies 
demonstrated flat dose- and exposure-response relationships across the doses studied,
representing an approximate 5- to 7.5-fold difference in exposure. The 2 mg/kg (or 200 mg 
fixed
dose) Q3W dose provided similar responses to the highest doses studied. 
Subsequently, flat dose- and exposure-response relationships were also observed in other 
tumor types, including head and neck cancer, bladder cancer, gastric cancer, and classical 
Hodgkin’s 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 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 fixed dosing 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 the 2 mg/kg Q3W dose. 
Supported by these PK characteristics, and given that the 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
Efficacy Endpoints
The primary efficacy objective of this study is to evaluate the anti-tumor activity of 
pembrolizumab in subjects with advanced gastric cancer.  Objective Response rates per 
RECIST 1.1 (Appendix 12.6) as assessed by the central imaging vendor will be used as the 
primary response rate efficacy endpoint.  Objective response rate will also be used as the 
primary endpoint due to the single-arm design of this study.
 
 
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RECIST 1.1 will be used by the local site for treatment decisions.  However, RECIST 1.1 
will be adapted to account for the unique tumor response profile seen with immunotherapies 
such as pembrolizumab. Refer to Section 7.1.2.7.4 for details.
A secondary objective of this trial is the evaluation of the relationship between PD-L1 
biomarker status as assessed by immunohistochemistry and response to pembrolizumab.  
This objective will be evaluated using data from both the 3L+ and the 1L monotherapy 
cohorts.  The data obtained in this trial with regard to the biomarker will inform the 
performance of PD-L1 assessment by IHC and may determine if the definition of PD-L1 
positivity should be modified for future trials or specific populations.  Fresh biopsies are 
currently used for PD-L1 assessment, although in this study archival biopsies will also be 
obtained to compare the performance of the PD-L1 IHC assay in archived versus fresh 
biopsies so that it may be possible to use archival biopsies in future studies.
Safety Endpoints
The primary safety objective of this trial is to characterize the safety and tolerability of 
pembrolizumab and pembrolizumab in combination with cisplatin + 5-FU or cisplatin +
capecitabine in subjects with gastric cancer.  The primary safety analysis will be based on 
subjects who experienced toxicities as defined by CTCAE criteria (Appendix 12.5).  Safety 
will be assessed by quantifying the toxicities and grades experienced by subjects who have 
received pembrolizumab and pembrolizumab in combination with cisplatin + 5-FU or 
cisplatin + capecitabine , including SAEs and ECIs.  
Safety will be assessed by reported adverse experiences using CTCAE, Version 4.0. The 
attribution to drug, time-of-onset, duration of the event, its resolution, and any concomitant 
medications administered will be recorded.  Adverse events will be analyzed including but 
not limited to all AEs, SAEs, fatal AEs, and laboratory changes.  
Exploratory Endpoints
4.2.3.3.1 Planned Exploratory Biomarker Research
Additional biomarker research to identify factors important for pembrolizumab therapy may 
also be pursued.  For example, tumor and blood samples (including serum and plasma) from 
this study may undergo proteomic, genomic, metabolomics, and transcriptional analyses.  
This research may evaluate factors important for predicting responsiveness or resistance to 
pembrolizumab therapy and other immunologic targets.
Assays may include but are not be limited to:
Immunohistochemistry
PD-L1 expression in tumor tissue will be characterized by immunohistochemistry to explore 
the relationship between PD-L1 expression and response to treatment with pembrolizumab
(this is a secondary objective of the trial).  Other exploratory biomarkers (e.g., PD-1 
expression, markers of T-cell phenotype) may also be evaluated.
 
 
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Transcriptional Analyses
Messenger RNA (mRNA) expression profiling in archival material (biopsy specimens, 
peripheral blood) will be completed to assess expression of approximately 700 genes and 
attempt to define a gene set critical for clinical response to pembrolizumab.  The hypothesis 
to be tested is that pembrolizumab induces responses in tumors that reflect an inflamed/ 
immune phenotype based on gene expression signatures capturing PD-L1 & interferon-
gamma transcriptional programs.  Global profiling will also be pursued.  Expression of 
individual genes related to the immune system may also be evaluated such as immune 
signatures and critical cytokines (e.g., IL-10).  MicroRNA profiling may also be pursued in 
serum samples.
Proteomic analysis
In addition to expression on the tumor tissue, PD-L1 can be shed from tumor and released 
into the blood.  Enzyme-linked immunoassay can measure PD-L1 in serum and correlate this 
expression with response to pembrolizumab therapy, as well as levels of PD-L1 IHC or 
protein in the tumor.  Blood would be a less invasive component from which to measure PD-
L1 protein biomarker.  In addition to this specific protein biomarker, both tissue and blood 
derivatives can be subjected to proteomic profiling studies using a variety of platforms that 
could include but are not limited to immunoassay, Liquid Chromatography/Mass 
Spectrometry.  This approach could identify novel protein biomarker that could aid in subject
selection for pembrolizumab therapy.
Gene Analyses
The application of new technologies, such as next generation sequencing, has provided 
scientists the opportunity to define certain tumor types at the genetic level as being 
‘hypermutated’ or can detect the presence of specific T-cell clones within the tumor 
microenvironment or in the peripheral blood.  There is a potential that the hypermutated state 
and/or increased T-cell clonality may correlate with response to pembrolizumab therapy, 
and/or that the converse, ‘hypomutated’ state or lack of dominant T-cell clones may correlate 
with non-response.  
In addition, understanding genetic determinants of drug response is an important endeavor 
during medical research.  This research will evaluate whether genetic variation within a 
clinical trial population correlates with response to the treatment(s) under evaluation.  If 
genetic variation is found to predict efficacy or adverse events, the data might inform optimal 
use of therapies in the subject population.
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.
 
 
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Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main trial) and will only be conducted on specimens from 
appropriately consented subjects. The objective of collecting specimens for Future 
Biomedical Research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. For instance, exploratory 
pharmacogenetic 
(PGt) 
studies 
may 
be 
performed 
if 
significant 
Pharmacokinetic/Pharmacodynamic (PK/PD) relationships are observed or adverse events 
are identified.  Genomic markers of disease may also be investigated.  Such retrospective 
pharmacogenetic studies will be conducted with appropriate biostatistical design and analysis 
and compared to PK/PD results or clinical outcomes. Any significant PGt relationships to 
outcome would require validation in future clinical trials. The overarching goal is to use such 
information to develop safer, more effective drugs/vaccines, and/or to ensure that subjects 
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.
4.3
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 IB and Informed Consent documents.
5.0 METHODOLOGY
5.1
Entry Criteria
Diagnosis/Condition for Entry into the Trial
Male/Female subjects with gastric or gastroesophageal junction adenocarcinoma of at least 
18 years of age will be enrolled in this trial.
Subject Inclusion Criteria
In order to be eligible for participation in this trial, the subject must:
For potential subjects in Cohort 1 (3L+ cohort):
1. Have received, and progressed on, at least two prior chemotherapy regimens.  For the 
purposes of this study, perioperative, neoadjuvant, adjuvant chemotherapy regimens will 
not count as a prior regimen, unless the subject progressed while receiving adjuvant 
therapy or within 6 months of receiving adjuvant treatment.  The date of progression and 
how progression was determined must be known with documentation available
 
 
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confirming progression on or after treatment.  Previous treatment regimens must have 
included a fluoropyrimidine and platinum doublet (as part of either a line of therapy or 
adjuvant treatment.
2. Be HER-2/neu negative, or, if HER2/neu positive, must have previously received 
treatment with trastuzumab (Note:  If HER2/neu status was previously determined, that 
result is acceptable but documentation of status must be available; subjects with unknown 
status will have their HER2/neu status determined locally.  Documentation of previous 
treatment with trastuzumab must also be provided.)
For potential subjects in Cohort 2 or 3 (1L cohorts):
3. Is HER2/neu negative.
4. Have not received prior systemic anti-cancer therapy for their metastatic or advanced 
gastric or gastroesophageal junction adenocarcinoma.  For the purposes of this study, 
perioperative, neoadjuvant, adjuvant chemotherapy regimens will not count as a prior 
regimen, unless disease progression has occurred during or within 6 months of adjuvant 
chemotherapy.
For all potential subjects:
5. 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.
6. Be 18 years of age on day of signing informed consent.
7. Have histologically or cytologically confirmed recurrent or metastatic gastric or 
gastroesophageal junction adenocarcinoma that is considered incurable by local therapies.
8. Be willing to provide newly obtained or archived tissue for PD-L1 and MSI biomarker 
analysis and, based on the adequacy of the tissue sample quality for assessment of PD-L1 
status, have received notice of eligibility prior to non-random allocation.  Newly-obtained
tissue will be from the stomach and/or gastroesophageal junction (endoscopic tumor 
biopsy) or a metastatic location IF obtained as part of normal clinical practice.  Repeat 
samples may be required if adequate tissue is not provided.  
a. Note:  Newly-obtained is defined as a specimen obtained up to 6 weeks (42 days)
prior to initiation of treatment on Day 1 (Cycle 1) and with no additional anti-cancer 
treatment having been given after the specimen was obtained. Newly obtained biopsy 
specimens are preferred to archived; however, subjects for whom newly-obtained 
tissue sample cannot be submitted (e.g. inaccessible or subject safety concern), an 
archived specimen may be submitted.  Newly-obtained (FFPE block or tissue in 
formalin solution) or archived specimens are preferred to slides. Refer to Section 
7.1.2.8 for details.
 
 
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b. Note:  Where newly-obtained tissue sample is submitted, collection of an archived 
tissue sample will also be requested (where available) to support evaluation of the 
clinical utility of PD-L1 assessment in newly-obtained vs. archived tissue samples; 
however, a subject will not be precluded from participating in the study if an archived 
tissue sample is not available for collection or is otherwise insufficient for analysis.
c.
Note:  If emerging data demonstrates that there is no difference in the clinical utility 
of PD-L1 assessment in newly-obtained samples relative to archived ones, then 
archived samples may be acceptable in lieu of newly-obtained tissue samples.  If this 
is the case, sites will be notified via an Administrative Memo.
9. Be PD-L1 positive, if the subject is being allocated to a cohort which, at the time of 
enrollment, is only enrolling PD-L1 positive subjects.
a. Note: if at the time of enrollment all-comers with regard to PD-L1 status are being 
enrolled, then it is not necessary to know the subject’s PD-L1 status prior to 
enrollment, but it must be confirmed that the tissue sample obtained is adequate for 
retrospective assessment of PD-L1 status.
10. Have measurable disease based on RECIST 1.1 as determined by central imaging vendor. 
Tumor lesions situated in a previously irradiated area are considered measurable if 
progression has been demonstrated in such lesions.  
a. Note:  The exact same image acquisition and processing parameters should be used 
throughout the study.
11. Have a performance status of 0 or 1 on the ECOG Performance Scale (Appendix 12.4)
within 3 days prior to the first dose of study therapy.
12. Life expectancy of at least 3 months.
13. Female subjects 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 or 180 days after the last dose of study medication (Section 5.7.2).  
Duration of use will be determined when the subject is assigned to treatment.  Subjects of 
childbearing potential are those who have not been surgically sterilized or have not been 
free from menses for > 1 year.  
Male subjects should agree to use an adequate method of contraception starting with the 
first dose of study therapy through 120 or 180 days after the last dose of study therapy.  
Duration will be determined when the subject is assigned to treatment.
Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the 
subject.
14. Demonstrate adequate organ function as defined in Table 1.  All screening labs should be 
performed within 3 days prior to treatment initiation.
 
 
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Table 1
Adequate Organ Function Laboratory 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 of assessment)
Renal
Creatinine OR
Measured or calculated
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
Cisplatin product label should be followed for acceptable creatinine 
clearance rates for subjects in Cohort 2 (combination treatment)
Notes: Creatinine clearance should be calculated per institutional 
standard.  
Hepatic
Total bilirubin
≤ 1.0 X ULN 
AST 
(SGOT) 
and 
ALT 
(SGPT)
≤ 2.5 X ULN OR
≤ 5 X ULN for subjects with liver metastases
Albumin
>3.0 g/dL
Coagulation
International Normalized
Ratio (INR) or Prothrombin 
Time (PT)
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
≤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
15. 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.
Subject Exclusion Criteria
The subject must be excluded from participating in the trial if the subject:
1. Experienced weight loss >10% over 2 months prior to first dose of study therapy.
2. Has clinical evidence of ascites by physical exam.
3. Is currently participating and receiving study therapy or has participated in a study of an 
investigational agent and received study therapy or used an investigational device within 
4 weeks of the first dose of treatment.
4. Has 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.
 
 
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5. 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.  The use of physiologic doses of corticosteroids (prednisone 10 mg or 
equivalent) may be approved after consultation with the Sponsor.
6. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study 
Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due 
to agents administered more than 4 weeks earlier.
7. Has had prior 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 alopecia at screening are an exception to this criterion 
and may qualify for the study.
8. 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.
9. Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis.  Subjects with previously treated brain metastases may participate provided 
they are stable (without evidence of progression by imaging at least four weeks prior to 
the first dose of trial treatment and any neurologic symptoms have returned to baseline), 
have no evidence of new or enlarging brain metastases, and are not using steroids for at 
least 7 days prior to trial treatment.  This exception does not include carcinomatous 
meningitis which is excluded regardless of clinical stability.
10. Has history of (non-infectious) pneumonitis that required steroids or has current 
pneumonitis.
11. Has an active infection requiring systemic therapy.
12. Has a history or current evidence of a gastrointestinal (GI) condition (e.g., inflammatory 
bowel disease, Crohn’s disease, ulcerative colitis) or impaired liver function or diseases 
that in the opinion of the Investigator may significantly alter the absorption or 
metabolism of oral medications; any condition (e.g., known deficiency of the enzyme 
dihydropyrimidine dehydrogenase), therapy, or laboratory abnormality that might 
confound the results of the study, interfere with the participant’s participation for the full 
duration of the study, make administration of the study drugs hazardous, or make it 
difficult to monitor adverse effects such that it is not in the best interest of the subject to 
participate (e.g., any contraindication to the use of cisplatin,  5-FU, or capecitabine for 
subjects in Japan, in the opinion of the treating investigator.
13. Has known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the trial.
 
 
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14. 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 or 180 days 
after the last dose of trial treatment.  Duration is determined by the cohort to which the 
subject would be assigned.
15. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
16. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
17. Has known chronic or acute Hepatitis B (e.g., HBsAg reactive) or Hepatitis C infection 
(e.g., HCV RNA [qualitative] is detected).
18. Has received a live vaccine within 30 days of planned start of study therapy.
Note:  Seasonal influenza vaccines for injection are generally inactivated flu vaccines 
and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live 
attenuated vaccines, and are not allowed.
19. Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling or 
child) who is investigational site or Sponsor staff directly involved with this trial, unless 
prospective IRB approval (by chair or designee) is given allowing exception to this 
criterion for a specific subject.
20. Has had major surgery, open biopsy, or significant traumatic injury within 28 days prior 
to randomization, or anticipation of the need for major surgery during the course of study 
intervention. 
Note: If participant has had major surgery, they must have recovered adequately from 
the toxicity and/or complications from the treatment prior to starting study intervention.
21. Has severe hypersensitivity (≥Grade 3) to pembrolizumab or any of the study 
chemotherapy agents and/or to any excipients.
22. Has a known history of active tuberculosis (TB; Bacillus tuberculosis).
23. Has had an allogeneic tissue/solid organ transplant.
5.2
Trial Treatment(s)
The treatment to be used in this trial is outlined below in Table 2.
 
 
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Table 2
Trial Treatments 
Drug
Dose
Dose 
Frequency
Route of 
Administration
Regimen/Treatment 
Period
Use
Pembrolizumab
200 mg
Q3W
IV infusion
Day 1 of each 3 week 
cycle
Experimental
Cisplatin
80 mg/m2
Q3W
IV infusion
Day 1 of each 3 week 
cycle for 6 cycles
Combination 
agent
5-Fluorouracil a
(5-FU)
800 mg/m2
Q3W
Continuous IV 
infusionb
Day 1-5 of each 
3 week cycle
Combination 
agent
Capecitabine
(Japan only) a
1000 mg/m2,
BID
Q3W
Oral
Day 1-14 of each 
3 week cycle
Combination 
agent
a. For Cohort 2, sites in Japan will administer 5-FU or capecitabine in combination with cisplatin. 
b. 5-FU is continuously infused for the duration of 120 hours. Subjects enrolled prior to 059-04 should remain 
on the 5-FU infusion duration previously chosen for the remainder of the study.
Trial treatment should begin as close as possible to the date on which the subject is 
allocated/assigned.
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.
Dose Selection/Modification
Dose Selection (Preparation)
The rationale for selection of doses to be used in this trial is provided in Section 4.0 –
Background & Rationale.  Details on preparation and administration of pembrolizumab 
(MK-3475) are provided in the Pharmacy Manual.  Preparation and administration of the 
chemotherapy agents used in Cohort 2 should be completed as per the approved product
label.  See Sections 5.2.2.2 –5.2.2.4 for general recommendations for administration.
Body surface area (BSA) in m2 should be calculated per local guidance.
Dose Modification (Escalation/Titration/Other)
5.2.1.2.1 Definition of Dose Limiting Toxicity
All toxicities will be graded using NCI-CTCAE Version 4.0 based on the investigator 
assessment. 
 
 
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The occurrence of any of the following toxicities during the first 28 days of treatment will be 
considered a DLT, if assessed by the investigator to be related to study treatment:

Any Grade 3 to 4 toxicity other than: 
o
fatigue, or 
o
nausea, vomiting, or diarrhea lasting less than 72 hours; 

Grade 3 to 4 Nausea, vomiting or diarrhea lasting 72 hours or longer despite maximal 
supportive care including anti-emetics, intravenous hydration, anti-diarrhea agents 
and short term steroid use, if indicated. 

Grade 3 to 4 thrombocytopenia or neutropenia that leads to treatment delays for 
>14 days. 

Grade 4 febrile neutropenia if DPD deficiency is ruled out and subject requires delay 
for the next cycle >14 days.

Asymptomatic Grade 3 to 4 laboratory abnormalities will be discussed between the 
site investigator and sponsor before being assigned as DLT.
5.2.1.2.2 Guidelines for Dose Modification Due to Adverse Events
The Common Terminology Criteria for Adverse Events version 4.0 (CTCAE 4.0) must be
used to grade the severity of adverse events.
If appropriate, the investigator may attribute each toxicity event to any of the individual 
chemotherapy agents used or pembrolizumab alone in the combination arms and use
stepwise dose modifications according to Table 3.  Pembrolizumab dose reductions are not 
permitted. Pembrolizumab treatment may be interrupted or discontinued due to toxicity.  
If a dose level reduction for toxicity occurs with any agent, the dose may not be re-
escalated. Dose modifications are always based on the previous cycle.
Dose modification for cisplatin + 5-FU or capecitabine combination are detailed in Table 3.  
Subjects may have up to 2 dose level reductions per chemotherapy agent throughout the
course of the study ( Table 3).  If further toxicity occurs or the criteria for resuming
treatment are not met, the subject must be discontinued from chemotherapy treatment. Of 
note, in the event a subject in Cohort 2 is discontinued from chemotherapy treatment, the 
subject may still be eligible for continued treatment with pembrolizumab (DL -3 in Table 3).
Refer to Table 4, Table 6, and Table 7, for dose modification guidelines for AEs related to 
pembrolizumab, cisplatin, 5-FU, and capecitabine (Japan only), respectively. If a subject 
experiences several toxicities and there are conflicting recommendations, follow the most
conservative dose adjustment recommended (dose reduction appropriate to the most severe
toxicity).
Reduction or with-holding of one chemotherapy agent and not the other agent is
appropriate if, in the opinion of the investigator, the toxicity is clearly related to one of the
study treatment.
If, in the opinion of the investigator, the toxicity is related to the
 
 
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combination of 2 chemotherapy agents, both treatments should be reduced (if applicable), 
interrupted or discontinued according to recommended dose modifications. If the toxicity
is related to the combination of 3 agents, all three agents should be reduced or held 
according to the recommended dose modifications.
Exceptional circumstances to following the dose modification tables below may be
considered after consultation with the Sponsor.
Table 3
Dose Modifications for Trial Medication
Starting Dose
Dose Level -1
Dose Level -2
Dose Level -3
Pembrolizumab
200 mg fixed dose
Dose reductions are 
not permitted
Dose reductions 
are not permitted
Dose reductions 
are not permitted
Cisplatin
80 mg/m2
60 mg/m2
40 mg/m2
Discontinue
5-FU
800 mg/m2
600 mg/m2
400 mg/m2
Discontinue
Capecitabine
(Japan Only)
1000 mg/m2 BID
750 mg/m2 BID
500 mg/m2 BID
Discontinue
If a toxicity is not otherwise specified, investigators should refer to the label or local standard 
of care for dose adjustments.  At the investigator’s discretion, dose modification according to 
Table 3 is allowed for intolerable Grade 2-3 toxicities that are not specified in the tables 
below. These dose modification decisions must be documented in the subject’s study 
records.
In Cohort 2, the number of treated subjects versus the number of subjects with a dose 
reduction will be monitored continuously. 
Appendix 12.7 provides guidance for 
determination of lowering the dose for the chemotherapy agents for a treatment subgroup 
(i.e., Asian or non-Asian) according to a mTPI method.
5.2.1.2.3 Dose Modification for Pembrolizumab
Dose modification and toxicity management for immune-related AEs associated with 
pembrolizumab
Adverse events 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, or 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 4.
 
 
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Table 4
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 participants for signs and symptoms of 
pneumonitis

Evaluate participants with suspected pneumonitis 
with radiographic imaging and initiate corticosteroid 
treatment

Add prophylactic antibiotics for opportunistic 
infections
Grade 3 or 4, or 
recurrent Grade 2
Permanently 
discontinue
Diarrhea / colitis 
Grade 2 or 3
Withhold

Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper

Monitor participants for signs and symptoms of 
enterocolitis (i.e., diarrhea, abdominal pain, blood or 
mucus in stool with or without fever) and of bowel 
perforation (i.e., peritoneal signs and ileus)

Participants with ≥ Grade 2 diarrhea suspecting 
colitis should consider GI consultation and 
performing endoscopy to rule out colitis. 

Participants with diarrhea/colitis should be advised 
to drink liberal quantities of clear fluids.  If sufficient 
oral fluid intake is not feasible, fluid and electrolytes 
should be substituted via IV infusion.
Grade 4
Permanently 
discontinue
 
 
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Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with 
corticosteroid and/or other 
therapies 
Monitor and follow-up 
AST / ALT 
elevation or 
Increased 
Bilirubin
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 participants with 
T1DM 

Administer anti-hyperglycemic in 
participants with hyperglycemia 

Monitor participants for hyperglycemia or other 
signs and symptoms of diabetes
Hypophysitis
Grade 2
Withhold

Administer corticosteroids and 
initiate hormonal replacements as 
clinically indicated.  

Monitor for signs and symptoms of hypophysitis 
(including hypopituitarism and adrenal 
insufficiency) 
Grade 3 or 4 
Withhold or 
permanently 
discontinue1
Hyperthyroidism 
Grade 2
Continue 

Treat with non-selective beta-
blockers (e.g., 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 (e.g., levothyroxine or 
liothyronine) per standard of care

Monitor for signs and symptoms of thyroid 
disorders. 
Nephritis and 
renal dysfunction
Grade 2
Withhold 

Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by taper.

Monitor changes of renal function
Grade 3 or 4 
Permanently 
discontinue
 
 
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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:  GBS 
(Guillain-Barre 
Syndrome), SOTR 
(solid organ 
transplant 
rejection), 
encephalitis
Grade 4 or 
recurrent Grade 3 
Permanently 
discontinue
1.
Withhold or permanently discontinue pembrolizumab at the discretion of the investigator or treating physician.  
NOTE: 
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may be resumed when AE 
resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM).  
 
 
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5.2.1.2.4 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 5.
Table 5
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 hrs
Stop Infusion and monitor symptoms.
Additional appropriate medical therapy may 
include but is not limited to:
IV fluids
Antihistamines
NSAIDS
Acetaminophen
Narcotics
Increase monitoring of vital signs as medically 
indicated until the subject is deemed 
medically stable in the opinion of the 
investigator.
If symptoms resolve within one hour of 
stopping treatment infusion, the infusion may 
be restarted at 50% of the original infusion 
rate (e.g., from 100 mL/hr to 50 mL/hr).  
Otherwise dosing will be held until symptoms 
resolve and the subject should be 
premedicated for the next scheduled dose.
Subjects who develop Grade 2 toxicity 
despite adequate premedication should be 
permanently discontinued from further 
trial treatment administration.
Subject may be premedicated 
1.5h (± 30 minutes) prior to 
infusion of pembrolizumab
(MK-3475) with:
Diphenhydramine 50 mg po (or 
equivalent dose of 
antihistamine).
Acetaminophen 500-1000 mg 
po (or equivalent dose of 
antipyretic).
 
 
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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 trial treatment 
administration.
No subsequent dosing
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period of 
study treatment administration.
5.2.1.2.5 Dose Modifications for Cisplatin
Please refer to criteria for cisplatin dose modification included in Table 6. 
 
 
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Table 6
Dose Modification Guidelines for Cisplatin Drug-Related Adverse Events
Category
Toxicity
Hold 
Cisplatin
Treat-
ment for
Grade
Timing for
Restarting
Cisplatin
Treatment
Dose for
Restarting
Cisplatin
Treatment
Discontinue Cisplatin
Hematologic
Neutropenia
3
1
Neutrophil count
resolves to
>1,000/mm
3
No Reduction
*consider G-CSF
Toxicity does not resolve
within 12 weeks of last 
infusion or if >-2 DL
reductions exceeded
4
1
Neutrophil count
resolves to
>1,000/mm
3
Reduce by 1 DL
*consider G-CSF
Toxicity does not resolve
within 12 weeks of last 
infusion or if >-2 DL
reductions exceeded
Febrile
Neutropenia
3
1
Toxicity resolves
to Grade 0-1
Reduce by 1 DL
Toxicity does not resolve
within 12 weeks of last 
infusion or if >-2 DL
reductions exceeded
4
1
n/a
Discontinue
Permanently discontinue 
Cisplatin
Thrombocytopenia
3-4
1
Platelet count
resolves to
>75,000/mm3or
baseline
Reduce by 1 DL
Toxicity does not resolve
within 12 weeks of last 
infusion or if >-2 DL
reductions exceeded
Non-
hematologic
Creatinine
Increased
2
Toxicity resolves
to Grade 0-1
Reduce by 1 DL
Toxicity does not resolve
within 12 weeks of last 
infusion or if >-2 DL
reductions exceeded
3-4
1
Toxicity resolves
to Grade 0-1
Reduce by 1 DL
Toxicity does not resolve
within 12 weeks of last 
infusion or if >-2 DL
reductions exceeded
Ototoxicity or 
Sensory 
neuropathy
3-4
1
Toxicity resolves
to Grade 0-1
Reduce by 1 DL
Toxicity does not resolve
within 12 weeks of last 
infusion or if >-2 DL
reductions exceeded
All other non-
hematologic 
toxicities2
3-4
1
Toxicity resolves
to Grade 0-1
Reduce by 1 DL
Toxicity does not resolve
within 12 weeks of last 
infusion or if >-2 DL
reductions exceeded
Laboratory
Adverse Events
4
1
Toxicity resolves
to Grade 0-1
Reduce by 1 DL
Toxicity does not resolve
within 12 weeks of last 
infusion or if >-2 DL 
reductions exceeded
1Permanent discontinuation should be considered for any severe or life-threatening event. Consult Sponsor before restarting treatment after 
Grade 4 drug-related AE
2Subjects with intolerable or persistent Grade 2 drug-related AE may hold at physician discretion. Permanently discontinue from agent for 
persistent Grade 2 adverse reactions for which treatment has been held, and did not recover to Grade 0-1 within 12 weeks of the last dose.
 
 
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5.2.1.2.6 Dose Modifications for 5-FU/Capecitabine
Please refer to criteria for 5-FU and capecitabine dose modification included in Table 7.
Table 7
Dose Modification Guidelines for 5-FU/Capecitabine Drug-Related Adverse 
Events
Category
Toxicity
Hold 5-FU/
capecitabine3
Treatment 
for Grade
Timing for
Restarting
5- FU/
capecitabine3
Treatment
Dose for
Restarting
5-FU/
capecitabine3
Treatment
Discontinue 5-FU/
capecitabine3
Hematologic
Neutropenia
3
1
Neutrophil count
resolves to
>1,000/mm3
No Reduction
*consider
G-CSF
Toxicity does not resolve within
12 weeks of last infusion or if
>-2 DL reductions exceeded
4
1
Neutrophil count
resolves to
>1,000/mm3
Reduce by 1 DL
*consider
G-CSF
Toxicity does not resolve within
12 weeks of last infusion or if
>-2 DL reductions exceeded
Febrile
Neutropenia
3
1
Toxicity
resolves to
Grade 0-1
Reduce by 1 DL
Toxicity does not resolve within
12 weeks of last infusion or if
>-2 DL reductions exceeded
4
1
n/a
Discontinue
Permanently discontinue 
5-FU/capecitabine.
Thrombo-
cytopenia
3-4
1
Platelet count
resolves to
>75,000/mm3
Reduce by 1 DL
Toxicity does not resolve within
12 weeks of last infusion or if
>-2 DL reductions exceeded
Non-
hematologic
Diarrhea, 
Mucositis, or 
Hand-foot 
syndrome
2-3
Toxicity
resolves to
Grade
0-1
Reduce by 1 DL
Toxicity does not resolve within
12 weeks of last infusion or if
>-2 DL reductions exceeded
4
n/a
Discontinue
Permanently discontinue 
5-FU/capecitabine.
All other
non-
hematologic 
toxicities2
3-4
1
Toxicity
resolves to
Grade 0-1
Reduce by 1 DL
Toxicity does not resolve within
12 weeks of last infusion or if
>-2 DL reductions exceeded
Laboratory
Adverse
Events
4
1
Toxicity
resolves to
Grade 0-1
Reduce by 1 DL
Toxicity does not resolve within
12 weeks of last infusion or if
>-2 DL reductions exceeded
1Permanent discontinuation should be considered for any severe or life-threatening event. Consult Sponsor before restarting treatment after 
Grade 4 drug related AE.
2Subjects with intolerable or persistent Grade 2 drug-related AE may hold at physician discretion. Permanently discontinue from agent for 
persistent Grade 2 adverse reactions for which treatment has been held, and did not recover to Grade 0-1 within 12 weeks of the last dose.
3 Capecitabine applicable to sites in Japan
 
 
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Timing of Dose Administration
All trial treatments will be administered on an outpatient basis.
For the combination portions of the study (Cohort 2), treatment will be administered in the 
order presented below:
Cohort 2 (pembrolizumab + cisplatin + 5-FU or capecitabine [Japan]):
Cycle 1 Day 1: Study treatment with pembrolizumab must be administered on Day 1 Cycle 1, 
followed by cisplatin and 5-FU or capecitabine (Japan). For administrative reasons, cisplatin 
followed by 5-FU may be administered up to 3 days after Day 1 Cycle 1.
Cycle 2 Onwards: Study treatment with pembrolizumab, followed by cisplatin and 5-FU or 
capecitabine (Japan), may be administered up to 3 days before or after the scheduled Day 1 
of each cycle for administrative reasons.  It is not required that pembrolizumab is given on 
the same day as cisplatin and 5-FU, but it must be administered before cisplatin and 5-FU or 
capecitabine (Japan) are administered.
Dosing interruptions are permitted in the case of medical / surgical events or logistical 
reasons not related to study treatment (e.g., elective surgery, unrelated medical events, 
subject vacation, and/or holidays). Subjects may restart study treatment as soon as clinically 
appropriate at the investigator discretion, and not exceeding 3 weeks from the interrupted 
dosing. Discussion with Sponsor should occur the investigator determines a subject cannot 
restart study medication within 3 weeks. The reason for interruption should be documented 
in the subject's study record.
Pembrolizumab
Pembrolizumab should be administered on Day 1 of each 3-week cycle after all procedures 
and assessments have been completed as detailed on the Trial Flow Chart (Section 6.0).  
Pembrolizumab 200 mg will be administered as a 30 minute IV infusion Q3W.  Sites should 
make every effort to target infusion timing to be as close to 30 minutes as possible.  
However, given the variability of infusion pumps from site to site, a window of -5 minutes 
and +10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min).
Cisplatin (Cohort 2 only)
Cisplatin will be administered for up to 6 cycles of treatment.  Administration of cisplatin 
should begin on Day 1 of each 3-week cycle following administration of pembrolizumab, as 
detailed in Table 2 and the Trial Flow Chart (Section 6.0).  Cisplatin is given initially as a 
dose of 80 mg/m2 on Day 1 of each treatment cycle using an infusion duration of 60 minutes 
(or according to local practice).
 
 
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5-Fluorouracil (Cohort 2 only)
For Cohort 2, administration of 5-FU should begin on Day 1 of each 3-week cycle following 
administration of cisplatin, as detailed in Table 2 and the Trial Flow Chart (Section 6.0).  
5-FU will be administered as an initial dose of 800 mg/m2 per day as a continuous infusion 
for 120 hours from Day 1 to Day 5 of each treatment cycle. Subjects enrolled prior to 059-04 
should remain on the 5-FU infusion duration previously chosen for the remainder of the 
study.
Capecitabine (Cohort 2 only)
Sites in Japan will administer pembrolizumab in combination with cisplatin and capecitabine
as the doublet regimen.  Administration of capecitabine should begin on Day 1 of each 
3-week cycle following administration of cisplatin, as detailed in Table 2 and the Trial Flow 
Chart (Section 6.0).  Please refer to the product label for additional guidance on 
administration procedures for capecitabine.  Capecitabine will be administered orally as a 
dose of 1000 mg/m2 twice daily from Day 1 to Day 14 of each treatment cycle.
Trial Blinding/Masking
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered.
The study team will be blinded to PD-L1 expression status (positive or negative) for all 
subjects participating in the initial all-comers portion of Cohort 1 until the interim analysis of 
Cohort 1. Following the interim analysis, the Sponsor will be unblinded to PD-L1 data.  
Analyses or summaries of PD-L1 biomarker status will be limited and documented after the 
interim analysis. See additional details regarding blinding in Section 8.2.  
5.3
Randomization or Treatment Allocation
Subjects participating in this trial will be allocated by non-random assignment.
5.4
Stratification
No stratification based on age, sex or other characteristics will be used in this trial.
5.5
Concomitant Medications/Vaccinations (Allowed & Prohibited)
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for any medication or vaccination
specifically prohibited during the trial, discontinuation from trial therapy or vaccination 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.
 
 
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Acceptable Concomitant Medications
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.  All concomitant medication will be recorded on the electronic case report form 
(eCRF) 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 eCRF.
All concomitant medications received within 28 days before the first dose of trial treatment 
and 30 days after the last dose of trial treatment should be recorded.  Concomitant 
medications administered 30 days after the last dose of trial treatment should be recorded for 
SAEs and ECIs as defined in Section 7.2.
Prohibited Concomitant Medication
Subjects are prohibited from receiving the following therapies during the Screening and for 
the duration of the study (including Second Course Phase) of this trial:

Antineoplastic systemic chemotherapy or biological therapy not specified in this 
protocol

Immunotherapy not specified in this protocol

Investigational agents other than pembrolizumab

Radiation therapy
o
Note:  Radiation therapy to a symptomatic solitary lesion or to the brain may be 
allowed after consultation with 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, varicella/zoster, yellow fever, intranasal 
influenza, rabies, BCG, and typhoid vaccine.

Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
AE of suspected immunologic etiology.  The use of physiologic doses of 
corticosteroids (prednisone 10 mg or equivalent) may be approved after consultation 
with the Sponsor.
Note 1: For the purpose of preventing chemotherapy-induced nausea/vomiting, the 
administration of dexamethasone should be limited to those instances when the 
subject is receiving high (or moderate) emetic risk chemotherapy (Cohort 2).  The 
dose and duration of dexamethasone administration should be limited to the lowest 
needed to prevent and/or treat chemotherapy-related nausea and emesis.
Note 2: Anti-emetic prophylaxis with corticosteroids per NCCN or institutional 
guideline is permitted.
 
 
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Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial.  
Subjects may receive other medications that the investigator deems to be medically 
necessary.
Concomitant Medications to be used with caution:

Cimetidine, metronidazole and interferons may increase levels of 5-FU.

Subjects who are taking phenytoin in conjunction with 5-FU should be examined 
regularly due to a potential elevation in phenytoin plasma levels. Hepatotoxic effects 
(rise in alkaline phosphatase, transaminase, or bilirubin levels) are commonly
observed under the treatment with 5-FU and levamisole.
The Exclusion Criteria describes other medications which are prohibited in this trial.
There are no prohibited therapies during the Post-Treatment Follow-up Phase.
5.6
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 AEs with 
potential immunologic etiology are detailed in Section 5.2.1.2.3, Table 4. 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. 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event.
Supportive Care Guidelines for Chemotherapy Agents
Pre-cisplatin treatment with corticosteroids per NCCN or institutional guidelines is permitted 
for subjects in Cohort 2.
Please refer to the product label or local standards of care for additional supportive measures
for cisplatin, 5-FU, and capecitabine (Japan only).
 
 
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5.7
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.  Non-pregnant, 
non-breast-feeding women may be enrolled if they are willing to use 2 methods of birth 
control or are considered 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.  The two birth control methods can either 
be two barrier methods or a barrier method plus a hormonal method to prevent pregnancy. 
Subjects in Cohorts 1 & 3 should start using birth control from study Visit 1 throughout the 
study period up to 120 days after the last dose of study treatment.  Subjects in Cohort 2 
should start using birth control from study Visit 1 throughout the study period up to 180 days 
after the last dose of study treatment. 
The following are considered adequate barrier methods of contraception: diaphragm, condom 
(by the partner), copper intrauterine device, sponge, or spermicide as per local regulations or 
guidelines.  Appropriate hormonal contraceptives will include any registered and marketed 
contraceptive agent that contains an estrogen and/or a progestational agent (including oral, 
subcutaneous, intrauterine, or intramuscular agents).
Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the 
subject.
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 they must adhere to the contraception requirement (described above) for the 
duration of the study and during the follow-up period defined in Section 7.2.2 - Reporting of 
Pregnancy and Lactation to the Sponsor.  If there is any question that a subject will not 
reliably comply with the requirements for contraception, that subject should not be entered 
into the study.
Use in Pregnancy
If a subject inadvertently becomes pregnant while on treatment with study treatment, 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, 
 
 
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congenital anomaly, or other disabling or life-threatening complication to the mother or 
newborn).  The study investigator will make every effort to obtain permission to follow the 
outcome of the pregnancy and report the condition of the fetus or newborn to the Sponsor.  If 
a male subject impregnates his female partner, the study personnel at the site must be 
informed immediately and the pregnancy reported to the Sponsor and followed as described 
above and in Section 7.2.2.
Use in Nursing Women
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.  Specific additional information follows for individual agents used in this trial.
Pembrolizumab
It is unknown whether pembrolizumab is excreted in human milk.  
Cisplatin
Cisplatin has been reported to be found in human milk; subjects receiving Cisplatin injection 
should not breast-feed.
5-Fluorouracil
It is not known whether 5-fluorouracil is excreted in human milk. Because 5-fluorouracil 
inhibits DNA, RNA and protein synthesis, mothers should not nurse while receiving this 
treatment.
Capecitabine (Japan)
Lactating mice given a single oral dose of capecitabine excreted significant amounts of 
capecitabine metabolites into the milk. It is not known whether capecitabine is excreted in 
human milk. Subjects receiving capecitabine should not breast-feed.
Photosensitivity
Investigators are advised to counsel subjects assigned to receive capecitabine or 5-FU about 
the risk of photosensitivity and to take sun protection measures accordingly.
5.8
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 7.1.4 – Other 
Procedures.
 
 
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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.  For a 
subject who has discontinued treatment but is continuing to be monitored in the trial, he/she 
may be allowed to begin treatment again under certain protocol-defined circumstances 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.
A subject must be discontinued from treatment (but may 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 disease progression per the terms outlined in Section 7.1.2.7.4.1

Unacceptable adverse experiences as described in Section 5.2.1.2

Intercurrent illness that prevents further administration of treatment

Recurrent Grade 2 pneumonitis

Investigator’s decision to withdraw the subject

The subject has a confirmed positive serum pregnancy test

The subject is lost to follow-up

Completed 35 administrations of pembrolizumab (approximately 2 years) of study 
treatment, whichever is later.
Note: 35 administrations of study medication is calculated from the date of first dose. 
Subjects who stop study treatment after 35 administrations of pembrolizumab may be 
eligible for up to one year of additional pembrolizumab if they progress after stopping 
study treatment provided they meet the requirements detailed in Section 7.1.5.5.   

Administrative reasons
The End of Treatment and Follow-up visit procedures are listed in Section 6 (Trial Flow 
Chart) and Section 7.1.5 (Visit Requirements).  After the end of treatment, each subject will 
be followed for 30 days for AE monitoring (SAE and ECI 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, as described in Section 7.2.3.1).  Subjects who 
discontinue for reasons other than progressive disease will have post-treatment follow-up for 
disease status until disease progression, initiating a non-study cancer treatment, withdrawing 
consent or becoming lost to follow-up.  After documented disease progression each subject 
will be followed by telephone for overall survival until death, withdrawal of consent, or the 
end of the study, whichever occurs first.
 
 
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Discontinuation of Study Treatment after CR
Discontinuation of treatment may be considered for subjects who have attained a confirmed 
CR that have been treated for at least 8 administrations with pembrolizumab and had at least 
2 treatments with pembrolizumab) beyond the date when the initial CR was declared.  
Subjects who then experience radiographic disease progression may be eligible for up to one 
year of additional treatment with pembrolizumab via 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 safety parameters listed in the Inclusion/Exclusion 
criteria, and the trial is open.  Subjects will resume pembrolizumab at the same dose and 
schedule at the time of initial discontinuation.  Additional details are provided in Section 
7.1.5.5.
5.9
Subject Replacement Strategy
A subject who discontinues from the trial will not be replaced.
5.10 Beginning and End of the Trial
The overall trial begins when the first subject signs the informed consent form.  The overall 
trial ends when the last subject completes the last study-related phone-call or trial visit, 
discontinues from the trial or is lost to follow-up (i.e. the subject is unable to be contacted by 
the investigator). Upon study completion, subjects will be discontinued and may be enrolled 
in a pembrolizumab extension study. Enrollment in the extension study is conditional on 
subject consent.
5.11 Clinical Criteria for Early Trial Termination
Early trial termination will be the result of the criteria specified below:
1. Quality or quantity of data recording is inaccurate or incomplete
2. Poor adherence to protocol and regulatory requirements
3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential 
health hazard to subjects
4. Plans to modify or discontinue the development of the study treatment
In the event of Sponsor decision to no longer supply study treatment, ample notification will 
be provided so that appropriate adjustments to subject treatment can be made.
 
 
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6.0 TRIAL FLOW CHART
6.1
Initial Treatment Phase
Trial Period:
Screening 
Treatment Cycles a (3 weeks per cycle)
End of 
Treatment
(last dose) or 
Discontinuation
Post-Treatment
Treatment Cycle/Title:
Visit 1
1
2
3
4
To be repeated beyond 6 cycles
Safety Follow-
up (30 days
from last dose)
Follow Up 
Visits b
Survival 
Follow-
upr
(Phone)
5
6
Scheduling Window (Days):
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 7
± 7
± 7
Informed Consent
X
Informed Consent for FBR c
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
Clinical Procedures/Assessments
Review Adverse Events
X
X
X
X
X
X
X
X
X
X
12-Lead ECG (Local)
X
Full Physical Examination
X
X
Directed Physical Examination
X
X
X
X
X
X
Ht (V1 only), Wt, & Vital Signs (T/P/RR/BP)
X
X
X
X
X
X
X
X
ECOG Performance Status
X.q
X
X
X
X
X
X
Trial Treatment Administration p
X
X
X
X
X
X
Post-study Anticancer Therapy Status
X
Q12W
Survival Status r
˂--------------------------------------------------------------------------------------------------------------------˃
Q12W
LOCAL Laboratory Assessments
Pregnancy Test – Urine or Serum -HCG d
X
PT/INR and aPTT e
X
Chemistry Panel e, f
X
X
X
X
X
X f
X
X
CBC with Differential e, g
X
X
X
X
X
X g
X
X
T3, FT4, and TSH e, h
X
X
X
X, then Q2 
cycles
X
Serum carcinoembryonic antigen (CEA) e, i
X
X
X
X
X
Urinalysis e
X
CENTRAL Laboratory Assessments
Blood for Future Biomedical Research c
X
Blood for Proteomics and Genetics k
X
Blood for RNA and DNA Analysis k
X
X
X
X
 
 
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Trial Period:
Screening 
Treatment Cycles a (3 weeks per cycle)
End of 
Treatment
(last dose) or 
Discontinuation
Post-Treatment
Treatment Cycle/Title:
Visit 1
1
2
3
4
To be repeated beyond 6 cycles
Safety Follow-
up (30 days
from last dose)
Follow Up 
Visits b
Survival 
Follow-
upr
(Phone)
5
6
Scheduling Window (Days):
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 7
± 7
± 7
Efficacy Measurements
Tumor Imaging
X l
X m
X m
X n
X n
Tumor Tissue Collection o
X
optional biopsy (close to dosing after 9 weeks of treatment)
X optional
a. Unless otherwise specified, assessments/procedures are to be performed prior to dose administration on Day 1 of each cycle.
b. Subjects who discontinue study treatment without documented disease progression should continue to be monitored for disease status by radiologic imaging every 6 weeks (± 7 
days), and after the 1st year, every 9 weeks (±7 days) until (1) the start of new anti-cancer treatment, (2) disease progression as assessed by the central imaging vendor, (3) death, 
or (4) the end of the study, whichever occurs first.
c. Informed consent for the optional Future Biomedical Research (FBR) samples must be obtained before the DNA sample is collected.  DNA sample for analysis should be 
obtained predose, on Day 1 (or with the next scheduled blood draw) as the last sample drawn or at a later date as soon as the informed consent is obtained.  Detailed instructions 
for the collection and management of specimens for FBR are provided in the Procedures Manual and Section 12.2.
d. For women of reproductive potential, a negative pregnancy test should be performed within 72 hours prior to first dose of trial treatment. Pregnancy tests (serum and/or urine 
tests) should be repeated if required by local guidelines. 
e. Laboratory Screening Tests should be performed within 3 days prior to first dose of treatment. For all subjects, unresolved abnormal labs resulting in drug-related AEs should
be followed until resolution. Post dose lab may be collected up to 72 hours prior to the scheduled time point.
f.
Chemistry will be collected on Day 1 of Cycles 2-6, then every 2 cycles. For subjects in Cohort 2 who are receiving chemotherapy, chemistry will be collected every cycle on 
Day 1. Japan only - for subjects receiving capecitabine, chemistry should be collected as follows for Cycles 1 and 2: Cycle 1 - Days 8 and 15 (screening chemistry labs satisfy 
requirement for Day 1); Cycle 2 - Days 1, 8, and 15
g. CBC w/differentials will be collected on Day 1 of Cycles 2-6, then every 2 cycles.  For subjects in Cohort 2 who are receiving chemotherapy, CBC w/differentials will be 
collected every cycle on Day 1, 8, and 15 of Cycles 1-6 (screening CBC w/differentials labs satisfy requirement for Day 1 of Cycle 1); then on Day 1 of every cycle thereafter.  
h. T3, FT4 and TSH may be analyzed by the central laboratory if cannot be done locally. FT3 may be tested locally (not via central laboratory) if T3 is not locally available
i.
On treatment CEA – starting at Cycle 3, CEA will be collected every 2 cycles through Cycle 12, then every 3 cycles until end of treatment.
k. Collect prior to study treatment administration. Whole blood for Genetics/RNA and DNA analyses. Serum and plasma for Proteomics. 
l.
Tumor imaging at screening: Cohorts 2 & 3 - imaging will be performed within 28 days prior to the first dose of trial treatment.  Cohort 1 - imaging will be performed within 
14 days prior to the first dose of trial treatment; at sites where the local regulatory body and/or IRB/ERC will not permit a second tumor imaging within a 28-day period, an 
already available imaging scan obtained within 28 days prior to first dose may be used with the approval of the Sponsor Clinical Director.  For all subjects, already available 
imaging scans performed as part of routine clinical management are acceptable if they are of diagnostic quality and performed within the acceptable timeframe for each cohort.
m. The first on-study tumor imaging will be performed after 9 weeks (±7 days) of study treatment, and then every 6 weeks (±7 days) thereafter (or more frequently if clinically 
indicated). After 1 year, imaging will be performed every 9 weeks (±7 days). Timing of imaging follows calendar days and should not be adjusted due to dose interruptions. 
The same imaging technique, acquisition, and processing parameters for a subject should be used throughout the trial. All scans (scheduled and unscheduled) should be 
submitted to the central imaging vendor as soon as possible after imaging is complete.
n. Subjects without confirmed PD who discontinue treatment will have imaging performed at the time study treatment is discontinued (i.e., date of discontinuation ± 4 week 
window).  If a scan was obtained within 4 weeks prior to discontinuation of treatment, then imaging at treatment discontinuation is not required. Continue to monitor disease 
status as indicated in Section 7.1.2.7.2.  Subjects who discontinue treatment after confirmed PD will not need further imaging performed during the follow-up period.
o. Tumor Tissue collection at screening may be collected up to 42 days prior to first dose of study treatment.  An optional newly obtained endoscopic biopsy (if applicable) is
requested during the study (preference is as close as possible to dosing after 9 weeks of treatment). An optional biopsy is also requested at the time of discontinuation for PD.  
p. Refer to Section 5.2.2 regarding window for timing of dose administrations (for Day 1 Cycle 1 and Cycle 2 onwards).
q. Screening ECOG should be performed within 3 days prior to first dose of study therapy.  
 
 
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Trial Period:
Screening 
Treatment Cycles a (3 weeks per cycle)
End of 
Treatment
(last dose) or 
Discontinuation
Post-Treatment
Treatment Cycle/Title:
Visit 1
1
2
3
4
To be repeated beyond 6 cycles
Safety Follow-
up (30 days
from last dose)
Follow Up 
Visits b
Survival 
Follow-
upr
(Phone)
5
6
Scheduling Window (Days):
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 7
± 7
± 7
r. After the start of new anti-cancer treatment or documented disease progression by the central imaging vendor, whichever occurs first, the subject enters the Survival Follow-Up 
Phase and should be contacted by telephone approximately every 12 weeks 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 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 death event previously recorded).
 
 
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6.2
Second Course Phase (Retreatment)
Trial Period:
Treatment Cyclesa (3 weeks per cycle)
End of Treatment
(last dose)
or 
Discontinuation
Post-Treatment
Treatment Cycle/Title:
1g
2
3
4
To be repeated beyond 6 cycles
Safety Follow-up
(30 days from last 
dose)
Follow Up 
Visits b
Survival 
Follow-up i
(Phone)
5
6
Scheduling Window (Days):
± 3
± 3
± 3
± 3
± 3
± 7
± 7
± 7
Administrative Procedures
Eligibility Criteria
X
Concomitant Medication Review
X
X
X
X
X
X
X
X
Clinical Procedures/Assessments
Review Adverse Events
X
X
X
X
X
X
X
X
X
Full Physical Examination
X
X
Directed Physical Examination
X
X
X
X
X
Weight and Vital Signs (T, P, RR, BP)
X
X
X
X
X
X
X
X
ECOG Performance Status
Xh.
X
X
X
X
X
X
X
Pembrolizumab Administration
X
X
X
X
X
X
Post-study Anticancer Therapy Status
X
Q12W
Survival Status i
˂-----------------------------------------------------------------------------------------------------------------------------------˃
Q12W
Local Laboratory Assessments
Pregnancy Test – Urine or Serum -HCGc
X
PT/INR and aPTT
X
Chemistry 
Paneld
& 
CBC 
with 
Differentiald
Xd
X
X
X
X
X, then Q2 cycles
X
X
T3, FT4, and TSHd
X
X
X, then Q2 cycles
X
Urinalysis
X
Efficacy Measurements
Tumor Imaginge
X
X
Xf
Xf
a. Unless otherwise specified, assessments/procedures are to be performed prior to dose administration on Day 1 of each cycle. 
b. Subjects who discontinue study treatment without documented disease progression should continue to be monitored for disease status by radiologic imaging as indicated in 
Section 7.1.2.7.2.
c. For women of reproductive potential, a negative pregnancy test should be confirmed within 72 hours prior to first dose of trial retreatment. Pregnancy tests (serum and/or urine 
tests) should be repeated if required by local guidelines.
d. Lab test done for determining eligibility for retreatment (within 3 days prior to the first dose of trial treatment) will not need to be repeated on Day 1 of Cycle 1.  After Cycle 1, 
lab samples can be collected up to 72 hours prior to the scheduled time point.  Unresolved labs that are drug related AEs should be followed until resolution.  Labs do not need 
to be repeated after the end of trial treatment if labs are within normal range.
e. Tumor imaging must be performed within 28 days prior to restarting treatment with pembrolizumab.  Imaging should be performed every 6 weeks (42 ± 7 days) after the first 
dose of trial treatment or more frequently if clinically indicated.  Imaging timing should follow calendar days and should not be adjusted for any dose interruptions.  The same 
image technique, acquisition, and processing parameters should be used throughout this retreatment phase. See Section 7.1.2.7.3
 
 
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Trial Period:
Treatment Cyclesa (3 weeks per cycle)
End of Treatment
(last dose)
or 
Discontinuation
Post-Treatment
Treatment Cycle/Title:
1g
2
3
4
To be repeated beyond 6 cycles
Safety Follow-up
(30 days from last 
dose)
Follow Up 
Visits b
Survival 
Follow-up i
(Phone)
5
6
Scheduling Window (Days):
± 3
± 3
± 3
± 3
± 3
± 7
± 7
± 7
f. Subjects without confirmed PD who discontinue study treatment should have imaging performed at the time study treatment is discontinued (i.e., date of discontinuation ±4 
weeks). If a scan was obtained within 4 weeks prior to discontinuation of treatment, then imaging at treatment discontinuation is not required.  Every effort should be made to 
continue to monitor disease status by radiologic imaging as indicated in Section 7.1.2.7.2.  Subjects who discontinue treatment after confirmed PD will not need further 
imaging.
g. All laboratory tests for determining eligibility for retreatment are to be performed within 3 days prior to the first retreatment dose of pembrolizumab, and clinical 
procedures/assessments are to be performed within 3 days prior to the first retreatment dose of pembrolizumab.
h. ECOG for determining eligibility for retreatment is to be performed within 3 days prior to first dose of study therapy. ECOG for eligibility for retreatment (within 3 days prior 
to the first dose of trial treatment) will not need to be repeated on Day 1 of Cycle 1.
i.
After the start of new anti-cancer treatment or documented disease progression by the central imaging vendor, whichever occurs first, the subject enters the Survival Follow-up 
Phase and should be contacted by telephone approximately every 12 weeks 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 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 death event previously recorded).
 
 
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7.0 TRIAL PROCEDURES
7.1
Trial Procedures
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to 
perform these procedures at unscheduled time points if deemed clinically necessary by the 
investigator.
Furthermore, additional evaluations/testing may be deemed necessary by the investigator and 
or the Sponsor for reasons related to subject safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations 
may require that additional informed consent be obtained from the subject.  In these cases, 
such evaluations/testing will be performed in accordance with those regulations.
Administrative Procedures
Informed Consent
The investigator or 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.
7.1.1.1.1 General Informed Consent
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion. 
A copy of the signed and dated consent form should be given to the subject before 
participation in the trial.
The initial informed consent form, any subsequent revised written informed consent form 
and any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The subject or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the trial.  The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the subject’s dated signature or 
by the subject’s legally acceptable representative’s dated signature.
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.  
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements.
 
 
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7.1.1.1.2 Consent and Collection of Specimens for Future Biomedical Research
The investigator or qualified designee will explain the Future Biomedical Research consent 
to the subject, answer all of his/her questions, and obtain written informed consent before 
performing any procedure related to Future Biomedical Research.  A copy of the informed 
consent will be given to the subject.
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.
Subject Identification Card
All subjects will be given a Subject Identification Card identifying them as participants in a 
research trial.  The card will contain trial site contact information (including direct telephone 
numbers) to be utilized in the event of an emergency.  The investigator or qualified designee 
will provide the subject with a Subject Identification Card 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.
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.  Details regarding the subject’s 
gastric or gastroesophageal junction adenocarcinoma 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.
7.1.1.4.1 Disease Details
The investigator or qualified designee will obtain prior and current details regarding the 
subject’s gastric or gastroesophageal junction adenocarcinoma.
Prior and Concomitant Medications Review
7.1.1.5.1 Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject 
 
 
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within 28 days before the screening visit.  Prior treatment for gastric or gastroesophageal 
junction adenocarcinoma will be recorded separately and not listed as a prior medication.
7.1.1.5.1.1 Prior Treatment Details for Gastric or Gastroesophageal Junction 
Adenocarcinoma
The investigator or qualified designee will review all prior cancer treatments including 
systemic treatments, radiation and surgeries.
7.1.1.5.2 Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial beginning at Treatment Cycle 1 through the Safety Follow-Up Visit for the 
Initial Treatment Phase.  All medications related to reportable SAEs and ECIs should be 
recorded as defined in Section 7.2.
During the Second Course Phase, new medications started during the trial through the Safety 
Follow-Up visit should be recorded.  Record all medications taken for SAEs as defined in 
Section 7.2.
7.1.1.5.2.1 Subsequent 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.  
Assignment of Screening Number
All consented subjects will be given a unique screening number that will be used to identify 
the subject for all procedures that occur prior to randomization or allocation.  Each subject 
will be assigned only one screening number.  Screening numbers must not be re-used for 
different subjects.
Any subject who is screened multiple times will retain the original screening number 
assigned at the initial screening visit.
Specific details on the screening visit requirements (screening/rescreening) are provided in 
Section 7.1.5.1.  
Assignment of Randomization Number
All eligible subjects will be allocated, by non-random assignment, and will receive a 
randomization number.  The randomization number identifies the subject for all procedures 
occurring after treatment allocation.  Once a randomization number is assigned to a subject, it 
can never be re-assigned to another subject.
 
 
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A single subject cannot be assigned more than 1 randomization number.
Trial Compliance (Medication/Diet/Activity/Other)
Interruptions from the protocol specified treatment plan for greater than 12 weeks between 
pembrolizumab doses require consultation between the investigator and the Sponsor and 
written documentation of the collaborative decision on subject management.
Administration of trial medication will be monitored by the investigator and/or trial staff
while the subject is in the treatment center.
Clinical Procedures/Assessments
Adverse Event (AE) Monitoring
The investigator or qualified designee will assess each subject to evaluate for potential new 
or worsening AEs as specified in the Trial Flow Chart and more frequently if clinically 
indicated.  Adverse events will be graded and recorded throughout the study and during the 
follow-up period according to NCI CTCAE Version 4.0 (see Appendix 12.5).  Toxicities will 
be characterized in terms regarding seriousness, causality, toxicity grading, and action taken 
with regard to trial treatment.  
For subjects receiving treatment with pembrolizumab, all AEs of unknown etiology 
associated with pembrolizumab exposure should be evaluated to determine if the AE is of 
potentially immunologic etiology (termed immune-related adverse events, or irAEs).  
Please refer to Section 7.2 for detailed information regarding the assessment and recording of 
AEs.
Physical Exam
7.1.2.2.1 Full Physical Exam
The investigator or clinical designee will perform a complete physician exam during the 
screening period.  Clinically significant abnormal findings should be recorded as medical 
history.  A full physical exam should be performed as specified in the Trial Flow Chart.  
After the first dose of trial treatment new clinically significant abnormal findings should be 
recorded as AEs.
7.1.2.2.2 Directed Physical Exam
For cycles that do not require a full physical exam per the Trial Flow Chart, the investigator 
or qualified designee will perform a directed physical exam as clinically indicated prior to 
dosing on Day 1 of each treatment cycle.  New clinically significant abnormal findings 
should be recorded as AEs.
 
 
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Vital Signs
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment and at treatment discontinuation as specified in 
the Trial Flow Chart.  Vital signs should include temperature, pulse, respiratory rate, weight 
and blood pressure.  Height will be measured at screening only.
12-Lead Electrocardiogram
A standard 12-lead ECG will be performed using local standard procedures once at 
screening.  Clinically significant abnormal findings should be recorded as medical history. 
Additional time points may be performed as clinically necessary.
Eastern Cooperative Oncology Group (ECOG) Performance Status
The investigator or qualified designee will assess ECOG status (see Appendix 12.4) at 
screening, prior to dosing on Day 1 of each treatment cycle (except Cycle 1) and at 
discontinuation of trial treatment as specified in the Trial Flow Chart.
Pharmacokinetic/Pharmacodynamic Evaluations
The accumulation of robust PK and anti-drug antibodies (ADA) data has allowed for the 
adequate characterization of the clinical pharmacology of pembrolizumab across indications. 
Therefore, upon approval of Amendment 10, each site should stop the collection of PK and 
ADA samples for all subjects. Blood samples for PK and ADA collected prior to 
Amendment 10 will be stored and analysis will be performed if required.
7.1.2.6.1 Blood Collection for Serum Pembrolizumab (MK-3475)
Sample collection, storage and shipment instructions for serum PK samples will be provided 
in the Procedures Manual.  PK samples should be drawn for subjects who receive 
pembrolizumab.  Every effort should be taken to collect samples at 30 days and 3 months 
after end of pembrolizumab treatment.  
7.1.2.6.2 Blood Collection for Anti-Pembrolizumab (MK-3475)
Sample collection, storage and shipment instructions for anti- pembrolizumab antibody 
samples will be provided in the Procedures Manual.  Anti- pembrolizumab antibody samples 
should be drawn for subjects who receive pembrolizumab.  Every effort should be taken to 
collect samples at 30 days and 3 months after end of pembrolizumab treatment for ADA. 
Simultaneous PK sampling is required for interpretation of ADA analysis.  
Tumor Imaging and Assessment of Disease
The process for image collection and transmission to the central vendor can be found in the 
Site Imaging Manual.  Tumor imaging may be performed by computed tomography (CT) 
(preferred) or magnetic resonance imaging (MRI), but the same imaging technique, 
acquisition, and processing parameters should be used in a subject throughout the trial.  
 
 
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All scans, scheduled and unscheduled should be submitted to the central imaging vendor as 
soon as possible.
In determining whether or not the tumor burden has increased or 
decreased, investigators should consider all target lesions as well as non-target lesions.
A central imaging read based on RECIST 1.1 will be used to determine subject eligibility.  
The central imaging vendor will receive all images from the sites and conduct the disease 
assessment.  The Sponsor will also receive radiologic images for a retrospective analysis of 
subject eligibility and treatment response to be performed by the central vendor, using 
RECIST 1.1. Treatment decisions will be based on the investigator’s radiographic assessment 
of disease, and not based on central imaging vendor’s assessment.
7.1.2.7.1 Baseline Tumor Imaging
To meet screening criteria, baseline tumor imaging must be performed within 14 days prior 
to the first dose of study treatment for potential Cohort 1 (3L+) subjects, and 28 days for 
potential Cohort 2, or 3 (1L) subjects.  The baseline imaging scan must be submitted to the 
central imaging vendor for determination of measurable disease per RECIST 1.1 and 
inclusion into the study.
Scans performed as part of routine clinical management are acceptable for use as the baseline
scan if they are of diagnostic quality and performed within 14 or 28 days prior to the first 
dose of study treatment, as required for the respective cohort.
For subjects enrolled in Cohort 1, a scan performed outside 14 days but within 28 days prior 
to the first dose of pembrolizumab may be acceptable as the baseline scan if (1) it was 
performed as part of routine clinical management, (2) the subject is participating at a site 
where the local regulatory body and/or IRB/ERC would not permit a repeat scan to be 
performed to meet the 14 day criteria, and (3) permission is given by the Sponsor.
7.1.2.7.2 Tumor Imaging During Trial
The first on-study imaging assessment will be performed at 9 weeks (63 days ± 7 days) after 
the first dose of study treatment.  Subsequent imaging will be performed every 6 weeks (42 
days ± 7 days), or more frequently if clinically indicated through the first year.  After the first 
year, tumor imaging will be performed every 9 weeks.  Tumor imaging will be performed 
every 6 weeks during the second course treatment. 
Imaging should continue to be performed until whichever one of the following occurs first:

disease progression (refer to Table 8)

start of new anti-cancer treatment

withdrawal of consent

death

end of study  
 
 
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Imaging should follow calendar days and not be delayed for any dose interruptions that may 
occur.
Timing of Repeat Imaging 
Per RECIST 1.1, response should be confirmed by a repeat radiographic assessment not less 
than 4 weeks from the date the response was first documented.  The scan for confirmation of 
response may be performed at the earliest 4 weeks after the first indication of response, or at 
the next scheduled scan (6 weeks later if during the first year or during second course 
treatment, or 9 weeks later if after the first year during the initial treatment phase), whichever 
is clinically indicated.
7.1.2.7.3 Second Course (Retreatment) Tumor Imaging
Tumor imaging must be performed within 21 days prior to restarting treatment with 
pembrolizumab. Imaging should continue to be performed every 6 weeks (42 days ± 7 days) 
after the restart of treatment or more frequently, if clinically indicated. Imaging timing 
should follow calendar days and should not be adjusted for any dose modifications. The 
exact same image acquisition and processing parameters should be used throughout the 
study. Local reading (investigator assessment with site radiology reading) will be used to 
determine eligibility. All Second Course imaging should be submitted to the imaging Contract 
Research Organization (iCRO) for quality control, storage, and possible retrospective review.
For participants who discontinue Second Course study intervention, tumor imaging should be 
performed at the time of intervention discontinuation (±4-week window). If previous imaging 
was obtained within 4 weeks prior to the date of discontinuation, then imaging at intervention 
discontinuation is not mandatory. For participants who discontinue study intervention due to 
documented disease progression, this is the final required tumor imaging.
For participants who discontinue Second Course study intervention without documented disease 
progression, every effort should be made to continue monitoring their disease status by radiologic
imaging every 6 weeks (42 days ±7 days) until either the start of a new anticancer treatment, 
disease progression, death, or the end of the study, whichever occurs first.
7.1.2.7.4 Assessment of Disease – RECIST 1.1 and irRECIST 
RECIST 1.1 will be applied by the central imaging vendor as the primary measure for 
assessment of tumor response.   
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 apparent initial increase in tumor volume or even the appearance of new 
lesions.
Standard RECIST may not provide an accurate response assessment of 
immunotherapeutic agents such as pembrolizumab. Immune-related RECIST (irRECIST) is 
 
 
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RECIST 1.1 adapted as described below to account for the unique tumor response seen with 
immuno-therapeutics. 
7.1.2.7.4.1 Application of irRECIST
irRECIST will be used by investigators to assess tumor response and progression after 
initial radiographic progression per RECIST 1.1, and make treatment decisions
accordingly.  In this study, there will be no confirmation from central review for 
irRECIST. Therefore, determination of disease status per irRECIST and subsequent 
decision of treatment continuation/discontinuation is per the treating physician.
If radiologic imaging verifies initial disease progression per RECIST 1.1, treatment may 
continue at the discretion of the investigator until repeat imaging ≥ 4 weeks later.  The 
investigator’s decision to continue treatment while awaiting repeat imaging should be based 
on the subject’s overall clinical condition guided by the following criteria:

Absence of signs and symptoms indicating disease progression

No decline in ECOG performance status

Absence of rapid progression of disease

Absence of progressive tumor at critical anatomical sites (eg, cord compression) 
requiring urgent alternative medical intervention
If repeat imaging shows < 20% increase in tumor burden compared to nadir, stable or 
improved previous new lesion (if identified as cause for initial disease progression), and 
stable/improved non-target disease (if identified as cause for initial disease progression), 
treatment may be continued / resumed, and subsequent tumor imaging follows protocol 
schedule.
If repeat imaging confirms disease progression due to any of the scenarios listed below, 
subjects will be discontinued from study therapy.

Tumor burden remains ≥20% and at least 5 mm absolute increase compared to nadir

Non-target disease resulting in initial disease progression is worse (qualitative)

New lesion resulting in initial disease progression is worse (qualitative)

Additional new lesion(s) since last evaluation
In determining whether or not the tumor burden has increased or decreased, investigators 
should consider all target lesions as well as non-target lesions.  
When feasible, study treatment should not be discontinued until progression is confirmed.  
Subjects that are deemed clinically unstable are not required to have repeat imaging for 
confirmation of progressive disease. Guidance for treatment continuation/discontinuation and 
repeat imaging per irRECIST is described in Table 8.
 
 
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Table 8
Imaging and Treatment after 1st Radiologic Evidence of PD
Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
1st
radiologic 
evidence 
of PD
Repeat imaging 
at > 4 weeks at 
site to confirm 
PD
May 
continue 
study 
treatment 
at 
the 
investigator’s discretion 
while 
awaiting 
confirmatory scan by site
Repeat imaging 
at > 4 weeks to 
confirm PD per 
physician 
discretion only
Discontinue treatment
Repeat 
scan 
confirms 
PD
No 
additional 
imaging 
required
Discontinue 
treatment
(exception is possible 
upon consultation with 
Sponsor).
No 
additional 
imaging required
N/A
Repeat 
scan 
shows SD, 
PR or CR
Continue 
regularly 
scheduled 
imaging 
assessments 
Continue study treatment 
at 
the 
investigator’s 
discretion
Continue 
regularly 
scheduled 
imaging 
assessments 
May restart study treatment if 
condition has improved and/or 
clinically 
stable 
per 
investigator’s discretion. 
CR = complete response; PD = progressive disease; PR = partial response; SD = stable disease
NOTE: If a subject has confirmed radiographic progression (ie, 2 scans at least 4 weeks apart 
demonstrating progressive disease) per irRECIST, but the subject is achieving a clinically 
meaningful benefit, an exception to continue treatment may be considered following 
consultation with the Sponsor.
Tumor Tissue Collection
Tumor tissue will be evaluated as part of screening to determine if the sample is adequate for 
assessment of PD-L1 status (per inclusion 8 in Section 5.1.2). 
Tumor tissue sample submitted in either formalin solution or FFPE block is acceptable. If 
submitting unstained cut slides from FFPE block, freshly cut slides must be received by the
central laboratory within 14 days from when the slides are cut.
A fine needle aspirate (FNA) or cytologic specimen will not be acceptable. Tumor tissue 
should be submitted in the condition described in the procedure manual.
If the subject signs the Future Biomedical Research (FBR) consent, any leftover tissue that 
would ordinarily be discarded at the end of the main study will be retained for FBR.  Details 
regarding time points for collection of tumor tissue are outlined in the Trial Flow Chart –
Section 6.1.
Detailed instructions for tissue collection, processing and shipment are provided in the 
Procedures Manual.
 
 
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Blood Collections – Genetics, Proteomics and Transcriptional Analyses
Details regarding time points for blood collection to support analysis of exploratory 
biomarkers presented in Section 4.2.3.3.1 are outlined in the Trial Flow Chart – Section 6.1.
Samples for planned, exploratory genetic analysis of DNA should be drawn unless there is a 
documented law or regulation prohibiting collection, or unless the IRB/IEC does not approve 
of the collection.
Detailed instructions for tissue collection, processing and shipment are provided in the 
Procedures Manual.
Any leftover specimens may be used for future biomedical research provided the subject has 
provided the relevant informed consent.
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.
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
Laboratory tests for hematology, chemistry and urinalysis are specified in Table 9.
 
 
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Table 9
Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Hematocrit
Albumin
Blood
Serum β-human chorionic 
gonadotropin (β-hCG)a
Hemoglobin
Alkaline phosphatase
Glucose
PT (INR)d
Platelet Count
Alanine aminotransferase 
(ALT)
Protein
aPTTd
WBC (total and 
differential) f
Aspartate aminotransferase 
(AST)
Specific gravity 
Total Triiodothyronine
(T3)e
Red Blood Cell Count
Calcium
Microscopic exam, if 
abnormal results are 
noted
Free thyroxine (free T4)
Absolute Neutrophil 
Countf
Bicarbonate/carbon dioxideb
Urine pregnancy testa
Thyroid stimulating 
hormone (TSH)
Absolute Lymphocyte 
Countf
Carcinoembryonic antigen 
(CEA)
Blood for FBR
Chloride
Blood for Proteomics
Creatinine
Blood for Genetics
Glucose
Blood for Transcriptional 
Analysis
Phosphorus
Potassium
Sodium
Total Bilirubin  
Direct Bilirubin, if total 
bilirubin is elevated above 
ULN
Total protein
Blood Urea Nitrogen
Uric acid
Ureac
a Perform on women of childbearing potential only.  Urine pregnancy test is preferred.  If the urine test is positive or cannot 
be confirmed as negative, a serum pregnancy test will be required.
b. Test only if part of Standard of Care locally.
c Blood Urea Nitrogen is preferred; if not available, urea may be tested.
d Coagulation factors (PT/INR and aPTT) should be tested as part of the screening procedures for all subjects.  Any subject 
receiving anticoagulant therapy should have coagulation factors monitored closely throughout the trial.
e Total T3 is preferred; if not available, free T3 may be tested locally. T3 and TSH may be tested centrally if testing is not 
available locally.
f. Absolute values or percentage per local laboratory.
 
 
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Laboratory tests for screening should be performed within 3 days prior to the first dose of 
trial treatment.  After Cycle 1, pre-dose laboratory procedures can be conducted up to 72 
hours prior to dosing.  Results must be reviewed by the investigator or qualified designee and 
found to be acceptable prior to each dose of trial treatment.  For all subjects, unresolved 
abnormal labs resulting in drug-related AEs should be followed until resolution. 
Chemistry labs will be collected on Day 1 of Cycles 2-6, then every 2 cycles for subjects in 
Cohort 1 and 3 (pembrolizumab monotherapy) and for subjects in Cohort 2 (Combination 
treatment) who are receiving only pembrolizumab (both chemotherapy agents were
discontinued). For subjects in Cohort 2 who are receiving chemotherapy (with or without 
pembrolizumab), chemistry will be collected every cycle on Day 1. 
Japan only - for subjects receiving capecitabine, chemistry should be collected as follows for 
Cycles 1 and 2: Cycle 1 - Days 8 and 15 (screening chemistry labs satisfy requirement for 
Day 1); Cycle 2 - Days 1, 8, and 15.  After Cycle 2, chemistry labs will be collected every 
cycle on Day 1 as long as the subject is receiving treatment with either capecitabine and/or 
cisplatin.
CBC w/differentials will be collected on Day 1 of Cycles 2-6, then every 2 cycles for 
subjects in Cohort 1 and 3 (pembrolizumab monotherapy) and for subjects in Cohort 2 
(Combination treatment) who are receiving only pembrolizumab (in the event both 
chemotherapy agents were discontinued).  For subjects in Cohort 2 who are receiving 
chemotherapy (with or without pembrolizumab), CBC w/differentials will be collected every 
cycle on Day 1, 8 and 15 of Cycles 1-6 (screening CBC w/differentials labs satisfy 
requirement for Day 1 of Cycle 1); then on Day 1 of every cycle thereafter.  
Please refer to the Trial Flow Chart (Section 6.1 and Section 6.2) for additional details 
regarding timing for laboratory tests.
Future Biomedical Research
The following specimens are to be obtained as part of Future Biomedical Research:

Blood (DNA) for future use

Leftover tumor tissue

Leftover blood, plasma, and serum specimens (PK/ADA, blood samples for genetics, 
proteomics and transcriptional (RNA and DNA) analysis)
Details for collection and management as well as the use of specimens for Future Biomedical 
Research can be found in Appendix 12.2 and Appendix 12.3.
 
 
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Other Procedures
Withdrawal/Discontinuation
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 a) attain a CR or b) complete 35 administrations 
(approximately 2 years) of study treatment may discontinue treatment with the option of 
restarting treatment if they meet the criteria specified in Section 7.1.5.5.  After discontinuing 
treatment following assessment of CR or 35 administrations of study treatment, these 
subjects should return to the site for a Safety Follow-up Visit (described in Section 7.1.5.4.1) 
and then proceed to the Follow-up Period of the study (described in Section 7.1.5.4.2).
7.1.4.1.1 Withdrawal From Future Biomedical Research
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   Subjects may withdraw consent at any time by 
contacting the principal investigator for the main trial.  If medical records for the main trial 
are still available, the investigator will contact the Sponsor using the designated mailbox 
(clinical.specimen.management@merck.com), and a form will be provided by the Sponsor to 
obtain appropriate information to complete specimen withdrawal.  Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed.  A letter will 
be sent from the Sponsor to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for destruction or already performed prior to the 
request being received by the Sponsor will continue to be used as part of the overall research 
trial data and results.   No new analyses would be generated after the request is received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial records) or 
the specimens have been completely anonymized, there will no longer be a link between the 
subject’s personal information and their specimens.  In this situation, the request for 
specimen destruction cannot be processed.
Blinding/Unblinding
This is an open label trial; there is no blinding for this trial.
The study team will be blinded to PD-L1 expression status (positive or negative) for all 
subjects participating in the initial all-comers portion of Cohort 1 until the interim analysis of 
Cohort 1. Following the interim analysis, the Sponsor will be unblinded to PD-L1 data.  
Analyses or summaries of PD-L1 biomarker status will be limited and documented after the 
interim analysis. See additional details regarding blinding in Section 8.2.  
 
 
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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 study 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 
study site.
Visit Requirements
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures.
Screening
Approximately 28 days prior non-random assignment to one of 3 cohorts and study 
treatment, potential subjects will be evaluated to determine that they fulfill the entry 
requirements as set forth in Section 5.1.  Screening procedures may be repeated after 
consultation with the Sponsor.  Visit requirements are outlines in Section 6.0 – Trial Flow 
Chart.
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 performance status are to be performed within 3 days 
prior to the first dose of trial treatment.

For women of reproductive potential, a urine pregnancy test will be performed within 
72 hours prior to the first dose of trial treatment.  

Biopsy collections may be collected up to 42 days prior to the first dose of trial 
treatment as presented in Sections 5.1.1 and 6.1.
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 a repeat screening test if performed within the specified time frame and the 
inclusion/exclusion criteria is met.
Treatment Cycles
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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Discontinuation Visit
The Discontinuation Visit should occur at the time study treatment is discontinued for any
reason.  If the Discontinuation Visit occurs 30 days from the last dose of study treatment, at
the time of the Safety Follow up Visit, procedures do not need to be repeated.  Visit 
requirements are outlined in Section 6.0 – Trial Flow Chart.  Specific procedure-
related details are provided above in Section 7.1 – Trial Procedures.  Additional details 
regarding subject withdrawal and discontinuation are presented in Section 5.8.
Post-Treatment 
7.1.5.4.1 Safety Follow-up 
The Safety Follow-Up Visit will be conducted approximately 30 days after the last dose of 
study treatment or before the initiation of a new anti-cancer treatment, whichever comes first.  
Subjects who are eligible for retreatment with pembrolizumab (as described in Section 
7.1.5.5) may have up to 2 safety follow-up visits, one after the Treatment Period and one 
after the Second Course Phase.
7.1.5.4.2 Follow-up Visits
Subjects who discontinue trial treatment for a reason other than disease progression will 
move into the Follow-Up Phase and should be assessed every 6 weeks (42 ± 7 days) by 
radiologic imaging to monitor disease status.  After 1 year, the imaging time point will occur 
every 9 weeks (± 7 days).
The Sponsor may request survival status to be assessed at 
additional time points during the course of the study (not to exceed approximately 12 weeks).  
Every effort should be made to collect information regarding disease status until the start of 
new anti-cancer therapy, disease progression, death, end of study or if the subject begins 
retreatment with pembrolizumab as detailed in Section 7.1.5.5.  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 7.1.5.5 will move from the Follow-Up Phase to the Second Course Phase when 
they experience disease progression.  Details are provided in Section 6.2 – Trial Flow Chart 
for retreatment with pembrolizumab.
7.1.5.4.3 Survival Follow-up
Once a subject experiences confirmed disease progression or starts a new anti-cancer 
therapy, the subject moves into the Survival Follow-Up Phase and should be contacted by 
telephone approximately every 12 weeks to assess for survival status until death, explicit 
withdrawal of consent for survival follow up, or the end of the study, whichever occurs first.
Information regarding post-study anti-cancer treatment will be collected if new treatment is 
initiated.
 
 
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Second Course Phase (Retreatment Period)
All subjects who stop study treatment with SD or better may be eligible for up to one year of 
additional pembrolizumab treatment if they progress after stopping study treatment from the 
initial treatment phase.  This retreatment is termed the Second Course Phase of this study and 
is only available if the study remains open and the subject meets the following conditions:

Either 
o
Stopped initial treatment with study treatment after attaining an investigator-
determined confirmed CR according to RECIST 1.1, and

Was treated for at least 8 administrations with study treatment before 
discontinuing treatment.

Received at least 2 treatments with pembrolizumab beyond the date when the 
initial CR was declared.
OR
o
Had SD, PR or CR and stopped study treatment after completion of 35 
administrations of pembrolizumab (approximately 2 years) of study treatment for 
reasons other than disease progression or intolerability.
AND

Experienced an investigator-determined radiographic disease progression after 
stopping their initial treatment.

Did not receive any anti-cancer treatment since the last dose of study treatment.

Has a performance status of 0 or 1 on the ECOG Performance Scale within 3 days 
prior to the first dose of trial treatment.

Demonstrates adequate organ function as detailed in Section 5.1.2.  Laboratory tests 
are to be performed within 3 days prior to the first dose of trial treatment.

Female subject of childbearing potential should have a negative serum or urine 
pregnancy test within 72 hours prior to receiving retreatment with study medication.  

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 or 180 days after the last dose of study medication (Section 
5.7.2).  Duration of use of contraceptives will depend on which cohort a subject is 
assigned.  Subjects of child bearing potential are those who have not been surgically 
sterilized or have been free from menses for > 1 year. 

Male subject should agree to use an adequate method of contraception starting with 
the first dose of study treatment through 120 or 180 days after the last dose of study 
treatment (Section 5.7.2).  Duration of use of contraceptives will depend on which 
cohort a subject is assigned.
 
 
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
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 restart treatment will be retreated at the same dose and dose interval as when 
they last received pembrolizumab.  Treatment will be administered for up to one additional 
year.
Visit requirements are outlined in Section 6.0 – Trial Flow Chart.
Survival Status
To ensure current and complete survival data are 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 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 previously recorded a death event in the collection tool). 
7.2
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.
 
 
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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
For this trial, an overdose of:

pembrolizumab will be defined as any dose of 1,000 mg or greater (≥5 times the 
indicated dose)

any standard treatment is any dose ≥ 20% over the prescribed dose.  
No specific information is available on the treatment of overdose of pembrolizumab.  In the 
event of overdose, the subject should be observed closely for signs of toxicity.  Appropriate 
supportive treatment should be provided if clinically indicated.
Overdoses of cisplatin, 5-FU and capecitabine (Japan only), will be managed in accordance 
with the respective product label.
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 within 24 hours 
to the Sponsor either by electronic media or paper.  Sponsor Contact information can be 
found in the Investigator Trial File Binder (or equivalent).
 
 
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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
Serious Adverse Events
A serious adverse event is any adverse event occurring at any dose or during any use of 
Sponsor's product that:
●
Results in death;
●
Is life threatening;
●
Results in persistent or significant disability/incapacity;
●
Results in or prolongs an existing inpatient hospitalization;
●
Is a congenital anomaly/birth defect;
●
Is an other important medical event 
Note: In addition to the above criteria, adverse events meeting either of the below criteria, 
although not serious per ICH definition, are reportable to the Sponsor in the same timeframe 
as SAEs to meet certain local requirements. Therefore, these events are considered serious by 
the Sponsor for collection purposes.
●
Is a new cancer (that is not a condition of the study);
●
Is associated with an overdose.
 
 
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Refer to Table 10 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 at any time following consent through the end of the specified safety follow-up 
period specified in the paragraph above, or at any time outside of the time period specified in 
the previous paragraph also must be reported immediately to the Sponsor.  
All subjects with serious adverse events must be followed up for outcome.
Events of Clinical Interest
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported to the Sponsor.
For the time period beginning when the 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).
 
 
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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).
ECIs (both non-serious and serious adverse events) from the date of first dose through 
90 days following cessation of treatment, or 30 days after the initiation of a new anticancer 
therapy, whichever is earlier, need to be reported to the SPONSOR within 24 hours of the 
event, regardless of attribution to study treatment, consistent with standard SAE reporting 
guidelines and either by electronic media or paper.  Sponsor Contact information can be 
found in the administrative binder.
Subjects should be assessed for possible ECIs prior to each dose.  
Protocol-Specific Exceptions to Serious Adverse Event Reporting
Efficacy endpoints as outlined in this section will not be reported to the Sponsor as described 
in Section 7.2.3 - Immediate Reporting of Adverse Events to the Sponsor.
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study.  
The Sponsor will monitor unblinded aggregated efficacy endpoint events and safety data to 
ensure the safety of the subjects in the trial.  Any suspected endpoint which upon review is 
not progression of the cancer under study will be forwarded to global safety as a SAE within 
24 hours of determination that the event is not progression of the cancer under study.
Evaluating Adverse Events
An investigator who is a qualified physician will evaluate all adverse events 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.
Refer to Table 10 when evaluating adverse events in this study.
 
 
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Table 10
Evaluating Adverse Events
An investigator who is a qualified physician, will evaluate all adverse events as to:
V4.0 CTCAE 
Grading
Grade 1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated.
Grade 2
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL.
Grade 3
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; 
disabling; limiting self-care ADL.
Grade 4
Life threatening consequences; urgent intervention indicated.
Grade 5
Death related to AE
Seriousness
A serious adverse event is any adverse event occurring at any dose or during any use of Sponsor’s product that:
†Results in death; or
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include an 
adverse event that, had it occurred in a more severe form, might have caused death.); or
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation. (Note: Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not a serious adverse event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of a Merck product and is documented in 
the patient’s medical history.); or
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or
Is a new cancer (that is not a condition of the study) (although not serious per ICH definition, is reportable to the Sponsor within 24 hours to meet certain local 
requirements); or
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event for collection purposes. An 
overdose that is not associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 hours.
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes 
listed previously (designated above by a †).
Duration
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units
Action taken 
Did the adverse event cause the Sponsor’s product to be discontinued?
Relationship to 
Sponsor’s 
Product
Did the Sponsor’s product cause the adverse event? The determination of the likelihood that the Sponsor’s product caused the adverse event will be provided by an 
investigator who is a qualified physician. The investigator’s signed/dated initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed document must be retained for the required regulatory time frame. The 
criteria below are intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the adverse event 
based upon the available information.
The following components are to be used to assess the relationship between the Sponsor’s product and the AE; the greater the correlation with the components 
and their respective elements (in number and/or intensity), the more likely the Sponsor’s product caused the adverse event (AE):
Exposure
Is there evidence that the subject was actually exposed to the Sponsor’s product such as: reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen?
Time Course
Did the AE follow in a reasonable temporal sequence from administration of the Sponsor’s product?
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)?
Likely Cause
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental factors
 
 
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Relationship
The following components are to be used to assess the relationship between the test drug and the AE: (continued)
to Sponsor's 
Product
(continued) 
Dechallenge
Was the Sponsor’s product discontinued or dose/exposure/frequency reduced?
If yes, did the AE resolve or improve?
If yes, this is a positive dechallenge. If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite continuation of 
the Sponsor’s product; or (3) the trial is a single-dose drug trial); or (4) Sponsor’s product(s) is/are only used one time.)
Rechallenge
Was the subject re-exposed to the Sponsor’s product in this study?
If yes, did the AE recur or worsen?
If yes, this is a positive rechallenge. If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose drug trial); or 
(3) Sponsor’s product(s) is/are used only one time).
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN 
CAUSED BY THE SPONSOR'S PRODUCT, OR IF REEXPOSURE TO THE SPONSOR'S PRODUCT POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR
CLINICAL DIRECTOR AS PER DOSE MODIFICATION GUIDELINES IN THE PROTOCOL.
Consistency 
with Trial 
Treatment 
Profile
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the Sponsor’s product or drug class pharmacology 
or toxicology?
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements.
Record one of the following
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a Sponsor’s product relationship).
Yes, there is a reasonable 
possibility of Sponsor's product 
relationship.
There is evidence of exposure to the Sponsor's product.  The temporal sequence of the AE onset relative to the administration of the Sponsor's 
product is reasonable.  The AE is more likely explained by the Sponsor's product than by another cause.
No, there is not a reasonable 
possibility of Sponsor's product 
relationship
Subject did not receive the Sponsor's product OR temporal sequence of the AE onset relative to administration of the Sponsor's product is not 
reasonable OR the AE is more likely explained by another cause than the Sponsor’s product.  (Also entered for a subject with overdose without an 
associated AE.)
 
 
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Sponsor Responsibility for Reporting Adverse Events
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations, i.e., per ICH Topic E6 (R1) 
Guidelines for Good Clinical Practice.
7.3
TRIAL GOVERNANCE AND OVERSIGHT
Executive Oversight Committee
The Executive Oversight Committee (EOC) comprises members of Sponsor Senior 
Management.  The EOC will receive and decide upon any recommendations made by the
Data Monitoring Committee (DMC) regarding the trial.
Data Monitoring Committee
To supplement the routine trial monitoring outlined in this protocol, an external Data 
Monitoring Committee (DMC) will monitor the interim data from this trial.  The voting 
members of the committee are external to the Sponsor.  The members of the DMC must not 
be involved with the trial in any other way (e.g., they cannot be trial investigators) and must 
have no competing interests that could affect their roles with respect to the trial. 
The DMC will make recommendations to the EOC regarding steps to ensure both subject 
safety and the continued ethical integrity of the trial.  Also, the DMC will review interim trial 
results, consider the overall risk and benefit to trial participants (see Section 8.7 - Interim 
Analyses) and recommend to the Executive Oversight Committee if the trial should continue 
in accordance with the protocol.
Specific details regarding composition, responsibilities, and governance, including the roles 
and responsibilities of the various members and the DMC; meeting facilitation; the trial 
governance structure; and requirements for and proper documentation of DMC reports, 
minutes, and recommendations will be described in a separate charter that is reviewed and 
approved by the DMC.  The DMC will monitor the trial at an appropriate frequency, as 
described in the detailed DMC charter.  
Scientific Advisory Committee
The MK3475 Gastric Cancer Program Scientific Advisory Committee (SAC) has global 
membership. The objective of the SAC is to engage in an end-to-end and collaborative 
process to obtain external scientific input on program and/or protocol design, interpretation 
of study results and resulting publications.
8.0 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 unblinding, 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 
 
 
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unblinding, 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.  
8.1
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Sections 8.2 to Section 8.12.
Study Design 
Overview
A Phase II Clinical Trial of Pembrolizumab as Monotherapy and in Combination with 
Cisplatin+5-Fluorouracil in Subjects with Recurrent or Metastatic Gastric or 
Gastroesophageal Junction Adenocarcinoma (KEYNOTE-059). 
Treatment
Assignment
Treatment assignment is open label. 
Analysis 
Populations
Efficacy: All Subjects as Treated (ASaT)
Safety: All Subjects as Treated (ASaT)
Primary 
Endpoint(s)
Cohort 2:  Safety and tolerability (see Section 4.2.1.2)
Cohort 1/3: Objective response rate (ORR) per RECIST 1.1 assessed by central imaging 
vendor
Statistical 
Methods for Key 
Efficacy Analyses
Cohort 1 (3L+ gastric cancer subjects/monotherapy): 95% CI for ORR will be calculated
using Exact method based on binomial distribution.
Cohort 2 (1L gastric cancer subjects/combination treatment): The primary objective is 
safety evaluation, and the secondary objective is the estimation of the ORR. 95% CI for 
ORR will be calculated using Exact method based on binomial distribution. 
Cohort 3 (1L gastric cancer subjects/monotherapy): 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 1, an interim analysis will be performed for PD-L1 negative subjects in this 
study.  Results will be reviewed by an external data monitoring committee.  The interim 
analysis is summarized below.  
Details are provided in Section 8.7. 

Interim Analysis 1: 
o
Timing: To be performed when ~40 all-comer subjects have response 
assessment available
o
Testing: Futility check based on ORR assessed by central imaging vendor in
PD-L1 negative subjects 
Multiplicity
This is an estimation study. No multiplicity adjustment will be applied.
Sample Size 
Cohort 1 (3L+ gastric cancer subjects/monotherapy): Since the futility criterion was not 
met, the overall sample size for Cohort 1 is approximately 210. The enrollment of 
Cohort 1 will stop when at least 80 all-comer subjects meeting the revised eligibility 
criteria are enrolled. 
Cohort 2
(1L gastric cancer subjects/combination treatment): There will be 
approximately 18 subjects enrolled. 
Cohort 3 (1L gastric cancer subjects/monotherapy): There will be ~25 PD-L1 positive 
subjects enrolled. 
 
 
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8.2
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. There is no randomization in the study. 
The Clinical Biostatistics department will generate the allocation schedule.
One planned interim analysis for Cohort 1 is described in Section 8.7. The study team will 
remain blinded to the PD-L1 expression level (positive or negative) for the subjects 
participating in the initial all-comers portion of Cohort 1 until the interim analysis of Cohort 
1. Results of the interim analysis will be provided by the external unblinded statistician to the 
Data Monitoring Committee (DMC). The DMC will serve as the primary reviewer of the 
results of the interim analysis and will make recommendations in terms of whether to resume 
the enrollment of the PD-L1 negative subjects in Cohort 1 to the SPONSOR. Prior to study 
completion, the external unblinded statistician will not be involved in any discussions 
regarding modifications to the protocol, statistical methods, identification of protocol 
violators, or data validation efforts after the interim analyses. Analyses or summaries of PD-
L1 biomarker status before the interim analysis will be limited and documented after the 
interim analysis. Following the interim analysis, the Sponsor will be unblinded to PD-L1 
data.  
8.3
Hypotheses/Estimation
This is an estimation study. Objectives of the study are stated in Section 3.0.
8.4
Analysis Endpoints
Efficacy Endpoints
Objective Response Rate (ORR): proportion of subjects in the analysis population who have 
complete response (CR) or partial response (PR).
Duration of Response (DOR): 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.
Disease Control Rate (DCR): for 1L subjects, DCR is defined as proportion of subjects in the 
analysis population who have CR or PR or stable disease (SD) for at least 6 months; for 3L+ 
subjects, DCR is defined as proportion of subjects in the analysis population who have CR or 
PR or stable disease (SD) for at least 2 months.
Progression-Free Survival (PFS): time from the date of the first dose of study medication to 
the first documented disease progression or death.
Overall Survival (OS): time from the date of the first dose of study medication to death due 
to any cause.
 
 
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Safety Endpoints
The primary safety objective of this trial is to characterize the safety and tolerability of 
pembrolizumab and pembrolizumab in combination with cisplatin + 5-FU or cisplatin +
capecitabine in subjects with gastric cancer.  The primary safety analysis will be based on 
subjects who experienced toxicities as defined by CTCAE criteria.  Safety will be assessed 
by quantifying the toxicities and grades experienced by subjects who have received 
pembrolizumab, including serious adverse events (SAEs) and events of clinical interest 
(ECIs).  
Safety will be assessed by reported adverse experiences using CTCAE, Version 4.0. The 
attribution to study treatment, 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.  Consider referring to 
Section 4.2.3 for the initial description of safety measures.
8.5
Analysis Populations
Efficacy Analysis Populations
The All Subjects as Treated (ASaT) population will be used for the analysis of ORR, DCR, 
PFS, and OS. ASaT population consists of all subjects who received at least one dose of 
study treatment.
The analysis population for DOR consists of responders.
Safety Analysis Populations
The All Subjects as Treated (ASaT) population will be used for the analysis of safety data in 
this study.  
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.
8.6
Statistical Methods
Statistical Methods for Efficacy Analyses
In Cohorts 1 and 3, the primary endpoints are ORR per RECIST 1.1 assessed by central 
imaging vendor for all subjects and in PD-L1 positive subjects. The point estimate and 95% 
confidence interval will be provided using exact binomial method proposed by Clopper and 
Pearson (1934) [34]. Subjects in the primary analysis population (ASaT) without ORR data 
will be counted as non-responder.
 
 
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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 11. 
Table 11
Censoring Rules for DOR
Situation
Date of progression or censoring
Outcome
No progression nor death, no new anti-
cancer therapy initiated
Last adequate assessment
Censor 
(non-event)
No progression nor death, new anti-cancer 
therapy initiated
Last adequate assessment before new 
anti-cancer therapy initiated
Censor 
(non-event)
Death 
or 
progression 
after 
≥2 
consecutive missed 
adequate 
disease 
assessments
Last adequate assessment prior to ≥2 
missed adequate disease assessments
Censor 
(non-event)
Death 
or 
progression 
after 
≤1 missed 
adequate disease assessments
Death or progression
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 each Cohort, the efficacy endpoints, analysis population, and statistical methods
(including missing data handling) that will be employed for the efficacy analyses are 
presented in Table 12.
 
 
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Table 12
Summary of Analysis Strategy for Efficacy Endpoints
Endpoint
Statistical 
Method
Analysis Population
Missing data 
approach
Primary Endpoint
ORR

RECIST 1.1, central 
imaging vendor 

irRECIST, central 
imaging vendor 
Exact method 
based on 
binomial 
distribution
ASaT in all below populations:
Cohort 1*

all 

PD-L1+
Cohort 2

all

PD-L1+
Cohort 3 (PD-L1+ only)
Subjects with 
missing data are 
considered non-
responders
Secondary Endpoints
DCR

RECIST 1.1, central 
imaging vendor

irRECIST, central 
imaging vendor
Exact method
based on 
binomial 
distribution
ASaT in all below populations:
Cohort 1

all 

PD-L1+
Cohort 2

all 

PD-L1+
Cohort 3 (PD-L1+ only)
Subjects with 
missing data are 
considered as 
disease not under 
control
PFS

RECIST 1.1, central 
imaging vendor

irRECIST, central 
imaging vendor
OS
Summary 
statistics using 
Kaplan-Meier 
method
ASaT in all below populations:
Cohort 1

all 

PD-L1+
Cohort 2

all 

PD-L1+
Cohort 3 (PD-L1+ only)
Censored at last 
assessment date
DOR

RECIST 1.1, central 
imaging vendor

irRECIST, central 
imaging vendor
Summary 
statistics using 
Kaplan-Meier 
method
Responders in all below 
populations:
Cohort 1

all 

PD-L1+
Cohort 2

all 

PD-L1+
Cohort 3 (PD-L1+ only)
Censored at last 
assessment date
* In Cohort 1, ORR, per RECIST 1.1 assessed by central imaging vendor for all subjects and in PD-L1+ subjects, is 
considered primary; all other efficacy analyses are considered supportive.
** In Cohort 2, ORR, per RECIST 1.1 assessed by central imaging vendor, for all subjects and in PD-L1+ subjects is 
considered secondary; all other efficacy analyses are considered supportive. 
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. 
 
 
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Summaries of Baseline Characteristics, and Demographics
The number and percentage of subjects screened, enrolled, the primary reasons for screening 
failure, and the primary reason for discontinuation will be displayed.  Demographic 
variables, baseline characteristics, primary and secondary diagnoses, and prior and 
concomitant therapies will be summarized by treatment either by descriptive statistics or 
categorical tables.
8.7
Interim Analyses
For Cohort 1, an interim analysis will be performed for PD-L1 negative subjects.
The 
endpoint, timing, and purpose of the interim analyses are summarized in Table 13.  
The detailed process is described as below:
1. Enrollment will begin with an all-comer population. After both the PD-L1 assay is 
ready and ~40 all-comers enrolled, PD-L1 positive subjects will be continued 
enrollment, and PD-L1 negative subject enrollment will be paused.
2. An interim analysis (reviewed by external DMC) will be performed when the initially 
enrolled all-comers (n~40) have response assessment available. The purpose of this 
interim analysis is to check treatment futility on the PD-L1 negative subjects. It is 
estimated that approximately 25 PD-L1 negative subjects will be included in this 
interim analysis.
3. If the futility criterion is not met, the PD-L1 negative subject enrollment will be 
resumed. The trial enrollment will end when at least 80 all-comer subjects meeting 
the revised eligibility criteria are enrolled. If the futility criterion is met for the PD-L1 
negative subjects, the trial will continue to only enroll PD-L1 positive subjects until 
there are at least 90 PD-L1 positive subjects.
For the PD-L1 negative subjects, the futility criterion is met if the upper bound of the 95% 
confidence interval of ORR is less than 20%. If the futility criterion is met then the 
enrollment of PD-L1 negative subjects will not be resumed. 
Among the initially enrolled ~40 all-comers, the actual number of PD-L1 negative subjects 
could vary depending on prevalence rate. According to the futility rule defined above, if 25 
PD-L1 negative subjects are included in the interim analysis, and if no responder is observed, 
the enrollment of PD-L1 negative subjects in Cohort 1 will not resume. Otherwise, if 1 or 
more responders are observed among the 25 PD-L1 negative subjects, the enrollment of the 
PD-L1 negative subjects will be re-opened.
 
 
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Table 13
Summary of Interim Analysis Strategy
Key Endpoints for 
Interim Analysis
Timing of 
Interim Analysis
Purpose of 
Interim Analysis
ORR
(confirmed 
or 
unconfirmed*)
By RECIST 1.1, central imaging 
vendor assessment
Initially enrolled ~40 all-comers 
have response assessment available 
(~25 
PD-L1 
negative 
subjects 
provided)
Check 
futility 
for 
PD-L1 
negative subjects
* Unconfirmed responders include those with confirmed responses and those who don’t have confirmation scan yet at 
the cut-off date for Interim Analysis.
As of Oct 19, 2015, an interim analysis has been performed and the external DMC has 
reviewed the data. The futility criterion was not met and the DMC recommended that the 
enrollment of PD-L1 negative subjects could be resumed.
8.8
Multiplicity
This is an estimation study. 95% confidence intervals of ORR will be provided. No 
multiplicity adjustment will be applied.
8.9
Sample Size and Power Calculations
Cohort 1 (3L+ gastric cancer subjects/monotherapy): 

Enrollment began with an all-comer population. By 23 July 2015, 42 all-comer 
subjects were enrolled and included in the interim analysis.

Then only PD-L1 positive subjects were enrolled until the outcome of the interim 
analysis was determined on 19 October 2015. From 23 July 2015 to 19 October 
2015, approximately 33 PD-L1 positive subjects were enrolled.

Since the futility criterion was not met at the interim analysis, the enrollment of PD-
L1 negative subjects will resume. Enrollment after the interim analysis will not stop 
until at least 80 all-comer subjects meeting the revised eligibility criteria are 
enrolled. Since the implementation of the amendment takes time, it is estimated that 
approximately 135 all-comer subjects will be enrolled after the interim analysis, 
including about 55 all-comer subjects enrolled under the original protocol and 80 
under the amendment.
Thus, it is estimated that the overall sample size for Cohort 1 is approximately 210.
Table 14 shows the two-sided 95% CI of ORR with 210 subjects for different observed 
response rates. With 210 subjects, if there are at least 31 responders observed, the lower 
bound of the 95% confidence interval for ORR will be above 10%.
 
 
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Table 14
Two-sided 95% CI of ORR with 210 Subjects
Number of observed responders
ORR estimates
95% CI of ORR (%)
30
14.3%
(9.9, 19.8)
31
14.8%
(10.3, 20.3)
32
15.2%
(10.7, 20.8)
33
15.7%
(11.1, 21.4)
Assuming the prevalence of PD-L1 positive is 50% based on the interim analysis and ~33
PD-L1 positive subjects are enrolled during the period of enrolling only PD-L1 positive 
subjects; there will be a total of approximately 120 PD-L1 positive subjects in Cohort 1. 
Table 15 shows the two-sided 95% CI of ORR with 120 PD-L1 positive subjects for different 
response rates. 
Table 15
Two-sided 95% CI of ORR with 120 PD-L1 Positive Subjects
Number of observed responders
ORR estimates
95% CI of ORR (%)
19
15.8%
(9.8, 23.6)
20
16.7%
(10.5, 24.6)
21
17.5%
(11.2, 25.5)
22
18.3%
(11.9, 26.4)
Table 16 shows the two-sided 95% CI of ORR with 80 all-comer subjects meeting the 
revised eligibility criteria for different observed response rates.
Table 16
Two-sided 95% CI of ORR with 80 Subjects Meeting Revised Eligibility Criteria 
Number of observed responders
ORR estimates
95% CI of ORR (%)
14
17.5%
(9.9, 27.6)
15
18.8%
(10.9, 29.0)
16
20.0%
(11.9, 30.4)
17
21.3%
(12.9, 31.8)
Cohort 2 (1L gastric cancer subjects/combination treatment): There will be approximately 18
subjects enrolled for all-comer population. Table 17 shows the two-sided 95% CI of AE rate 
with 18 subjects.
 
 
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Table 17
Two-sided 95% CI of AE incidence rate with 18 Subjects
Number of AE
AE incidence rate estimates
95% CI of incidence rate (%)
2
11.1%
(1.4, 34.7)
4
22.2%
(6.4, 47.6)
5
27.7%
(9.7, 53.5)
7
38.9%
(17.3, 64.2)
9
50.0%
(26.0, 73.9)
Cohort 3 (1L gastric cancer subjects/monotherapy): There will be ~25 PD-L1 positive 
subjects enrolled in Cohort 3. Using Bayesian sample size methods and assuming a uniform 
prior for the response rate (beta-binomial prior with beta (1, 1)), if we observe no more than 
8 responders (i.e. observed ORR ≤32%), there is ≥77% posterior probability that the true 
ORR is less than 40% (ORR from Standard of Care). 
8.10 Subgroup Analyses and Effect of Baseline Factors
Efficacy analyses will be performed within the following subgroups:

Subjects classified based on PD-L1 biomarker status as appropriate;

Subjects in Cohort 1 meeting the revised eligibility criteria.
8.11 Compliance (Medication Adherence)
Study drug accountability data for MK-3475 will be collected during the study. Any 
deviation from protocol-directed administration will be reported.
8.12 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.
9.0 LABELING, PACKAGING,
STORAGE AND RETURN OF CLINICAL 
SUPPLIES
9.1
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 18.  
 
 
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Clinical supplies will be packaged to support enrollment and replacement subjects as 
required.  When a replacement subject is required, the Sponsor or designee needs to be 
contacted prior to dosing the replacement supplies.
Table 18
Product Descriptions
Product Name & Potency
Dosage Form
Additional Information
MK-3475 25 mg/mL, 4 mL
Injection
Provided centrally by the Sponsor
Cisplatin 1 mg/mL, 50 mL
Injection
Provided centrally by the Sponsor or locally 
by the trial site, subsidiary or designee
5-Fluorouracil 50 mg/mL, 20 mL
Injection
Provided centrally by the Sponsor or locally 
by the trial site, subsidiary or designee
All supplies indicated in Table 18 will be provided per the Additional Information field 
depending on local country operational or regulatory requirements.
Any commercially available product not included in Table 18 will be provided by the trial
site, subsidiary or designee. Every attempt should 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.
9.2
Packaging and Labeling Information
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
Subjects will receive open label vials and/or kits for every 3-week dosing.
9.3
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.
9.4
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.
 
 
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9.5
Discard/Destruction/Returns and Reconciliation
The investigator is responsible for keeping accurate records of the clinical supplies received 
from the Sponsor or designee, the amount dispensed to and returned by the subjects and the 
amount remaining at the conclusion of the trial. For all trial sites, the local country Sponsor 
personnel or designee will provide appropriate documentation that must be completed for 
drug accountability and return, or local discard and destruction if appropriate.   Where local 
discard and destruction is appropriate, the investigator is responsible for ensuring that a local 
discard/destruction procedure is documented.
9.6
Standard Policies
Trial site personnel will have access to a central electronic randomization system 
(IVRS/IWRS system) to allocate subjects, to assign treatment to subjects and to manage the 
distribution of clinical supplies. Each person accessing the IVRS system must be assigned an 
individual unique PIN.  They must use only their assigned PIN to access the system, and they 
must not share their assigned PIN with anyone.
10.0 ADMINISTRATIVE AND REGULATORY DETAILS
10.1 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.
 
 
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Confidentiality of Investigator Information
By signing this protocol, the investigator recognizes that certain personal identifying 
information with respect to the investigator, and all subinvestigators and trial site personnel, 
may be used and disclosed for trial management purposes, as part of a regulatory 
submissions, and as required by law.  This information may include:
1. name, address, telephone number and e-mail address;
2. hospital or clinic address and telephone number;
3. curriculum vitae or other summary of qualifications and credentials; and
4. other professional documentation.
Consistent with the purposes described above, this information may be transmitted to the 
Sponsor, and subsidiaries, affiliates and agents of the Sponsor, in your country and other 
countries, including countries that do not have laws protecting such information.  
Additionally, the investigator’s name and business contact information may be included 
when reporting certain serious adverse events to regulatory authorities or to other 
investigators.  By signing this protocol, the investigator expressly consents to these uses and 
disclosures.
If this is a multicenter trial, in order to facilitate contact between investigators, the Sponsor 
may share an investigator’s name and contact information with other participating 
investigators upon request.
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC member that 
reviews and approves this trial.  The Sponsor is also required to document that each IRB/IEC 
meets regulatory and ICH GCP requirements by requesting and maintaining records of the 
names and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
10.2 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 
 
 
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Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor or through a secure password-protected electronic portal provided by the 
Sponsor.  The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes.  This may involve the 
transmission of information to countries that do not have laws protecting personal data.
10.3 Compliance with Law, Audit and Debarment
By signing this protocol, the investigator agrees to conduct the trial in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of Good 
Clinical Practice (e.g., International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice: 
Consolidated Guideline and other generally accepted standards of good clinical practice); and 
all applicable federal, state and local laws, rules and regulations relating to the conduct of the 
clinical trial.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by Merck, is provided in Section 12.1 -
Merck Code of Conduct for Clinical Trials.
The investigator also agrees to allow monitoring, audits, IRB/ERC review and regulatory 
authority inspection of trial-related documents and procedures and provide for direct access 
to all trial-related source data and documents.
The investigator agrees not to seek reimbursement from subjects, their insurance providers or 
from government programs for procedures included as part of the trial reimbursed to the 
investigator by the Sponsor.
The investigator shall prepare and maintain complete and accurate trial documentation in 
compliance with Good Clinical Practice standards and applicable federal, state and local 
laws, rules and regulations; and, for each subject participating in the trial, provide all data, 
and, upon completion or termination of the clinical trial, submit any other reports to the 
Sponsor as required by this protocol or as otherwise required pursuant to any agreement with 
the Sponsor.
Trial documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the trial site upon request for inspection, 
copying, review and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities.  The investigator agrees to promptly take any reasonable steps that are 
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, 
 
 
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correspondence with regulatory authorities and IRBs/ERCs, consent forms, investigator’s 
curricula vitae, monitor visit logs, laboratory reference ranges, laboratory certification or 
quality control procedures and laboratory director curriculum vitae.  By signing this protocol, 
the investigator agrees that documentation shall be retained until at least 2 years after the last 
approval of a marketing application in an ICH region or until there are no pending or 
contemplated marketing applications in an ICH region or until at least 2 years have elapsed 
since the formal discontinuation of clinical development of the investigational product.  
Because the clinical development and marketing application process is variable, it is 
anticipated that the retention period can be up to 15 years or longer after protocol database 
lock. The Sponsor will determine the minimum retention period and notify the investigator 
when documents may be destroyed.  The Sponsor will determine the minimum retention 
period and upon request, will provide guidance to the investigator when documents no longer 
need to be retained.  The sponsor also recognizes that documents may need to be retained for 
a longer period if required by local regulatory requirements. All trial documents shall be 
made available if required by relevant regulatory authorities. The investigator must consult 
with and obtain written approval by the Sponsor prior to destroying trial and/or subject files.  
ICH Good Clinical Practice guidelines recommend that the investigator inform the subject’s 
primary physician about the subject’s participation in the trial if the subject has a primary 
physician and if the subject agrees to the primary physician being informed.
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 
 
 
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enrollment of subject cohort, timely achievement of trial milestones).  The Protocol CI must 
be a participating trial investigator.
10.4 Compliance with Trial Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements 
for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov.  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 FDAMA/FDAAA mandated trials. 
Information posted will allow subjects to identify potentially appropriate trials for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate trial locations and trial site contact information.    
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAMA/FDAAA are that of the Sponsor and agrees not to submit any information about this 
trial or its results to the Clinical Trials Data Bank.
10.5 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.
10.6 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.
10.7 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 
 
 
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OTC trials.  For trials intended for pediatric-related regulatory filings, the investigator agrees 
to delay publication of the trial results until the Sponsor notifies the investigator that all 
relevant regulatory authority decisions on the trial drug have been made with regard to 
pediatric-related regulatory filings. Merck will post a synopsis of trial results for approved 
products on www.clinicaltrials.gov by 12 months after the last subject's last visit for the 
primary outcome, 12 months after the decision to discontinue development, or product 
marketing (dispensed, administered, delivered or promoted), whichever is later.
These timelines may be extended for products that are not yet marketed, if additional time is 
needed for analysis, to protect intellectual property, or to comply with confidentiality 
agreements with other parties.  Authors of the primary results manuscript will be provided 
the complete results from the Clinical Study Report, subject to the confidentiality agreement. 
When a manuscript is submitted to a biomedical journal, the Sponsor's policy is to also 
include the protocol and statistical analysis plan to facilitate the peer and editorial review of 
the manuscript.  If the manuscript is subsequently accepted for publication, the Sponsor will 
allow the journal, if it so desires, to post on its website the key sections of the protocol that 
are relevant to evaluating the trial, specifically those sections describing the trial objectives 
and hypotheses, the subject inclusion and exclusion criteria, the trial design and procedures, 
the efficacy and safety measures, the statistical analysis plan, and any amendments relating to 
those sections.  The Sponsor reserves the right to redact proprietary information.
For multicenter trials, subsequent to the multicenter publication (or after public disclosure of 
the results online at www.clinicaltrials.gov if a multicenter manuscript is not planned), an 
investigator and his/her colleagues may publish their data independently.  In most cases, 
publication of individual trial site data does not add value to complete multicenter results, 
due to statistical concerns.  In rare cases, publication of single trial site data prior to the main 
paper may be of value.  Limitations of single trial site observations in a multicenter trial 
should always be described in such a manuscript.
Authorship credit should be based on 1) substantial contributions to conception and design, 
or acquisition of data, or analysis and interpretation of data; 2) drafting the article or revising 
it critically for important intellectual content; and 3) final approval of the version to be 
published. Authors must meet conditions 1, 2 and 3.  Significant contributions to trial 
execution may also be taken into account to determine authorship, provided that 
contributions have also been made to all three of the preceding authorship criteria.  Although 
publication planning may begin before conducting the trial, final decisions on authorship and 
the order of authors’ names will be made based on participation and actual contributions to 
the trial and writing, as discussed above. The first author is responsible for defending the 
integrity of the data, method(s) of data analysis and the scientific content of the manuscript.
The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or 
presentations regarding this trial 45 days prior to submission for publication/presentation. 
Any information identified by the Sponsor as confidential must be deleted prior to 
submission; this confidentiality does not include efficacy and safety results. Sponsor review 
can be expedited to meet publication timelines.
 
 
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11.0 LIST OF REFERENCES
1. Disis ML.  Immune regulation of cancer. J Clin Oncol 2010; 28(29):4531-8.
2. Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, et al. Tumor-
associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune 
evasion. Nat Med 2002;8(8):793-800.  
3. Sharpe AH, Freeman GJ. The B7-CD28 superfamily. Nature 2002;2:116-26.
4. Brown JA, Dorfman DM, Ma F-R, Sullivan EL, Munoz O, Wood CR, et al. Blockade 
of programmed death-1 ligands on dendritic cells enhances T cell activation and 
cytokine production. J Immunol 2003;170:1257-66.  
5. Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and 
autoimmunity. Immunol Rev 2010;236:219-42.
6. Thompson RH, Dong H, Lohse CM, Leibovich BC, Blute ML, Cheville JC, et al. PD-
1 expressed by tumor-infiltrating immune cells and is associated with poor outcome 
for patients with renal cell carcinoma. Clin Caner Res 2007;13(6):1757-61.
7. Talmadge JE, Donkor M, Scholar E. Inflammatory cell infiltration of tumors: Jekyll 
or Hyde. Cancer Metastasis Rev 2007;26:373-400.
8. Usubütün A, Ayhan A, Uygur MC, Ozen H, Toklu C, Ruacan S. Prognostic factors in 
renal cell carcinoma. J Exp Clin Cancer Res 1998;17(1):77-81.
9. Deschoolmeester V, Baay M, Van Marck E, Weyler J, Vermeulen p, Lardon F, et al. 
Tumor infiltrating lymphocytes: an intriguing player in the survival of colorectal 
cancer patients. BMC Immunol 2010;11:19.
10. Diez M, Pollán M, Enriquez JM, Dominguez P, Santana A, Tobaruela E, et al. 
Histopathologic prognostic score in colorectal adenocarcinomas. Anticancer Res 
1998;18:689-94.  
11. Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pagès C, et 
al. Type, density, and location of immune cells within human colorectal tumors 
predict clinical outcome. Science 2006;313:1960-4.
12. Hiraoka N. Tumor-infiltrating lymphocytes and hepatocellular carcinoma: molecular 
biology. Int J Clin Oncol 2010;15:544-51.
13. Nobili C, Degrate L, Caprotti R, Franciosi C, Leone BE, Trezzi R, et al. Prolonged 
survival of a patient affected by pancreatic adenocarcinoma with massive lymphocyte 
and dendritic cell infiltration after interleukin-2 immunotherapy. Report of a case. 
Tumori 2008;94:426-30.
 
 
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14. Hodi FS, Dranoff G. The biologic importance of tumor-infiltrating lymphocytes. J 
Cutan Pathol 2010;37(Suppl 1):48-53.  
15. Kloor M. Lymphocyte infiltration and prognosis in colorectal cancer. Lancet 
2009;10:840-841.
16. Hillen F, Baeten CIM, van de Winkel A, Creytens D, van der Schaft DWJ, 
Winnepenninckx V, et al. Leukocyte infiltration and tumor cell plasticity are 
parameters of aggressiveness in primary cutaneous melanoma. Cancer Immunol 
Immunother 2008;57:97-106.  
17. Lee HE, Chae SW, Lee YJ, Kim MA, Lee HS, Lee BL, et al. Prognostic implications 
of type and density of tumour-infiltrating lymphocytes in gastric cancer. Br J Cancer 
2008;99(10):1704-11.  
18. Leffers N, Gooden MJM, de Jong RA, Hoogeboom B-N, ten Hoor KA, Hollema H, et 
al. Prognostic significance of tumor-infiltrating T-lymphocytes in primary and 
metastatic lesions of advanced stage ovarian cancer. Cancer Immunol Immunother 
2009;58:449-59.  
19. Nishimura H, Honjo T, Minato N. Facilitation of β selection and modification of 
positive selection in the thymus of PD-1-deficient mice. J Exp Med 2000;191(5):
891-7.
20. Liotta F, Gacci M, Frosali F, Querci V, Vittori G, Lapini A, et al. Frequency of 
regulatory T cells in peripheral blood and in tumour-infiltrating lymphocytes 
correlates with poor prognosis in renal cell carcinoma. BJU Intern 2010;107:1500-6.
21. Bass, AJ et.al, Comprehensive molecular characterization of gastric adenocarcinoma. 
Nature 513:202-209, 2014.
22. Ropponen KM, Eskelinen MJ, Lipponen PK, Alhava E, Kosma V-M. Prognostic 
value of tumour-infiltrating lymphocytes (TILs) in colorectal cancer. J Pathol 
1997;182:318-24.  
23. Dudley ME, Wunderlich JR, Yang JC, Sherry RM, Topalian SL, Restifo NP, et al. 
Adoptive cell transfer therapy following non-myeloablative but lymphodepleting 
chemotherapy for the treatment of patients with refractory metastatic melanoma. J 
Clin Oncol 2005;23(10):2346-57.  
24. Hunder NN, Wallen H, Cao J, Hendricks DW, Reilly JZ, Rodmyre R, et al. Treatment 
of metastatic melanoma with autologous CD4+ T cells against NY-ESO-1. N Engl J 
Med 2008;358(25):2698-703.  
 
 
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25. Ölcher M, Braun M, Friedrichs N, Rudlowski C, Bercht E, Fimmers R, et al. Foxp3+ 
cell infiltration and granzyme B+/Foxp3+ cell ratio are associated with outcome in 
neoadjuvant chemotherapy-treated ovarian carcinoma. Cancer Immunol Immunother 
2010;59:909-19.  
26. Okazaki T, Maeda A, Nishimura H, Kurosaki T, Honjo T. PD-1 immunoreceptor 
inhibits B cell receptor-mediated signaling by recruiting src homology 2-domain-
containing tyrosine phosphatase 2 to phosphotyrosine. PNAS 2001;98(24):13866-71.
27. Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisted. Annu Rev Immunol 
2005;23:515-48.
28. Muro K, et al. A Phase Ib Study of MK-3475 in Patients with Gastric Cancer. Ann 
Oncol. 2014;25(Suppl 4)
29. Im, CK, Rha, SY, Jeung, H-C, Jeong, J, Lee, SL, Noh, SH, Roh, JK, Chung, HC. A 
Phase II feasibility study of weekly paclitaxel in heavily pretreated advanced gastric 
cancer patients with poor performance status. Oncology 77:349-357, 2009.
30. Fuchs, CS, et al. Ramucirumab monotherapy for previously treated advanced gastric 
or gastro-oesophageal junction adenocarcinoma (REGARD): an international, 
randomized, multicenter, placebo-controlled, phase 3 trial.  Lancet 383: 31-39, 2014.
31. Aaronson NK, et al. The European Organization for Research and Treatment of 
Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in 
oncology. J Natl Cancer Inst 1993;85(5):365-76).
32. E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. 
Dancey, S. Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. 
Kaplan, D. Lacombe, J. Verweij. New response evaluation criteria in solid tumors: 
Revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47.
33. Ji, YA, et al.  A modified toxicity probability interval method for dose-finding trials.  
Clinical Trials. 2010 Dec;7(6):653-663.
34. Clopper CJ, Pearson ES. The use of confidence or fiducial limits illustrated in the 
case of binomial. Biometricka 1934;26(4):404-13. 
 
 
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12.0 APPENDICES
12.1 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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12.2 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 7.1.3.2 – Future Biomedical 
Research 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 Merck focused on the study of biomarkers 
responsible for how a drug/vaccine enters and is removed by the body, how a 
drug/vaccine works, other pathways a drug/vaccine may interact with, or other aspects of 
disease.  The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need.  All specimens will be used by Merck or designees and research 
will be monitored and reviewed by a committee of our scientists and clinicians.
3. Summary of Procedures for Future Biomedical Research
a.
Subjects for Enrollment
All subjects enrolled in the clinical trial will be considered for enrollment in Future 
Biomedical Research.
b. Informed Consent
Informed consent for specimens (i.e., DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all subjects or legal guardians, at a trial 
visit by the investigator or his or her designate.  Informed consent for Future 
Biomedical Research should be presented to the subjects on Visit 1.  If delayed, 
present consent at next possible Subject Visit. Informed consent must be obtained 
prior to collection of all Future Biomedical Research specimens.  Consent forms 
signed by the subject will be kept at the clinical trial site under secure storage for 
regulatory reasons.  Information contained on the consent form alone cannot be traced 
 
 
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to any specimens, test results, or medical information once the specimens have been 
rendered de-identified
A template of each trial site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.  Each consent will be assessed for 
appropriate specimen permissions.  
Each informed consent approved by an ethics committee is assigned a unique tracking 
number.  The tracking number on this document will be used to assign specimen 
permissions for each specimen into the Entrusted Keyholder’s Specimen Database.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of both consent and acquisition of Future Biomedical Research 
specimens will be captured in the electronic Case Report Forms (eCRFs).  
Reconciliation of both forms will be performed to assure that only appropriately-
consented specimens are used for this sub-trial's research purposes. Any specimens 
for which such an informed consent cannot be verified will be destroyed.
d. Future Biomedical Research Specimen Collections
Blood specimens for DNA or RNA isolation will usually be obtained at a time when 
the subject is having blood drawn for other trial purposes. Specimens like tissue and 
bone marrow will usually be obtained at a time when the subject is having such a 
procedure for clinical purposes.
Specimens will be collected and sent to the laboratory designated for the trial where 
they will be processed (e.g., DNA or RNA extraction, etc) following the Merck 
approved policies and procedures for specimen handling and preparation.
If specimens are collected for a specific genotype or expression analysis as an 
objective to the main trial, this analysis is detailed in the main body of this protocol 
(Section 8.0 – Statistical Analysis Plan).  These specimens will be processed, 
analyzed, and the remainder of the specimen will be destroyed.  The results of these 
analyses will be reported along with the other trial results.  A separate specimen will 
be obtained from properly-consented subjects in this protocol for storage in the 
biorepository for Future Biomedical Research.
4. Confidential Subject Information for Future Biomedical Research 
In order to optimize the research that can be conducted with Future Biomedical Research 
specimens, it is critical to link subject' clinical information with future test results. In fact 
little or no research can be conducted without connecting the clinical trial data to the 
specimen. The clinical data allow specific analyses to be conducted. Knowing subject 
characteristics like gender, age, medical history and treatment outcomes are critical to 
understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for Future 
Biomedical Research, Merck has developed secure policies and procedures.  All 
specimens will be de-identified as described below. 
 
 
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At the clinical trial site, unique codes will be placed on the Future Biomedical Research 
specimens for transfer to the storage facility.  This first code is a random number which 
does not contain any personally identifying information embedded within it. The link (or 
key) between subject identifiers and this first unique code will be held at the trial site.  No 
personal identifiers will appear on the specimen tube.  
This first code will be replaced with a second code at a Merck designated storage/lab 
facility.  The second code is linked to the first code via a second key. The specimen is 
now double coded.  Specimens with the second code are sometimes referred to as de-
identified specimens. The use of the second code provides additional confidentiality and 
privacy protection for subjects over the use of a single code.  Access to both keys would 
be needed to link any data or specimens back to the subject's identification.
The second code is stored separately from the first code and all associated personal 
specimen identifiers.  A secure link, the second key, will be utilized to match the second 
code to the first code to allow clinical information collected during the course of the trial 
to be associated with the specimen.  This second key will be transferred under secure 
procedures by the Merck designated facility to an Entrusted Keyholder at Merck.  The 
second code will be logged into the primary biorepository database at Merck and, in this 
database, this identifier will not have identifying demographic data or identifying clinical 
information (i.e., race, sex, age, diagnosis, lab values) associated with it. The specimen 
will be stored in a designated biorepository site with secure policies and procedures for 
specimen storage and usage.
The second key can be utilized to reconstruct the link between the results of future 
biomedical research and the clinical information, at the time of analysis.  This linkage 
would not be possible for the scientist conducting the analysis, but can only be done by 
the Merck Entrusted Keyholder under strict security policies and procedures.  The Merck 
Entrusted Keyholder will link the information and then issue a de-identified data set for 
analysis.  The only other circumstance by which future biomedical research data would 
be directly linked to the full clinical data set would be those situations mandated by 
regulatory authorities (e.g., EMEA, FDA), whereby this information would be directly 
transferred to the regulatory authority.
5. Biorepository Specimen Usage
Specimens obtained for the Merck Biorepository will be used for analyses using good 
scientific practices.  However, exploratory analyses will not be conducted under the 
highly validated conditions usually associated with regulatory approval of diagnostics.  
The scope of research performed on these specimens is limited to the investigation of the 
variability in biomarkers that may correlate with a clinical phenotype in subjects.
Analyses utilizing the Future Biomedical Research specimens may be performed by 
Merck, or an additional third party (e.g., a university investigator) designated by Merck.  
The investigator conducting the analysis will be provided with double coded specimens.  
Re-association of analysis results with corresponding clinical data will only be conducted 
by the Merck Entrusted Keyholder.  Any contracted third party analyses will conform to 
the specific scope of analysis outlined in future biomedical research protocol and consent.  
 
 
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Future Biomedical Research specimens remaining with the third party after the specific 
analysis is performed will be reported to the Sponsor.
6. Withdrawal From Future Biomedical Research 
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   Subjects may withdraw consent at any time by 
contacting the principal investigator for the main trial.  If medical records for the main 
trial are still available, the investigator will contact Merck using the designated mailbox 
(clinical.specimen.management@merck.com) and a form will be provided by Merck to 
obtain appropriate information to complete specimen withdrawal.  Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed. A letter 
will be sent from Merck to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for destruction or already performed prior to 
the request being received by the Sponsor will continue to be used as part of the overall 
research trial data and results. No new analyses would be generated after the request is 
received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the subject’s personal information and their specimens. In this situation, the 
request for specimen destruction can not be processed. 
7. Retention of Specimens 
Future Biomedical Research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from acquisition.  Specimens may be stored for longer if a 
regulatory or governmental authority has active questions that are being answered.  In 
this special circumstance, specimens will be stored until these questions have been 
adequately addressed.
Specimens from the trial site will be shipped to a central laboratory and then shipped to 
the Merck designated biorepository.  The specimens will be stored under strict 
supervision in a limited access facility which operates to assure the integrity of the 
specimens.  Specimens will be destroyed according to Merck policies and procedures and 
this destruction will be documented in the biorepository database.
8. Data Security
Separate databases for specimen information and for results from the Future Biomedical 
Research sub-trial will be maintained by Merck.  This is done to separate the future 
exploratory test results (which include genetic data) from the clinical trial database 
thereby maintaining a separation of subject number and these results.  The separate 
databases are accessible only to the authorized Sponsor and the designated trial 
administrator research personnel and/or collaborators.  Database user authentication is 
highly secure, and is accomplished using network security policies and practices based in 
international standards (e.g., ISO17799) to protect against unauthorized access.  The 
Merck Entrusted Keyholder maintains control over access to all specimen data.  These 
 
 
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data are collected for future biomedical research purposes only as specified in this sub-
trial will not be used for any other purpose.
9. Reporting of Future Biomedical Research Data to Subjects
There is no definitive requirement in either authoritative ethical guidelines or in relevant 
laws/regulations globally that research results have to be, in all circumstances, returned to 
the trial participant.  Some guidelines advocate a proactive return of data in certain 
instances.  No information obtained from exploratory laboratory studies will be reported 
to the subject or family, and this information will not be entered into the clinical database 
maintained by Merck on subjects.  Principle reasons not to inform or return results to the 
subject include: lack of relevance to subject health, limitations of predictive capability, 
concerns of misinterpretation and absence of good clinical practice standards in 
exploratory research typically used for diagnostic testing.
If any exploratory results are definitively associated with clinical significance for subjects 
while the clinical trial is still ongoing, investigators will be contacted with information as 
to how to offer clinical diagnostic testing (paid for by Merck) to subjects enrolled and 
will be advised that counseling should be made available for all who choose to participate 
in this diagnostic testing. 
If any exploratory results are definitively associated with clinical significance after 
completion of a clinical trial, Merck will publish the results without revealing specific 
subject information, inform all trial sites who participated in the Merck clinical trial and 
post anonymized results on our website or other accredited website(s) that allow for 
public access (e.g., disease societies who have primary interest in the results) in order that 
physicians and patients may pursue clinical diagnostic testing if they wish to do so.
10. Gender, Ethnicity and Minorities
Although many diagnoses differ in terms of frequency by ethnic population and gender, 
every effort will be made to recruit all subjects diagnosed and treated on Merck clinical 
trials for future biomedical research.  When trials with specimens are conducted and 
subjects identified to serve as controls, every effort will be made to group specimens 
from subjects and controls to represent the ethnic and gender population representative of 
the disease under current investigation.
11. Risks Versus Benefits of Future Biomedical Research 
For future biomedical research, risks to the subject have been minimized.  Risks include 
those associated with venipuncture to obtain the whole blood specimen.  This specimen 
will be obtained at the time of routine blood specimens drawn in the main trial.
Merck has developed strict security, policies and procedures to address subject data 
privacy concerns.  Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality.  In this highly unlikely situation there is risk that the 
information, like all medical information, may be misused.
It is necessary for subject-related data (i.e., ethnicity, diagnosis, drug therapy and dosage, 
age, toxicities, etc.) to be re-associated to double coded specimens at the time of data 
analysis.  These subject data will be kept in a separate, secure Merck database, and all 
 
 
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specimens will be stripped of subject identifiers.  No information concerning results 
obtained from future biomedical research will be entered into clinical records, nor will it 
be released to outside persons or agencies, in any way that could be tied to an individual 
subject.
12. Self-Reported Ethnicity
Subjects who participate in future biomedical research will be asked to provide self-
reported ethnicity.  Subjects who do not wish to provide this data may still participate in 
future biomedical research.
13. Questions
Any questions related to the future biomedical research should be e-mailed directly to 
clinical.specimen.management@merck.com.
14. References
1. National Cancer Institute: http://www.cancer.gov/dictionary/?searchTxt=biomarker
2. International Conference on Harmonization: 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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12.3 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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12.4 ECOG Performance Status
Grade
Description
0
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction.
1
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work).
2
In bed <50% of the time. Ambulatory and capable of all self-care, 
but unable to carry out any work activities. Up and about more than 
50% of waking hours.
3
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any self-
care. Totally confined to bed or chair.
5
Dead.
* As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative 
Oncology Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, 
Robert Comis M.D., Group Chair.
 
 
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12.5 Common Terminology Criteria for Adverse Events (CTCAE) version 4.0
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.html).
 
 
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12.6 Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for 
Evaluating Response in Solid Tumors
RECIST version 1.1* will be used in this study for assessment of tumor response. While 
either CT or MRI may be utilized, as per RECIST 1.1, CT is the preferred imaging technique 
in this study.
* As published in the European Journal of Cancer [32].
 
 
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12.7 Dose Modification Table (based on modified Toxicity Profile Interval [33])
Sample size = 18a; Target probability pT = 30%; ε1= ε2 = 0.05.
Any doses with a dose reduction probability falling into the interval (pT – ε1, pT + ε2) will be 
considered an acceptable dose level.
Number of Toxicity
Number of Patients
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18
0
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
1
D
S
S
S
S
E
E
E
E
E
E
E
E
E
E
E
E
E
2
D
D
S
S
S
S
S
S
S
E
E
E
E
E
E
E
E
3
D
D
D
S
S
S
S
S
S
S
S
S
S
E
E
E
4
D
D
D
D
D
S
S
S
S
S
S
S
S
S
S
5
D
D
D
D
D
D
S
S
S
S
S
S
S
S
6
D
D
D
D
D
D
D
S
S
S
S
S
S
7
D
D
D
D
D
D
D
D
S
S
S
S
8
D
D
D
D
D
D
D
D
D
D
S
9
D
D
D
D
D
D
D
D
D
D
10
D
D
D
D
D
D
D
D
D
11
D
D
D
D
D
D
D
D
12
D
D
D
D
D
D
D
13
D
D
D
D
D
D
14
D
D
D
D
D
15
D
D
D
D
16
D
D
D
17
D
D
18
D
LEGEND
E: Stay at same dose or escalate to the next higher dose (escalation will only apply if the initial dose has been lowered, as 
doses higher than 800 mg/m2 for 5-FU, 1000 mg/m2 twice daily for capecitabine (Japan only) and 80 mg/m2 for cisplatin 
will not be studied); S: Stay at the same dose; D: De-escalate to a lower dose; 
a.  Subjects enrolled at Asian sites and non-Asian sites will be assessed separately.  If the dose level for one subgroup has 
been lowered while the other remains at the higher starting dose, then consideration may be made to increase the dose back 
to the starting dose based on tolerability in the individual subgroup and the overall population across subgroups.
 
 
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12.8 List of Abbreviations
Abbreviation/Term
Definition
1L
First-line
3L/3L+
Third-line
5-FU
5-fluorouracil
AE
Adverse Event
ADA
Anti-Drug Antibodies
ALT
Alanine Aminotransferase
APaT/ASaT
All Patients/Subjects as Treated Population
AST
Aspartate Aminotransferase
ß-HCG
Beta Human Chorionic Gonadotropin
CBC
Complete Blood Count
CI
Confidence Interval
CIS
Carcinoma in situ
CR
Complete Response
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
CTU
Computed Tomography Urography
DL
Dose Level
DLT
Dose Limiting Toxicity
DNA
Deoxyribonucleic acid
DOCR
Duration of Complete Response
ECI
Events of Clinical Interest
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EORTC
European Organisation for Research and Treatment of Cancer
ERC
Ethics Review Committee
FAS
Full Analyses Set
FBR
Future Biomedical Research
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FDAMA
Food and Drug Administration Modernization Act
FFPE
Formalin-fixed Paraffin Embedded
GCP
Good Clinical Practice
GFR
Glomerular Filtration Rate
HCV
Hepatitis C
HIV
Human Immunodeficiency Virus
 
 
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Abbreviation/Term
Definition
ICF
Informed Consent Form
ICH
International Conference on Harmonization
IHC
Immunohistochemistry
INR
International Normalized Ratio
irAEs
Immune-related Adverse Events
IRB
Institutional Review Board
ITIM
Immunoreceptor Tyrosine-based Inhibition Motif
ITSM
Immunoreceptor Tyrosine-based Switch Motif
ITT
Intent-to-Treat
IV
Intravenous
IVRS/IWRS
Interactive Voice Response System/Interactive Web Response 
System
KM
Kaplan-Meier
mAb
Monoclonal Antibody
mcL
Microliters
MEL
Melanoma 
mg
Milligram
mg/kg
Milligram per Kilogram
mL
milliliter
MRI
Magnetic Resonance Imaging
miRNA
Micro RNA
mRNA
Messenger RNA
mTPI
Modified Toxicity Probability Interval
MSD
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
NA or N/A
Not Applicable
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
PBPK
Physiologically Based Pharmacokinetic
PD
Progressive Disease
PD-1
Programmed death-1
PD-L1
Programmed death-ligand 1
PFS
Progression Free Survival
PGt
Pharmacogenetic
PK
Pharmacokinetic
PK/PD
Pharmacokinetic-Pharmacodynamic
PO
Oral Administration
PR
Partial Response
RECIST
Response Evaluation Criteria in Solid Tumors
 
 
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Abbreviation/Term
Definition
irRECIST
Immune-related RECIST
RNA
Ribonucleic Acid
Q2W
Every 2 Weeks
Q3W
Every 3 Weeks
SAC
Scientific Advisory Committee
SAE
Serious Adverse Events
SAP
Statistical Analysis Plan
SGOT
Serum Glutamic Oxaloacetic Transaminase
SGPT
Serum Glutamic Pyruvic Transaminase
SOC
Standard of Care
TIL
Tumor-Infiltrating Lymphocytes
TSH
Thyroid Stimulating Hormone
ULN
Upper Limit of Normal
WHO
World Health Organization
 
 
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13.0 SIGNATURES
13.1 Sponsor's Representative
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
13.2 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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PAGE 1
Supplemental SAP
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 
This is the original sSAP and thus no changes are indicated here.
3. ANALYTICAL AND METHODOLOGICAL DETAILS
3.1
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive 
plan is provided in Sections 3.2 to Section 3.12.
 
 
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Study Design Overview
A Phase II Clinical Trial of Pembrolizumab as Monotherapy and in 
Combination with Cisplatin+5-Fluorouracil in Subjects with Recurrent or 
Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma 
(KEYNOTE-059)
Treatment Assignment
Treatment assignment is open label. 
Analysis Populations
Efficacy: All Subjects as Treated (ASaT)
Safety: All Subjects as Treated (ASaT)
Primary Endpoint(s)
Cohort 2:  Safety and tolerability (see Section 4.2.1.2)
Cohort 1: objective response rate (ORR) per RECIST 1.1 assessed by 
central imaging vendor
Cohort 3:  Objective response rate (ORR) per RECIST 1.1 assessed by 
central imaging vendor
Statistical Methods for Key 
Efficacy Analyses
Cohort 1 (3L+ gastric cancer subjects/monotherapy): 95% CI for ORR 
will be calculated using Exact method based on binomial distribution.
Cohort 2 (1L gastric cancer subjects/combination treatment): The 
primary objective is safety evaluation, and the secondary objective is the 
estimation of the ORR. 95% CI for ORR will be calculated using Exact 
method based on binomial distribution. 
Cohort 3 (1L gastric cancer subjects/monotherapy): 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 1, an interim analysis will be performed for PD-L1 negative 
subjects in this study.  Results will be reviewed by an external data 
monitoring committee.  The interim analysis is summarized below.  
Details are provided in Section 3.7. 

Interim Analysis 1: 
o Timing: To be performed when ~40 all-comer subjects have 
response assessment available
o Testing: Futility check based on ORR assessed by central 
imaging vendor in PD-L1 negative subjects 
Multiplicity
This is an estimation study. No multiplicity adjustment will be applied.
Sample Size and Power 
Cohort 1 (3L+ gastric cancer subjects/monotherapy): Since the futility 
criterion was not met, the overall sample size for Cohort 1 is 
approximately 210. The enrollment of Cohort 1 will stop when at least 80 
all-comer subjects meeting the revised eligibility criteria are enrolled. 
Cohort 2 (1L gastric cancer subjects/combination treatment): There will 
be approximately 18 subjects enrolled. 
Cohort 3 (1L gastric cancer subjects/monotherapy): There will be ~25
PD-L1 positive subjects enrolled in Cohort 3.
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.
 
 
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Supplemental SAP
This trial is being conducted as an open-label study. There is no randomization in the 
study. The Clinical Biostatistics department will generate the allocation schedule.
One planned interim analysis for Cohort 1 is described in Section 8.7. The study team 
will remain blinded to the PD-L1 expression level (positive or negative) for the subjects 
participating in the initial all-comers portion of Cohort 1 until the interim analysis of 
Cohort 1. Results of the interim analysis will be provided by the external unblinded 
statistician to the Data Monitoring Committee (DMC). The DMC will serve as the 
primary reviewer of the results of the interim analysis and will make recommendations in 
terms of whether to resume the enrollment of the PD-L1 negative subjects in Cohort 1 to 
the SPONSOR. Prior to study completion, the external unblinded statistician will not be 
involved in any discussions regarding modifications to the protocol, statistical methods, 
identification of protocol violators, or data validation efforts after the interim analyses.
Analyses or summaries of PD-L1 biomarker status before the interim analysis will be 
limited and documented after the interim analysis. Following the interim analysis, the 
Sponsor will be unblinded to PD-L1 data.  
3.3
Hypotheses/Estimation
This is an estimation study. Objectives of the study are stated in Section 3.0.
3.4
Analysis Endpoints
3.4.1
Efficacy Endpoints
Objective Response Rate (ORR): proportion of subjects in the analysis population who 
have complete response (CR) or partial response (PR).
Duration of Response (DOR): 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.
Disease Control Rate (DCR): for 1L subjects, DCR is defined as proportion of subjects in 
the analysis population who have CR or PR or stable disease (SD) for at least 6 months; 
for 3L+ subjects, DCR is defined as proportion of subjects in the analysis population who 
have CR or PR or stable disease (SD) for at least 2 months.
Progression-Free Survival (PFS): time from Day 1 Cycle 1 treatment administration to 
the first documented disease progression or death.
Overall Survival (OS): time from Day 1 Cycle 1 treatment administration to death due to 
any cause.
3.4.2
Safety Endpoints
The primary safety objective of this trial is to characterize the safety and tolerability of 
pembrolizumab in subjects with gastric cancer.  The primary safety analysis will be based 
on subjects who experienced toxicities as defined by CTCAE criteria.  Safety will be 
assessed by quantifying the toxicities and grades experienced by subjects who have 
 
 
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received pembrolizumab, including serious adverse events (SAEs) and events of clinical 
interest (ECIs).  
Safety will be assessed by reported adverse experiences using CTCAE, Version 4.0. The 
attribution to drug, time-of-onset, duration of the event, its resolution, and any 
concomitant medications administered will be recorded.  AEs will be analyzed including 
but not limited to all AEs, SAEs, fatal AEs, and laboratory changes.  Furthermore, 
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.Consider 
referring to Section 4.2.3 for the initial description of safety measures
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. ASaT population consists of all subjects who received at least one 
dose of study treatment.
The analysis population for DOR consists of responders.
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.  
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.
3.6
Statistical Methods
3.6.1
Statistical Methods for Efficacy Analyses
In Cohorts 1 and 3, the primary endpoints are ORR per RECIST 1.1 assessed by central 
imaging vendor for all subjects and in PD-L1 positive subjects. The point estimate and 95% 
confidence interval will be provided using exact binomial method proposed by Clopper 
and Pearson (1934). Subjects in the primary analysis population (ASaT) without ORR 
data will be counted as non-responder.
In Cohort 1, the co-primary endpoint for PMDA submission is the 6-month overall 
survival rate (OS6) for all subjects and in PD-L1 positive subjects. The estimate of OS6 
and 95% confidence interval will be provided using Kaplan-Meier method.   
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 1.
 
 
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Table 1
Censoring Rules for DOR
Situation
Date of progression or censoring
Outcome
No progression nor death, no new anti-
cancer therapy initiated
Last adequate assessment
Censor 
(non-event)
No progression nor death, new anti-cancer 
therapy initiated
Last adequate assessment before new
anti-cancer therapy initiated
Censor 
(non-event)
Death or progression after ≥ 2 
consecutive missed adequate disease 
assessments
Last adequate assessment prior to ≥ 
2 missed adequate disease assessments
Censor 
(non-event)
Death or  progression after ≤1 missed 
adequate disease assessments
Death or progression
End of response 
(Event)
Patients 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 each cohort, the efficacy endpoints, analysis population, and statistical methods
(including missing data handling) that will be employed for the efficacy analyses are 
presented in Table 2. 
 
 
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Table 2
Summary of Analysis Strategy for Efficacy Endpoints
Endpoint
Statistical Method
Analysis Population
Missing data 
approach
ORR

RECIST 1.1, central 
imaging vendor 

RECIST 1.1, 
investigator

irRECIST 1.1, central 
imaging vendor
Exact method 
based on binomial 
distribution
FAS in all below populations:
Cohort 1*

all

PD-L1+
Cohort 2

all

PD-L1+
Cohort 3 (PD-L1+ only)
Subjects with missing 
data are considered 
non-responders
OS
Summary statistics 
using Kaplan-Meier 
method
ASaT in all below populations:
Cohort 1

all 

PD-L1+
Cohort 2

all 

PD-L1+
Cohort 3 (PD-L1+ only)
Censored at last 
assessment date
DCR

RECIST 1.1, central 
imaging vendor

RECIST 1.1, 
investigator

irRECIST 1.1, central 
imaging vendor
Exact method 
based on binomial 
distribution
ASaT in all below populations:
Cohort 1

all 

PD-L1+
Cohort 2

all 

PD-L1+
Cohort 3 (PD-L1+ only)
Subjects with missing 
data are considered 
as disease not under 
control
PFS

RECIST 1.1, central 
imaging vendor

RECIST 1.1, 
investigator

irRECIST 1.1, central 
imaging vendor
Summary statistics 
using Kaplan-Meier 
method
ASaT in all below populations:
Cohort 1

all 

PD-L1+
Cohort 2

all 

PD-L1+
Cohort 3 (PD-L1+ only)
Censored at last 
assessment date
DOR

RECIST 1.1, central 
imaging vendor

RECIST 1.1, 
investigator

irRECIST 1.1, central 
imaging vendor
Summary statistics 
using Kaplan-Meier 
method
Responders in all below populations:
Cohort 1

all

PD-L1+
Cohort 2

all 

PD-L1+
Cohort 3 (PD-L1+ only)
Censored at last 
assessment date
HRQOL assessments
Summary statistics 
ASaT in all below populations:
Cohort 1

all 

PD-L1+
Cohort 2

all 

PD-L1+
Cohort 3 (PD-L1+ only)
Missing data will not 
be included in 
summary
* In Cohort 1, ORR per RECIST 1.1 assessed by central imaging vendor for all subjects and in PD-L1+ subjects is 
considered primary; all other efficacy analyses are considered supportive.
 
 
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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. Counts and 
percentages of AEs will be provided.
3.6.3
Summaries of Baseline Characteristics, and Demographics
The number and percentage of subjects screened, enrolled, the primary reasons for 
screening failure, and the primary reason for discontinuation will be displayed.  
Demographic variables, baseline characteristics, primary and secondary diagnoses, and 
prior and concomitant therapies will be summarized by treatment either by descriptive 
statistics or categorical tables.
3.7
Interim Analyses
For Cohort 1, an interim analysis will be performed for PD-L1 negative subjects. The 
endpoint, timing, and purpose of the interim analyses are summarized in
Table 3.  
The detailed process is described as below:
1. Enrollment will begin with an all-comer population. After both the PD-L1 assay is 
ready and ~40 all-comers enrolled, enrollment of PD-L1 positive subjects will be 
continued, and PD-L1 negative subject enrollment will be paused.
2. An interim analysis (reviewed by external DMC) will be performed when the 
initially enrolled all-comers (n~40) have response assessment available. The 
purpose of this interim analysis is to check treatment futility on the PD-L1 
negative subjects. It is estimated that approximately 25 PD-L1 negative subjects 
will be included in this interim analysis.
3. If the futility criterion is not met, the PD-L1 negative subject enrollment will be 
resumed. The trial enrollment will end when at least 80 all-comer subjects 
meeting the revised eligibility criteria are enrolled. If the futility criterion is met 
for the PD-L1 negative subjects, the trial will continue to only enroll PD-L1 
positive subjects until there are at least 90 PD-L1 positive subjects.
For the PD-L1 negative subjects, the futility criterion is met if the upper bound of the 
95% confidence interval of ORR is less than 20%. If the futility criterion is met then the 
enrollment of PD-L1 negative subjects will not be resumed. 
Among the initially enrolled ~40 all-comers, the actual number of PD-L1 negative 
subjects could vary depending on prevalence rate. According to the futility rule defined 
above, if 25 PD-L1 negative subjects are included in the interim analysis, and if no 
responder is observed, enrollment of PD-L1 negative subjects in Cohort 1 will not 
resume. Otherwise, if 1 or more responders are observed among the 25 PD-L1 negative 
subjects, the enrollment of the PD-L1 negative subjects will be re-opened.
 
 
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Table 3:  Summary of Interim Analysis Strategy
Key Endpoints for 
Interim Analysis
Timing of 
Interim Analysis
Purpose of 
Interim Analysis
ORR (confirmed or unconfirmed)
By RECIST 1.1,central imaging 
vendor assessment
Initially enrolled ~40 all-comers 
have response assessment available 
(~25 PD-L1 negative subjects 
provided)
Check futility for PD-L1 
negative subjects
As of Oct 19, 2015, an interim analysis has been performed and the external DMC has 
reviewed the data. The futility criterion was not met and the DMC recommended that the 
enrollment of PD-L1 negative subjects could be resumed.
3.8
Multiplicity
This is an estimation study. 95% confidence intervals of ORR will be provided. No 
multiplicity adjustment will be applied.
3.9
Sample Size and Power Calculations
Cohort 1 (3L+ gastric cancer subjects/monotherapy): 

Enrollment began with an all-comer population. By 23 July 2015, 42 all-comer 
subjects were enrolled and included in the interim analysis.

Then only PD-L1 positive subjects were enrolled until the outcome of the interim 
analysis was determined on 19 October 2015. From 23 July 2015 to 19 October 
2015, approximately 33 PD-L1 positive subjects were enrolled.

Since the futility criterion was not met at the interim analysis, the enrollment of 
PD-L1 negative subjects will resume. Enrollment after the interim analysis will 
not stop until at least 80 all-comer subjects meeting the revised eligibility criteria 
are enrolled. Since the implementation of the amendment takes time, it is 
estimated that approximately 135 all-comer subjects will be enrolled after the 
interim analysis, including about 55 all-comer subjects enrolled under the original 
protocol and 80 under the amendment.
Thus, it is estimated that the overall sample size for Cohort 1 is approximately 210.
Table 4 shows the two-sided 95% CI of ORR with 90 evaluable subjects for different 
observed response rates. With 90 PD-L1 positive subjects, if there are at least 16 
responders observed, the lower bound of the 95% confidence interval for ORR will be 
above 10%.
 
 
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Table 4
Two-sided 95% CI of ORR with 210 Subjects
Number of observed responders
ORR estimates
95% CI of ORR (%)
30
14.3%
(9.9, 19.8)
31
14.8%
(10.3, 20.3)
32
15.2%
(10.7, 20.8)
33
15.7%
(11.1, 21.4)
Assuming the prevalence of PD-L1 positive is 50% based on the interim analysis and ~33
PD-L1 positive subjects are enrolled during the period of enrolling only PD-L1 positive 
subjects; there will be a total of approximately 120 PD-L1 positive subjects in Cohort 1. 
Table 5 shows the two-sided 95% CI of ORR with 120 PD-L1 positive subjects for 
different response rates. 
   Table 5
Two-sided 95% CI of ORR with 120 PD-L1 Positive Subjects
Number of observed responders
ORR estimates
95% CI of ORR (%)
19
15.8%
(9.8, 23.6)
20
16.7%
(10.5, 24.6)
21
17.5%
(11.2, 25.5)
22
18.3%
(11.9, 26.4)
Table 6 shows the two-sided 95% CI of ORR with 80 all-comer subjects meeting the 
revised eligibility criteria for different observed response rates.
Table 6
Two-sided 95% CI of ORR with 80 Subjects Meeting Revised Eligibility 
Criteria 
Number of observed responders
ORR estimates
95% CI of ORR (%)
14
17.5%
(9.9, 27.6)
15
18.8%
(10.9, 29.0)
16
20.0%
(11.9, 30.4)
17
21.3%
(12.9, 31.8)
Cohort 2 (1L gastric cancer subjects/combination treatment): There will be approximately 
18 subjects enrolled for all-comer population. Table 7 shows the two-sided 95% CI of AE 
rate with 18 subjects.
 
 
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Table 7
Two-sided 95% CI of AE incidence rate with 18 Subjects
Number of AE
AE incidence rate estimates
95% CI of incidence rate (%)
2
11.1%
(1.4, 34.7)
4
22.2%
(6.4, 47.6)
5
27.7%
(9.7, 53.5)
7
38.9%
(17.3, 64.2)
9
50.0%
(26.0, 73.9)
Cohort 3 (1L gastric cancer subjects/monotherapy): There will be ~25 PD-L1 positive 
subjects enrolled in Cohort 3. Using Bayesian sample size methods and assuming a 
uniform prior for the response rate (beta-binomial prior with beta (1, 1)), if we observe no 
more than 8 responders (i.e. observed ORR <=32%), there is >= 77% posterior 
probability that the true ORR is less than 40% (ORR from Standard of Care).
3.10
Subgroup Analyses and Effect of Baseline Factors
Efficacy analyses will be performed within the following subgroups: 

Subjects classified based on PD-L1 biomarker status as appropriate;

Subjects in Cohort 1 meeting the revised eligibility criteria.
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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