A Randomized, Active-Controlled, Partially Blinded, Biomarker Select, Phase III Clinical Trial of Pembrolizumab as Monotherapy and in Combination With Cisplatin+5-Fluorouracil Versus Placebo+Cisplatin+5-Fluorouracil as First-Line Treatment in Subjects With Advanced Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma
Phase: PHASE3
Conditions: Gastric Adenocarcinoma
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
NCT02494583
23-Jan-2019
Document Date: 
A Randomized, Active-Controlled, Partially Blinded, Biomarker Select, 
Phase III Clinical Trial of Pembrolizumab as Monotherapy and in 
Combination with Cisplatin+5-Fluorouracil versus Placebo+Cisplatin+5-
Fluorouracil as First-Line Treatment in Subjects with Advanced Gastric 
or Gastroesophageal Junction (GEJ) Adenocarcinoma

Product:  MK-3475 
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THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., 
WHITEHOUSE STATION, NJ, U.S.A.
This protocol amendment is applicable only to United Kingdom 
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 Randomized, Active-Controlled, Partially Blinded, Biomarker Select, Phase III Clinical 
Trial of Pembrolizumab as Monotherapy and in Combination with Cisplatin+5-Fluorouracil 
versus Placebo+Cisplatin+5-Fluorouracil as First-Line Treatment in Subjects with Advanced
Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma
IND NUMBER:  123,482
EudraCT NUMBER:  2015-000972-88
 
 
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TABLE OF CONTENTS
DOCUMENT HISTORY ..................................................................................................... 11
SUMMARY OF CHANGES................................................................................................ 13
1.0
TRIAL SUMMARY.................................................................................................. 16
2.0
TRIAL DESIGN........................................................................................................ 17
Trial Design ........................................................................................................... 17
Trial Diagram........................................................................................................ 20
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 21
Primary Objective(s) & Hypothesis(es).............................................................. 21
Secondary Objective(s) & Hypothesis(es)........................................................... 22
Exploratory Objectives......................................................................................... 23
4.0
BACKGROUND & RATIONALE.......................................................................... 23
Background ........................................................................................................... 23
Pharmaceutical and Therapeutic Background .................................................... 23
4.1.1.1
Pembrolizumab ............................................................................................ 23
Pre-clinical and Clinical Trials ........................................................................... 24
Ongoing Clinical Trials....................................................................................... 25
4.1.3.1
Ongoing Clinical Trials in Gastric Cancer................................................... 25
Information on Other Trial-Related Therapy...................................................... 25
Rationale................................................................................................................ 26
Rationale for the Trial and Selected Subject Population .................................... 26
Rationale for Dose Selection/Regimen/Modification......................................... 26
4.2.2.1
Rationale for Use of Cisplatin + 5-Fluorouracil in First Line Gastric 
Cancer.......................................................................................................... 27
Rationale for Endpoints ...................................................................................... 28
4.2.3.1
Rationale for Efficacy Endpoints................................................................. 28
4.2.3.1.1
Primary Efficacy Endpoints.................................................................. 28
4.2.3.1.2
RECIST and Immune-related RECIST................................................. 29
4.2.3.2
Rationale for Patient Reported Outcomes (PRO)........................................ 29
4.2.3.2.1
EORTC QLQ-C30 and eEORTC QLQ-STO22 ................................... 29
 
 
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4.2.3.2.2
eEuroQoL-5D -3L................................................................................. 30
4.2.3.3
Rationale for Safety Endpoints .................................................................... 30
4.2.3.4
Planned Exploratory Biomarker Research................................................... 30
4.2.3.5
Future Biomedical Research........................................................................ 32
Benefit/Risk ........................................................................................................... 32
5.0
METHODOLOGY ................................................................................................... 33
Entry Criteria........................................................................................................ 33
Diagnosis/Condition for Entry into the Trial ...................................................... 33
Subject Inclusion Criteria.................................................................................... 33
Subject Exclusion Criteria .................................................................................. 35
Trial Treatment(s) ................................................................................................ 37
Dose Selection/Modification .............................................................................. 39
5.2.1.1
Dose Selection (Preparation) ....................................................................... 39
5.2.1.2
Dose Modification ....................................................................................... 39
5.2.1.2.1
Dose Modification and Toxicity Management Guidelines for 
Pembrolizumab/Placebo ....................................................................... 40
5.2.1.2.2
Dose Modification for Cisplatin and 5-FU........................................... 46
Second Course Phase (Retreatment Period)........................................................ 49
Timing of Dose Administration.......................................................................... 49
5.2.3.1
Pembrolizumab ............................................................................................ 50
5.2.3.2
Placebo......................................................................................................... 50
5.2.3.3
Cisplatin....................................................................................................... 50
5.2.3.4
5-Fluorouracil (5-FU) .................................................................................. 51
5.2.3.5
Capecitabine................................................................................................. 51
Trial Blinding/Masking....................................................................................... 51
Randomization or Treatment Allocation............................................................ 52
Stratification.......................................................................................................... 52
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 52
Acceptable Concomitant Medications ................................................................ 52
Prohibited Concomitant Medication................................................................... 53
Rescue Medications & Supportive Care............................................................. 54
Supportive Care Guidelines for Pembrolizumab ................................................ 54
 
 
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Supportive Care Guidelines for Cisplatin........................................................... 58
Supportive Care Guidelines for 5-Fluorouracil .................................................. 58
Supportive Care Guidelines for Capecitabine..................................................... 58
Diet/Activity/Other Considerations..................................................................... 58
Diet...................................................................................................................... 58
Contraception...................................................................................................... 58
Use in Pregnancy ................................................................................................ 60
Use in Nursing Women....................................................................................... 60
5.7.4.1
Pembrolizumab ............................................................................................ 60
5.7.4.2
Cisplatin....................................................................................................... 61
5.7.4.3
5-Fluorouracil .............................................................................................. 61
5.7.4.4
Capecitabine................................................................................................. 61
Subject Withdrawal/Discontinuation Criteria................................................... 61
Discontinuation of Treatment ............................................................................. 61
Withdrawal from the Trial .................................................................................. 63
Subject Replacement Strategy............................................................................. 63
Beginning and End of the Trial ........................................................................... 63
Clinical Criteria for Early Trial Termination ................................................... 63
6.0
TRIAL FLOW CHART ........................................................................................... 64
Initial Treatment Phase........................................................................................ 64
Treatment Arm 1:  Pembrolizumab Monotherapy.............................................. 64
Treatment Arm 2 and 3: Pembrolizumab + Chemotherapy and Placebo + 
Chemotherapy..................................................................................................... 68
Second Course Phase (Retreatment with Pembrolizumab).............................. 72
7.0
TRIAL PROCEDURES ........................................................................................... 74
Trial Procedures ................................................................................................... 74
Administrative Procedures.................................................................................. 74
7.1.1.1
Informed Consent......................................................................................... 74
7.1.1.1.1
General Informed Consent.................................................................... 74
7.1.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research................................................................................................ 75
7.1.1.2
Inclusion/Exclusion Criteria ........................................................................ 75
 
 
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7.1.1.2.1
Submitting Tumour Sample.................................................................. 75
7.1.1.3
Subject Identification Card .......................................................................... 75
7.1.1.4
Medical History ........................................................................................... 76
7.1.1.5
Disease Details............................................................................................. 76
7.1.1.6
Prior and Concomitant Medications Review............................................... 76
7.1.1.6.1
Prior Medications.................................................................................. 76
7.1.1.6.2
Concomitant Medications..................................................................... 76
7.1.1.7
Assignment of Screening Number............................................................... 76
7.1.1.8
Assignment of Randomization Number....................................................... 77
7.1.1.9
Trial Compliance (Medication/Diet/Activity/Other)................................... 77
Clinical Procedures/Assessments........................................................................ 77
7.1.2.1
Adverse Event (AE) Monitoring.................................................................. 77
7.1.2.2
Physical Exam.............................................................................................. 78
7.1.2.2.1
Full Physical Exam ............................................................................... 78
7.1.2.2.2
Directed Physical Exam........................................................................ 78
7.1.2.3
Vital Signs.................................................................................................... 78
7.1.2.4
12-Lead Electrocardiogram (ECG).............................................................. 78
7.1.2.5
Eastern Cooperative Oncology Group (ECOG) Performance Status .......... 78
7.1.2.6
Tumour Imaging and Assessment of Disease.............................................. 78
7.1.2.6.1
Initial Tumour Imaging......................................................................... 79
7.1.2.6.2
Tumour Imaging During Trial .............................................................. 79
7.1.2.6.3
End of Treatment and Follow-up Tumour Imaging.............................. 80
7.1.2.6.4
Second Course (Retreatment) Tumour Imaging................................... 80
7.1.2.6.5
RECIST 1.1........................................................................................... 81
7.1.2.6.6
Immune-related RECIST (irRECIST) .................................................. 81
7.1.2.7
Electronic Patient Reported Outcomes (ePROs) ......................................... 83
Laboratory Procedures/Assessments .................................................................. 83
7.1.3.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) .. 83
7.1.3.2
Pregnancy..................................................................................................... 85
7.1.3.3
Pharmacokinetic/Pharmacodynamic Evaluations........................................ 85
7.1.3.3.1
Blood Collections – Samples for Correlative and Genetic Analyses ... 85
7.1.3.4
Planned Genetic Analysis Sample Collection.............................................. 85
 
 
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7.1.3.5
Future Biomedical Research........................................................................ 86
Other Procedures................................................................................................. 86
7.1.4.1
Withdrawal/Discontinuation........................................................................ 86
7.1.4.1.1
Withdrawal From Future Biomedical Research ................................... 86
7.1.4.1.2
Lost to Follow-up.................................................................................. 87
7.1.4.2
Blinding/Unblinding .................................................................................... 87
7.1.4.3
Calibration of Equipment............................................................................. 88
Visit Requirements.............................................................................................. 88
7.1.5.1
Screening...................................................................................................... 88
7.1.5.2
Treatment Period.......................................................................................... 89
7.1.5.3
Post-Treatment Visits................................................................................... 89
7.1.5.3.1
Safety Follow-up Visit.......................................................................... 89
7.1.5.3.2
Follow-up Visits ................................................................................... 89
7.1.5.3.3
Survival Follow-up ............................................................................... 89
7.1.5.4
Survival Status ............................................................................................. 89
Assessing and Recording Adverse Events .......................................................... 90
Definition of an Overdose for This Protocol and Reporting of Overdose to 
the Sponsor.......................................................................................................... 91
Reporting of Pregnancy and Lactation to the Sponsor ....................................... 91
Immediate Reporting of Adverse Events to the Sponsor.................................... 92
7.2.3.1
Serious Adverse Events ............................................................................... 92
7.2.3.2
Events of Clinical Interest............................................................................ 93
7.2.3.3
Protocol-Specific Exceptions to Serious Adverse Event Reporting............ 94
Evaluating Adverse Events................................................................................. 94
Sponsor Responsibility for Reporting Adverse Events ...................................... 97
TRIAL GOVERNANCE AND OVERSIGHT................................................... 97
Scientific Advisory Committee........................................................................... 97
Executive Oversight Committee......................................................................... 97
Data Monitoring Committee............................................................................... 97
8.0
STATISTICAL ANALYSIS PLAN ........................................................................ 98
Statistical Analysis Plan Summary ..................................................................... 98
Responsibility for Analyses/In-House Blinding ............................................... 100
 
 
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Hypotheses/Estimation ....................................................................................... 101
Analysis Endpoints ............................................................................................. 101
ANALYSIS POPULATIONS ............................................................................ 101
Efficacy Analysis Populations .......................................................................... 101
Safety Analysis Populations ............................................................................. 102
STATISTICAL METHODS.............................................................................. 102
Statistical Methods for Efficacy Analyses ........................................................ 102
Statistical Methods for Safety Analyses ........................................................... 105
Statistical Methods for Patient Reported Outcome (PRO) Analyses: EORTC 
QLQ-C30 and EORTC QLQ-STO22 ............................................................... 106
Summaries of Baseline Characteristics, Demographics, and Other Analyses.. 106
8.6.4.1
Demographic and Baseline Characteristics ............................................... 106
INTERIM ANALYSES...................................................................................... 107
Safety Interim Analysis..................................................................................... 107
Efficacy Interim Analyses................................................................................. 107
Multiplicity .......................................................................................................... 110
Sample Size and Power Calculations ................................................................ 111
Subgroup Analyses and Effect of Baseline Factors ......................................... 112
COMPLIANCE (MEDICATION ADHERENCE).......................................... 113
EXTENT OF EXPOSURE................................................................................. 113
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ............................................................................................................... 113
Investigational Product ...................................................................................... 113
Packaging and Labeling Information ............................................................... 114
Clinical Supplies Disclosure............................................................................... 114
Storage and Handling Requirements................................................................ 115
Discard/Destruction/Returns and Reconciliation ............................................ 115
Standard Policies................................................................................................. 116
10.0
ADMINISTRATIVE AND REGULATORY DETAILS..................................... 116
Confidentiality..................................................................................................... 116
Confidentiality of Data ..................................................................................... 116
Confidentiality of Subject Records................................................................... 116
 
 
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Confidentiality of Investigator Information...................................................... 116
Confidentiality of IRB/IEC Information........................................................... 117
Compliance with Financial Disclosure Requirements..................................... 117
Compliance with Law, Audit and Debarment ................................................. 117
Compliance with Trial Registration and Results Posting Requirements ...... 119
Quality Management System............................................................................. 120
Data Management............................................................................................... 120
Publications ......................................................................................................... 120
11.0
LIST OF REFERENCES....................................................................................... 121
12.0
APPENDICES......................................................................................................... 126
Merck Code of Conduct for Clinical Trials...................................................... 126
Collection and Management of Specimens for Future Biomedical 
Research............................................................................................................... 128
Understanding the Intent, Scope and Public Health Benefits of 
Exploratory Biomarker Research: A Guide for IRBs/IECs and 
Investigational Site Staff .................................................................................... 134
ECOG Performance Status................................................................................ 145
Common Terminology Criteria for Adverse Events V4.0 (CTCAE)............. 146
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for 
Evaluating Response in Solid Tumors .............................................................. 147
Dose Modification Table (based on modified Toxicity Profile Interval [33]. 148
List of Abbreviations .......................................................................................... 149
13.0
SIGNATURES......................................................................................................... 152
Sponsor's Representative ................................................................................... 152
Investigator.......................................................................................................... 152
 
 
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LIST OF TABLES
Table 1
Treatments Dose and Schedule............................................................................... 18
Table 2
Adequate Organ Function Laboratory Values........................................................ 35
Table 3
Trial Treatments...................................................................................................... 38
Table 4
Dose Modifications for Trial Medications.............................................................. 40
Table 5
Dose Modification and Toxicity Management Guidelines for Immune-
related AEs Associated With pembrolizumab........................................................ 41
Table 6
Pembrolizumab Infusion Reaction Dose Modification and Treatment 
Guidelines............................................................................................................... 45
Table 7
Dose Modification Guidelines for Cisplatin Drug-Related Adverse Events.......... 46
Table 8
Dose Modification Guidelines for 5-Fluorouracil (5-FU) /Capecitabine 
Drug-Related Adverse Events................................................................................ 48
Table 9
Infusion Reaction Treatment Guidelines................................................................ 57
Table 10 Laboratory Tests ..................................................................................................... 84
Table 11 Evaluating Adverse Events..................................................................................... 95
Table 12 Censoring Rules for Primary and Sensitivity Analyses of PFS............................ 103
Table 13 Analysis Strategy for Key Efficacy Endpoints..................................................... 104
Table 14 Analysis Strategy for Safety Parameters .............................................................. 106
Table 15 Decision Guidance at Each Efficacy Analysis ..................................................... 108
Table 16 Product Descriptions............................................................................................. 114
 
 
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LIST OF FIGURES
Figure 1 Phase III Trial Design for Enrolment of PD-L1 Positive, HER2/neu 
Negative Subjects with Advanced Gastric or Gastroesophageal Junction 
(GEJ) Adenocarcinoma. ......................................................................................... 21
Figure 2 Multiplicity Strategy............................................................................................. 111
 
 
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
3475-062-13
23-Jan-2019
Clarification of language in various 
protocol sections related to AEs, follow-
up, and supportive care
3475-062-12
08-Jan-2019
Clarification of language in various 
protocol sections related to AEs, follow-
up, and supportive care
3475-062-11
27-Apr-2018
Added 2 more primary OS hypotheses; 
clarified AE language
3475-062-10
05-Apr-2018
Added 2 more primary OS hypotheses; 
clarified AE language
3475-062-09
08-Jan-2018
Revised dose modification table and 
survival 
status 
data 
collection 
requirements; updated SAP
3475-062-08
01-Dec-2017
Revised dose modification table and 
survival 
status 
data 
collection 
requirements; updated SAP
3475-062-07
24-Mar-2017
Revised primary and secondary objectives
3475-062-06
07-Mar-2017
Revised primary and secondary objectives
3475-062-05
08-Sep-2016
Update information related to pregnancy 
and contraception
 
 
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Document
Date of Issue
Overall Rationale
3475-062-04
08-Sep-2016
Clarify 
that 
subjects 
with 
locally 
advanced adenocarcinoma only include 
those whose tumors are unresectable.
3475-062-03
15-Jul-2016
Clarify 
that 
subjects 
with 
locally 
advanced adenocarcinoma only include 
those whose tumors are unresectable
3475-062-02
29-Sep-2015
Addition of monitoring for SOC side 
effects 
and 
prohibited 
concomitant 
medications that are contraindicated with 
SOC therapies.
3475-062-01
25-Sep-2015
Capecitabine must be provided centrally 
by the Sponsor for Japan.
3475-062-00
05-May-2015
Original Protocol
 
 
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SUMMARY OF CHANGES
PRIMARY REASON(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title(s)
Description of Change (s)
Rationale
4.2.3.3
Rationale for Safety Endpoints
Last sentence deleted
To remove outdated reference to 
Section 7.2.3.2 since the content 
in that section has been changed
5.5.2
Prohibited Concomitant Medication
Language adjustment in 
“Prohibited systemic 
glucocorticoids for any 
purpose other than to modulate 
symptoms from an AE of 
suspected immunologic 
etiology or cisplatin supportive 
care.”
Editorial change
5.6.1
Supportive Care Guidelines
Section heading changed into 
"Supportive Care Guidelines 
for Pembrolizumab"; ; deleted 
note related to ECIs
To add clarification 
5.6.1
Supportive Care Guidelines
Updated reference to 
supportive care procedures for 
the management of AE with 
potential immunologic 
etiology
To update reference
 
 
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Section Number (s)
Section Title(s)
Description of Change (s)
Rationale
6.1.1
Treatment Arm 1: Pembrolizumab 
Monotherapy
Safety Follow-up changed 
from "30 days post last dose 
into "30 days post 
discontinuation"
To add clarification 
6.1.2
Treatment Arm 2 and 3: 
Pembrolizumab + Chemotherapy and 
Placebo + Chemotherapy
Follow-up Visit changed from 
"Every 6 weeks post last dose" 
into "Every 6 weeks post 
discontinuation"
To add clarification 
6.2
Second Course Phase (Retreatment 
with Pembrolizumab)
Safety Follow-up changed 
from "30 days post last dose" 
into "30 days post 
discontinuation"
To add clarification 
7.1.2.1
Adverse Event (AE) Monitoring
Deleted the paragraph about 
ECI identification and 
management with reference to 
the ECI guidance document
To remove redundant and 
obsolete information as the 
ECI Guidance Document was 
retired in 2015.
7.2.3.2
Events of Clinical Interest
Deleted Item #3 Additional 
adverse events
To remove redundant and 
obsolete information as the 
ECI Guidance Document was 
retired in 2015.
 
 
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ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
Throughout the protocol
Correct typographical errors
Correct typographical errors 
for better clarity
Throughout the protocol
No additional changes.
 
 
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1.0 TRIAL SUMMARY
Abbreviated Title
Phase III Trial of Pembrolizumab (MK-3475), pembrolizumab+FP/XP
vs. Placebo+FP/XP in Biomarker Select, Advanced Gastric or GEJ 
Adenocarcinoma
Trial Phase
III
Clinical Indication
Advanced Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma
Trial Type
Interventional
Type of control
Active control 
Route of administration
Intravenous
Trial Blinding
Partially Blinded: 
Treatment Arm 1: Pembrolizumab (monotherapy); the subject, the trial 
site personnel, the Sponsor and/or designee will not be blinded to this 
treatment arm since only one type of study medication will be 
administered on this arm.
Treatment Arms 2 and 3: pembrolizumab/placebo is blinded in the 
combination chemotherapy arms (pembrolizumab+chemotherapy and 
placebo+chemotherapy, respectively) of this trial to the subject, site 
personnel and SPONSOR. 
Pembrolizumab monotherapy (Arm 1) and pembrolizumab/placebo in 
the combination chemotherapy arms (Arms 2 & 3) will be prepared in a 
blinded fashion by an assigned unblinded pharmacist or qualified trial 
site personnel. The investigator or qualified site personnel will 
administer pembrolizumab/placebo to subjects in Treatment Arms 2 and 
3 in a blinded fashion, therefore subjects, site personnel and sponsor 
personnel are blinded to pembrolizumab/placebo treatment for these 2 
arms.  
Treatment Groups
Treatment Arm 1: Pembrolizumab monotherapy 200 mg fixed dose 
administered every 3 weeks (Q3W)
Treatment Arm 2: Pembrolizumab 200 mg fixed dose Q3W + Cisplatin 
80 mg/m2 Q3W + 5-FU* 800 mg/m2/day continuous IV infusion Days 
1-5 (120 hours)
Treatment Arm 3: Placebo Q3W + Cisplatin 80 mg/m2 Q3W + 5-FU*
800 mg/m2/day continuous IV infusion Days 1-5 (120 hours)
*Although use of 5-FU infusion is preferred, capecitabine 1000 mg/m2
twice a day (BID) D1-14 Q3W may be permitted according to local 
guidelines.  Investigator decision regarding the type of comparator used 
(5-FU or capecitabine) should be determined prior to randomization. 
Subjects should continue on the therapy chosen prior to randomization 
throughout the study.  Exceptions may be permitted after consultation 
with the Sponsor.
Number of trial subjects
Approximately 750 subjects will be enrolled.
Estimated duration of trial
The sponsor estimates that the trial will require approximately 44 months
from the time the first subject signs the informed consent until the last 
subject’s last visit.
Duration of Participation
Each subject will participate in the trial from the time the subject signs 
the Informed Consent Form (ICF) through the final protocol-specified
contact.  
 
 
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After a screening phase 28 days, each subject will be assigned to receive 
trial treatment until disease progression is radiographically documented 
and verified by blinded independent central review (BICR), when 
clinically appropriate, confirmed by the site per immune related 
Response Evaluation Criteria in Solid Tumors (irRECIST) for subjects 
treated with pembrolizumab, unacceptable adverse event(s) (AEs), 
intercurrent illness that prevents further administration of treatment, 
investigator’s decision to withdraw the subject, noncompliance with 
trial treatment or procedure requirements, or administrative reasons 
requiring cessation of treatment, or until the subject has received 35 
administrations of pembrolizumab (approximately 2 years).
Subjects who stop trial treatment after receiving 35 administrations of 
pembrolizumab
for reasons other than
disease progression or 
intolerability, or subjects who attain a complete response (CR) and 
stop trial treatment may be eligible for up to 17 additional 
administrations of pembrolizumab (approximately 1 year) upon 
experiencing disease progression (Section 7.1.5.3).  
After the end of treatment, each subject will be followed for the 
occurrence of AEs and spontaneously reported pregnancy as described 
under Section 7.2.
Subjects who discontinue for reasons other than radiographic disease 
progression will have post-treatment follow-up imaging for disease 
status until disease progression, is documented radiographically per 
RECIST 1.1, confirmed by the site per irRECIST (for subjects treated 
with pembrolizumab), initiating a non-trial cancer treatment, 
withdrawing consent, or becoming lost to follow-up. All subjects will 
be followed by telephone for overall survival until death, withdrawal 
of consent, or the end of the study.  
Randomization Ratio
1:1:1
A list of abbreviations used in this document can be found in Section 12.8.
2.0 TRIAL DESIGN
Trial Design
This is a randomized, active-controlled, multi-site, partially blinded, trial of pembrolizumab, 
or pembrolizumab+cisplatin+5-fluorouracil (5-FU) versus placebo+cisplatin+5-FU, as first-
line treatment in programmed death-ligand 1 (PD-L1) positive (ie Combined Positive Score
(CPS)≥1), human epidermal growth factor receptor 2 (HER2/neu) negative subjects with 
advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma. 
Approximately 750 subjects will be randomized to compare the efficacy and safety of 
pembrolizumab or pembrolizumab+cisplatin +5-FU versus placebo+cisplatin+5-FU as first-
line treatment. Although use of 5-FU infusion is preferred, capecitabine may be used 
according to local guidelines at the investigator’s discretion. Investigator decision regarding 
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randomization in the trial.  Subjects should continue on the backbone therapy chosen prior to 
randomization throughout the study.  Exceptions may be permitted after consultation with the 
Sponsor.
Study treatment in all arms will begin on Day 1 of each 3-week dosing cycle.
Subjects will be randomized in a 1:1:1 ratio among the three treatment arms as listed below 
(Table 1), stratified by geographic region, disease status, and backbone therapy treatment
(see Section 5.4 Stratification for more details).
Table 1
Treatments Dose and Schedule
Treatment Arm
Treatment Dose and Schedule
Treatment Arm 1
Pembrolizumab 200 mg every 3 weeks (Q3W)
Treatment Arm 2*
Pembrolizumab 200 mg Q3W+ Cisplatin 80 mg/m2 Q3W+5-FU 800 
mg/m2/day continuous IV infusion Days 1-5 (120 hours)
Treatment Arm 3*
Placebo Q3W +Cisplatin 80 mg/m2 Q3W+5-FU 800 mg/m2/day 
continuous IV infusion Days 1-5 (120 hours)
  The body surface area (BSA) in m2 should be calculated per local guidance.
*Although use of 5-FU infusion is preferred, capecitabine1000 mg/m2 bid D1-14 Q3W can be used 
according to the local guideline. Investigator decision regarding the type of comparator used (5-FU or 
capecitabine) should be determined prior to randomization in the trial. Subjects should continue on the 
backbone therapy chosen prior to randomization throughout the study. Exceptions may be permitted after 
consultation with the Sponsor. Duration of cisplatin treatment may be capped at 6 cycles as per local 
country guidelines, however treatment with 5-FU/capecitabine may continue per protocol.
Trial treatment should begin on the day of randomization or as close as possible to the date 
on which the subject is allocated/assigned.
This study is partially blinded:
Treatment Arm 1 (pembrolizumab monotherapy); the subject, the trial site personnel, the 
Sponsor and/or designee will not be blinded to this treatment arm since only one type of 
study medication will be administered on this arm.
Treatment Arms 2 and 3 pembrolizumab/placebo is blinded in the combination 
chemotherapy arms of this trial to the subject, site personnel and SPONSOR personnel.
Pembrolizumab monotherapy (Arm 1) and pembrolizumab/placebo in the combination 
chemotherapy arms (Arms 2 & 3) will be prepared in a blinded fashion by an assigned 
unblinded pharmacist or qualified trial site personnel. The investigator or qualified site 
personnel will administer pembrolizumab/placebo to subjects in Treatment Arms 2 and 3 in a 
blinded fashion, therefore subject, site personnel and sponsor personnel are blinded to 
pembrolizumab/placebo treatment for these 2 arms.
 
 
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Participation in this trial will be dependent upon supplying a tumour tissue specimen. Newly 
obtained endoscopic biopsy or core biopsy of a metastatic site if obtained as part of 
normal clinical practice is preferred to archive samples. Both formalin solution and
formalin-fixed, paraffin embedded (FFPE) block specimens are acceptable. If submitting 
unstained slides, the slides should be freshly cut and received at the testing laboratory within 
14 days from site slide section date, otherwise a new specimen will be requested. The 
specimen will be evaluated at a central laboratory facility for expression status of PD-L1 in a 
prospective manner. Only subjects whose tumours express PD-L1 (are PD-L1+) as 
determined by the central laboratory facility will be eligible for randomization in this study. 
Subjects will also be required to be HER-2/neu negative.
Subjects will undergo the first imaging evaluation at week 6 (± 7 days) after subject has been 
randomized. Subsequently, subjects will be evaluated every 6 weeks (42 days ± 7 days),
independent of any treatment delays, with radiographic imaging to assess response to 
treatment using Response Evaluation Criteria in Solid Tumors version 1.1. (RECIST.1.1). 
Study treatment will continue until first evidence of Progressive Disease (PD). RECIST 1.1 
responses as assessed by the central vendor will be used as the primary efficacy endpoint; ie, 
Progression Free Survival (PFS). RECIST 1.1 will be used by the local site for treatment 
decisions until verification of PD by the central imaging vendor. Following verification of 
PD by central vendor, treatment decision may be made by the adaptation of RECIST 1.1 [1], 
as described in Section 7.1.2.7.1.1., termed immune-related RECIST (irRECIST) to 
accommodate for the tumour response patterns seen with pembrolizumab treatment (eg, 
tumour flare).
Adverse events (AE) 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. 
Treatment will continue until documented clinical PD, unacceptable AE(s), intercurrent 
illness that prevents further administration of treatment, investigator’s decision to withdraw 
the subject, subject withdraws consent, pregnancy of the subject, noncompliance with trial 
treatment or procedure requirements, completion of 35 administrations (approximately 2 
years) of treatment with study medication or achievement of a complete response, or 
administrative reasons.
Subjects receiving monotherapy or combination therapy that have evidence of PD by 
imaging and are clinically stable may continue to be treated at the discretion of the 
investigator. In addition, subjects who attain an investigator-determined confirmed complete 
response (CR) may consider stopping trial treatment after receiving at least 8 trial 
administrations in total and at least two additional administrations of study drug after 
achieving confirmed CR prior to treatment discontinuation.
Furthermore, subjects who stop pembrolizumab with stable disease (SD) or better may be 
eligible for up to 17 additional pembrolizumab therapies if they have experienced 
radiographic disease progression while off study treatment according to the criteria in Section 
7.1.5.2.1. This retreatment is termed the Second Course Phase of this study and is only 
 
 
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available if the study remains open. Response or progression in the Second Course Phase will 
not count towards the PFS of the primary endpoint in this trial. The decision to retreat will be 
at the discretion of the investigator only if no cancer treatment was administered since the 
last dose of study treatment and the subject still meets the safety parameters listed in the 
Inclusion/Exclusion criteria (refer to Section 7.1.5.2.1 for further details).
For the abovementioned reasons, if treatment identification information for the combination 
treatment arms (pembrolizumab+chemotherapy and placebo+chemotherapy) is required then 
unblinding is allowed as per criteria in Section 7.1.4.2. 
After the end of treatment, each subject will have a 30-day follow-up assessment for AE
monitoring (serious adverse events [SAEs] and events of clinical interest [ECIs] will be 
collected for 90 days after the end of treatment or 30 days after the end of treatment if the 
subject initiates new anticancer therapy, whichever is earlier). Subjects who discontinue 
treatment for reasons other than PD will have post-treatment follow-up for disease status 
until PD, initiating a non-study cancer treatment, withdrawing consent, or becoming lost to 
follow-up. All subjects will be followed by telephone every 12 weeks (±7 days), or more 
often as needed, for overall survival (OS) until death, withdrawal of consent or the end of the 
trial, whichever comes first.
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.
This trial will use a group sequential design based on pre-specified criteria, using an 
independent, external Data Monitoring Committee (eDMC) to monitor safety and efficacy.  
There will be two interim efficacy analyses, one planned interim safety analysis, and periodic 
safety monitoring.  The interim efficacy analyses are event-driven. The interim safety 
analysis will be conducted when at least 10 subjects in each treatment arm (at least 30 
subjects total) have completed 1 cycle of treatment.  Results of the interim analyses will be 
reviewed by an eDMC.  More details are in Section 8.7.
There will be no pause in enrolment during the planned interim analyses.
Trial Diagram
The trial design is depicted in Figure 1 below.
 
 
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*Although use of 5-FU infusion is preferred, capecitabine 1000 mg/m2 bid Day1-14 Q3W may be permitted 
according to local guideline. Investigator decision regarding the type of comparator used (5-FU or capecitabine) 
should be determined prior to randomization in the trial. Subjects should continue on the fluoropyrimidine 
chosen prior to randomization throughout the study. Exceptions may be permitted after consultation with the 
Sponsor.
HER2/neu negative is defined as: IHC (0, or 1+), or FISH negative (HER2:CEP17 ratio < 2). FISH can be 
replaced with locally available ISH methods acceptable as per institutional guidelines (eg DISH).
Note that depending on emerging internal/external data, one or more of the arms may not be pursued.
Figure 1
Phase III Trial Design for Enrolment of PD-L1 Positive, HER2/neu Negative 
Subjects with Advanced Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma.
3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
Primary Objective(s) & Hypothesis(es)
(1) In subjects with advanced gastric or GEJ adenocarcinoma treated with 
pembrolizumab monotherapy or a combination of pembrolizumab with chemotherapy 
versus chemotherapy alone, as first-line treatment in subjects with PD-L1 positive 
expression Objective 1:  Evaluate Progression Free Survival (PFS) per RECIST 1.1 
as assessed by blinded central radiologists’ review in subjects with PD-L1 Combined 
Positive Score (CPS) ≥1.
 
 
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Hypothesis (H1):  Pembrolizumab in combination with chemotherapy is superior to 
chemotherapy alone in terms of PFS per RECIST 1.1 by blinded central radiologists’ 
review in subjects with PD-L1 CPS≥1.
(2) Objective 2: Evaluate overall survival (OS).
Hypothesis (H2): Pembrolizumab in combination with chemotherapy is superior to 
chemotherapy alone in terms of OS in subjects with PD-L1 CPS≥1.
Hypothesis (H3): Pembrolizumab in combination with chemotherapy is superior to 
chemotherapy alone in terms of OS in subjects with PD-L1 CPS ≥10.
Hypothesis (H4):  Pembrolizumab monotherapy is non-inferior to chemotherapy 
alone in terms of OS in subjects with PD-L1 CPS≥1.
The statistical criterion for the success of Hypothesis H4 is that, if the upper bound of 
the confidence interval, based on the alpha level allocated to the analysis, for the 
hazard ratio (HR: monotherapy arm vs control) is < 1.2, the pembrolizumab 
monotherapy arm could be considered as non-inferior to the control arm in terms of 
OS.
Hypothesis (H5):  Pembrolizumab monotherapy is superior to chemotherapy alone in 
terms of OS in subjects with PD-L1 CPS≥1.
Hypothesis (H6):  Pembrolizumab monotherapy is superior to chemotherapy alone in 
terms of OS in subjects with PD-L1, CPS ≥10.
PD-L1 positive expression defined by CPS≥1 and by CPS ≥10 CPS; is henceforth 
abbreviated as PD-L1 CPS1 and PD-L1 CPS10, respectively.
The study is considered to have met its primary objective if at least one hypothesis, H1-H6 is 
significant at the interim or final analysis as defined in Section 8.8 Multiplicity.
Secondary Objective(s) & Hypothesis(es)
(1) Objective:  Evaluate Overall Response Rate (ORR), and Duration of Response 
(DOR), per RECIST 1.1 as assessed by central radiologists in subjects with PD-L1 
CPS≥1.
(2) .Hypothesis (H7):  Pembrolizumab in combination with chemotherapy is superior to 
chemotherapy alone in terms of ORR per RECIST 1.1 as assessed by blinded central 
radiologists in subjects with PD-L1 CPS≥1.
(3) Objective:  Evaluate Progression Free Survival (PFS) per RECIST 1.1 as assessed by 
blinded central radiologists’ review in subjects treated with pembrolizumab.
(4) Objective:  Evaluate the safety and tolerability profile.
 
 
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(5) Objective:  Evaluate changes in health-related quality-of-life assessments from 
baseline using the EORTC QLQ-C30 and the EORTC QLQ-STO22.
Exploratory Objectives
(1) Objective:  Characterize utilities using the EuroQoL EQ5D-3L.
4.0 BACKGROUND & RATIONALE
Background
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody
(mAb) with high specificity of binding to the programmed cell death 1 (PD-1) receptor, thus
inhibiting its interaction with programmed cell death ligand 1 (PD-L1) and programmed cell
death ligand 2 (PD-L2). Based on preclinical in vitro data, pembrolizumab has high affinity
and potent receptor blocking activity for PD-1. Pembrolizumab has an acceptable preclinical
safety profile and is in clinical development as an intravenous (IV) immunotherapy for
advanced malignancies. Keytruda™ (pembrolizumab) is indicated for the treatment of
patients across a number of indications. For more details on specific indications refer to the
Investigator brochure.
Pharmaceutical and Therapeutic Background
4.1.1.1
Pembrolizumab
Keytruda® (pembrolizumab) has recently been approved in the United States for the 
treatment of patients with unresectable or metastatic melanoma and disease progression 
following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor.
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades [2].  Accumulating evidence shows a correlation 
between tumour-infiltrating lymphocytes (TILs) in cancer tissue and favourable prognosis in 
various malignancies [3; 4; 5; 6; 7].  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 tumours.
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumours 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 signalling upon engagement of its ligands (PD-L1 and/or PD L2) 
[8;9].  The structure of murine PD-1 has been resolved [10].  PD-1 and family members are 
type I transmembrane glycoproteins containing an Ig Variable-type (V-type) domain 
responsible for ligand binding and a cytoplasmic tail which is responsible for the binding of 
signalling molecules.  The cytoplasmic tail of PD-1 contains 2 tyrosine-based signalling
motifs, an immunoreceptor tyrosine-based inhibition motif (ITIM) and an immunoreceptor 
 
 
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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 signalling cascade [8; 11; 12; 13].  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 signalling proteins [14; 15].  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 [16; 17].  Expression has also been shown during thymic 
development on CD4-CD8- (double negative) T-cells as well as subsets of macrophages and 
dendritic cells [18].   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 tumours [19; 20; 21; 14].  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 signalling 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 [14].  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 tumour-specific T-cell expansion in subjects with melanoma (MEL) 
[22].  
In gastric cancer PD-L1 and PD-L2 overexpression have recently been associated with EBV-
positive tumours [23].  This suggests that the PD-1/PD-L1 pathway plays a critical role in 
tumour immune evasion and can be an attractive target for therapeutic intervention.
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 tumour-specific CD8+ T-cells and leads 
ultimately to tumour 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-tumour responses as a mono-therapy in models of squamous cell carcinoma, pancreatic 
carcinoma, MEL and colorectal carcinoma.  Blockade of the PD-1 pathway effectively 
promoted CD8+ T-cell infiltration into the tumour and the presence of IFN-γ, granzyme B 
and perforin, indicating that the mechanism of action involved local infiltration and 
activation of effector T-cell function in vivo [24; 25; 26; 27; 28; 29].  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 tumour models (see the Investigator’s Brochure 
[IB]).
Clinical trials have demonstrated efficacy in subjects with advanced melanoma, non-small 
cell lung cancer, head and neck cancer, bladder cancer, Hodgkin’s lymphoma, triple-negative 
breast cancer, and gastric adenocarcinoma.
 
 
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Ongoing Clinical Trials
Ongoing clinical trials are being conducted in advanced melanoma, non-small cell lung 
cancer, a number of advanced solid tumour indications and hematologic malignancies.  For 
study details please refer to the IB.
4.1.3.1
Ongoing Clinical Trials in Gastric Cancer
Preliminary interim data is available from a cohort of gastric adenocarcinoma subjects 
studied in trial [KEYNOTE (KN012)] [30].  KEYNOTE-012 trial is a multi-cohort Phase IB
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). The primary endpoint was overall 
response rate (ORR).  Although 67% of subjects had received 2 or more prior chemotherapy 
lines, pembrolizumab monotherapy demonstrated an interim ORR of 33.3% 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 subjects from Asia and outside of Asia, while the DCR was numerically 
higher in Asia. Responses were observed across all lines of treatment.  Fifty-three percent of 
the subjects with measurable disease displayed some degree of tumour shrinkage from 
baseline.  As of the data cut-off 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 subjects in KN012, single agent pembrolizumab at 10 mg/kg q2weeks 
was generally well tolerated, with the type, severity, and frequency of AEs similar to that 
observed in other indications (see the IB for information about AEs in other indications).  
There was 1 death reported in the gastric cancer cohort.  This was a subject who had AEs of 
tracheomalacia (Grade 3) and hypoxia (Grade 5).  The investigator considered the Grade 5 
hypoxia related to study treatment.
Information on Other Trial-Related Therapy
A variety of chemotherapies are used for subjects with advanced, first line gastric and GEJ 
adenocarcinoma. Early studies demonstrated small survival benefits after treatment with 
cisplatin or chemotherapy combinations.
A number of ongoing Phase 3 trials are evaluating the addition of targeted monoclonal 
antibodies or small molecules to standard chemotherapy regimens.  First positive result was 
shown  from ToGA study comparing cisplatin/fluoropyrimidine plus trastuzumab, a 
monoclonal antibody against the human epidermal growth factor receptor 2 (HER2), with the 
same chemotherapy alone in subjects with HER2-positive gastric or gastroesophageal 
adenocarcinoma. The study demonstrated significantly improved OS associated with the 
trastuzumab-containing regimen over chemotherapy alone (median 13.5 and 11.1 months, 
respectively, p=.0048). The outcome of ToGA study supported the approval of Trastuzumab 
for HER2-positive gastric cancer subjects [31].
 
 
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Rationale
Rationale for the Trial and Selected Subject Population
Trials evaluating pembrolizumab (MK-3475) in gastric cancer have demonstrated clinical 
activity in subjects with recurrent and/or metastatic disease.  Refer to Section 4.1.3, Ongoing 
Clinical Trials, for results from the Phase Ib study of pembrolizumab in subjects with
gastric cancer (KN012).
The gastric cancer proof-of-concept from KN012 data was obtained in subjects with a PD-L1 
positive expression only; no data is currently available regarding the performance of 
pembrolizumab in subjects without a detectable PD-L1 expression. 
Rationale for Dose Selection/Regimen/Modification
The planned dose of pembrolizumab for this trial is 200 mg every 3 weeks (Q3W). Based on
the totality of data generated in the Keytruda development program, 200 mg Q3W is the
appropriate dose of pembrolizumab across all indications and regardless of tumour type. As
outlined below, this dose is justified by:

Clinical data from eight randomized studies demonstrating flat dose- and exposure
efficacy relationships from 2 mg/kg Q3W to 10 mg/kg every two weeks (Q2W)

Clinical data showing meaningful improvement in benefit-risk including overall
survival at 200 mg Q3W across multiple indications

Pharmacology data showing full target saturation in both systemic circulation
(inferred from pharmacokinetic [PK] data) and tumour (inferred from physiologically
based pharmacokinetic [PBPK] analysis) at 200 mg Q3W
Among the eight randomized dose-comparison studies, a total of 2262 subjects with 
melanoma and NSCLS were enrolled 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 three studies 
compared 10 mg/kg Q3W vs. 10 mg/kg Q2W (KN001 B3, KN001 F2 and KN006). All of 
these studies demonstrated flat dose- and exposure-response relationships across the doses 
studied representing an approximate 5- to 7.5-fold difference in exposure. The 2 mg/kg (or 
200 mg fixed-dose) Q3W provided similar responses to the highest doses studied. 
Subsequently, flat dose-/exposure-response relationships were also observed in other tumour
types including head and neck cancer, bladder cancer, gastric cancer, and classical Hodgkin 
Lymphoma, confirming 200 mg Q3W as the appropriate dose independent of the tumour
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.
 
 
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Additionally, pharmacology data clearly show target saturation at 200 mg Q3W. First, PK
data in KN001 evaluating
target-mediated drug disposition (TMDD) conclusively
demonstrated saturation of PD-1 in systemic circulation at doses much lower than 200 mg
Q3W. Secondly, a PBPK analysis was conducted to predict tumour PD-1 saturation over a
wide range of tumour penetration and PD-1 expression. This evaluation concluded that
pembrolizumab at 200 mg Q3W achieves full PD-1 saturation in both blood and tumour.
Finally, population PK analysis of pembrolizumab, which characterized the influence of
body weight and other subject covariates on exposure, has shown that the fixed –dosing
provides similar control of PK variability as weight-based dosing, with considerable overlap
in the distribution of exposures from the 200 mg Q3W fixed dose and 2 mg/kg Q3W dose. A 
fixed-dose regimen is expected to simplify the dosing regimen (potentially reducing dosing
errors), as well as be more convenient for physicians. A fixed dosing scheme will also reduce 
complexity in the logistical chain at treatment facilities, as well as reduce waste.
4.2.2.1
Rationale for Use of Cisplatin + 5-Fluorouracil in First Line Gastric Cancer
Systemic chemotherapy is the mainstay of treatment for advanced and metastatic gastric 
cancer and combination chemotherapy regimens containing cisplatin/5-fluorouracil (5-FU) 
for 1st line treatment have been investigated in the following randomized Phase 3 trials [32;
33].
The V325 trial [34] was the randomized Phase 3 study to compare docetaxel/cisplatin/5-FU 
with cisplatin/5-FU, and  showed statistically significant OS time (median 9.2 months and 
8.6 months, respectively, p = 0.02) PFS time (median 5.6 months and 3.7 months, 
respectively, p = 0.001), response rate (37% and 25%, respectively, p = 0.01) associated with 
docetaxel/cisplatin/5-FU. Regarding the safety, the addition of docetaxel was associated with 
increased Grade 3-4 neutropenia (82%, versus 57% with 5 FU/cisplatin alone), complicated 
neutropenia (29% vs. 12%), Grade 3-4 diarrhoea (19% vs. 8%), and Grade 3-4 lethargy (19% 
vs. 14%).  The result of V325 supported the registration of docetaxel and 
docetaxel/cisplatin/5-FU as one of the standard regimen for 1st line treatment for gastric 
cancer. However, due in part to this increased toxicity; incorporation of docetaxel into first-
line gastric cancer regimens has been limited.
The Real-2 trial [35] was a phase 3 study to compare epirubicin + oxaliplatin + 5-FU [EOF], 
epirubicin + cisplatin + capecitabine [ECX], epirubicin + cisplatin + 5-FU [ECF], and 
epirubicin + oxaliplatin + capecitabine [EOX] in advanced esophagogastric cancer.  OS was 
significantly longer among subjects receiving EOX versus ECF (9.9 months, 9.3 months, 9.9 
months, and 11.2 months for ECF, EOF, ECX, and EOX, respectively).  No significant 
differences were observed in terms of response rate or PFS.  As an outcome of the Real-2 
trial, cisplatin/5-FU/epirubicin became one of the popular regimens for 1st line treatment for 
gastric cancer in EU.  However, according to the ESMO guideline (2013), the use of triplet 
regimen should be limited because of increased toxicity. There are no Phase 3 trials directly 
comparing cisplatin/5-FU and cisplatin/5-FU/epirubicin.
 
 
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ML17032 study [36] compared cisplatin/capecitabine with cisplatin/5-FU.  The primary 
objective was to show non-inferiority in terms of PFS time.  Median PFS was 5.6 months 
among subjects receiving cisplatin/capecitabine and 5.0 months among subjects receiving 
cisplatin/5-FU; median OS times were 10.5 months and 9.3 months, and ORR were 46% and 
32%, in these groups respectively. Based on this study, capecitabine has been approved in 
combination with a platinum-based regimen for the first-line therapy of advanced gastric 
cancer in US and Japan.
The SPIRITS study [37] was Phase 3 trial to compare the oral fluoropyrimidine S1 plus 
cisplatin vs S1 in Japanese subjects. Median OS was 13 months vs 11 months. PFS was 6 
months vs. 4 months; p < 0.001). Based on these data, S1 plus cisplatin became the most 
popular regimen for the first-line therapy of advanced gastric cancer in Japan. 
The FLAGS trial [38] was phase 3 trial to compare the oral fluoropyrimidine S1 plus 
cisplatin vs 5-FU plus cisplatin in western population. The trial failed to show superiority for 
S1 plus cisplatin over 5-FU plus cisplatin; median OS was 8.6 months and 7.9 months, for 
S1/cisplatin and 5-FU/cisplatin, respectively. More toxicity of S1 and dose reduction due to 
AEs was observed in Western population.
In summary, platinum/fluoropyrimidine doublet regimens are the most broadly used for first-
line chemotherapy regimen for advanced gastric cancer. The comparable efficacy of 
regimens substituting capecitabine for infused 5-fluorouracil has been directly studied in two 
phase III trials: the REAL-2 study and the ML17032 study. The combination of infused or 
oral 5-fluorouracil and cisplatin is therefore recognized worldwide as one of the standard 
first-line chemotherapy regimens for subjects with mGC.
Rationale for Endpoints
4.2.3.1
Rationale for Efficacy Endpoints
4.2.3.1.1 Primary Efficacy Endpoints 
Although OS is the gold standard for a “hard endpoint” in clinical studies in the area of 
oncology, OS as a primary endpoint for a 1st line gastric trial with PD-1/ PD-L1 pathway 
inhibitors may be extremely difficult to achieve. In US/ EU, gastric cancer is a rare tumour
type and most subjects have advanced or metastatic disease at the time of diagnosis. Because 
of the limited number of subjects in western countries and the multiple companies 
developing this class of drugs for gastric cancer, it is expected that there will be a high cross 
over rate for the chemotherapy arm subjects. Therefore, this trial will use a dual endpoint of 
OS and PFS.  PFS is an acceptable scientific endpoint for a randomized Phase III trial to 
demonstrate superiority of a new antineoplastic therapy.  RECIST 1.1 will be used to 
determine the dates of progression as this methodology is accepted by regulatory authorities.  
Because the treatment assignment is unblinded for pembrolizumab monotherapy, images will 
be read by central radiologists blinded to treatment assignment to minimize bias in the 
response.
 
 
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4.2.3.1.2 RECIST and Immune-related RECIST
RECIST 1.1 will be adapted to account for the unique tumour response characteristics seen 
with treatment of pembrolizumab. Immunotherapeutic agents such as pembrolizumab may 
produce antitumour effects by potentiating endogenous cancer-specific immune responses.
The response patterns seen with such an approach may extend beyond the typical time course 
of responses seen with cytotoxic agents, and can manifest a clinical response after an initial 
increase in tumour burden or even the appearance of new lesions. Standard RECIST 1.1 may, 
thus, not provide an accurate response assessment of immunotherapeutic agents such as 
pembrolizumab. Based on an analysis of subjects with melanoma enrolled in KEYNOTE-001
(KN001), 7% of evaluable subjects experienced delayed or early tumour pseudoprogression.
Of note, subjects who had progressive disease by RECIST 1.1 but not by immune-related 
response criteria had longer OS than subjects with progressive disease by both criteria.
Additionally, the data suggest that RECIST 1.1 may underestimate the benefit of 
pembrolizumab in approximately 15% of subjects. These findings support the need to apply a 
modification to RECIST 1.1 that takes into account the unique patterns of atypical response 
in immunotherapy and enable treatment beyond initial radiographic progression. 
Immune-related RECIST (irRECIST) is RECIST 1.1 adapted to account for the unique 
tumour response seen with immuno-therapeutics as described in [51]. The assessment of 
unidimensional target lesions and response categories per irRECIST are identical to RECIST 
1.1. However, Sponsor has implemented an adaptation related to new lesions, non-target and 
tumour burden assessment in order to confirm radiographic progression. irRECIST will be 
used by local site investigators to assess tumour response and progression, and make 
treatment decisions as well as by BICR in support of primary endpoint.
For further information on irRECIST, see Section 7.1.2.6.6.
4.2.3.2
Rationale for Patient Reported Outcomes (PRO)
The EORTC QLQ-C30 and EuroQoL-5D (EQ-5D) patient reported outcomes (PROs) are not 
pure efficacy or safety endpoints because they are affected by both disease progression and 
treatment tolerability. 
4.2.3.2.1 EORTC QLQ-C30 and eEORTC QLQ-STO22
The EORTC QLQ-C30 is the most widely used cancer specific HRQoL instrument, which 
contains 30 items and measures five functioning dimensions (physical, role, cognitive, 
emotional, and social), three symptom items (fatigue, nausea/vomiting, pain), six single items 
(dyspnea, sleep disturbance, appetite loss, constipation, diarrhoea, and financial impact), and 
a global health and quality of life scale [39]. This instrument has been translated and 
validated into 81 languages and used in more than 3,000 studies worldwide.
The EORTC QLQ-STO22 is a disease-specific questionnaire developed and validated to 
address measurements specific to gastric cancer. It is one of multiple disease-specific 
modules developed by the EORTC QLG (Quality of Life Group) designed for use in clinical 
 
 
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trials, to be administered in addition to the QLQ-C30 to assess disease-specific treatment 
measurements. It contains 22 items with symptoms of dysphagia (four items), pain or 
discomfort (three items), upper GI symptoms (three items), eating restrictions (five items), 
emotional (three items), dry mouth, hair loss, and body image.
The EORTC QLQ-C30 and EORTC QLQ-STO22 are to be completed at various time points 
as specified in the Trial Flow Chart, beginning with Cycle 1 until 30 days post-treatment 
discontinuation.
4.2.3.2.2 eEuroQoL-5D -3L
The eEuroQol-5D-3L (eEQ5D-3L) is a standardized instrument for use as a measure of 
health outcome.  The eEQ5D-3L will provide data for use in economic models and analyses 
including developing health utilities or quality adjusted life years (QALYs).  The five health 
state dimensions in this instrument include the following: mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression.  Each dimension is rated on a three-point scale from 
1 (extreme problem) to 3 (no problem).  The eEQ5D-3L also includes a graded (0 to 100) 
vertical visual analog scale on which the subject rates his or her general state of health at the 
time of the assessment.  The eEQ5D-3L will always be completed by subjects first before 
completing the EORTC QLQ-C30 and QLQ-STO22 and is to be completed at various time 
points as specified in the Trial Flow Chart, beginning with Cycle 1 until 30 days post-
treatment discontinuation. 
4.2.3.3
Rationale for Safety Endpoints
The safety objective of this trial is to characterize the safety and tolerability of
pembrolizumab monotherapy and in combination therapy in subjects with gastric or GEJ
adenocarcinoma. The 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 study treatments, including SAEs and ECIs.
Safety and tolerability will be assessed by clinical review of all relevant parameters including
AEs, laboratory tests, and vital signs, 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 
analysed including but not limited to all AEs, SAEs, fatal AEs, and laboratory changes. 
4.2.3.4
Planned Exploratory Biomarker Research
Additional biomarker research to identify factors important for pembrolizumab monotherapy 
and in combination therapy may also be pursued.  For example, tumour and blood samples 
(including serum and plasma) from this trial may undergo proteomic, genomic, 
metabolomics, and transcriptional analyses.  This research may evaluate factors important for 
predicting responsiveness or resistance to pembrolizumab monotherapy or combination 
therapy and other immunologic targets. Assays may include but are not be limited to:
 
 
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Immunohistochemistry
PD-L1 expression in tumour tissue will be characterized by immunohistochemistry to 
explore the relationship between PD-L1 expression
and response to treatment 
with pembrolizumab monotherapy or combination therapy.  Other exploratory biomarkers 
(eg PD-1 expression, markers of T-cell phenotype) may also be evaluated.
Transcriptional Analyses
Messenger RNA (mRNA) expression profiling in archival material (biopsy specimens, 
peripheral blood) will be completed using the NanoString platform to assess expression of 
approximately 700 genes and attempt to define a gene set critical for clinical response to 
pembrolizumab monotherapy or combination.  The hypothesis to be tested is that 
pembrolizumab induces responses in tumours 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 
(eg, IL-10).  MicroRNA profiling may also be pursued in serum samples.
Proteomic analysis
In addition to expression on the tumour tissue, PD-L1 can be shed from tumour and released 
into the blood.  Enzyme-linked immunoassay can measure PD-L1 in serum and correlate this 
expression with response to pembrolizumab monotherapy or combination therapy, as well as 
levels of PD-L1 IHC or protein in the tumour.  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 monotherapy or combination therapy.
Gene Analyses
The application of new technologies, such as next generation sequencing, has provided 
scientists the opportunity to define certain tumour types at the genetic level as being 
‘hypermutated’ or can detect the presence of specific T-cell clones within the tumour
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 
monotherapy or combination 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 endeavour
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 AEs, the data might inform optimal use of 
 
 
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therapies in the subject population. This research contributes to understanding genetic 
determinants of efficacy and safety associated with the treatments in this study.
Other exploratory biomarkers (eg PD-1 expression, markers of T-cell phenotype) may also 
be evaluated.
4.2.3.5
Future Biomedical Research
The Sponsor will conduct Future Biomedical Research on specimens collected for future 
biomedical research during this clinical trial.  This research may include genetic analyses 
(DNA), gene expression profiling (RNA), proteomics, metabolomics (serum, plasma) and/or 
the measurement of other analytes.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main trial) and will only be conducted on specimens from 
appropriately consented subjects. The objective of collecting specimens for Future 
Biomedical Research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. 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.
Benefit/Risk
Subjects in clinical trials generally cannot expect to receive direct benefit from treatment 
during participation, as clinical trials are designed to provide information about the safety 
and effectiveness of an investigational medicine.
Additional details regarding specific benefits and risks for subjects participating in this 
clinical trial may be found in the accompanying Investigators Brochure (IB) and Informed 
Consent documents.
Beneficial effects of pembrolizumab have been seen in several trials to date. Publications of a 
significantly positive benefit/risk ratio have been reported for melanoma both in a single arm 
study encompassing nearly 1000 subjects (KN001), which led to USFDA approval in 
September 2014, and in a randomized comparison to chemotherapy (KEYNOTE-002 
[KN002]– detailed in the IB). Additional potential benefits are addressed in section 4.1.3.1 
 
 
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which details responses of KN012 trial; a multi-cohort Phase Ib study of which one cohort 
enrolled subjects with recurrent or metastatic gastric or GEJ adenocarcinoma that expressed 
PD-L1 (≥1% by immunohistochemistry). Although two-thirds of subjects had received at 
least two prior therapies for advanced disease, pembrolizumab monotherapy achieved an 
interim ORR of 33.3% 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%), and the interim median duration of response was 24 weeks (range 
8+ to 33+ weeks).
In KN012 the most common AEs included fatigue (17.9%), decreased appetite (12.8%), 
hypothyroidism (12.8%), and arthralgia (10.3%). Three Grade 3 AEs were observed, one 
each for peripheral sensory neuropathy, fatigue, and decreased appetite. In addition, one 
Grade 4 pneumonitis and one Grade 5 hypoxia were reported. 
An early safety analysis will be performed to evaluate the safety of each treatment arm.  This 
interim safety analysis will occur when at least10 subjects from each arm (30 total subjects) 
have completed at least 1 cycle of treatment.  The safety data will be submitted to an external 
DMC.
5.0 METHODOLOGY
Entry Criteria
Diagnosis/Condition for Entry into the Trial
Male/Female subjects with locally advanced unresectable or metastatic gastric or GEJ
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:
1. Be willing and able to provide written informed consent/assent for the trial. The 
subject may also provide consent/assent for Future Biomedical Research.  However, 
the subject may participate in the main trial without participating in Future 
Biomedical Research.
2. Be ≥ 18 years of age on day of signing informed consent (or acceptable age according 
to local regulations, whichever is older).
3. Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group 
(ECOG) Performance Scale within 3 days prior to the first dose of trial treatment.
4. Have histologically or cytologically confirmed diagnosis of locally advanced
unresectable or metastatic gastric or GEJ adenocarcinoma.
5. Be HER2/neu negative and PD-L1 positive.
 
 
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6. Have measurable disease as defined by RECIST 1.1 as determined by investigator 
assessment. Tumour 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.
7. Have provided tumour tissue sample deemed adequate for PD-L1 biomarker analysis. 
Refer to Section 7.1.1.2.1 for details
a.
Notification of eligibility must be received prior to randomization.
b. Additional samples may be required if adequate tissue is not provided.
8. Female subjects of childbearing potential must 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.
9. Female subjects of childbearing potential (Section 5.7.2) must be willing to use an 
adequate method of contraception as outlined in Section 5.7.2 – Contraception, for 
the course of the study through 120 days after the last dose of study medication.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception 
for the subject.
10. Male subjects of childbearing potential (Section 5.7.2) must agree to use an adequate 
method of contraception as outlined in Section 5.7.2- Contraception, starting with the 
first dose of study therapy through 120 days after the last dose of study therapy.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception 
for the subject.
11. Demonstrate adequate organ function as defined in Table 2.  All screening labs 
should be performed within 10 days of treatment initiation.
 
 
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Table 2
Adequate Organ Function Laboratory Values
System
Laboratory Value
Haematological
Absolute neutrophil count (ANC)
≥1,500 /mcL
Platelets
≥100,000 / mcL
Haemoglobin
≥9 g/dL – transfusion is acceptable if necessary to 
increase haemoglobin levels
Renal
Creatinine OR
Measured 
or 
calculateda
creatinine 
clearance
(GFR can also be used in place of 
creatinine or CrCl)
≤1.5 X upper limit of normal (ULN) OR
≥60 mL/min for subject with creatinine levels > 1.5 X 
institutional ULN
Cisplatin product label should be followed for 
acceptable creatinine clearance rates for subjects in 
Arms 2 and 3 (combination treatment)
Hepatic
Total bilirubin
≤ 1.5 X ULN OR
Direct bilirubin ≤ULN for subjects with total bilirubin 
levels > 1.5 ULN
AST (SGOT) and ALT (SGPT)
≤ 2.5 X ULN OR
≤ 5 X ULN for subjects with liver metastases
Albumin
≥ 2.5 g/dL
Coagulation
International Normalized Ratio (INR) or 
Prothrombin Time (PT)
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
aCreatinine clearance should be calculated per institutional standard.
Subject Exclusion Criteria
The subject must be excluded from participating in the trial if the subject:
1. Has squamous cell or undifferentiated gastric cancer.
2. Has had previous therapy for locally advanced, unresectable or metastatic gastric/GEJ 
cancer. Subjects may have received prior neoadjuvant or adjuvant therapy as long as 
it was completed at least 6 months prior to randomization.
 
 
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3. 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 treatment.
4. Has had radiotherapy within 14 days of randomization. Subjects who received 
radiotherapy >14 days prior to randomization must have completely recovered from 
any radiotherapy related AEs/toxicities.
5. Has a known additional malignancy that is progressing or requires active treatment.  
Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the 
skin that has undergone potentially curative therapy or in situ cervical cancer.
6. 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 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.
7. Has an active autoimmune disease that has required systemic treatment in past 2 years 
(ie with use of disease modifying agents, corticosteroids or immunosuppressive 
drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a 
form of systemic treatment.   
8. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy 
(in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of 
immunosuppressive therapy within 7 days prior the first dose of trial drug.
9. Has a history of (non-infectious) pneumonitis that required steroids or current 
pneumonitis
10. Has an active infection requiring systemic therapy.
11. Has a history or current evidence of any condition (eg known deficiency of the 
enzyme 
dihydropyrimidine 
dehydrogenase 
[DPD]), 
therapy, 
or 
laboratory 
abnormality that might confound the results of the trial, interfere with the subject’s 
participation for the full duration of the trial, or is not in the best interest of the 
subject to participate, in the opinion of the treating investigator.
12. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial.
13. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the screening visit through 120 days after 
the last dose of trial treatment.
 
 
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14. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
15. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
16. Has known active Hepatitis B (eg, HBsAg reactive) or Hepatitis C (eg, HCV RNA 
[qualitative] is detected).
17. Is currently participating in and receiving study therapy or has participated in a trial 
of an investigational agent or has used an investigational device within 4 weeks prior 
to the first dose of trial treatment.
18. Has received a live vaccine within 30 days prior to the first dose of trial drug.
Note: Examples of live vaccines include, but are not limited to, the following: measles, 
mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-
Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally 
killed virus vaccines and are allowed; however intranasal influenza vaccines (eg, FluMist®) 
are live attenuated vaccines, and are not allowed.
Trial Treatment(s)
The treatments to be used in this trial are outlined below in Table 3.
 
 
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Table 3
Trial Treatments
Drug
Dose
Dose 
Frequency
Route of 
Administration
Regimen/Treatment 
Period/Vaccination 
Regimen
Use
Pembrolizumab
200 mg
Q3W
IV infusion
Day 1 of each cycle
Experimental
Normal Saline
NA
Q3W
IV infusion
Day 1 of each cycle
Placebo
Cisplatin*
80 mg/m2
Q3W
IV infusion
Day 1 of each cycle 
Comparator 
regimen 
and 
combination 
agent
5-FU**
800 mg/m2
Q3W
IV infusion
Continuous Days 1-5 
(120 hours) of each 
cycle 
Comparator 
regimen 
and 
combination 
agent
Capecitabine**
1000 mg/m2 
BID
Q3W
Oral
D1-14
Comparator 
regimen 
and 
combination 
agent
* Duration of cisplatin treatment may be capped at 6 cycles as per local country guidelines, however 
treatment with 5-FU/capecitabine may continue per protocol.
**Although use of 5-FU infusion is preferred, capecitabine 1000 mg/m2 bid D1-14 Q3W may be permitted 
according to local guideline. Investigator decision regarding the type of comparator used (5-FU or 
capecitabine) should be determined prior to randomization in the trial.
All trial treatments will be administered on an out-patient basis. 
Trial treatment should begin on the day of randomization or as close as possible to the date 
on which the subject is allocated/assigned.
All supplies indicated in Table 3 above will be provided centrally by the Sponsor or locally 
by the trial site, subsidiary or designee, depending on local country operational or regulatory 
requirements.
For any commercially available product that is provided by the trial site, subsidiary or 
designee every attempt will be made to source these supplies from a single lot/batch number. 
The trial site will be responsible for recording the lot number, manufacturer and expiry date 
of any locally purchased product.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of trial 
treatments in accordance with the protocol and any applicable laws and regulations.
 
 
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Dose Selection/Modification
5.2.1.1
Dose Selection (Preparation)
The rationale for selection of dose of pembrolizumab to be used in this trial is provided in 
Section 4.0– Background & Rationale.  Details on preparation and administration of 
pembrolizumab are provided in the Pharmacy Manual.
Preparation of cisplatin, 5-FU and capecitabine should follow the local product label.  The 
body surface area (BSA) in m2 should be calculated per local guidance.
5.2.1.2
Dose Modification 
If appropriate, the Investigator may attribute each toxicity event to cisplatin, 5-FU (or 
capecitabine) or pembrolizumab alone in the combination arms and use a stepwise dose 
reduction according to Table 4 to Table 8.  For individual subjects requiring a dose 
modification, treatment for each new cycle may be delayed if the scheduled off-drug periods 
are not adequate to allow for recovery to Grade ≤1 or the baseline status of the subject.  
Pembrolizumab/placebo dose reductions are not permitted.  Pembrolizumab/placebo
treatment may be interrupted or discontinued due to toxicity. If a dose reduction for toxicity 
occurs with any agent, the dose may not be re-escalated. Subjects can have a maximum of 2 
dose modifications (if applicable) to each of the components of study therapy throughout the 
course of the study for toxicities.  If a subject experiences several toxicities and there are 
conflicting recommendations, please follow the most conservative dose adjustment 
recommended (dose reduction appropriate to the most severe toxicity).  Subjects who require 
a 3rd dose modification to any particular component will have that agent discontinued.
Reduction 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 treatments. If, in the opinion of 
the Investigator, the toxicity is related to the combination of both chemotherapy agents, both 
drugs should be reduced according to recommended dose modifications. If the toxicity is 
related to the combination of three agents, chemotherapy should be reduced, interrupted or 
discontinued; pembrolizumab/placebo should be interrupted or discontinued according to the 
recommended dose modifications. 
If a decision is made to discontinue combination 
chemotherapy due to treatment related AE(s), the subject can be unblinded after discussion 
with sponsor to identify study treatment. Subjects receiving pembrolizumab therapy may 
have both the cisplatin and 5-FU or capecitabine discontinued and continue on 
pembrolizumab alone, while subjects on combination with placebo (arm 3) may discontinue 
from study treatment.
The Common Terminology Criteria for Adverse Events version 4.0 (CTCAE 4.0) must be 
used to grade the severity of AEs. All dose modifications should be based on the AE
requiring the greatest dose modification. Dose modifications are detailed in Table 4 through
Table 8.  Exceptional circumstances to following the dose modification tables below may be 
considered after consultation with the Sponsor.
 
 
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Table 4
Dose Modifications for Trial Medications
Dose level 0
Dose level -1
Dose level -2
Dose level -3
Cisplatin
80 mg/m2
60 mg/ m2
40 mg/ m2
Discontinue
5-FU
Capecitabine
800 mg/ m2
1000mg/ m2 BID
600 mg/ m2
750mg/ m2 BID
400 mg/ m2
500mg/ m2 BID
Discontinue
Pembrolizumab/placebo
200 mg fixed dose
Dose 
reductions 
are not permitted
Dose 
reductions 
are not permitted
Dose reductions 
are 
not 
permitted
If a toxicity is not otherwise specified, investigators should refer to the label or local 
guidelines for cisplatin and 5-FU, (or capecitabine) for dose adjustments. 
5.2.1.2.1 Dose 
Modification 
and 
Toxicity 
Management 
Guidelines 
for 
Pembrolizumab/Placebo
Dose modification and toxicity management for immune-related AEs associated with 
pembrolizumab
Adverse events associated with pembrolizumab exposure may represent an immunologic 
aetiology. 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 aetiology or exclude other causes. Additional procedures or tests such as 
bronchoscopy, endoscopy, skin biopsy may be included as part of the evaluation. Based on 
the severity of irAEs, withhold or permanently discontinue pembrolizumab and administer 
corticosteroids. Dose modification and toxicity management guidelines, for irAEs associated 
with pembrolizumab are provided in Table 5. 
 
 
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Table 5
Dose Modification and Toxicity Management Guidelines for Immune-related AEs Associated With pembrolizumab
General instructions:
1.
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks.
2.
For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and 
corticosteroid has been tapered. Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last dose or 
corticosteroids cannot be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks. 
3.
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive treatment 
should be initiated if irAEs cannot be controlled by corticosteroids.
Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with 
corticosteroid and/or other 
therapies 
Monitor and follow-up 
Pneumonitis 
Grade 2
Withhold 

Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper

Monitor subjects for signs and symptoms of 
pneumonitis

Evaluate 
subjects 
with 
suspected 
pneumonitis with radiographic imaging and 
initiate corticosteroid treatment

Add 
prophylactic 
antibiotics 
for 
opportunistic infections
Grade 3 or 4, or 
recurrent Grade 2
Permanently 
discontinue

Diarrhoea / 
Colitis 
Grade 2 or 3
Withhold

Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper

Monitor subjects for signs and symptoms of 
enterocolitis (ie, diarrhoea, abdominal pain, 
blood or mucus in stool with or without 
fever) 
and 
of 
bowel 
perforation 
(ie, peritoneal signs and ileus).

Subjects 
with 
≥ 
Grade 
2 
diarrhoea
suspecting 
colitis 
should 
consider 
GI 
consultation and performing endoscopy to 
rule out colitis. 

Subjects with diarrhoea/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 
Hyperglycaemia
Newly onset 
T1DM or 
Grade 3 or 4 
hyperglycaemia
associated with 
evidence of -cell 
failure
Withhold

Initiate 
insulin 
replacement 
therapy for subjects with T1DM 

Administer anti-hyperglycaemic in 
subjects with hyperglycaemia

Monitor subjects for hyperglycaemia or 
other signs and symptoms of diabetes.
Hypophysitis
Grade 2
Withhold

Administer 
corticosteroids 
and 
initiate hormonal replacements as 
clinically indicated.  

Monitor for signs and symptoms of 
hypophysitis (including hypopituitarism and 
adrenal insufficiency)
Grade 3 or 4 
Withhold or 
permanently 
discontinue1
Hyperthyroidism 
Grade 2
Continue 

Treat with non-selective beta-
blockers 
(eg, 
propranolol) 
or 
thionamides as appropriate 

Monitor for signs and symptoms of thyroid 
disorders. 
Grade 3 or 4 
Withhold or 
permanently 
discontinue1
Hypothyroidism
Grade 2-4
Continue 

Initiate 
thyroid 
replacement 
hormones (eg, levothyroxine or 
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 
aetiology 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 
aetiology and/or exclude other causes
Grade 3
Withhold or 
discontinue based 
on the type of 
event.  Events that 
require 
discontinuation 
include and not 
limited to:  
Guillain-Barre 
Syndrome, 
encephalitis
Grade 4 or 
recurrent Grade 3 
Permanently 
discontinue
1.
Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.  
NOTE: 
For subjects with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may be resumed when 
AE resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM).  
 
 
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Dose modification and toxicity management of infusion-reactions related to 
pembrolizumab
Pembrolizumab may cause severe or life-threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion. 
Dose modification and toxicity management guidelines on pembrolizumab-associated 
infusion reaction are provided in Table 6. 
 
 
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Table 6
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 
(eg, 
antihistamines, 
NSAIDs, 
narcotics, 
IV 
fluids); 
prophylactic 
medications indicated for 
≤24 hrs
Stop Infusion.
Additional appropriate medical therapy may include but 
is not limited to:
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Increase monitoring of vital signs as medically indicated 
until the subject is deemed medically stable in the 
opinion of the investigator.
If symptoms resolve within 1 hour of stopping drug 
infusion, the infusion may be restarted at 50% of the 
original infusion rate (eg from 100 mL/hr to 50 mL/hr).  
Otherwise dosing will be held until symptoms resolve 
and the subject should be premedicated for the next 
scheduled dose.
Subjects who develop Grade 2 toxicity despite adequate 
premedication should be permanently discontinued from 
further study drug treatment
Subject may be premedicated 
1.5h (± 30 minutes) prior to 
infusion of _____ with:
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine).
Acetaminophen 500-1000 mg po 
(or equivalent dose of analgesic).
Grades 3 or 4
Grade 3:
Prolonged (ie, not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following 
initial 
improvement; 
hospitalization 
indicated 
for other clinical sequelae 
(eg, 
renal 
impairment, 
pulmonary infiltrates)
Grade 4:
Life-threatening; 
pressor 
or 
ventilatory 
support 
indicated
Stop Infusion.
Additional appropriate medical therapy may include but 
is not limited to:
Epinephrine**
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Increase monitoring of vital signs as medically indicated 
until the subject is deemed medically stable in the 
opinion of the investigator.
Hospitalization may be indicated.
**In cases of anaphylaxis, epinephrine should be used 
immediately.
Subject is permanently discontinued from further 
study drug treatment.
No subsequent dosing
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of
drug administration.
For further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) at 
http://ctep.cancer.gov
 
 
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Other allowed dose interruption for pembrolizumab 
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as 
medical / surgical events or logistical reasons not related to study therapy. Subjects should be 
placed back on study therapy within 3 weeks of the scheduled interruption, unless otherwise 
discussed with the Sponsor. The reason for interruption should be documented in the 
subject’s study record.
5.2.1.2.2 Dose Modification for Cisplatin and 5-FU 
Please refer to criteria for cisplatin and 5-FU (or capecitabine) dose modification included in 
Table 7 and Table 8, respectively. 
Table 7
Dose Modification Guidelines for Cisplatin Drug-Related Adverse Events
Category
Toxicity
Hold 
Cisplatin
Treatment 
for Grade
Timing for
Restarting
Cisplatin
Treatment
Dose for
Restarting
Cisplatin
Treatment
Discontinue Cisplatin
Haematologic3
Neutropenia
31
Neutrophil count
resolves to
>1,000/mm3
No Reduction
*consider G-
CSF
Toxicity
does not
resolve
within
4
weeks
of
last 
infusion
or if >2
Dose
Level
reductions
exceeded
41
Neutrophil count
resolves to
>1,000/mm3
Reduce by 1 DL
*consider G-
CSF
Toxicity
does not
resolve
within
4
weeks
of
last 
infusion
or if >2
Dose
Level
reductions
exceeded
Febrile
Neutropenia
31
Toxicity
resolves to
Grade 0-1
Reduce by 1 DL
Toxicity
does not
resolve
within
4
weeks
of
last 
infusion
or if >2
Dose
Level
reductions
exceeded
41
n/a
Discontinue
Permanently 
discontinue 
Cisplatin
Thrombocytope
nia
3-4
1
Platelet count
resolves to 
>75,000/mm3or
baseline
Reduce by 1 DL
Toxicity
does not
resolve
within
4
weeks
of
last 
infusion
or if >2
Dose
Level
reductions
exceeded
 
 
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Category
Toxicity
Hold 
Cisplatin
Treatment 
for Grade
Timing for
Restarting
Cisplatin
Treatment
Dose for
Restarting
Cisplatin
Treatment
Discontinue Cisplatin
Non-
haematologic
Creatinine
Increased
2
Toxicity
resolves to
Grade 0-1
Reduce by 1 DL
Toxicity
does not
resolve
within
4
weeks
of
last 
infusion
or if >2
Dose
Level
reductions
exceeded
3-41
Toxicity
resolves to
Grade 0-1
Reduce by 1 DL
Toxicity
does not
resolve
within
4
weeks
of
last 
infusion
or if >2
Dose
Level
reductions
exceeded
Ototoxicity or 
Sensory 
neuropathy
3-41
Toxicity
resolves to
Grade 0-1
Reduce by 1 DL
Toxicity
does not
resolve
within
4
weeks
of
last 
infusion
or if >2
Dose
Level
reductions
exceeded
All other non-
haematologic 
toxicities2
3-41
Toxicity
resolves to
Grade 0-1
Reduce by 1 DL
Toxicity
does not
resolve
within
4
weeks
of
last 
infusion
or if >2
Dose
Level
reductions
exceeded
Laboratory
Adverse
Events
41
Toxicity
resolves to
Grade 0-1
Reduce by 1 DL
Toxicity
does not
resolve
within
4
weeks
of
last 
infusion
or if >2
Dose
Level
reductions
exceeded
1
Permanent discontinuation should be considered for any severe or life-threatening event. Consult Sponsor before restarting treatment
after Grade 4 drug-related AE
2
Subjects 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
Subjects with intolerable or persistent Grade 2 drug-related AE may hold at physician discretion.
 
 
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Table 8
Dose Modification Guidelines for 5-Fluorouracil (5-FU) /Capecitabine Drug-
Related Adverse Events
Category
Toxicity
Hold 5-FU/
Capecitabine
Treatment for
Grade
Timing for
Restarting 5-FU/
Capecitabine
Treatment
Dose for
Restarting 5-FU/
Capecitabine
Treatment
Discontinue
5-FU/Capecitabine
Haematologic3
Neutropenia
31
Neutrophil count
resolves to
>1,000/mm3
No Reduction
*consider G-CSF
Toxicity
does
not
resolve
within
4-5
weeks of last infusion
or if > 2 Dose Level
reductions exceeded
41
Neutrophil count
resolves to
>1,000/mm3
Reduce by 1 DL
*consider G-CSF
Toxicity
does
not
resolve
within
4-5
weeks of last infusion
or if > 2 Dose Level
reductions exceeded
Febrile
Neutropenia
31
Toxicity resolves to
Grade 0-1
Reduce by 1 DL
Toxicity
does
not
resolve
within
4-5
weeks of last infusion
or if > 2 Dose Level
reductions exceeded
41
n/a
Discontinue
Permanently discontinue 
Thrombocytop
enia
3-41
Platelet count 
resolves to 
>75,000/mm3
Reduce by 1 DL
Toxicity
does
not
resolve
within
4-5
weeks of last infusion
or if > 2 Dose Level
reductions exceeded
Non-
haematologic
Diarrhea, 
Mucositis, or 
Hand-foot 
syndrome
2-3
Toxicity resolves to
Grade 0-1
Reduce by 1 DL
Toxicity
does
not
resolve
within
4-5
weeks of last infusion
or if > 2 Dose Level
reductions exceeded
4
N?A
Discontinue
Permanently discontinue 
All other non-
hematologic 
toxicities2
3-41
Toxicity resolves to
Grade 0-1
Reduce by 1 DL
Toxicity
does
not
resolve
within
4-5
weeks of last infusion
or if > 2 Dose Level
reductions exceeded
Laboratory
Adverse
Events
41
Toxicity resolves to
Grade 0-1
Reduce by 1 DL
Toxicity
does
not
resolve
within
4-5
weeks of last infusion
or if > 2 Dose Level
reductions exceeded
1 Permanent discontinuation should be considered for any severe or life-threatening event. Consult Sponsor before
restarting treatment after Grade 4 drug related AE.
2 Subjects 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 Subjects with intolerable or persistent Grade 2 drug-related AE may hold at physician discretion.
 
 
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Second Course Phase (Retreatment Period)
All subjects who stop trial treatment with SD or better may be eligible for up to an additional 
17 cycles (approximately 1 year) of pembrolizumab treatment if they progress after stopping 
trial treatment from the initial treatment phase.  This retreatment is termed the Second Course 
Phase of this trial and is only available if the trial remains open and the subject meets the 
following conditions:
Either

Stopped 
initial 
treatment 
with 
trial 
treatment 
after 
attaining 
an 
investigator-determined confirmed CR based on RECIST 1.1, and
o
Was treated with at least 8 cycles of trial treatment before discontinuing 
treatment, and
o
Received at least 2 treatments with pembrolizumab beyond the date when the 
initial CR was declared
OR

Had SD, PR, or CR and stopped trial treatment after completion of 35 administrations 
(approximately 2 years) of trial treatment for reasons other than disease progression 
or intolerability
AND

Experienced an investigator-determined radiographic disease progression by 
RECIST 1.1 after stopping initial treatment, and
o
Upon unblinding at the time of centrally verified disease progression were found 
to have received pembrolizumab, and
o
No new anticancer treatment was administered after the last dose of trial 
treatment, and
o
The subject meets all of the safety parameters listed in the inclusion criteria and 
none of the safety parameters listed in the exclusion criteria, and
o
The trial is ongoing
An objective response or disease progression that occurs during the Second Course Phase for 
a subject will not be counted as an event for the primary analysis of either endpoint in this 
trial.
Timing of Dose Administration
Study treatment in all arms will begin on Day 1 of each 3-week dosing cycle after all 
procedures/assessments have been completed as detailed on the Trial Flow Chart (Section 
6.0).  Trial treatments may be administered up to 3 days before or after the scheduled Day 1 
of each cycle due to administrative reasons.
 
 
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All trial treatments may be administered on an outpatient basis.
For subjects randomized to the combination arms treatment will be administered in the order 
presented below:

Pembrolizumab or placebo infusion is administered first followed by the cisplatin 
infusion and then 5-FU infusion (or capecitabine).
Treatment may continue with pembrolizumab+chemotherapy or placebo+chemotherapy until 
documented confirmed disease progression, unacceptable AE(s), intercurrent illness that 
prevents further administration of treatment, Investigator’s decision to withdraw the subject, 
subject withdraws consent, pregnancy of the subject, noncompliance with trial treatment or 
procedure requirements, subject receives 35 administrations (approximately 2 years) of study 
medication, or administrative reasons requiring cessation of treatment.
Note: Dosing interruptions are permitted in the case of medical / surgical events or logistical
reasons (ie elective surgery, unrelated medical events, subject vacation, and holidays) not 
related to study therapy. Subjects should be placed back on study therapy as soon as 
clinically appropriate per the investigator, and not exceeding 3 weeks from the interrupted 
dosing. Day 1 of subsequent cycles should be adjusted accordingly to adhere to every 3-week
dosing schedule. Discuss with the Sponsor if subjects cannot restart study medication within 
3 weeks. The reason for interruption should be documented in the subject's study record.
5.2.3.1
Pembrolizumab
Regardless of clinical benefit, subjects may only receive 35 administrations (approximately 2 
years) with study treatment.  Pembrolizumab 200 mg fixed dose will be administered as a 30-
minute IV infusion Q3W.  Sites should make every effort to target infusion timing to be as 
close to 30 minutes as possible.  However, given the variability of infusion pumps from site 
to site, a window of -5 minutes and +10 minutes is permitted (ie, infusion time is 30 minutes: 
-5 min/+10 min).
The Pharmacy Manual contains specific instructions for the preparation of the 
pembrolizumab infusion fluid and administration of infusion solution.  
5.2.3.2
Placebo
Placebo will be normal saline solution prepared by the local pharmacist. Placebo will be
dosed and administered by blinded qualified trial site personnel in the same manner as the 
investigational product (pembrolizumab).
5.2.3.3
Cisplatin 
Cisplatin 80 mg/m2 will be administered as a 60 or 120-minute IV infusion or per site’s 
standard practice Q3W on Day 1 of each treatment cycle after completion of all procedures 
and assessments are completed according to the Trial Flow Chart in Section 6.0. Duration of 
cisplatin treatment may be capped at 6 cycles as per local country guidelines.
 
 
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5.2.3.4
5-Fluorouracil (5-FU)
5-FU 800 mg/m2/day will be administered as a continuous IV infusion from Day 1 to Day 5
(120 hours) of each treatment cycle, after completion of all procedures and assessments 
according to the Trial Flow Chart in Section 6.0.
Investigators are advised to counsel subjects assigned to receive 5-FU about risk of 
photosensitivity and to take sun protection measures accordingly.
5.2.3.5
Capecitabine
Although use of 5-FU infusion is preferred, capecitabine 1000 mg/m2 bid Day1 to Day 14 
Q3W may be permitted according to local guidelines at the Investigator’s discretion.  
Investigator decision regarding the type of comparator (5-FU or capecitabine) used should be 
determined prior to randomization in the trial. The evening dose of capecitabine should be 
taken approximately 12 hours after the morning dose and should be taken with food, or 
within 30 minutes after food/meal, with approximately 200 ml of water. Please refer to the 
product label for additional guidance on administration procedures for capecitabine.  Note: If 
subject is enrolled later in the day, it is acceptable for only 1 dose taken on Day 1, and BID 
dosing can resume on Days 2-14 and the final dose will be taken in the morning of D15.
Investigators are advised to counsel subjects assigned to receive capecitabine about risk of 
photosensitivity and to take sun protection measures accordingly.
Trial Blinding/Masking
This study is partially blinded:
Treatment Arm 1: Pembrolizumab monotherapy, the subject, the trial site personnel, the 
Sponsor and/or designee will not be blinded to this treatment arm since only one type of 
study medication will be administered in this arm. 
Treatment Arm 2 and Treatment Arm 3: Pembrolizumab or placebo treatment in the
combination 
chemotherapy 
arms 
(pembrolizumab+chemotherapy
and 
placebo+chemotherapy, respectively) is blinded to the subject, study site personnel and 
SPONSOR personnel.  
Pembrolizumab monotherapy (Arm 1) and pembrolizumab/placebo in the combination 
chemotherapy arms (Arms 2 & 3) will be prepared in a blinded fashion by an assigned 
unblinded pharmacist or qualified trial site personnel.  The investigator or qualified site 
personnel will administer pembrolizumab/placebo to subjects in Treatment Arms 2 and 3 in a 
blinded fashion, therefore subjects, site personnel and sponsor personnel are blinded to 
pembrolizumab/placebo treatment for these 2 arms.   
Even though the trial is only partially blinded (ie treatment arm 1 is open label), the 
following measures will be taken to help maintain internal blinding: 1) imaging data are 
 
 
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centrally reviewed and the central reviewer is blinded to subject treatment assignment; 2) 
allocation schedule is blinded in the database preventing aggregate analysis.
See Section 7.1.4.2, Blinding/Unblinding, for a description of the method of unblinding a 
subject during the trial, should such action be warranted.
Randomization or Treatment Allocation
Randomization will occur centrally using an interactive voice response system / integrated 
web response system (IVRS/IWRS). There are 3 treatment arms.  Subjects will be assigned 
randomly in a 1:1:1 ratio to pembrolizumab monotherapy, pembrolizumab+chemotherapy, or
placebo+chemotherapy, respectively.  Although use of 5-FU infusion is preferred, 
capecitabine 1000 mg/m2 bid Day1 to Day 14 Q3W may be permitted according to local 
guidelines at the Investigator’s discretion. Investigator decision regarding the type of 
comparator used (5-FU or capecitabine) should be determined prior to randomization in the 
trial.  Documentation of the comparator to be used (5-FU or capecitabine) will be 
documented in IVRS/IWRS prior to randomization.
Stratification
Randomization will be stratified according to the following factors:
1. Geographic region
(Europe [including Israel]/North America/Australia vs. Asia 
[including East Asia, South Korea, Hong Kong, Taiwan, and South East Asia Malaysia, 
Thailand, Singapore, Japan] vs. Rest of the World (including South America)
2. Disease Status (locally advanced unresectable vs metastatic disease)
3. Fluoropyrimidine treatment (5-FU vs capecitabine)
Concomitant Medications/Vaccinations (Allowed & Prohibited)
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 CRF including all 
prescription, over-the-counter (OTC) products, herbal supplements, and IV medications and 
fluids. If changes occur during the trial period, documentation of drug dosage, frequency, 
route, and date should also be included on the CRF.
All concomitant medications received during the trial through 30 days after the last dose of 
trial treatment should be recorded. Concomitant medications administered after 90 days after 
the last dose of trial treatment should be recorded for SAEs and ECIs as defined in Section 
7.2.
 
 
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Prohibited Concomitant Medication
Subjects are prohibited from receiving the following therapies during Screening to the end of 
Treatment (including retreatment for post-CR relapse) of this trial:

Antineoplastic systemic chemotherapy or biological therapy not specified in the 
protocol

Immunotherapy not specified in this protocol

Investigational agents other than pembrolizumab

Radiation therapy; palliative radiation therapy to a symptomatic lesion (eg bony 
metastasis), or to the brain may be permitted after consultation with the Sponsor.

Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial. Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, and 
typhoid (oral) vaccine. The killed virus vaccines used for seasonal influenza vaccines 
for injection are allowed; however live attenuated intranasal influenza vaccines (eg
Flu - Mist®) are not allowed.

Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
AE of suspected immunologic aetiology or cisplatin supportive care. The use of 
physiologic doses of corticosteroids may be approved after consultation with the 
Sponsor (eg, for control of acute asthma symptoms).

For subjects randomized to 5-FU or capecitabine:
o
Brivudine, Sorivudine analogues, and other inhibitors of the enzyme 
dihydropyrimidine dehydrogenase (DPD)

For subjects randomized to cisplatin:
o
Phenytoin should not be started with cisplatin therapy.
Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from treatment.
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.
o
Subjects who are taking Phenytoin in conjunction with 5-Fluorouracil should 
be examined regularly due to a potential elevation in Phenytoin plasma levels. 
 
 
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Hepatotoxic effects (rise in alkaline phosphatase, transaminase or bilirubin 
levels) are commonly observed under the treatment with 5-Fluorouracil and 
Levamisole.
The Exclusion Criteria describes other medications which are prohibited during the treatment 
phase of this trial.
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 aetiology are outlined below and in greater detail in Section 5.2.1.2.1 
Table 5 . 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. Suggested conditional procedures, as 
appropriate, can be found in Section 5.2.1.2.1..

Pneumonitis: 
o
For Grade 2 events, treat with systemic corticosteroids. When symptoms 
improve to Grade 1 or less, steroid taper should be started and continued over 
no less than 4 weeks. For recurrent Grade 2 pneumonitis, please refer to
Table 5 for guidance.
o
For Grade 3-4 events, immediately treat with intravenous steroids.
Administer additional anti-inflammatory measures, as needed.
o
Add prophylactic antibiotics for opportunistic infections in the case of 
prolonged steroid administration.

Diarrhea/Colitis: 
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such 
as diarrhoea, abdominal pain, blood or mucus in stool, with or without fever) and of 
bowel perforation (such as peritoneal signs and ileus).
 
 
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o
All subjects who experience diarrhoea/colitis should be advised to drink 
liberal quantities of clear fluids. If sufficient oral fluid intake is not feasible, 
fluid and electrolytes should be substituted via IV infusion. For Grade 2 or 
higher diarrhoea, consider GI consultation and endoscopy to confirm or rule 
out colitis.
o
For Grade 2 diarrhoea/colitis that persists greater than 3 days, administer 
oral corticosteroids. 
o
For Grade 3 or 4 diarrhoea/colitis that persists > 1 week, treat with 
intravenous steroids followed by high dose oral steroids.
o
When symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks.

Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or 
≥ Grade 3 Hyperglycaemia, if associated with ketosis (ketonuria) or metabolic 
acidosis (DKA)
o
For T1DM or Grade 3-4 Hyperglycaemia

Insulin replacement therapy is recommended for Type I diabetes 
mellitus and for Grade 3-4 hyperglycaemia associated with metabolic 
acidosis or ketonuria. 

Evaluate subjects with serum glucose and a metabolic panel, urine 
ketones, glycosylated haemoglobin, and C-peptide. 

Hypophysitis:
o
For Grade 2 events, treat with corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 
4 weeks. Replacement of appropriate hormones may be required as the steroid 
dose is tapered.
o
For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed 
by oral corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. Replacement 
of appropriate hormones may be required as the steroid dose is tapered.

Hyperthyroidism or Hypothyroidism: 
Thyroid disorders can occur at any time during treatment. Monitor subjects for 
changes in thyroid function (at the start of treatment, periodically during treatment, 
and as indicated based on clinical evaluation) and for clinical signs and symptoms of 
thyroid disorders.
 
 
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o
Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism):

In hyperthyroidism, non-selective beta-blockers (eg propranolol) are 
suggested as initial therapy.

In hypothyroidism, thyroid hormone replacement therapy, with 
levothyroxine or liothyronine, is indicated per standard of care.
o
Grade 3-4 hyperthyroidism 

Treat with an initial dose of IV corticosteroid followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid 
dose is tapered.

Hepatic:
o
For Grade 2 events, monitor liver function tests more frequently until 
returned to baseline values (consider weekly).

Treat with IV or oral corticosteroids
o
For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 
hours. 
o
When symptoms improve to Grade 1 or less, a steroid taper should be started 
and continued over no less than 4 weeks.

Renal Failure or Nephritis:
o
For Grade 2 events, treat with corticosteroids.
o
For Grade 3-4 events, treat with systemic corticosteroids.
o
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
Management of Infusion Reactions: Signs and symptoms usually develop during or shortly 
after drug infusion and generally resolve completely within 24 hours of completion of 
infusion. Table 9 below shows treatment guidelines for subjects who experience an infusion 
reaction associated with administration of pembrolizumab (MK-3475).
 
 
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Table 9
Infusion Reaction Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at subsequent 
dosing
Grade 1
Mild 
reaction; 
infusion 
interruption 
not 
indicated; 
intervention not indicated
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator.
None
Grade 2
Requires infusion interruption but 
responds 
promptly 
to 
symptomatic 
treatment 
(eg, 
antihistamines, 
NSAIDS, 
narcotics, IV fluids); prophylactic 
medications indicated for ≤24 hrs.
Stop Infusion and monitor symptoms.
Additional appropriate medical therapy 
may include but is not limited to:
IV fluids
Antihistamines
NSAIDS
Acetaminophen
Narcotics
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator.
If symptoms resolve within one hour of 
stopping drug infusion, the infusion may be 
restarted at 50% of the original infusion rate 
(eg, from 100 mL/hr to 50 mL/hr).  
Otherwise dosing will be held until 
symptoms resolve and the subject should be 
premedicated for the next scheduled dose.
Subjects who develop Grade 2 toxicity 
despite adequate premedication should 
be 
permanently 
discontinued 
from 
further 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).
Grades 3 or 4
Grade 3:
Prolonged 
(ie, 
not 
rapidly 
responsive 
to 
symptomatic 
medication 
and/or 
brief 
interruption 
of 
infusion); 
recurrence of symptoms following 
initial 
improvement; 
hospitalization indicated for other 
clinical 
sequelae 
(eg, 
renal 
impairment, pulmonary infiltrates)
Grade 4:
Life-threatening; 
pressor 
or 
ventilator support indicated
Stop Infusion.
Additional appropriate medical therapy may 
include but is not limited to:
IV fluids
Antihistamines
NSAIDS
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Epinephrine
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator.
Hospitalization may be indicated.
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 drug administration.
 
 
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Supportive Care Guidelines for Cisplatin
Prevention and/or treatment of nausea and vomiting should be managed with:
1. IV EMEND (fosaprepitant) 150 mg IV or oral EMEND (aprepitant) 3-day pack 125 
mg day 1, 80 mg day 2, 80 mg day 3
2. Plus Aloxi (Palonosetron) 0.25 mg IV
Nausea may also be managed with:
1. Zofran (Ondansetron) 8 mg twice a day
2. Or Compazine (Prochlorperazine) 10 mg 3-4 times per day
Additionally, use of steroids for cisplatin associated anti-emetic support is allowed and is to 
follow the NCCN or institutional guidelines. 
Please refer to the product label or local standards of care for additional cisplatin supportive 
measures.
Supportive Care Guidelines for 5-Fluorouracil
Please refer to the product label or local standards of care for fluorouracil supportive 
measures.
Supportive Care Guidelines for Capecitabine
Please refer to the product label or local standards of care for capecitabine supportive 
measures.
Diet/Activity/Other Considerations
Diet
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhoea, nausea or vomiting.
Contraception
Pembrolizumab may have adverse effects on a foetus in utero.  Furthermore, it is not known 
if pembrolizumab has transient adverse effects on the composition of sperm.  
For this trial, male subjects will be considered to be of non-reproductive potential if they 
have azoospermia (whether due to having had a vasectomy or due to an underlying medical 
condition).
 
 
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Female subjects will be considered of non-reproductive potential if they meet 1 of the 
following criteria: 

She is postmenopausal defined as at least 12 months with no menses without an 
alternative medical cause. In women < 45 years of age who are not using hormonal 
contraception or hormonal replacement therapy, a high follicle stimulating hormone 
(FSH) level in the postmenopausal range may be used to confirm a post-menopausal 
state. In the absence of 12 months of amenorrhea, a single FSH measurement is 
insufficient.

She had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or 
bilateral tubal ligation/occlusion, at least 6 weeks prior to screening; 

She has a congenital or an acquired condition that prevents childbearing.

Female and male subjects of reproductive potential must agree to avoid becoming 
pregnant or impregnating a partner, respectively, while receiving trial drug and for 
120 days after the last dose of trial drug by complying with 1 of the following:

Practice abstinence† from heterosexual activity.
†Abstinence (relative to heterosexual activity) can be used as the sole method of 
contraception if it is consistently employed as the subject’s preferred and usual lifestyle and 
if considered acceptable by local regulatory agencies and European Research Councils 
(ERCs)/Institutional Review Boards (IRBs). Periodic abstinence (eg, calendar, ovulation, 
symptothermal, post-ovulation methods, etc.) and withdrawal are not acceptable methods of 
contraception. 

Use (or have their partner use) acceptable contraception during heterosexual activity.  
Acceptable methods of contraception area:
o
Single method (1 of the following is acceptable):
o
Intrauterine device (IUD)
o
Vasectomy of a female subject’s male partner
o
Contraceptive rod implanted into the skin

Combination method (requires use of 2 of the following):
o
Diaphragm with spermicide (cannot be used in conjunction with cervical
cap/spermicide)
o
Cervical cap with spermicide (nulliparous women only)
 
 
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o
Contraceptive sponge (nulliparous women only)
o
Male condom or female condom (cannot be used together)
o
Hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or 
progestin-only pill), contraceptive skin patch, vaginal contraceptive ring, or 
subcutaneous contraceptive injection
a If a contraceptive method listed above is restricted by local regulations/guidelines, then it 
does not qualify as an acceptable method of contraception for subjects participating at sites in 
this country/region.
Subjects should be informed that taking the trial medication may involve unknown risks to 
the foetus (unborn baby) if pregnancy were to occur during the trial. In order to participate in 
the trial subjects of childbearing potential must adhere to the contraception requirement 
(described above) from the day of study medication initiation (or 14 days prior to the 
initiation of trial medication for oral contraception) throughout the study period up to 120 
days after the last dose of trial medication. If there is any question that a subject of 
childbearing potential will not reliably comply with the requirements for contraception, that 
subject should not be entered into the trial.
Use in Pregnancy
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab the 
subject will be immediately discontinued from trial treatment. The site will contact the 
subject at least monthly and document the subject’s status until the pregnancy has been 
completed or terminated. The outcome of the pregnancy will be reported to the Sponsor
without delay and within 24 hours if the outcome is a serious adverse experience (eg, death, 
abortion, congenital anomaly, or other disabling or life-threatening complication to the 
mother or newborn). The study investigator will make every effort to obtain permission to 
follow the outcome of the pregnancy and report the condition of the foetus or newborn to the 
Sponsor. If a male subject impregnates his female partner, the trial personnel at the site must 
be informed immediately and the pregnancy must be reported to the Sponsor and followed as 
described in Section 7.2.
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 
enrolment. Specific additional information follows for individual agents used in this trial.
5.7.4.1
Pembrolizumab
It is unknown whether pembrolizumab is excreted in human milk.
 
 
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5.7.4.2
Cisplatin
Cisplatin has been reported to be found in human milk; subjects receiving Cisplatin injection 
should not breast-feed.
5.7.4.3
5-Fluorouracil
It is not known whether fluorouracil is excreted in human milk. Because fluorouracil inhibits 
DNA, RNA and protein synthesis, mothers should not nurse while receiving this drug.
5.7.4.4
Capecitabine
Lactating mice given a single oral dose of capecitabine excreted significant amounts of 
capecitabine metabolites into the milk. It is not known whether this drug is excreted in 
human milk. Subjects receiving capecitabine should not breast-feed.
Subject Withdrawal/Discontinuation Criteria
Discontinuation of Treatment
Discontinuation of treatment does not represent withdrawal from the trial.
As certain data on clinical events beyond treatment discontinuation may be important to the 
study, they must be collected through the subject’s last scheduled follow-up, even if the 
subject has discontinued treatment.  Therefore, all subjects who discontinue trial treatment
prior to completion of the trial will still continue to participate in the trial as specified in 
Section 6.0 - Trial Flow Chart and Section 7.1.5.3 – Post-Treatment Visits.
Subjects may discontinue treatment at any time for any reason or be dropped from treatment
at the discretion of the investigator should any untoward effect occur.  In addition, a subject 
may be discontinued from treatment by the investigator or the Sponsor if treatment is 
inappropriate, the trial plan is violated, or for administrative and/or other safety reasons.  
Specific details regarding procedures to be performed at treatment discontinuation are 
provided in Section 7.1.4 – Other Procedures.
A subject must be discontinued from treatment but continue to be monitored in the trial for 
any of the following reasons:
○
The subject or subject’s legally acceptable representative requests to discontinue 
treatment.
o
Confirmed radiographic disease progression outlined in Section 7.1.5 (exception if 
the Sponsor approves treatment continuation).
o
Unacceptable adverse experiences as described in Section 7.2.
 
 
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o
Any progression or recurrence of any malignancy, or any occurrence of another 
malignancy that requires active treatment
o
Intercurrent illness other than another malignancy as noted above that prevents 
further administration of treatment
o
Recurrent Grade 2 pneumonitis
o
A confirmed positive serum pregnancy test
o
Noncompliance with trial treatment or procedure requirements
o
Investigator’s decision to withdraw the subject.
o
Completed 35 administrations (approximately 2 years) of treatment.
Note: 35 administrations of study medication are calculated from the date of first dose. 
Subjects who stop study medication after 35 administrations may be eligible for up to 17
additional study treatments if they progress after stopping study treatment provided they 
meet the requirements detailed in Section 7.1.2.6.4.

Discontinuation of treatment may be considered for subjects who have attained a
confirmed complete response (CR) and have been treated for at least 8 cycles (at 
least 24 weeks), receiving 2 cycles of the combination including 2 doses of 
pembrolizumab and at least 80% of the planned doses of cisplatin, 5-Fluotouracil 
or capecitabine] beyond the date when the initial CR was declared. 
Subjects who stop [pembrolizumab or the combination] with stable disease (SD), 
partial response (PR), or CR, may be eligible for up to 1 year (17 cycles) of 
[pembrolizumab or additional combination therapy] if they experience disease 
progression after stopping [pembrolizumab or combination trial treatment]. This 
retreatment is termed the Second Course Phase (Retreatment) and is described in 
detail in Section 5.2.2. 
o
Administrative reasons
The End of Treatment and Follow-up visit procedures are listed in Section 6.0 (Protocol 
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 (SAEs and ECIs will be collected for 90 days 
after the end of treatment or 30 days after the end of treatment if the subject initiates new 
anticancer therapy, whichever occurs first, as described in Section 7.2.3.1). Subjects who 
discontinue for reasons other than PD will have post-treatment follow-up for disease status 
until 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 OS until death, withdrawal of consent, or the end of the study, 
whichever occurs first.
 
 
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For subjects who are discontinued from treatment but continue to be monitored in the trial, 
all visits and procedures, as outlined in the trial flowchart, should be completed.
Withdrawal from the Trial
A subject must be withdrawn from the trial if the subject or subject’s legally acceptable 
representative withdraws consent from the trial.
If a subject withdraws from the trial, they will no longer receive treatment or be followed at 
scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the trial 
including the procedures to be performed should a subject repeatedly fail to return for 
scheduled visits and/or if the study site is unable to contact the subject, as well as specific 
details regarding withdrawal from Future Biomedical Research are outlined in Section 7.1.4 
– Other Procedures.
Subject Replacement Strategy
A subject who discontinues from the trial will not be replaced.
Beginning and End of the Trial
The overall trial begins when the first subject signs the informed consent form.  The overall 
trial ends when the last subject completes the last study-related phone-call or visit,
discontinues from the trial or is lost to follow-up (i.e. the subject is unable to be contacted by 
the investigator).
Clinical Criteria for Early Trial Termination
The clinical trial may be terminated early if the extent (incidence and/or severity) of 
emerging effects/clinical endpoints is such that the risk/benefit ratio to the trial population as 
a whole is unacceptable. In addition, further recruitment in the trial or at (a) particular trial 
site(s) may be stopped due to insufficient compliance with the protocol, Good Clinical 
Practice (GCP) and/or other applicable regulatory requirements, procedure-related problems 
or the number of discontinuations for administrative reasons is too high.
     
 
 
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6.0 TRIAL FLOW CHART
Initial Treatment Phase
Treatment Arm 1:  Pembrolizumab Monotherapy
Trial Period:
Screening Phase
Treatment Cyclesa
End of 
Treatment
Post-Treatment
Treatment Cycle
Tumour Tissue 
collection/submission
Screening
1
2
3
4
5
Cycle 6 
and  
beyond
Last Dose
Safety Follow-
up
Follow Up 
Visitsb
Survival 
Follow-
upc
At time of 
treatment 
discon
30 days
post 
discontinuation
Every 6 weeks
post 
discontinuation
Every 12 
weeks
Scheduling Window (Days)d:
-28 to -1
-21 to -1
± 
3
± 
3
± 
3
± 
3
± 3
± 3
± 7
± 7
± 7
Administrative Procedures
Informed Consente
X
Informed 
Consent 
for 
Future 
Biomedical Researchf
X
Inclusion/Exclusion Criteria
X
Subject Identification Card
X
Demographics and Medical History
X
Prior 
and 
Concomitant 
Medication 
Reviewg
X
X
X X X
X
X
X
X
Clinical Procedures/Assessments
Review Adverse Eventsh
X
X
X
X X X
X
X
X
X
X
ePROs (HRQoL Measures)i
X
X X X Xi
X
X
12-Lead ECG (Local)
X
Full Physical Examination
X
X
Directed Physical Examination
X
X X X
X
X
Vital Signs and Weightj
X
X
X X X
X
X
X
ECOG Performance Statusn
X
X
X X X
X
X
X
Post-study Anticancer Therapy Status
X
X
Survival Statusc
X
Trial Treatment Administration
Pembrolizumabk
X
X X X
X
X
Laboratory Procedures/Assessments:  
Analysis 
performed 
by 
LOCAL 
 
 
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Trial Period:
Screening Phase
Treatment Cyclesa
End of 
Treatment
Post-Treatment
Treatment Cycle
Tumour Tissue 
collection/submission
Screening
1
2
3
4
5
Cycle 6 
and  
beyond
Last Dose
Safety Follow-
up
Follow Up 
Visitsb
Survival 
Follow-
upc
At time of 
treatment 
discon
30 days
post 
discontinuation
Every 6 weeks
post 
discontinuation
Every 12 
weeks
Scheduling Window (Days)d:
-28 to -1
-21 to -1
± 
3
± 
3
± 
3
± 
3
± 3
± 3
± 7
± 7
± 7
laboratory
Pregnancy Test – Serum or Urinel
X
X
X X X
X
X
X
PT/INR and aPTTm
X
CBC with Differentialn
X
X X X
X
X
X
X
Chemistry Paneln
X
X X X
X
X
X
X
Urinalysisn
X
T3(or Free T3), FT4 and TSHn
X
X
X
X
X
Serum 
carcinoembryonic 
antigen 
(CEA)o
X
X
X
Xo
Serum CA19-9o
X
X
X
Xo
Laboratory Procedures/Assessments:
Analysis performed by CENTRAL 
laboratory
Blood for Geneticsp
X
Correlative Blood Samples (DNA)q
X
X X
X
Correlative Blood Samples (RNA)q
X
X X
X
Correlative Blood Samples (plasma)q
X
Correlative Blood Samples (serum)q
X
Efficacy Measurements
Tumour Imagingr
X
X
X
X
Xs
Xs
Tumour Tissue Collection
Archival and/or Newly Obtained Tissue 
Collectiont
X
X
 
 
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a.
Unless otherwise specified, assessments/procedures are to be performed on Day 1 and prior to the first dose of treatment for each cycle unless otherwise specified.
b.
In subjects who discontinue study therapy without documented disease progression, every effort should be made to continue monitoring their disease status by 
radiologic imaging every 6 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.
After documented local site assessed disease progression or the start of new anticancer treatment; contacts are approximately every 12 weeks by telephone. Updated
survival status may be requested by the Sponsor at any time during the course of the study.  Upon Sponsor notification all subjects who do not /will not have a 
scheduled study visit or study contact during the Sponsor defined time period will be contacted for their survival status (excluding subjects that have a death event 
previously recorded).
d.
Unless otherwise specified, the window for each visit is ± 3 days.  Cycle 1 treatment should be given within 3 days of randomization.
e.
Written consent must be obtained prior to performing any protocol specified procedure.  Results of a test performed prior to the subject signing consent as part of 
routine clinical management are acceptable in lieu of a screening test if performed within the specified time frame (eg, within 21 days prior to the first dose of trial 
treatment).  Screening number will be assigned when the study informed consent is signed.
f.
Signing the informed consent for future biomedical research (FBR) sample is optional.  Detailed instructions for the collection and management of specimens for FBR 
are provided in the Procedures Manual and Section 12.2 of this protocol.
g.
Prior medications – Record all medications taken within 30 days of first dose. Concomitant medications – Enter new medications started during the trial through the 
Safety Follow-up visit.  Record all medications taken for SAEs as defined in Section 7.2.  
h.
Record all AEs occurring within 30 days after the last dose of trial treatment.  Report all SAEs (related and unrelated to trial treatment) and ECIs occurring up until 90 
days after the last dose of trial treatment or 30 days after the end of treatment if the subject initiates new anticancer therapy, whichever occurs first.  Afterwards, report 
only SAEs and ECIs that are related to trial treatment.
i.
It is strongly recommended that electronic Patient Reported Outcomes (ePROs) are administered prior to drug administration, adverse event evaluation and disease 
status notification starting with the EQ5D-3L, followed by EORTC QLQ-C30, and EORTC QLQ-ST022; an exception to this recommendation may occur at the 
treatment discontinuation visit where subjects may have already been notified of their disease status or an AE evaluation is known prior to them arriving to the clinic. 
All ePROs are to be performed at Cycle 1, Cycle 2, Cycle 3, Cycle 4, Cycle 5 and every 2 cycles thereafter (eg, Cycle 7, Cycle 9) up to a year or End of Treatment, 
whichever comes first, and the 30-day post-treatment discontinuation follow-up visit. If the subject does not complete the ePROs the MISS_MODE form must be 
completed to capture the reason the assessment was not performed.  
j.
Vital signs to include temperature, pulse, respiratory rate, weight and blood pressure.  Height will be measured at Visit 1 only.
k.
Pembrolizumab should be administered on Day 1 of each 3-week cycle after all procedures/assessments have been completed. Pembrolizumab 200 mg fixed dose
should be administered as a 30-minute IV infusion Q3W. Sites should make every effort to target infusion timing to be as close to 30 minutes as possible. However, 
given the variability of infusion pumps from site to site, a window of -5 minutes and +10 minutes is permitted (ie, infusion time is 30 minutes: -5 min/+10 min). Study
treatment is discontinued after completion of 35 administrations (approximately 2 years).
l.
For women of reproductive potential, a serum pregnancy test should be performed within 72 hours prior to each cycle of trial treatment and 30 days post treatment. A 
urine test can be considered if serum is not appropriate.  Pregnancy tests (serum and/or urine tests) should be repeated if required by local guidelines.
m.
Coagulation factors (PT/INR and aPTT) should be tested as part of the screening procedures for all subjects.  And to be performed within 10 days of the first dose of 
trial treatment.
n.
ECOG PS for screening is to be performed within 3 days prior to the first dose of trial treatment.  Laboratory tests for screening are to be performed within 10 days prior 
to the first dose of trial treatment.  See Section 7.1.3 for details regarding laboratory tests.   After Cycle 1, lab samples can be collected up to 72 hours prior to the 
scheduled time point.  CBC with Differential, Chemistry panel, are to be repeated every 2 cycles after Cycle 6 (eg, Cycle 8-Day 1, Cycle 10-Day 1).  Thyroid function 
tests should be collected every 6 weeks (every 2 cycles, eg, Cycles, 8, 10, 12, etc). Unresolved abnormal labs that are drug related AEs should be followed until 
resolution.  Labs do not need to be repeated after the end of treatment if labs are within normal range.  
o.
Serum CEA and CA19-9 tests for screening are to be performed within 10 days prior to the first dose of trial treatment.  See Section 7.1.3 for details regarding 
laboratory tests.   After Cycle 1, lab samples can be collected up to 72 hours prior to the scheduled time point.  Serum CEA and CA19-9 should be collected at screening 
(baseline), Cycle 3 and every 6 weeks (conducted at corresponding study visits; Cycle 5, Cycle 7, etc.) until study treatment discontinuation.
 
 
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p.
This sample should be drawn for planned genetic analysis of DNA and drug response unless there is either a documented law or regulation prohibiting collection, or 
unless the IRB/IEC does not approve of the collection of the sample for these purposes. If the sample is collected, any leftover extracted DNA will be stored for future 
biomedical research if the subject signs the FBR consent.  Detailed instructions for the collection and management of specimens are provided in the Procedures Manual 
and Section 12.2.
q.
Whole blood sample for correlative studies should be collected at Cycle 1, Day 1- Pre-dose, Cycle 2 Day 1- Pre-dose, Cycle 3 Day 1 Pre-dose and again at treatment 
discontinuation.   Blood for serum and blood for plasma to be collected only prior to the first dose of trial treatment. See Procedures Manual.
r.
Baseline tumour imaging will be performed within 21 days prior to randomization.  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 the allotted screening window for each cohort.  The exact same image acquisition and processing 
parameters should be used throughout the study. The first on-study imaging time point will be performed 6 weeks (± 7 days) after the subject has been randomized, or 
earlier if clinically indicated and will continue to be performed every 6 weeks (± 7 days) until PD.  Imaging timing should follow calendar days.  All on-study scans
(scheduled and unscheduled) should be submitted to the central imaging vendor.
s.
In subjects who discontinue study therapy without centrally verified disease progression, a radiologic evaluation should be performed at the time of treatment 
discontinuation (ie, date of discontinuation ± 4-week window).  If a previous scan was obtained within 4 weeks prior to the date of discontinuation, then a scan at 
treatment discontinuation is not required.  These subjects should be assessed every 6 weeks (42 ± 7 days) by radiologic imaging to monitor disease status until the start 
of new anti-cancer therapy, disease progression determined by the central imaging vendor, death, or end of study.  
t.
Baseline tumour tissue for biomarker analysis from newly obtained core or excisional biopsy (FNA not adequate) and archival tissue sample (where available) should be 
tested for PD-L1.  Only PD-L1 positive subjects will be eligible for this trial.  Tumour submission can occur up to 28 days prior to randomization. Consent must be 
obtained prior to tumour tissue submission/collection. Detailed instructions for tissue collection, process and shipment are provided in the Procedures 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. An optional newly-obtained core or excisional biopsy (FNA not adequate) can be collected at Discontinuation for PD.  This biopsy is requested but not required.  
Endoscopic biopsies are permitted.
 
 
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Treatment Arm 2 and 3: Pembrolizumab + Chemotherapy and Placebo + Chemotherapy
Trial Period:
Screening Phase
Treatment Cyclesa
End of 
Treatment
Post-Treatment
Treatment Cycle
Tumour Tissue 
collection/submission
Screening
1
2
3
4
5
Cycle 
6 and  
beyond
Last Dose
Safety Follow-
up
Follow Up 
Visitsb
Survival 
Follow-
upc
At time of 
treatment 
discon
30 days
post
discontinuation
Every 6 weeks
post 
discontinuation
Every 
12 
weeks
Scheduling Window (Days)d:
-28 to -1
-21 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 7
± 7
± 7
Administrative Procedures
Informed Consente
X
Informed 
Consent 
for 
Future 
Biomedical Researchf
X
Inclusion/Exclusion Criteria
X
Subject Identification Card
X
Demographics and Medical History
X
Prior and Concomitant Medication 
Reviewg
X
X
X
X
X
X
X
X
X
Clinical Procedures/Assessments
Review Adverse Eventsh
X
X
X
X
X
X
X
X
X
X
X
ePROs (HRQoL Measures)i
X
X
X
X
Xi
X
X
12-Lead ECG (Local)
X
Full Physical Examinationw
X
X
Directed Physical Examinationw
X
X
X
X
X
X
Vital Signs and Weightj
X
X
X
X
X
X
X
X
ECOG Performance Statusp
X
X
X
X
X
X
X
X
Post-study Anticancer Therapy Status
X
X
Survival Statusx
X
Trial Treatment Administration
Pembrolizumab/Placebok 
X
X
X
X
X
X
Cisplatinl
X
X
X
X
X
X
5-FU or Capecitabinem
X
X
X
X
X
X
Laboratory 
Procedures/Assessments:  Analysis 
performed by LOCAL Laboratory
Pregnancy Test – Serum or Urinen
X
X
X
X
X
X
X
PT/INR and aPTTo
X
CBC with Differentialp
X
X
X
X
X
X
X
X
 
 
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Trial Period:
Screening Phase
Treatment Cyclesa
End of 
Treatment
Post-Treatment
Treatment Cycle
Tumour Tissue 
collection/submission
Screening
1
2
3
4
5
Cycle 
6 and  
beyond
Last Dose
Safety Follow-
up
Follow Up 
Visitsb
Survival 
Follow-
upc
At time of 
treatment 
discon
30 days
post
discontinuation
Every 6 weeks
post 
discontinuation
Every 
12 
weeks
Scheduling Window (Days)d:
-28 to -1
-21 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 7
± 7
± 7
Chemistry Panelp
X
X
X
X
X
X
X
X
Urinalysisp
X
T3 (or Free T3), FT4 and TSHp
X
X
X
X
X
Serum 
carcinoembryonic 
antigen 
(CEA)q
X
X
X
Xq
Serum CA19-9q
X
X
X
Xq
Laboratory 
Procedures/Assessments:
Analysis 
performed 
by 
CENTRAL 
laboratory
Blood for Geneticsr
X
Correlative Blood Samples (DNA)s
X
X
X
X
Correlative Blood Samples (RNA) s
X
X
X
X
Correlative Blood Samples (plasma)s
X
Correlative Blood Samples (serum)s
X
Efficacy Measurements
Tumour Imagingt
X
X
X
Xt
Xu
Xu
Tumour Tissue Collection
Archival or Newly Obtained Tissue 
Collectionv
X
X
 
 
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a.
Unless otherwise specified, assessments/procedures are to be performed on Day 1 and prior to the first dose of treatment for each cycle unless otherwise specified.
b.
In subjects who discontinue study therapy without documented disease progression, every effort should be made to continue monitoring their disease status by 
radiologic imaging every 6 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.
After the start of new anti-cancer treatment or documented disease progression by the central imaging vendor, the subject should be contacted by telephone every 12 
weeks to assess for survival status. Note: Every effort should be made to ensure telephone contact at least 90 days post discontinuation to capture SAEs/ECIs The 
Sponsor may request survival status be assessed at additional time points during the course of the study. For example, these additional time points may be requested 
prior to; an eDMC safety review, efficacy interim analysis, and/or final analysis. All subjects who are not known to have died prior to the request for these additional 
survival status time points will be contacted at that time.
d.
Unless otherwise specified, the window for each visit is ± 3 days. Cycle 1 treatment must be given within 3 days of randomization.
e.
Written consent must be obtained prior to performing any protocol specified procedure. Results of a test performed prior to the subject signing consent as part of 
routine clinical management are acceptable in lieu of a screening test if performed within the specified time frame (eg, within 21 days prior to the first dose of trial 
treatment). Screening number will be assigned when the study informed consent is signed.
f.
Signing the informed consent for future biomedical research (FBR) sample is optional. Detailed instructions for the collection and management of specimens for FBR 
are provided in the Procedures Manual and Section 12.2.
g.
Prior medications – Record all medications taken within 30 days of first dose. Concomitant medications – Enter new medications started during the trial through the 
Safety Follow-up visit. Record all medications taken for SAEs as defined in Section 7.2.
h.
Record all AEs occurring within 30 days after the last dose of trial treatment. Report all SAEs (related and unrelated to trial treatment) and ECIs occurring up until 90 
days after the last dose of trial treatment or 30 days after the end of treatment if the subject initiates new anticancer therapy, whichever occurs first. Afterwards, report 
only SAEs and ECIs that are related to trial treatment.
i.
It is strongly recommended that electronic patient reported outcomes (ePROs) are administered prior to drug administration, adverse event evaluation and disease 
status notification starting with the EQ5D-3L, followed by EORTC QLQ-C30, and EORTC QLQ-ST022; an exception to this recommendation may occur at the 
treatment discontinuation visit where subjects may have already been notified of their disease status or an AE evaluation is known prior to them arriving to the clinic.
All ePROs All ePROs are to be performed at Cycle 1, Cycle 2, Cycle 3, Cycle 4, Cycle 5 and every 2 cycles thereafter (eg, Cycle 7, Cycle 9) up to a year or End of 
Treatment, whichever comes first, and the 30-day post-treatment discontinuation follow-up visit. If the subject does not complete the ePROs the MISS_MODE form 
must be completed to capture the reason the assessment was not performed.
j.
Vital signs to include temperature, pulse, respiratory rate, weight and blood pressure. Height will be measured at Visit 1 only.
k.
Pembrolizumab should be administered on Day 1 of each 3-week cycle after all procedures/assessments have been completed. Pembrolizumab 200 mg or placebo 
should be administered as a 30-minute IV infusion Q3W. Sites should make every effort to target infusion timing to be as close to 30 minutes as possible. However, 
given the variability of infusion pumps from site to site, a window of -5 minutes and +10 minutes is permitted (ie, infusion time is 30 minutes: -5 min/+10 min). For 
subjects randomized to the pembrolizumab/placebo plus cisplatin +5-FU arm, the pembrolizumab/placebo infusion is administered first followed by the cisplatin 
infusion and then 5-FU infusion.
l.
Cisplatin 80 mg/m2 will be administered as a 60 or 120-minute IV infusion or per site’s standard practice Q3W on Day 1 of each treatment cycle.
m.
5-FU 800 mg/m2/day will be administered as a continuous IV infusion from Day 1 to Day 5 (120 hours) of each treatment cycle. Although use of 5-FU infusion is 
preferred, Capecitabine1000 mg/m2 bid Day 1 to Day 14 Q3W may be permitted according to local guideline at Investigator decision. Decision regarding the type of 
comparator used (5-FU or capecitabine) should be determined prior to randomization in the trial.
n.
For women of reproductive potential, a serum pregnancy test should be performed within 72 hours prior to each cycle of trial treatment and 30 days post treatment. A 
urine test can be considered if serum is not appropriate. Pregnancy tests (serum and/or urine tests) should be repeated if required by local guidelines.
o.
Coagulation factors (PT/INR and aPTT) should be tested as part of the screening procedures for all subjects. And to be performed within 10 days prior to the first dose 
of trial treatment.
p.
ECOG PS for screening is to be performed within 3 days prior to the first dose of trial treatment. Laboratory tests for screening are to be performed within 10 days 
prior to the first dose of trial treatment. See Section 7.1.3 for details regarding laboratory tests. After Cycle 1, lab samples can be collected up to 72 hours prior to the 
scheduled time point. CBC with Differential, Chemistry panel, are to be repeated every 2 cycles after Cycle 6 (eg, Cycle 8-Day 1, Cycle 10-Day 1). Thyroid function 
 
 
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tests should be collected every 6 weeks (every 2 cycles, eg, Cycles, 8, 10, 12, etc). Unresolved abnormal labs that are drug related AEs should be followed until 
resolution. Labs do not need to be repeated after the end of treatment if labs are within normal range.
q.
Serum CEA and CA 19-9 should be collected at screening (baseline), Cycle 3 and every 6 weeks (conducted at corresponding study visit; Cycle 5, Cycle 7, etc.) until 
study treatment discontinuation.
r.
This sample should be drawn for planned genetic analysis of DNA and drug response unless there is either a documented law or regulation prohibiting collection, or 
unless the IRB/IEC does not approve of the collection of the sample for these purposes. If the sample is collected, any leftover extracted DNA will be stored for future 
biomedical research if the subject signs the FBR consented. Detailed instructions for the collection and management of specimens are provided in the Procedures 
Manual and Section 12.2
s.
Whole blood sample for correlative studies should be collected at Cycle 1, Day 1- Pre-dose, Cycle 2 Day 1- Pre-dose, Cycle 3 Day 1 Pre-dose and again at treatment 
discontinuation. Blood for serum and blood for plasma to be collected only prior to the first dose of trial treatment. See Procedures Manual.
t.
Baseline tumour imaging will be performed within 21 days prior to randomization. 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 the allotted screening window for each cohort. The exact same image acquisition and 
processing parameters should be used throughout the study. The first on-study imaging time point will be performed 6 weeks (± 7 days) after the subject has been 
randomized, or earlier if clinically indicated and will continue to be performed every 6 weeks (± 7 days) until PD. Imaging timing should follow calendar days. On-
study scans (scheduled and unscheduled) should be submitted to the central imaging vendor.
u.
In subjects who discontinue study therapy without centrally verification of disease progression, a radiologic evaluation should be performed at the time of treatment 
discontinuation (ie, date of discontinuation ± 4-week window). If a previous scan was obtained within 4 weeks prior to the date of discontinuation, then a scan at 
treatment discontinuation is not required. These subjects should be assessed every 6 weeks (42 ± 7 days) by radiologic imaging to monitor disease status until the start
of new anti-cancer therapy, disease progression determined by the central imaging vendor, death, or end of study.
v.
Baseline tumour tissue for biomarker analysis from newly obtained core or excisional biopsy (FNA not adequate) and archival tissue sample (where available) should 
be tested for PD-L1. Only PD-L1 positive subjects will be eligible for this trial. Tumour submission can occur up to 28 days prior to randomization. Consent must be 
obtained prior to tumour tissue submission/collection. Detailed instructions for tissue collection, process and shipment are provided in the Procedures 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. An optional newly obtained core or excisional biopsy (FNA not adequate) can be collected at Discontinuation for PD. This biopsy is requested but not required.
Endoscopic biopsies are permitted
w.
Full physical exam and directed physical exam will include neurologic exam to be performed by the treating physician or designee. Audiometry testing will be 
performed at baseline, and is repeated during the study as clinically indicated per the treating physician or designee.
x.
After documented local site assessed disease progression, or the start of new anticancer treatment; contacts are approximately every 12 weeks by telephone. Updated
survival
status may be requested by the Sponsor at any time during the course of the study. Upon Sponsor notification, all subjects who do not/will not have a scheduled study visit or 
study contact during the Sponsor defined time period will be contacted for their survival status (excluding subjects that have a death event previously recorded).
 
 
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Second Course Phase (Retreatment with Pembrolizumab)
Trial Period:
Treatment Cyclesa
End of 
Treatment
Post-Treatment
Treatment Cycle:
1
2
3
4
5
Cycle 
6 and 
beyond
Last Dose
Safety Follow-
up
Follow Up 
Visitsb
Survival 
Follow-upc
At time of 
treatment discon
30 days post 
discontinuation
Every 6 weeks 
post 
discontinuation
Every 12 
weeks
Scheduling Window (Days)d:
-3
± 3
± 3
± 3
± 3
± 3
± 3
± 7
± 7
± 7
Administrative Procedures
Eligibility Criteriae
X
Concomitant Medication Reviewf
X
X
X
X
X
X
X
X
Clinical Procedures/Assessments
Review Adverse Eventsg
X
X
X
X
X
X
X
X
X
Full Physical Examination
X
X
Directed Physical Examination
X
X
X
X
X
Vital Signs and Weighth
X
X
X
X
X
X
X
X
ECOG Performance Statusk
X
X
X
X
X
X
X
Pembrolizumab Administration
X
X
X
X
X
X
Post-study Anticancer Therapy Status
X
X
Survival Statusn
X
Laboratory 
Procedures/Assessments:  
Analysis performed by LOCAL laboratory
Pregnancy Test – Urine or Serumi
X
X
X
X
X
X
X
PT/INR and aPTTj
X
CBC with Differentialk
X
X
X
X
X
Xk
X
X
Chemistry Panelk
X
X
X
X
X
Xk
X
X
Urinalysisk
X
T3(or Free T3), FT4 and TSHk
X
X
X
X
Efficacy Measurements
Tumour Imagingl
X
X
X
X
Xm
Xm
a.
In general, assessments/procedures are to be performed on Day 1 and prior to the first dose of treatment for each cycle unless otherwise specified.  Treatment cycles are 3 
weeks.
b. In subjects who discontinue study therapy without documented disease progression, every effort should be made to continue monitoring their disease status by radiologic 
imaging every 6 weeks (42 ± 7 days) up to week 30 or every 9 weeks (± 7 days) if after Week 30, 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.
After the start of new anti-cancer treatment or documented disease progression by the central imaging vendor, the subject should be contacted by telephone every 12 
 
 
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weeks to assess for survival status. The Sponsor may request survival status be assessed at additional time points during the course of the study.  For example, these 
additional time points may be requested prior to; an eDMC safety review, efficacy interim analysis, and/or final analysis.  All subjects who are not known to have died 
prior to the request for these additional survival status time points will be contacted at that time.
d. In general, the window for each visit is ± 3 days unless otherwise noted.
e.
Subjects who either a) attain a CR and discontinue treatment or b) discontinue treatment after 35 administrations (approximately 2 years) on study treatment for reasons 
other than disease progression or intolerability may restart trial treatment if they meet the criteria specified in Section 7.1.5.2.1.  
f.
Concomitant medications – Enter new medications started during the trial through the Safety Follow-up visit.  Record all medications taken for SAEs as defined in 
Section 7.2.
g. Record all AEs occurring within 30 days after the last dose of trial treatment.  Report all SAEs (related and unrelated to trial treatment) and ECIs occurring up until 90 
days after the last dose of trial treatment or 30 days after the end of treatment if the subject initiates new anticancer therapy, whichever occurs first.  Afterwards, report 
only SAEs and ECIs that are related to trial treatment.
h. Vital signs to include temperature, pulse, respiratory rate, weight and blood pressure.
i.
For women of reproductive potential, a serum pregnancy test should be performed within 72 hours prior to each cycle of trial treatment and 30 days post treatment. A 
urine test can be considered if serum is not appropriate.  Pregnancy tests (serum and/or urine tests) should be repeated if required by local guidelines.
j.
Coagulation factors (PT/INR and aPTT) should be tested as part of the screening procedures for all subjects. And may be performed within 10 days prior to the first 
retreatment dose of pembrolizumab.
k. ECOG PS for screening is to be performed within 3 days prior to the first dose of trial treatment.  Laboratory tests for screening are to be performed within 10 days prior 
to the first dose of trial treatment.  See Section 7.1.3 for details regarding laboratory tests.   After Cycle 1, lab samples can be collected up to 72 hours prior to the 
scheduled time point.  See Section 7.1.3 for details regarding laboratory tests. To be repeated every 2 cycles after Cycle 5.  CBC with Differential, Chemistry panel, are to 
be repeated every 2 cycles after Cycle 6 (eg, Cycle 8-Day 1, Cycle 10-Day 1).  Thyroid function tests should be collected every 6 weeks (every 2 cycles, eg, Cycles, 7, 9, 
11, etc). 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. 
l.
A scan must be performed within 21 days prior to restarting treatment with pembrolizumab.  Imaging should continue to be performed every 6 weeks (42 ± 7 days) after 
the first dose of trial retreatment 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.  
m. In subjects who discontinue study therapy without confirmed disease progression, a radiologic evaluation should be performed at the time of treatment discontinuation (ie, 
date of discontinuation ± 4-week window).  If a previous scan was obtained within 4 weeks prior to the date of discontinuation, then a scan at treatment discontinuation 
isn’t mandatory
n. After documented local site assessed disease progression, or the start of new anticancer treatment; contacts are approximately every 12 weeks by telephone.
Updated survival status may be requested by the Sponsor at any time during the course of the study. Upon Sponsor notification, all subjects who do not/will not
have a scheduled study visit or study contact during the Sponsor defined time period will be contacted for their survival status (excluding subjects that have a death event 
previously recorded).
 
 
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7.0 TRIAL PROCEDURES
Trial Procedures
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to 
perform these procedures at unscheduled time points if deemed clinically necessary by the 
investigator.
Furthermore, additional evaluations/testing may be deemed necessary by the investigator and 
or the Sponsor for reasons related to subject safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations 
may require that additional informed consent be obtained from the subject.  In these cases, 
such evaluations/testing will be performed in accordance with those regulations.
Administrative Procedures
7.1.1.1
Informed Consent
The investigator or qualified designee must obtain documented consent from each potential 
subject or each subject’s legally acceptable representative prior to participating in a clinical 
trial or Future Biomedical Research.
7.1.1.1.1 General Informed Consent
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion. 
A copy of the signed and dated consent form should be given to the subject before 
participation in the trial.
The initial informed consent form, any subsequent revised written informed consent form 
and any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The subject or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the trial.  The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the subject’s dated signature or 
by the subject’s legally acceptable representative’s dated signature.
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.  
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements.
 
 
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7.1.1.1.2 Consent and Collection of Specimens for Future Biomedical Research
The investigator or qualified designee will explain the Future Biomedical Research consent 
to the subject, answer all of his/her questions, and obtain written informed consent before 
performing any procedure related to the Future Biomedical Research sub-trial.  A copy of the 
informed consent will be given to the subject.
7.1.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.
7.1.1.2.1 Submitting Tumour Sample
Per inclusion 7 in Section 5.1.2, tumour tissue sample for assessment of PD-L1 status must 
meet the following requirement: 
Either pre-existing archived or newly-obtained (fresh tissue) biopsy specimens from either 
primary or metastatic tumour of gastric origin, whichever most recent. 
o
Newly-obtained (fresh tissue) is defined as a specimen obtained up to 42 days prior to 
administration of study treatment on Day 1 of Cycle 1, and no additional anti-cancer 
treatment has been given after the specimen was obtained.
o
Pre-existing, archived tissue must be obtained prior to time point that any anti-cancer 
treatment was given. 
A fine needle aspirate (FNA) or cytologic specimen will not be acceptable. In the event the 
most recent available tumour tissue specimen is an FNA or cytologic specimen, a previous 
specimen obtained prior to any anti-cancer therapy was given may be submitted (provided it 
is not an FNA or cytologic specimen). 
Where available, both newly-obtained (fresh tissue) and pre-existing archived tissues are 
requested; however, the tissue specimen obtained closest to study treatment initiation on Day 
1 of Cycle 1 will be used to determine eligibility for study participation while the older tissue 
specimen will be used for subsequent analysis to compare performance of PD-L1 assessment 
in newly-obtained (fresh tissue) vs. archived tissue samples.
Tumour tissue specimen submitted in either formalin solution or FFPE block is acceptable. If 
submitting unstained cut slides from FFPE block, freshly cut slides should be received by the 
central laboratory within 14 days from when the slides are prepared. Please refer to the 
Procedures Manual for additional details.
7.1.1.3
Subject Identification Card
All subjects will be given a Subject Identification Card identifying them as participants in a 
research trial.  The card will contain trial site contact information (including direct telephone 
 
 
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numbers) to be utilized in the event of an emergency.  The investigator or qualified designee 
will provide the subject with a Subject Identification Card immediately after the subject 
provides written informed consent.
The subject identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about trial 
medication/vaccination in emergency situations where the investigator is not available.
7.1.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee.  The medical 
history will collect all active conditions and any condition diagnosed within the prior 10 
years that the investigator considers to be clinically significant.  Details regarding the disease 
for which the subject has enrolled in this trial will be recorded separately and not listed as 
medical history.
7.1.1.5
Disease Details
The investigator or qualified designee will obtain prior and current details regarding the 
subject’s gastric or GEJ adenocarcinoma.
7.1.1.6
Prior and Concomitant Medications Review
7.1.1.6.1 Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject 
within 28 days before starting the trial. Treatment for the disease for which the subject has 
enrolled in this trial will be recorded separately and not listed as a prior medication.
7.1.1.6.2 Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial from the time of signing the informed consent through the Safety Follow-up 
visit. In addition, new medications started during the Second Course Phase through the 
Second Course Safety Follow-up visit should be recorded.
All medications related to reportable SAEs and ECIs should be recorded as defined in 
Section 7.2.
7.1.1.7
Assignment of Screening Number
All consented subjects will be given a unique screening number that will be used to identify 
the subject for all procedures that occur prior to randomization or allocation.  Each subject 
will be assigned only one screening number.  Screening numbers must not be re-used for 
different subjects.
 
 
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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.  
7.1.1.8
Assignment of Randomization Number
All eligible subjects will be randomly allocated and will receive a randomization number.  
The randomization number identifies the subject for all procedures occurring after 
randomization.  Once a randomization number is assigned to a subject, it can never be re-
assigned to another subject.
A single subject cannot be assigned more than 1 randomization number.
Trial treatment should begin on the day of randomization or as close as possible to the date 
on which the subject is allocated/assigned.
7.1.1.9
Trial Compliance (Medication/Diet/Activity/Other)
Interruptions from the protocol specified treatment for greater than 12 weeks between 
pembrolizumab doses on the pembrolizumab treatment arms require consultation between the 
investigator and the Sponsor and written documentation of the collaborative decision on 
subject management.
Administration of trial medication will be witnessed by the investigator and/or trial staff
while the subject is in the treatment centre.
The total volume of pembrolizumab infused will be compared to the total volume prepared to 
determine compliance with each dose of pembrolizumab administered. The instructions for 
preparing and administering pembrolizumab are provided in the Pharmacy Manual.
For those medications taken at home, subjects will be provided a medication diary in which
they will record trial medication doses and will be instructed to bring this diary and trial
medication containers with them when they at the time of clinic visits.
Clinical Procedures/Assessments
7.1.2.1
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 trial and 
during the follow-up period according to NCI CTCAE Version 4.0 (see Section 12.6).
Toxicities will be characterized in terms regarding seriousness, causality, toxicity grading, 
and action taken with regard to trial treatment.
 
 
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Please refer to Section 7.2 for detailed information regarding the assessment and recording 
of AEs.
7.1.2.2
Physical Exam
7.1.2.2.1 Full Physical Exam
The investigator or qualified designee will perform a complete physical exam during the 
Screening period. Clinically significant abnormal findings should be recorded as medical 
history. The timepoints for full physical exams are described in Section 6. 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 as defined in Section 6, the investigator or 
qualified designee will perform a directed physical exam as clinically indicated prior to the 
administration of the trial treatment. New clinically significant abnormal findings should be 
recorded as AEs.
7.1.2.3
Vital Signs
Vital signs include temperature, pulse, respiratory rate, weight, and the blood pressure. The 
Investigator or qualified designee will take vital signs at screening, prior to the administration 
of each dose of trial treatment and during the follow-up period as specified in the Trial Flow 
Chart – (Section 6). Height will be measured at Visit 1 only. 
7.1.2.4
12-Lead Electrocardiogram (ECG)
A standard 12-lead ECG will be performed using local standard procedures once at 
screening. Clinically significant abnormal findings should be recorded in the medical history. 
7.1.2.5
Eastern Cooperative Oncology Group (ECOG) Performance Status
The investigator or qualified designee will assess ECOG status (see Section 12.5) at 
screening, prior to dosing on Day 1 of each treatment cycle and at discontinuation of trial 
treatment as specified in the Trial Flow Chart.
7.1.2.6
Tumour Imaging and Assessment of Disease
The process for image collection and transmission to the central imaging vendor can be 
found in the Site Imaging Manual (SIM). 
Tumour imaging is strongly preferred to be acquired by computed tomography (CT). 
Magnetic resonance imaging (MRI) should be used only when CT is contraindicated or for 
imaging of the brain. The same imaging technique regarding modality and the use of contrast
should be used in a subject throughout the trial to optimize the Visualization of existing and 
new tumour burden. 
 
 
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7.1.2.6.1 Initial Tumour Imaging
Initial tumour imaging at Screening must be performed within 21 days prior to the date of 
randomization. The site trial team must review screening images to confirm the subject has 
measurable disease per RECIST 1.1 prior to submitting to central imaging vendor.
The screening images must be submitted to the central imaging vendor for retrospective 
review.
Scans performed as part of routine clinical management are acceptable for use as screening 
tumour imaging if they are of diagnostic quality and performed within 21 days prior to the 
date of randomization and can be assessed by the central imaging vendor.
Subjects with previously treated brain metastases may participate provided they have stable
brain metastases, ie, without evidence of progression by imaging (confirmed by MRI if MRI
was used at prior imaging, or confirmed by CT imaging if CT was used at prior imaging) for
at least 4 weeks prior to the first dose of trial treatment. Any neurologic symptoms must have 
returned to baseline and subjects must have no evidence of new or enlarging brain
metastases, and have not used steroids for brain metastases for at least 14 days prior to trial
initiation as per local site assessment. This exception does not include carcinomatous
meningitis, as subjects with carcinomatous meningitis are excluded regardless of clinical
stability.
7.1.2.6.2 Tumour Imaging During Trial
The first on-study imaging assessment should be performed at 6 weeks (42 days ± 7 days) 
after the subject has been randomized. Subsequent imaging should be performed every 6 
weeks (42 days ± 7 days) or more frequently if clinically indicated. After 1 year, subjects 
who remain on treatment will have imaging performed every 6 weeks (42 ± 7 days). Imaging 
timing should follow calendar days and should not be adjusted for delays in cycle starts. 
Imaging should continue to be performed until disease progression verified by the central 
imaging vendor (unless the site Principal Investigator [PI] elects to continue treatment and 
follow irRECIST), the start of new anticancer treatment, withdrawal of consent, or death. All 
supplemental imaging must be submitted to the central imaging vendor.
Per RECIST 1.1, PR and CR should be confirmed by a repeat tumour imaging assessment 
obtained 4 weeks or longer from the date the response was first documented. of the tumour 
imaging performed to confirm a response may be performed, at the earliest, 4 weeks after the 
first indication of a response, or at the next scheduled scan (ie. 6 weeks later), whichever is 
clinically indicated.
Subjects will then report to regularly scheduled imaging, starting with the next scheduled 
imaging time point. Subjects who obtain a confirmation scan do not need to undergo the next 
scheduled tumour imaging if it is <4 weeks later; tumour imaging may resume at the 
subsequent scheduled imaging time point. Per irRECIST (Section 7.1.2.6.6 Immune-related 
RECIST (irRECIST)), disease progression on subjects treated with pembrolizumab should be 
 
 
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confirmed by the site at least 4 weeks after central verification of site-assessed first 
radiologic evidence of PD in clinically stable subjects. Subjects who have unconfirmed 
disease progression may continue on treatment at the discretion of the site Investigator until 
progression is confirmed by the site provided they have met the conditions detailed in 
Section 7.1.2.6.6. Subjects who obtain a confirmation scan do not need to undergo the next 
scheduled tumour imaging if it is <4 weeks later; tumour imaging may resume at the 
subsequent scheduled imaging time point if clinically stable. Subjects who have confirmed 
disease progression, as assessed by the site, will discontinue trial treatment. Exceptions are 
detailed in Section 7.1.2.6.6.
7.1.2.6.3 End of Treatment and Follow-up Tumour Imaging 
In subjects who discontinue trial treatment, tumour imaging should be performed at the time
of treatment discontinuation (±4-week window). If a previous scan was obtained within 4 
weeks prior to the date of discontinuation, then a scan at treatment discontinuation is not
mandatory. In subjects who discontinue trial treatment due to documented disease
progression, this is the final required tumour imaging. In subjects who discontinue trial 
treatment without documented disease progression, every effort should be made to continue 
monitoring their disease status by tumour imaging using the same imaging schedule used 
while on treatment to monitor disease status until the start of a new anticancer treatment, 
disease progression, death, or the end of the trial, whichever occurs first.
7.1.2.6.4 Second Course (Retreatment) Tumour Imaging 
A scan must be performed within 21 days prior to restarting treatment with pembrolizumab.
Local reading (investigator assessment with site radiology reading) will be used to determine
eligibility. Imaging should be submitted to the central imaging vendor for retrospective
review. The first on-trial imaging assessment should be performed at 6 weeks (42 ±7 days) 
after the restart of treatment. Subsequent tumour imaging should be performed every 6 weeks 
(42 ±7 days) or more frequently if clinically indicated. If tumour imaging shows initial PD 
per RECIST 1.1, tumour assessment should be repeated ≥4 weeks later in order to confirm 
PD with the option of continuing treatment while awaiting radiologic confirmation of 
progression. Subjects who obtain a confirmation scan do not need to undergo scheduled 
tumour imaging if it is <4 weeks later and may wait until the next scheduled imaging time 
point if clinically stable. Imaging should continue to be performed until disease progression, 
the start of a new anticancer treatment, withdrawal of consent, death, or notification by the 
Sponsor, whichever occurs first. Disease progression may be confirmed at least 4 weeks after 
the first tumour imaging indicating PD in clinically stable subjects. Additional irRECIST 
detail is described in Section 7.1.2.6.6.
In subjects who discontinue trial treatment, tumour imaging should be performed at the time
of treatment discontinuation (±4-week window). If a previous scan was obtained within 4 
weeks prior to the date of discontinuation, then a scan at treatment discontinuation is not
mandatory. In subjects who discontinue trial treatment due to documented disease
progression, this is the final required tumour imaging.
 
 
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In subjects who discontinue trial treatment without documented disease progression, every
effort should be made to continue monitoring their disease status by radiologic imaging every
6 weeks (42 ±7 days) until either the start of a new anticancer treatment, disease progression,
death, or the end of the trial, whichever occurs first.
Subjects on the placebo+cisplatin+ 5-FU arm are not eligible for this course of therapy.
7.1.2.6.5 RECIST 1.1
RECIST 1.1 will be used by BICR as the primary measure for assessment of tumour
response, date of disease progression, and as a basis for all protocol guidelines related to 
disease status (eg, discontinuation of trial therapy). Although RECIST 1.1 references a 
maximum of 5 target lesions in total and 2 per organ, the Sponsor allows a maximum of 10 
lesions in total and 5 per organ, if clinically relevant to enable a broader sampling of tumour
burden. 
Initial tumour imaging showing site-assessed PD should be submitted to the central imaging
vendor immediately for verification of PD by BICR. The site will be notified if the BICR
verifies PD using RECIST 1.1. The first half of the flow chart in Figure 1 illustrates the
imaging flow involving verification of PD for clinically stable subjects.
7.1.2.6.6 Immune-related RECIST (irRECIST)
irRECIST is RECIST 1.1 adapted as described below to account for the unique tumour
response seen with immunotherapeutic drugs. irRECIST will be used by the site
Investigator/local radiology reviewers to assess tumour response and progression, and make
treatment decisions. This data will be collected in the clinical database. When feasible, 
subjects treated with pembrolizumab should not be discontinued until progression is 
confirmed by the local site Investigator/radiology assessment. This allowance to continue 
treatment despite initial radiologic PD takes into account the observation that some subjects 
can have a transient tumour flare in the first few months after the start of immunotherapy, 
and then experience subsequent disease response. Subjects that are deemed clinically 
unstable are not required to have repeat tumour imaging for confirmation of PD. Tumour
flare includes any of the following scenarios:

Worsening of existing target lesion(s)

Worsening of existing non target lesion(s)

Development of new lesion(s)
In subjects treated with pembrolizumab who have shown initial evidence of radiological PD
by RECIST 1.1 as verified by the central imaging vendor, it is at the discretion of the PI
whether to continue a subject on trial medication until repeat imaging is obtained (using
irRECIST for subject management. This clinical judgment decision by the site investigator
should be based on the subject’s overall clinical condition, including performance status,
clinical symptoms, and laboratory data. Subjects may receive trial medication and the tumour
 
 
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assessment should be repeated ≥4 weeks later in order to confirm PD by irRECIST per site
assessment. Clinical stability is defined as the following:

Absence of symptoms and signs indicating clinically significant progression of
disease, including worsening of laboratory values

No decline in ECOG performance status

Absence of rapid progression of disease

Absence of progressive tumour at critical anatomical sites (eg, cord compression)
requiring urgent alternative medical intervention
Any subject deemed clinically unstable should be discontinued from trial treatment at
central verification of site-assessed first radiologic evidence of PD and is not required to have
repeat imaging for PD confirmation. In determining whether or not the tumour burden has 
increased or decreased per irRECIST, the local site Investigator should consider all target and 
non-target lesions, as well as any incremental new lesion(s).
Disease progression will be considered to be “not confirmed” at repeat imaging if ALL of the
following occur (as assessed by irRECIST):

Target lesion sum of diameters is <20% or <5 mm absolute increase compared to
nadir

Non-target disease resulting in initial PD is stable or qualitatively improved

New lesion resulting in initial PD is stable or qualitatively improved

No incremental new lesion(s) since last evaluation

No incremental new non-target lesion progression since last evaluation
If repeat imaging does not confirm PD per irRECIST as assessed by the local site
Investigator and the subject continues to be clinically stable, treatment may continue and
follow the regular imaging schedule.
Disease progression will be considered to be “confirmed” at repeat imaging if ANY of the
following occur (as assessed by irRECIST):

Target lesion sum of diameters remains ≥20% and at least 5 mm absolute increase
compared to nadir

Non-target disease resulting in initial PD is qualitatively worse

New lesion resulting in initial PD is qualitatively worse
 
 
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
Additional new lesion(s) since last evaluation

Additional new non-target lesion progression since last evaluation
If repeat imaging confirms PD due to any of the scenarios listed above, subjects will be
discontinued from trial therapy.
NOTE: If a subject has confirmed radiographic progression (ie, 2 scans at least 4 weeks apart
demonstrating PD) per irRECIST, but the subject is achieving a clinically meaningful
benefit, and there is no further increase in the tumour burden at the confirmatory tumour
imaging, an exception to continue treatment may be considered following consultation with
the Sponsor. In this case, if treatment is continued, tumour imaging should continue to be
performed following the intervals as outlined in Section 6.0 and be submitted to the central
imaging vendor.
Additional details about irRECIST are provided in Merck TIP Sheet for RECIST 1.1 and
irRECIST.
7.1.2.7
Electronic Patient Reported Outcomes (ePROs)
The EuroQol EQ5D-3L, EORTC QLQ-C30, and EORTC QLQ-STO22 questionnaires will 
be administered by trained study site personnel and completed electronically by subjects. It is 
strongly recommended that the electronic EORTC QLQ-C30, EORTC QLQ-STO22 and 
EuroQol EQ5D-3L are completed by the subject prior to drug administration, AE evaluation 
and disease status notification; an exception to this recommendation may occur at the 
treatment discontinuation visit. ePROs will be administrated in the following order: EuroQol 
EQ5D-3L first, then EORTC QLQ-C30, and lastly the EORTC QLQ-STO22 at the time 
points specified in the Trial Flow Chart.
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 Procedure Trial 
Procedures Manual. Refer to the TRIAL FLOW CHART (Section 6) for the timing of 
laboratory assessments. 
7.1.3.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
Laboratory tests for hematology, chemistry and urinalysis are specified in Table 10.
 
 
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Table 10
Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Hematocrit
Albumin
Blood
Serum β-human chorionic 
gonadotropin (β-hCG)c
Hemoglobin
Alkaline phosphatase
Glucose
PT (INR)
Platelet count
Alanine aminotransferase 
(ALT)
Protein
aPTT
WBC (total and 
differential)a
Aspartate 
aminotransferase (AST)
Specific gravity 
Total triiodothyronine 
(T3) or Free T3
Absolute 
Neutrophil Count
Carbon dioxide (CO2 or 
bicarbonate)b
Microscopic exam, if 
abnormal results are noted
Free thyroxine (T4)
Absolute 
Lymphocyte 
Count
Calcium
Urine pregnancy testc
Thyroid stimulating 
hormone (TSH)
Chloride
Creatinine
Glucose
Magnesium
Phosphorus
Potassium
Sodium
Total Bilirubin  
Direct Bilirubin, if total 
bilirubin is elevated 
above the upper limit of 
normal
Total protein
Blood Urea 
Nitrogen/Uread
Uric acid
a.
Absolute or % is acceptable.
b. If these tests are not done as part of standard of care in your region then these tests do not need to be performed.
c.
Perform on women of childbearing potential only. Serum pregnancy test is preferred but urine test can be considered if 
serum not appropriate.
d. Blood Urea Nitrogen is preferred; if not available urea may be tested.
Laboratory tests for screening should be performed within 10 days prior to the first dose of 
trial treatment. An exception is hepatitis and thyroid serologies, which may be performed 
within 28 days prior to first dose. Subjects eligible for trial retreatment should have imaging 
performed within 21 days and laboratory tests performed within 7 days prior to the first dose 
 
 
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of trial treatment in the Second Course Phase. After Cycle 1, in both the Initial Treatment
Phase and the Second Course Phase, pre-dose laboratory safety tests can be conducted up to 
72 hours prior to dosing unless otherwise noted on the flow charts. 
Laboratory test results must be reviewed by the investigator or qualified designee and found 
to be acceptable prior to administration of each dose of trial treatment.
Unresolved abnormal laboratory values that are drug-related AEs should be followed until
resolution. Laboratory tests do not need to be repeated after the end of treatment if laboratory 
results are within the normal range.
7.1.3.2
Pregnancy
All women who are being considered for participation in the trial, and who are not surgically 
sterilized or postmenopausal must be tested for pregnancy within 72 hours of each cycle of 
trial treatment and 30 days post-treatment. If a urine test is positive or not evaluable, a serum 
test will be required. Subjects must be excluded/discontinued from the trial in the event of a 
positive or borderline-positive test result. 
7.1.3.3
Pharmacokinetic/Pharmacodynamic Evaluations
7.1.3.3.1 Blood Collections – Samples for Correlative and Genetic Analyses
Details regarding time points for blood collection 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.
7.1.3.4
Planned Genetic Analysis Sample Collection
Sample collection, storage, and shipment instructions for Planned Genetic Analysis samples
will be provided in the Procedures Manual. Samples should be collected for planned analysis
of associations between genetic variants in germline/tumour DNA and drug response. If a
documented law or regulation prohibits (or local IRB/Independent Ethics Committee [IEC]
does not approve) sample collection for these purposes, then such samples should not be
collected at the corresponding sites. Leftover DNA extracted from planned genetic analysis 
samples will be stored for future biomedical research only if subject signs the Future
Biomedical Research consent.
 
 
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7.1.3.5
Future Biomedical Research
The following specimens are to be obtained as part of Future Biomedical Research:

Leftover DNA

Leftover archival tumour tissue or leftover newly obtained biopsy samples taken 
throughout the trial
Other Procedures
7.1.4.1
Withdrawal/Discontinuation
Subjects who discontinue/withdraw from treatment prior to completion of the treatment 
regimen should be encouraged to continue to be followed for all remaining study visits.
When a subject discontinues/withdraws from participation in the trial, all applicable activities 
scheduled for the end of treatment visit should be performed at the time of discontinuation.  
Any adverse events which are present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements outlined in Section 7.2 - Assessing and 
Recording Adverse Events. Subjects on the pembrolizumab arms 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
7.1.2.6.4.  After discontinuing treatment following assessment of CR or 35 administrations 
(approximately 2 years) of treatment, these subjects should return to the site for a Safety 
Follow-up Visit (described in Section 7.1.5.3.1) and then proceed to the Follow-up Period of 
the study (described in Section 7.1.5.3.2).
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 
 
 
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subject’s personal information and their specimens.  In this situation, the request for 
specimen destruction cannot be processed.
7.1.4.1.2 Lost to Follow-up
If a subject fails to return to the clinic for a required study visit and/or if the site is unable to 
contact the subject, the following procedures are to be performed:

The site must attempt to contact the subject and reschedule the missed visit. If the 
subject is contacted, the subject should be counselled on the importance of 
maintaining the protocol-specified visit schedule.

The investigator or designee must make every effort to regain contact with the subject 
at each missed visit (eg phone calls and/or a certified letter to the subject’s last known 
mailing address or locally equivalent methods). These contact attempts should be 
documented in the subject’s medical record.

Note: A subject is not considered lost to follow up until the last scheduled visit for the 
individual subject. The amount of missing data for the subject will be managed via
the pre-specified data handling and analysis guidelines.
7.1.4.2
Blinding/Unblinding
IVRS/IWRS should be used for emergency unblinding in the event that this is required for 
subject safety.
The study is partially blinded, refer to Section 5.2.3.
Even though the trial is only partially blinded (ie treatment arm 1 is open label), the 
following measures will be taken to help maintain internal blinding: imaging data are 
centrally reviewed, and the central reviewer is blinded to subject treatment assignment.
The emergency unblinding call centre will use the randomization schedule for the trial to 
unblind subjects and to unblind treatment identity for subjects enrolled in treatment group 2 
or 3 of this trial. In the event that the emergency unblinding call centre is not available for a 
given site in this trial, the central electronic randomization system (IVRS/IWRS) should be 
used in order to unblind subjects and to unblind treatment identity. The Sponsor will not 
provide random code/disclosure envelopes or lists with the clinical supplies. 
Treatment identification information is to be unblinded ONLY in following situation:
1.
For the welfare of the subject, if necessary. 
2.
Subjects requiring second course/re-retreatment who achieved SD or better during 
first course of treatment and has to discontinue for reason other than disease 
progression or intolerability. Such subject must have experienced radiographic 
 
 
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disease progression while off study treatment according to the criteria in Section 
7.1.5.2.1.
Every effort should be made to avoid unblinding the subject unless necessary. In the event 
that unblinding has occurred, the circumstances around the unblinding (eg, date and reason) 
must be documented promptly, and the Sponsor Clinical Director notified as soon as 
possible. Only the principal investigator or delegate and the respective subject’s code should 
be unblinded. 
7.1.4.3
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical 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.
7.1.5.1
Screening
Within 21 days prior to treatment randomization, potential subjects will be evaluated to 
determine that they fulfil the entry requirements as set forth in Section 5.1. Visit 
requirements are outlined in the TRIAL FLOW CHART (Section 6). Screening procedures 
may be repeated.
Written consent must be obtained prior to performing any protocol-specific procedure. 
Results of a test performed prior to the subject signing consent as part of routine clinical 
management are acceptable in lieu of a screening test if performed within the specified time 
frame. Screening procedures are to be completed within 21 days prior to the first dose of trial 
treatment except for the following:
ECOG PS for screening is to be performed within 3 days prior to the first dose of trial 
treatment. Laboratory tests for screening are to be performed within 10 days prior to the first 
dose of trial treatment. For women of reproductive potential, a serum pregnancy test will be 
performed within 72 hours prior to the first dose of trial treatment. A urine test may be 
considered if a serum test is not appropriate.
Subjects may be rescreened after initially failing to meet the inclusion/exclusion criteria.
Results from assessments performed during the initial screening period are acceptable in lieu 
of a repeat screening test if performed within the specified time frame and the 
inclusion/exclusion criteria is met. Subjects who are rescreened will retain their original 
screening number.
 
 
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7.1.5.2
Treatment Period
Visit requirements are outlined in Section 6.0. Specific procedure-related details are provided 
above in Section 7.1.
7.1.5.3
Post-Treatment Visits
7.1.5.3.1 Safety Follow-up Visit
The mandatory Safety Follow-up Visit should be conducted approximately 30 days after the 
last dose of trial treatment or before the initiation of a new anticancer treatment, whichever 
comes first.
Subjects who are eligible for retreatment/crossover with pembrolizumab may have up to 2
safety follow-up visits, 1 after the Initial Treatment Period and 1 after the Second Course 
Treatment.
7.1.5.3.2 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 6 weeks (42 ± 7 days) to monitor 
disease status. 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 
anticancer therapy, disease progression, death, end of trial (or if the subject begins 
retreatment with pembrolizumab as detailed in Section 7.1.2.6.4). Information regarding 
post-trial anticancer treatment will be collected if new treatment is initiated. 
Subjects who are eligible to receive retreatment with pembrolizumab according to the criteria 
in Section 5.2.2 will move from the Follow-Up Phase to the Second Course Phase when they 
experience disease progression. Details are provided in Trial Flow Chart (Section 6) for 
retreatment with pembrolizumab.
7.1.5.3.3 Survival Follow-up
Subjects who experience confirmed disease progression or start a new anticancer therapy, 
will move into the Survival Follow-Up Phase and should be contacted by telephone 
approximately every 12 weeks to assess for survival status until death, withdrawal of 
consent, or the end of the trial, whichever occurs first. 
7.1.5.4
Survival Status 
To ensure current and complete survival data is available at the time of database locks,
updated survival status may be requested during the course of the study by the Sponsor. For
example, updated survival status may be requested prior to but not limited to an external Data
Monitoring Committee (eDMC) review, interim and/or final analysis. Upon Sponsor
notification, all subjects who do not/will not have a scheduled study visit or study contact
 
 
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during the Sponsor defined time period will be contacted for their survival status (excluding
subjects that have a previously recorded death event in the collection tool).
Assessing and Recording Adverse Events
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavourable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the 
use of the Sponsor’s product, is also an adverse event.
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  
Examples of this may include, but are not limited to, teething, typical crying in infants and 
children and onset of menses or menopause occurring at a physiologically appropriate time.
Sponsor's product includes any pharmaceutical product, biological product, device, 
diagnostic agent or protocol-specified procedure, whether investigational (including placebo 
or active comparator medication) or marketed, manufactured by, licensed by, provided by or 
distributed by the Sponsor for human use.
Adverse events may occur during  clinical trials, or as prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal.
Progression of the cancer under study is not considered an adverse event.
All adverse events that occur after the consent form is signed but before 
randomization/treatment allocation must be reported by the investigator if they cause the 
subject to be excluded from the trial, or are the result of a protocol-specified intervention, 
including but not limited to washout or discontinuation of usual therapy, diet, placebo 
treatment or a procedure. From the time of  randomization/treatment allocation through 30
days following cessation of treatment, all adverse events must be reported by the 
investigator. Such events will be recorded at each examination on the Adverse Event case 
report forms/worksheets.  The reporting timeframe for adverse events meeting any serious 
criteria is described in section 7.2.3.1. The investigator will make every attempt to follow all 
subjects with non-serious adverse events for outcome.
Electronic reporting procedures can be found in the EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
 
 
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Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor
For purposes of this trial, an overdose will be defined as any dose exceeding the prescribed 
dose for the standard treatments by ≥20% and as ≥1000 mg (5 times the dose) of 
pembrolizumab. No specific information is available on the treatment of overdose of
pembrolizumab. In the event of overdose, study treatment should be discontinued and the 
subject should be observed closely for signs of toxicity.  Appropriate supportive treatment 
should be provided if clinically indicated.
If an adverse event(s) is associated with (“results from”) the overdose of Sponsor's product or 
vaccine, the adverse event(s) is reported as a serious adverse event, even if no other 
seriousness criteria are met.
If a dose of Sponsor's product or vaccine meeting the protocol definition of overdose is taken 
without any associated clinical symptoms or abnormal laboratory results, the overdose is 
reported as a non-serious Event of Clinical Interest (ECI), using the terminology “accidental 
or intentional overdose without adverse effect.”
All reports of overdose with and without an adverse event must be reported by the 
investigator within 24 hours to the Sponsor either by electronic media or paper. Electronic 
reporting procedures can be found in the EDC data entry guidelines. Paper reporting 
procedures can be found in the Investigator Trial File Binder (or equivalent).
Reporting of Pregnancy and Lactation to the Sponsor
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them) that occurs during the trial.
Pregnancies and lactations that occur after the consent form is signed but before 
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.
 
 
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Such events must be reported within 24 hours to the Sponsor either by electronic media or 
paper. Electronic reporting procedures can be found in the EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
Immediate Reporting of Adverse Events to the Sponsor
7.2.3.1
Serious Adverse Events
A serious adverse event is any adverse event occurring at any dose or during any use of 
Sponsor's product that:
●
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 cancer;
●
Is associated with an overdose.
Refer to Table 11 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).
 
 
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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.
7.2.3.2
Events of Clinical Interest
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported to the Sponsor.
For the time period beginning when the consent form is signed until randomization/treatment 
allocation, any ECI, or follow up to an ECI, that occurs to any subject must be reported 
within 24 hours to the Sponsor if it causes the subject to be excluded from the trial, or is the 
result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at randomization/treatment allocation through 90 days 
following cessation of treatment, or 30 days following cessation of treatment if the subject 
initiates new anticancer therapy, whichever is earlier, any ECI, or follow up to an ECI, 
whether or not related to the Sponsor’s product, must be reported within 24 hours to the 
Sponsor, either by electronic media or paper.  Electronic reporting procedures can be found 
in the EDC data entry guidelines. Paper reporting procedures can be found in the Investigator 
Trial File Binder (or equivalent).
Events of clinical interest for this trial include:
1. an overdose of Sponsor's product, as defined in Section 7.2.1 - Definition of an Overdose 
for This Protocol and Reporting of Overdose to the Sponsor, that is not associated with 
clinical symptoms or abnormal laboratory results. 
2. an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less 
than 2X the upper limit of normal, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.*
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology.  The trial site guidance for 
assessment and follow up of these criteria can be found in the Investigator Trial File 
Binder (or equivalent).
 
 
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7.2.3.3
Protocol-Specific Exceptions to Serious Adverse Event Reporting
Efficacy endpoints as outlined in this section will not be reported to the Sponsor as described 
in Section 7.2.3 - Immediate Reporting of Adverse Events to the Sponsor.
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study.
The Sponsor will monitor unblinded aggregated efficacy endpoint events and other 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.
For studies in which multiple agents are administered as part of a combination regimen, the 
investigator may attribute each adverse event causality to the combination regimen or to a 
single agent of the combination.  In general, causality attribution should be assigned to the 
combination regimen (i.e., to all agents in the regimen). However, causality attribution may 
be assigned to a single agent if in the investigator’s opinion, there is sufficient data to support 
full attribution of the adverse experience to the single agent.
 
 
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Table 11
Evaluating Adverse Events
An investigator who is a qualified physician, will evaluate all adverse events as to:
V4.0 
CTCAE 
Grading
Grade 1
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated.
Grade 2
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL.
Grade 3
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or hospitalization indicated; 
disabling; limiting self-care ADL.
Grade 4
Life threatening consequences; urgent intervention indicated.
Grade 5
Death related to AE
Seriousness
A serious adverse event is any adverse event occurring at any dose or during any use of Sponsor’s product that:
†Results in death; or
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include an 
adverse event that, had it occurred in a more severe form, might have caused death.); or
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation. (Note: Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not a serious adverse event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of a Merck product and is documented in 
the patient’s medical history.); or
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or
Is a cancer (although not serious per ICH definition, is reportable to the Sponsor within 24 hours to meet certain local requirements); or
Is associated with 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.
TRIAL GOVERNANCE AND OVERSIGHT
Scientific Advisory Committee
This trial was developed in collaboration with a Scientific Advisory Committee (SAC).  The 
SAC comprises both Sponsor and non-Sponsor scientific experts who provide input with 
respect to trial design, interpretation of trial results and subsequent peer-reviewed scientific 
publications.
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
external Data Monitoring Committee (eDMC) 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 EOC if the trial should continue in accordance with the 
protocol.
Specific details regarding composition, responsibilities, and governance, including the roles 
and responsibilities of the various members and the Sponsor protocol team; meeting 
facilitation; the trial governance structure; and requirements for and proper documentation of 
DMC reports, minutes, and recommendations will be described in a separate charter that is 
reviewed and approved by the DMC.  The DMC will monitor the trial at an appropriate 
frequency, as described in the detailed DMC charter.  The DMC will also make 
recommendations to the EOC regarding steps to ensure both subject safety and the continued 
ethical integrity of the trial.
 
 
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8.0 STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the trial. If, after the 
trial 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 unblinding, 
will be documented in a supplemental SAP (sSAP) and referenced in the Clinical Study 
Report (CSR) for the trial. Post hoc exploratory analyses will be clearly identified in the 
CSR.
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive 
plan is provided in Sections 8.2-8.12.
Study Design Overview
A Randomized, Active-Controlled, Partially Blinded, Biomarker Select,
Phase III Clinical Trial of Pembrolizumab as Monotherapy and in 
Combination 
with 
Cisplatin+5-Flourouracil 
(5-FU) 
versus 
Placebo+Cisplatin+5-FU,
as first-line treatment
in Subjects with 
Advanced Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma
Treatment Assignment
Approximately 
750 
subjects 
with 
advanced
gastric 
or 
GEJ 
adenocarcinoma will be randomized in a 1:1:1 ratio among three treatment 
arms in this trial, stratified by geographic region, backbone therapy (5-FU 
vs capecitabine) and disease status (See Section 5.4 Stratification for 
details). The three treatment arms are as follows:
Treatment 
Arm
Treatment Dose and Schedule
Treatment 
Arm 1
Pembrolizumab 200 mg every 3 weeks (Q3W)
Treatment 
Arm 2*
Pembrolizumab 200 mg + 5-FU 800 mg/m2/day 
continuous IV infusion Days 1-5 + Cisplatin 80 mg/m2
administrated Q3W
Treatment 
Arm 3*
Placebo+5-FU 800 mg/m2/day continuous IV infusion 
Days 1-5 + Cisplatin 80 mg/m2 administrated Q3W
Although use of 5-FU infusion is preferred, Capecitabine 1000 mg/m2
bid Day 1 to Day 14 Q3W may be permitted according to local 
guideline at Investigator’s discretion.  Investigator decision regarding 
the type of comparator used should be determined prior to 
randomization in the trial. 
*This is a partially blinded trial. Treatment Arm 1 is open label and 
Treatment Arm 2 and 3 are blinded.
Analysis Populations
Efficacy: Intention-to-treat (ITT) population.
Safety: All Subjects as Treated (ASaT)
 
 
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Primary Endpoint
1. Progression-free survival (PFS) – per RECIST 1.1 by blinded central 
radiologists’ review
2. Overall Survival (OS)
Statistical Methods for Key 
Efficacy Analyses
The primary hypothesis for OS (H2 and H3) and PFS (H1) will be 
evaluated by comparing pembrolizumab in combination with SOC 
(cisplatin+5-FU
or Capecitabine) versus SOC (cisplatin+5-FU
or 
Capecitabine) using a stratified log-rank test. Estimation of the hazard 
ratio will be done using a stratified Cox regression model. Event rates over 
time will be estimated within each treatment group using the Kaplan-
Meier method. The primary hypothesis for non-inferiority (H4) of 
pembrolizumab monotherapy vs. SOC for OS will be evaluated using a 
stratified Cox regression model. The OS primary
hypothesis for 
superiority (H5 and H6) of pembrolizumab monotherapy vs. SOC will be 
evaluated using stratified log-rank test.
Statistical Methods for Key 
Safety Analyses
The analysis of safety results will follow a tiered approach. The tiers differ 
with respect to the analyses that will be performed. Safety parameters or 
adverse experiences of special interest that are identified a priori
constitute “Tier 1” safety endpoints that will be subject to inferential 
testing for statistical significance with p-values and 95% confidence 
intervals provided for between-group comparisons.
Other safety 
parameters will be considered Tier 2 or Tier 3. Tier 2 parameters will be 
assessed via point estimates with 95% confidence intervals provided for 
between-group comparisons; only point estimates by treatment group are 
provided for Tier 3 safety parameters. The between-treatment difference 
will be analysed using the Miettinen and Nurminen method. 
Interim Analyses
Two efficacy and one safety interim analyses will be performed in this 
trial. Results will be reviewed by a DMC. These interim analyses and the 
final analysis are summarized below. Details are provided in Section 8.7.
Safety Interim Analysis
Timing: After 10 subjects in each treatment arm have completed one 
cycle of follow-up. Interim safety monitoring will include review of AE 
data by the DMC (see Section 8.6.2 for more details on the analyses 
methods). 
Efficacy Interim Analysis
Timing:
Interim analysis 1 (IA1) After: 1) all subjects have been enrolled, 2) 
minimum of 10 months of follow-up and 3) at least 317 OS events are
observed among subjects randomized to the SOC and combination arm
with PD-L1 CPS1.
Interim analysis 2 (IA2): 16 months after the last subject is randomized
to the trial and after at least 369 OS events are observed among subjects
randomized to the SOC and combination arm with PD-L1 CPS1.
Purpose:
IA1: Interim analysis for PFS (PD-L1 CPS1) (H1) and OS (PD-L1 
CPS1 and PD-L1 CPS10) (H2-H6).
IA2: Final efficacy analysis for PFS (PD-L1 CPS1) (H1) and interim 
analysis for OS (PD-L1 CPS1 and PD-L1 CPS10) (H2-H6).
Final analysis 
Timing: at least 22 months after the last subject is randomized to the trial 
and approximately 415 OS events are observed among subjects 
randomized to the SOC and combination arm with PD-L1 CPS1.
 
 
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Multiplicity
The multiplicity strategy specified in Section 8.8 will be applied to the 
primary hypotheses (PFS [PD-L1 CPS1] [H1] and OS [PD-L1 CPS1 and 
PD-L1 CPS10]) (H2-H6) and the secondary hypothesis (ORR PD-L1 
CPS1) (H7) to control the overall Type-I error at 2.5% (one-sided). The 
graphical approach of Mauer and Bretz [44] will be used. In this approach, 
when a particular null hypothesis is rejected, the arrow(s) leading to it are 
removed, and the Type I error allocated to the null hypothesis that was 
rejected is re-distributed to the other hypotheses. 
There are three treatment arms in the study. Initially α=0.10%, 1.25% 
0.75% and 0% is allocated to the PFS (PD-L1 CPS1) (H1) , OS(PD-L1 
CPS1) (H2), OS (PD-L1 CPS10) (H3) and ORR (PD-L1 CPS1) (H7)
hypotheses, respectively, for the Pembrolizumab in combination with SOC 
versus SOC comparisons and α=0.40%, 0% and 0% is allocate to OS
(non-inf PD-L1 CPS1) (H4), OS (PD-L1 CPS1) (H5) and OS (PD-L1 
CPS10) (H6) hypotheses, respectively, for the monotherapy vs. SOC 
(control) comparisons.
Sample Size and Power 
The planned sample size is approximately 750 subjects. For PFS (PD-L1 
CPS1) (H1), the study has ~91% power to detect a hazard ratio of 0.65 
(pembrolizumab in combination with SOC vs. SOC) at alpha = 0.10% 
(one-sided). For OS (PD-L1 CPS1) (H2), the study has ~91% power to 
detect a hazard ratio of 0.70 (pembrolizumab in combination with SOC vs. 
SOC) at alpha = 1.25% (one-sided).  For OS (PD-L1 CPS10) (H3), the 
study has ~80% (73%) power to detect a hazard ratio of 0.58(0.60)
(pembrolizumab in combination with SOC vs. SOC) at alpha = 0.75% 
(one-sided). For the monotherapy vs. SOC comparison of OS (PD-L1 
CPS1), the study has ~89% power to establish non-inferiority (H4) (NI 
margin = 1.2) of pembrolizumab vs SOC at alpha = 0.40% (one-sided) if 
HR = 0.8 and ~82% power (superiority, H5) to detect a hazard ratio of 
0.70 at alpha = 0.40% (one-sided). For OS (PD-L1 CPS10) (H6), the study 
has ~80%(63%)
power to detect a hazard ratio of 0.58(0.63)
(pembrolizumab monotherapy vs. SOC) at alpha = 0.75% (one-sided)
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.
Although the trial is partially blinded (pembrolizumab mono therapy arm open label and 
pembrolizumab in combination with standard of care and standard of care arms are 
blinded) analyses or summaries generated by randomized treatment assignment and actual 
treatment received will be limited and documented.
In addition, the independent 
radiologist(s) will perform the central imaging review without knowledge of treatment group 
assignment.
The SPONSOR will generate the randomized allocation schedule(s) for study treatment 
assignment for this protocol, and the randomization will be implemented in IVRS. 
The DMC will serve as the primary reviewer of the unblinded results of the interim analysis 
and will make recommendations for discontinuation of the study or modification to an 
 
 
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executive oversight committee of the SPONSOR. Depending on the recommendation of the 
DMC, the Sponsor may prepare a regulatory submission. If the DMC recommends 
modifications to the design of the protocol or discontinuation of the study, this executive 
oversight committee and limited additional sponsor personnel may be unblinded to results at 
the treatment level in order to act on these recommendations. Additional logistical details, 
revisions to the above plan and data monitoring guidance will be provided in the DMC 
Charter. 
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.0.
Analysis Endpoints
Primary Efficacy Endpoints
Progression-free survival (PFS) – RECIST 1.1 by blinded central radiologists’ review
PFS is defined as the time from randomization to the first documented disease progression 
per RECIST 1.1 based on blinded central radiologists’ review or death due to any cause, 
whichever occurs first. See Section 8.6.1 for definition of censoring.
Overall Survival (OS)
OS is defined as the time from randomization to death due to any cause. Subjects without 
documented death at the time of the final analysis will be censored at the date of the last 
follow-up.
Secondary Efficacy Endpoint
Overall Response Rate (ORR) – RECIST 1.1 by blinded central radiologists’ review
ORR is defined as the proportion of the subjects in the analysis population who have a CR or 
partial response (PR).  
ANALYSIS POPULATIONS
Efficacy Analysis Populations
The Intention-to-Treat (ITT) population will serve as the population for primary efficacy 
analysis. All randomized subjects will be included in this population. Subjects will be 
included in the treatment group to which they are randomized. Details on the approach to 
handling missing data are provided in Section 8.6 Statistical Methods.
 
 
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Safety Analysis Populations
The All Subjects as Treated (ASaT) population will be used for the analysis of safety data in 
this study. The ASaT population consists of all randomized subjects who received at least 
one dose of study treatment. Subjects will be included in the treatment group corresponding 
to the study treatment they actually received for the analysis of safety data using the ASaT 
population. For most subjects this will be the treatment group to which they are randomized.
Subjects who take incorrect study treatment for the entire treatment period will be included in 
the treatment group corresponding to the study treatment actually received. Any subject who 
receives the incorrect study medication for one cycle but receives the correct treatment for all 
other cycles will be analysed according to the correct treatment group and a narrative will be 
provided for any events that occur during the cycle for which the subject is incorrectly dosed.
At least one laboratory or vital sign measurement obtained subsequent to at least one dose of 
study treatment is required for inclusion in the analysis of each specific parameter. To assess 
change from baseline, a baseline measurement is also required.
STATISTICAL METHODS
Statistical Methods for Efficacy Analyses
This section describes the statistical methods that address the primary and secondary 
objectives. Methods related to exploratory objectives and exploratory endpoints will be 
described in the supplemental statistical analysis plan (sSAP), this includes the ePRO data 
described in Section 7.1.2.9.
Efficacy results that will be deemed to be statistically significant after consideration of the 
Type I error control strategy are described in Section 8.8, Multiplicity and Section 8.7 
Interim Analysis. Nominal p-values will be provided for other efficacy analyses, but should 
be interpreted with caution due to potential issues of multiplicity.
Progression-free Survival (PFS)
The non-parametric Kaplan-Meier method will be used to estimate the PFS curve in each 
treatment group. The treatment difference in PFS will be assessed by the stratified log-rank 
test. A stratified Cox proportional hazards model with Efron’s method of tie handling will be 
used to assess the magnitude of the treatment difference (ie, hazard ratio) between the 
treatment arms. The hazard ratio and its 95% confidence interval from the stratified Cox 
model with Efron's method of tie handling and with a single treatment covariate will be 
reported. Geographic region, backbone therapy (5-FU or Capecitabine) and disease status
will be used as the stratification factors in both the stratified log-rank test and the stratified 
Cox model.
Since disease progression is assessed periodically, PD can occur any time in the time interval 
between the last assessment where PD was not documented and the assessment when PD is 
documented. For the primary analysis, for the subjects who have PD, the true date of disease 
progression will be approximated by the date of the first assessment at which PD is 
 
 
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objectively documented per RECIST 1.1, regardless of discontinuation of study drug. Death 
is always considered as a confirmed PD event. Subjects without documented PD/death will 
be censored at the last disease assessment date.
In order to evaluate the robustness of the primary endpoint PFS per RECIST 1.1 by blinded 
central radiologists’ review, we will perform two sensitivity analyses with a different set of 
censoring rules. The first sensitivity analysis is the same as the primary analysis except that it 
censors at the last disease assessment without PD when PD or death is documented after 
more than one missed disease assessment. The second sensitivity analysis is the same as the 
primary analysis except that it considers discontinuation of treatment or initiation of an 
anticancer treatment subsequent to discontinuation of study-specified treatments, whichever 
occurs later, to be a PD event for subjects without documented PD or death. The censoring 
rules for primary and sensitivity analyses are summarized in Table 12 below. 
Table 12
Censoring Rules for Primary and Sensitivity Analyses of PFS
Situation
Primary Analysis
Sensitivity
Analysis 1
Sensitivity
Analysis 2
No PD and no 
death; 
new 
anticancer 
treatment is not 
initiated
Censored 
at 
last 
disease assessment 
Censored 
at 
last 
disease assessment 
Censored 
at 
last 
disease assessment if 
still on study therapy; 
progressed 
at 
treatment 
discontinuation 
otherwise
No PD and no 
death;
new 
anticancer 
treatment 
is 
initiated
Censored 
at 
last 
disease 
assessment 
before 
new 
anticancer treatment
Censored 
at 
last 
disease assessment 
before 
new 
anticancer treatment
Progressed at date of 
new 
anticancer 
treatment
PD 
or 
death 
documented after 
≤ 1 missed disease 
assessment
Progressed at date of 
documented PD or 
death
Progressed at date 
of documented PD 
or death
Progressed at date of 
documented 
PD 
or 
death
PD 
or 
death 
documented after 
≥ 2 missed disease 
assessments
Progressed at date of 
documented PD or 
death
Censored 
at 
last 
disease assessment 
prior to the  ≥ 2 
missed 
disease 
assessment
Progressed at date of 
documented 
PD 
or 
death
Overall Survival (OS)
The non-parametric Kaplan-Meier method will be used to estimate the survival curves. The 
treatment difference in survival will be assessed by the stratified log-rank test for superiority 
hypotheses. A stratified Cox proportional hazards model with Efron's method of tie handling 
will be used to assess the magnitude of the treatment difference (ie, the hazard ratio). The 
hazard ratio and its 95% confidence interval from the stratified Cox model with a single 
treatment covariate will be reported. Geographic region, backbone therapy (5-FU or 
 
 
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Capecitabine) and disease status will be used as the stratification factors in both the stratified 
log-rank test and the stratified Cox model.
The non-inferiority hypothesis (H4) for pembrolizumab monotherapy vs. SOC will be 
evaluated using a stratified Cox regression model. The statistical criterion for the success of 
hypothesis H4 is that, if the upper bound of the confidence interval, based on the alpha level 
allocated to the analysis, for the hazard ratio (HR: monotherapy arm vs. control) is < 1.2, the 
pembrolizumab monotherapy arm could be considered as non-inferior to the control arm in 
terms of OS.
Overall Response Rate (ORR)
Stratified Miettinen and Nurminen’s method with strata weighting by sample size will be 
used for comparison of the ORR between the treatment groups. Geographic region, backbone 
therapy (5-FU or Capecitabine) and disease status will be used as the stratification factors in 
the analysis.  
Table 13 summarizes the primary analysis approach for primary and secondary efficacy 
endpoints. Sensitivity analysis methods are described above for each endpoint.
Table 13
Analysis Strategy for Key Efficacy Endpoints
Endpoint/Variable
(Description, Time 
Point)
Statistical Method†
Analysis 
Populatio
n
Missing Data Approach
Primary Endpoints
PFS per RECIST 
1.1 by 
blinded 
central
radiologists’ 
review
Testing: Stratified Log-rank test. 
Estimation: Stratified Cox model 
with Efron's tie handling method 
ITT
Primary censoring rule 
Sensitivity analysis 1
Sensitivity analysis 2 (More 
details in Table 12)
OS
Testing: Stratified Log-rank test
Estimation: Stratified Cox model 
with Efron's tie handling method
ITT
Censored at last date known alive 
Secondary Endpoint
ORR
Per  RECIST 1.1 
by blinded central 
radiologists’ 
review 
Stratified Miettinen and Nurminen 
method
ITT
Subjects with missing data are 
considered non-responders
† Statistical models are described in further detail in the text. For stratified analyses, Geographic region,
backbone therapy and disease status will be used as the stratification factors in both the stratified log-rank 
test and the stratified Cox model.
 
 
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Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
adverse experiences (AEs), laboratory tests, vital signs, etc.
The analysis of safety results will follow a tiered approach (Table 14). The tiers differ with 
respect to the analyses that will be performed. Safety parameters or adverse experiences of 
special interest that are identified a priori constitute “Tier 1” safety endpoints that will be 
subject to inferential testing for statistical significance with p-values and 95% confidence 
intervals provided for between-group comparisons. Other safety parameters will be 
considered Tier 2 or Tier 3. Tier 2 parameters will be assessed via point estimates with 95% 
confidence intervals provided for between-group comparisons; only point estimates by 
treatment group are provided for Tier 3 safety parameters.
Adverse experiences (specific terms as well as system organ class terms) and predefined 
limits of change in laboratory, vital signs, and ECG parameters that are not pre-specified as 
Tier-1 endpoints will be classified as belonging to "Tier 2" or "Tier 3", based on the number 
of events observed. Membership in Tier 2 requires that at least 4 subjects in any treatment 
group exhibit the event; all other adverse experiences and predefined limits of change will 
belong to Tier 3.
The threshold of at least 4 events was chosen because the 95% confidence interval for the 
between-group difference in percent incidence will always include zero when treatment 
groups of equal size each have less than 4 events and thus would add little to the 
interpretation of potentially meaningful differences. Because many 95% confidence intervals 
may be provided without adjustment for multiplicity, the confidence intervals should be 
regarded as a helpful descriptive measure to be used in review, not a formal method for 
assessing the statistical significance of the between-group differences in adverse experiences 
and predefined limits of change.
Continuous measures such as changes from baseline in laboratory, vital signs, and ECG 
parameters that are not pre-specified as Tier-1 endpoints will be considered Tier 3 safety 
parameters. Summary statistics for baseline, on-treatment, and change from baseline values 
will be provided by treatment group in table format.
Based on a review of historic chemotherapy data and data from ongoing pembrolizumab 
clinical trials in gastric cancer, there are no AEs of interest that warrant inferential testing for 
comparison between treatment arms in this study. Therefore, there are no Tier I events in 
this study. The broad clinical and laboratory AE categories consisting of the percentage of 
subjects with any AE, any drug related AE, any serious AE, any Grade 3-5 AE, an AE which 
is both Grade 3-5 and drug-related, an AE which is both drug-related and serious, dose 
modification due to AE, and who discontinued due to an AE, and death will be considered 
Tier 2 endpoints. Ninety Five percent (95%) confidence intervals Tier 2) will be provided for 
between-treatment differences in the percentage of subjects with events; these analyses will 
be performed using the Miettinen and Nurminen method (1985), an unconditional, 
asymptotic method.
 
 
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Table 14
Analysis Strategy for Safety Parameters
Safety Tier
Safety Endpoint
p-Value
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 2
Any AE
X
X
Any Grade 3-5 AE
X
X
Any Serious AE 
X
X
Any Drug-Related AE
X
X
Any Serious and Drug-Related AE
X
X
Any Grade3-5 and Drug-Related AE
X
X
Dose Modification due to AE
X
X
Discontinuation due to AE
X
X
Death
X
X
Specific AEs, SOCs (including ≥4 of subjects 
in one of the treatment groups)
X
X
Tier 3
Specific AEs, SOCs (incidence <4 of subjects 
in all of the treatment groups)
X
Change from Baseline Results (Labs, ECGs, 
Vital Signs)
X
Statistical Methods for Patient Reported Outcome (PRO) Analyses: EORTC 
QLQ-C30 and EORTC QLQ-STO22
Changes in health-related quality-of-life assessments from baseline using the EORTC QLQ-
C30 and EORTC QLC-STO22 will be evaluated using a constrained longitudinal data 
analysis (cLDA) model.
Time to deterioration (10 points worse than baseline) in EORTC QLQ-C30 global health 
status, nausea/vomiting symptom, appetite loss symptom, and QLQ-STO22 abdominal 
pain/discomfort symptom will be analysed using the same methods used for the primary 
endpoint, PFS (stratified Cox model and Kaplan Meier plot). Rate of improvement (10 points 
better than baseline) for these endpoints will be analysed using the same method used for 
ORR (ie stratified Miettinen and Nurminen’s method).
Details of PRO analyses will be described in the sSAP.
Summaries of Baseline Characteristics, Demographics, and Other Analyses
8.6.4.1
Demographic and Baseline Characteristics
The comparability of the treatment groups for each relevant characteristic will be assessed by 
the use of tables and/or graphs. No statistical hypothesis tests will be performed on these 
characteristics. The number and percentage of subjects randomized, and the primary reason 
for discontinuation will be displayed. Demographic variables (such as age) and baseline 
 
 
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characteristics will be summarized by treatment either by descriptive statistics or categorical 
tables. 
INTERIM ANALYSES
Safety Interim Analysis
An interim safety analysis will take place after 10 subjects in each treatment arm have 
completed 1 cycle of therapy. Interim periodic safety monitoring will include review of AE 
data by the eDMC as specified in the DMC charter. 
Efficacy Interim Analyses
There are two interim analyses planned in this study. The first interim analysis (IA1) will 
take place when all subjects are enrolled and followed for 10 months and at least 317 OS 
events are observed across the pembrolizumab in combination with SOC and SOC arms, in 
subjects with PD-L1 CPS1. The second interim analysis (IA2) will take place after a 
minimum of 16 months follow-up and at least 369 OS events are observed across the
pembrolizumab in combination with SOC and SOC arms, in subjects with PD-L1 CPS1. In 
order to account for potential delayed treatment effect, which was observed with 
immunotherapy study data external to this study, the final analysis (FA) will be 22 months 
after the last subject is randomized and approximately 415 OS events are observed across the 
pembrolizumab in combination with SOC and SOC arms, in subjects with PD-L1 CPS1 [48; 
49; 50]. The additional follow-up time is incorporated into the trial to ensure that the final 
analysis is conducted at an appropriate time to characterize the potential benefit of 
immunotherapy, where the treatment effect is most pronounced towards the tail of the 
survival curve. Table 15 summarizes the key features of the interim analysis.
For PFS (H1) and OS (H2, H3, H5, and H6), a Hwang-Shih-DeCani alpha-spending function 
with gamma parameter (-4) is used to construct group sequential boundaries to control the 
type I error rate. For OS (H4 – NI monotherapy vs. SOC in the CPS1 population), a Hwang-
Shih-DeCani alpha-spending function with gamma parameter (-15) is used to construct group 
sequential boundaries to control the type I error rate.
For H2, the actual boundaries and the alpha level will be determined from the number of 
events observed at the time of the interim analyses using the corresponding alpha-spending 
function. The boundary for the final analysis will be adjusted according to the actual alpha 
spent at the IAs and the actual number of events observed at the IA and FA.
For H1, H3, H4, H5, and H6, since the timing of the IAs are not driven by these hypotheses; 
alpha is spent as a function of the minimum of the actual event information fraction and the 
expected event information fraction.  This ensures that the actual spending will be no more 
aggressive than the planned, while at the same time ensuring that not all alpha is spent prior 
to final planned event counts. If events accrue more slowly than expected or the same as 
expected, spending will be based on actual information fraction. If events accrue more 
quickly than expected, cumulative spending based on the expected information fraction will 
be used in order to save some alpha for analyses that will be performed with more than the 
 
 
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originally planned maximum events.  For example, at IA1 for H3, if 125 OS events have 
occurred (ie, more than the expected 111 OS events), the alpha spending at IA1 will be 
according to the expected information fraction (111/147 = 76%) instead of the actual 
information fraction (125/147 = 85%).
Table 15 summarizes the timing, sample size, and decision guidance of the interim analyses
and FA. Bounds are based on estimated number of events and the alpha allocated at the 
design stage of the study and will be updated at the time of the analyses using the observed 
number of events, the alpha re-allocation and spending functions as noted above.
Table 15
Decision Guidance at Each Efficacy Analysis
Analysis
Criteria for 
Conduct of 
Analysis
Testing
Value
Efficacy
Interim Analysis 1 
(Interim OS 
analysis/ PFS 
analysis)
10 months after last 
subject randomized 
and at least 317 OS 
events in the 
combination arm 
and SOC arm, in 
subjects with PD-
L1 CPS1 whichever 
comes later
PFS (H1) :
pembrolizumab 
in
combination 
with 
SOC vs. SOC, in 
subjects with PD-L1 
CPS1
p value (1-sided)
≤0.0007
~ HR at bound (~
389 events)
0.723
OS (H2):
Pembrolizumab 
in
combination 
with 
SOC 
vs. 
SOC in 
subjects with PD-L1 
CPS1
p value (1-sided) 
≤0.0047
~ HR at bound
(~317 events)
0.747
OS 
(H3): 
Pembrolizumab 
in 
combination 
with 
SOC 
vs. 
SOC 
in 
subjects with PD-L1 
CPS10
p value (1-sided)
<=0.0027
~ HR at bound
(~111 events)
0.590
OS 
(H4): 
Non-
inferiority 
of 
Pembrolizumab mono 
therapy vs. SOC in 
subjects with PD-L1 
CPS1
p value (1-sided)
≤0.0001
~ HR at bound 
(~ 317 events) 
0.7935
OS 
(H5): 
Pembrolizumab mono 
therapy vs. SOC in 
subjects with PD-L1 
CPS1
p value (1-sided)
≤ 0.0015
~ HR at bound 
(~ 317 events) 
0.717
OS (H6): 
Pembrolizumab mono 
therapy vs. SOC, in 
subjects with PD-L1 
CPS10
p value (1-sided)
≤0.0027
~ HR at bound 
(~ 112 events)
0.592
 
 
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Analysis
Criteria for 
Conduct of 
Analysis
Testing
Value
Efficacy
Interim Analysis 2
(Interim OS
analysis/ Final PFS 
analysis)
16 months after the
last subject is
randomized and at
least 369 OS events
are observed in the
Combination arm
and SOC arm,
whichever comes
later
PFS (H1):
pembrolizumab 
in
combination 
with 
SOC
vs. SOC, in 
subjects with PD-L1 
CPS1
p value (1-sided)
≤0.0007
~ HR at bound
(~430 events)
0.735
OS (H2):
Pembrolizumab 
in
combination 
with 
SOC vs. SOC, in 
subjects with PD-L1 
CPS1
p value (1-sided)
≤0.0063
~ HR at bound
(~ 369 events)
0.771
OS (H3):
Pembrolizumab 
in 
combination 
with 
SOC vs. SOC, in 
subjects with PD-L1 
CPS10
p value (1-sided)
≤0.0037
~ HR at bound
(~130 events)
0.624
OS 
(H4) 
Non-
inferiority: 
Pembrolizumab 
vs. 
SOC, in subjects with 
PD-L1 CPS1
p value (1-sided)
≤0.0007
~ HR at bound 
(~ 369 events)
0.862
OS (H5) superiority: 
Pembrolizumab 
vs. 
SOC, in subjects with 
PD-L1 CPS1
p value (1-sided)
≤0.0019
~ HR at bound (~ 
369 events)
0.740
OS (H6) superiority: 
Pembrolizumab 
vs. 
SOC, in subjects with 
PD-L1 CPS10
p value (1-sided)
≤0.0037
~ HR at bound 
(~ 131 events)
0.626
 
 
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Analysis
Criteria for 
Conduct of 
Analysis
Testing
Value
Efficacy
Final Analysis: OS 
analysis
22 months after the
last 
subject 
is
randomized 
and
approximate 
415
OS 
events 
are
observed 
in 
the
combination 
arm
and SOC arm, in 
subjects with PD-
L1 CPS1.
OS (H2):
Pembrolizumab 
in
combination 
with 
SOC vs. SOC, in 
subjects with PD-L1 
CPS1.
p value (1-sided)
≤0.0099
~ HR at bound
( ~ 415 events)
0.795
OS 
(H3) 
Pembrolizumab 
in 
combination 
with 
SOC vs. SOC, in 
subjects with PD-L1 
CPS10 
p value (1-sided)
≤0.0058
~ HR at bound
(~ 147 events)
0.659
OS 
(H4) 
non-
inferiority 
pembrolizumab mono 
therapy vs. SOC, in 
subjects with PD-L1 
CPS1
p value (1-sided)
≤0.0039
HR 
at 
bound
( ~ 415 events)
0.925
OS (H5) superiority: 
Pembrolizumab 
vs. 
SOC, in subjects with 
PD-L1 CPS1
p value (1-sided)
≤0.003
~ HR at bound 
(~415 events)
0.763
OS (H6) superiority: 
Pembrolizumab 
vs. 
SOC, in subjects with 
PD-L1 CPS10
p value (1-sided)
≤0.0058
~ HR at bound 
(~ 148 events) 
0.661
For ORR, the analysis population is subjects with 10 months follow up. Based on the current 
timing of IA1, all subjects will have 10 months follow-up by IA1. Interim analysis 1 will be 
the final analysis for ORR (H7).
Multiplicity
The multiplicity strategy specified in this section will be applied to the primary hypotheses 
PFS(H1) and OS(H2, H3, H4, H5, H6) and the secondary hypothesis ORR(H7) to control the 
overall Type-I error at 2.5% (one-sided). The graphical approach of Mauer and Bretz [44] is 
followed.
Figure 2 provides the multiplicity strategy diagram of the trial. In this approach, when a 
particular null hypothesis is rejected, the arrow(s) leading to it are removed, and the Type I 
error allocated to the null hypothesis that was rejected is re-distributed to the other 
hypotheses. 
There are three treatment arms in the study. Initially α=0.1%, 1.25%, 0.75% and 0% is 
allocated to the PFS-PD-L1 CPS1 (H1), OS-PD-L1 CPS1 (H2), OS- PD-L1 CPS10 (H3) and 
ORR- PD-L1 CPS1 (H7) hypotheses, respectively for the Pembrolizumab in combination 
 
 
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with SOC versus SOC comparisons and α=0.4% is allocated to the non-inferiority hypothesis 
of monotherapy vs. SOC (control)- OS non-inf PD-L1 CPS1 (H4).
Figure 2
Multiplicity Strategy
Sample Size and Power Calculations
The study will randomize approximately 750 subjects in a 1:1:1 ratio among the three 
treatment arms: pembrolizumab as monotherapy (mono therapy), pembrolizumab in 
combination with SOC (combination therapy), and SOC (control).
The study is event driven (ie, follow-up times are subject to change but number of events is 
not). 
PFS:
At the final PFS-PD-L1 CPS1 (H1) analysis (IA2), approximately 16 months after the last 
subject is randomized approximately 430 PFS events will be accumulated in the combination 
therapy arm and control arm.  With 430 events, the study has ~91% power to detect a hazard 
ratio of 0.65 (pembrolizumab in combination with SOC vs. SOC) at alpha = 0.10% (one-
sided).  The sample size calculation is based on the following assumptions: 1) progression-
free survival follows an exponential distribution with a median of 6 months in the control 
arm, 2) an enrollment period of 19 months, and 3) a yearly dropout rate of 5%.
 
 
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OS:
At the FA, approximately 415 OS PD-L1 CPS1 (H2) events will be accumulated in the 
combination therapy arm and control arm. With 415 events, the study has ~91% power to 
detect a hazard ratio of 0.70 (pembrolizumab in combination with SOC vs. SOC) at alpha = 
1.25% (one-sided). These calculations are based on the following assumptions: 1) OS follows 
an exponential distribution with a median of 10 months in the control arm, 2) an enrolment
period of 19 months, and 3) a yearly dropout rate of 2%. 
At the final analysis, approximately 147 OS-PD-L1 CPS10 (H3) events will be accumulated 
in the combination therapy arm and control arm. With 147 events, the study has ~ 80% 
(73%) power to detect a hazard ratio of 0.58(0.60) (pembrolizumab in combination with SOC
vs. SOC in subgroup of subjects with PD-L1 CPS10) at alpha = 0.75% (one-sided)
For the monotherapy arm and the control arm, if there are 415 OS PD-L1 CPS1 events, the 
study has ~89% power to establish non-inferiority (H4) (NI margin =1.2) of pembrolizumab 
vs SOC (H4) at alpha=0.40% (one-sided) if HR = 0.82, and ~82% power (superiority, H5) to 
detect a HR = 0.70 at alpha = 0.40%. Following the FDA Guidance for Non-Inferiority 
Clinical Trials [52], the non-inferiority margin was based on retaining 50% of the control 
effect size (cisplatin and 5-fluorouracil vs. BSC), ie the lower bound of the confidence 
interval of the estimated control effect based on past studies. The control effect size is 
estimated as 0.67 based on Wagner 2006 [53] 
At the final analysis, approximately 148 OS-PD-L1 CPS10 (H6) events will be accumulated 
in the pembrolizumab and control arm. With 148 events, the study has ~ 80% (63%) power 
to detect a hazard ratio of 0.58(0.63) (pembrolizumab vs. SOC in subgroup of subjects with 
PD-L1 CPS10) at alpha = 0.75% (one-sided) 
The assumed median PFS and OS in the control arm are observed from standard of care in 
1L treatment of gastric cancer [45] [46]. 
The sample size and power calculations were performed in the software EAST 5.4. 
Subgroup Analyses and Effect of Baseline Factors
To determine whether the treatment effect is consistent across various subgroups, the 
estimate of the between-group treatment effect (with a nominal 95% CI) for the primary 
endpoint will be estimated and plotted within each category of the following classification 
variables:

Stratification factors

Geographic region of enrolling site (US and EU, ROW, Asia).

Disease Status: Locally advanced vs metastatic

Backbone therapy (5-FU vs. Capecitabine)
 
 
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
Age category (≤65 vs. >65 years)

Sex (female vs. male)

ECOG status (0 vs. 1)

Primary location: Stomach vs GEJ

Histological subtype: Diffuse vs intestinal vs mixed

Tumor Burden ( above and below median)

Number of metastasis: ≤2 vs ≥3

Prior Gastrectomy: yes vs no
COMPLIANCE (MEDICATION ADHERENCE)
Drug accountability data for trial treatment will be collected during the study. Any deviation 
from protocol-directed administration will be reported. 
EXTENT OF EXPOSURE
The extent of exposure will be summarized as duration of treatment in cycles.
9.0 LABELING, PACKAGING,
STORAGE AND RETURN OF CLINICAL 
SUPPLIES
Investigational Product
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations.
Clinical Supplies will be provided by the Sponsor as summarized in Table 16.  
Clinical supplies will be packaged to support enrollment and replacement subjects as 
required.  When a replacement subject is required, the Sponsor or designee needs to be 
contacted prior to dosing the replacement supplies.
 
 
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Table 16
Product Descriptions
Product Name & Potency
Dosage Form
Additional Information
Pembrolizumab (MK-3475), 
25 mg/mL
Injection
Provided 
centrally 
by 
the 
Sponsor
Cisplatin, 
1 mg/mL
Injection
Provided 
centrally 
by 
the 
Sponsor or locally by the trial 
site, subsidiary, or designee
Fluorouracil (5-FU), 
50 mg/mL
Injection
Provided 
centrally 
by 
the 
Sponsor or locally by the trial 
site, subsidiary, or designee
Capecitabine
150mg and 500 mg
Tablet
Provided 
centrally 
by 
the 
Sponsor or locally by the trial 
site, subsidiary, or designee
All supplies indicated in Table 16 will be provided per the “Additional Information” field 
depending on local country operational or regulatory requirements.
Any commercially available product not included in Table 16 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.
Packaging and Labeling Information
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
Study sites will receive open label MK-3475 vials and open label cisplatin and fluorouracil 
kits. Each kit will contain 1 commercial vial.
Study sites supplied with capecitabine centrally from the Sponsor will receive kit boxes 
containing 60 tablets of the 150 mg strength and kit boxes containing 120 tablets of the 500 
mg strength.
Clinical Supplies Disclosure
Treatment Arm 1 (pembrolizumab monotherapy) of the 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.
 
 
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Treatment in Arms 2 and 3 (pembrolizumab+chemotherapy and placebo+chemotherapy, 
respectively) 
of the trial is blinded but provided open label; therefore, an unblinded 
pharmacist or qualified trial site personnel will be used to blind supplies. Treatment identity 
(name, strength or potency) is included in the label text; random code/disclosure envelopes or 
lists are not provided.
The emergency unblinding call center will use the treatment/randomization schedule for the 
trial to unblind subjects and to unmask Treatment in Arms 2 and 3 (pembrolizumab+
chemotherapy and placebo+ chemotherapy, respectively) of the 
trial]. The emergency 
unblinding call center should only be used in cases of emergency (see Section 7.1.4.2). In 
the event that the emergency unblinding call center is not available for a given site in this 
trial, the central electronic treatment allocation/randomization system (IVRS/IWRS) should 
be used in order to unblind subjects and to unmask treatment/vaccine identity.  The Sponsor 
will not provide random code/disclosure envelopes or lists with the clinical supplies.
Treatment identification information is to be unmasked ONLY if necessary for the welfare of 
the subject.  Every effort should be made not to unblind the subject unless necessary. 
In the event that unblinding has occurred, the circumstances around the unblinding (e.g., date 
and reason) must be documented promptly, and the Sponsor Clinical Director notified as 
soon as possible.  Once an emergency unblinding has taken place, the principal investigator, 
site personnel, and Sponsor personnel may be unblinded so that the appropriate follow-up 
medical care can be provided to the subject.
Storage and Handling Requirements
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.  
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site.
Clinical supplies may not be used for any purpose other than that stated in the protocol.
Discard/Destruction/Returns and Reconciliation
The investigator is responsible for keeping accurate records of the clinical supplies received 
from the Sponsor or designee, the amount dispensed to and returned, 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.
 
 
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Standard Policies
Trial site personnel will have access to a central electronic randomization system 
(IVRS/IWRS system) to allocate subjects, to assign treatment to subjects and to manage the 
distribution of clinical supplies. Each person accessing the IVRS system must be assigned an 
individual unique PIN.  They must use only their assigned PIN to access the system, and they 
must not share their assigned PIN with anyone.
10.0
ADMINISTRATIVE AND REGULATORY DETAILS
Confidentiality
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the institutional review board, ethics review committee (IRB/ERC) or similar 
or expert committee; affiliated institution and employees, only under an appropriate 
understanding of confidentiality with such board or committee, affiliated institution and 
employees.  Data generated by this trial will be considered confidential by the investigator, 
except to the extent that it is included in a publication as provided in the Publications section 
of this protocol.
Confidentiality of Subject Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/ERC, or regulatory authority representatives may consult and/or copy trial documents in 
order to verify worksheet/case report form data.  By signing the consent form, the subject 
agrees to this process.  If trial documents will be photocopied during the process of verifying 
worksheet/case report form information, the subject will be identified by unique code only; 
full names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all subject data used and disclosed in 
connection with this trial in accordance with all applicable privacy laws, rules and 
regulations.
Confidentiality of Investigator Information
By signing this protocol, the investigator recognizes that certain personal identifying 
information with respect to the investigator, and all subinvestigators and trial site personnel, 
may be used and disclosed for trial management purposes, as part of a regulatory 
submissions, and as required by law.  This information may include:
1. name, address, telephone number and e-mail address;
2. hospital or clinic address and telephone number;
 
 
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3. curriculum vitae or other summary of qualifications and credentials; and
4. other professional documentation.
Consistent with the purposes described above, this information may be transmitted to the 
Sponsor, and subsidiaries, affiliates and agents of the Sponsor, in your country and other 
countries, including countries that do not have laws protecting such information.  
Additionally, the investigator’s name and business contact information may be included 
when reporting certain serious adverse events to regulatory authorities or to other 
investigators.  By signing this protocol, the investigator expressly consents to these uses and 
disclosures.
If this is a multicenter trial, in order to facilitate contact between investigators, the Sponsor 
may share an investigator’s name and contact information with other participating 
investigators upon request.
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC member that 
reviews and approves this trial.  The Sponsor is also required to document that each IRB/IEC 
meets regulatory and ICH GCP requirements by requesting and maintaining records of the 
names and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
Compliance with Financial Disclosure Requirements
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54).  It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required.  It is the investigator's/subinvestigator's 
responsibility to comply with any such request.  
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements.  
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor or through a secure password-protected electronic portal provided by the 
Sponsor.  The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes.  This may involve the 
transmission of information to countries that do not have laws protecting personal data.
Compliance with Law, Audit and Debarment
By signing this protocol, the investigator agrees to conduct the trial in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of Good 
Clinical Practice (e.g., International Conference on Harmonization of Technical 
 
 
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Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice: 
Consolidated Guideline and other generally accepted standards of good clinical practice); and 
all applicable federal, state and local laws, rules and regulations relating to the conduct of the 
clinical trial.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by Merck, is provided in Section 12.1 -
Merck Code of Conduct for Clinical Trials.
The investigator also agrees to allow monitoring, audits, IRB/ERC review and regulatory 
authority inspection of trial-related documents and procedures and provide for direct access 
to all trial-related source data and documents.
The investigator agrees not to seek reimbursement from subjects, their insurance providers or 
from government programs for procedures included as part of the trial reimbursed to the 
investigator by the Sponsor.
The investigator shall prepare and maintain complete and accurate trial documentation in 
compliance with Good Clinical Practice standards and applicable federal, state and local 
laws, rules and regulations; and, for each subject participating in the trial, provide all data, 
and, upon completion or termination of the clinical trial, submit any other reports to the 
Sponsor as required by this protocol or as otherwise required pursuant to any agreement with 
the Sponsor.
Trial documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the trial site upon request for inspection, 
copying, review and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities.  The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor as a result of an audit to cure deficiencies in the trial documentation 
and worksheets/case report forms.
The investigator must maintain copies of all documentation and records relating to the 
conduct of the trial in compliance with all applicable legal and regulatory requirements.  This 
documentation includes, but is not limited to, the protocol, worksheets/case report forms, 
advertising for subject participation, adverse event reports, subject source data, 
correspondence with regulatory authorities and IRBs/ERCs, consent forms, investigator’s 
curricula vitae, monitor visit logs, laboratory reference ranges, laboratory certification or 
quality control procedures and laboratory director curriculum vitae.  By signing this protocol, 
the investigator agrees that documentation shall be retained until at least 2 years after the last 
approval of a marketing application in an ICH region or until there are no pending or 
contemplated marketing applications in an ICH region or until at least 2 years have elapsed 
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 
 
 
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period and upon request, will provide guidance to the investigator when documents no longer 
need to be retained.  The sponsor also recognizes that documents may need to be retained for 
a longer period if required by local regulatory requirements. All trial documents shall be 
made available if required by relevant regulatory authorities. The investigator must consult 
with and obtain written approval by the Sponsor prior to destroying trial and/or subject files.  
ICH Good Clinical Practice guidelines recommend that the investigator inform the subject’s 
primary physician about the subject’s participation in the trial if the subject has a primary 
physician and if the subject agrees to the primary physician being informed.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this trial.
Persons debarred from conducting or working on clinical trials by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s trials.  The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the trial is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will 
promptly notify that trial site’s IRB/IEC.
According to European legislation, a Sponsor must designate an overall coordinating 
investigator for a multi-center trial (including multinational).  When more than one trial site 
is open in an EU country, Merck, as the Sponsor, will designate, per country, a national 
principal coordinator (Protocol CI), responsible for coordinating the work of the principal 
investigators at the different trial sites in that Member State, according to national 
regulations.  For a single-center trial, the Protocol CI is the principal investigator.  In 
addition, the Sponsor must designate a principal or coordinating investigator to review the 
trial report that summarizes the trial results and confirm that, to the best of his/her 
knowledge, the report accurately describes the conduct and results of the trial [Clinical Study 
Report (CSR) CI].  The Sponsor may consider one or more factors in the selection of the 
individual to serve as the Protocol CI and or CSR CI (e.g., availability of the CI during the 
anticipated review process, thorough understanding of clinical trial methods, appropriate
enrollment of subject cohort, timely achievement of trial milestones).  The Protocol CI must 
be a participating trial investigator.
Compliance with Trial Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Amendments Act (FDAAA) of 2007 
and the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, the Sponsor 
of the trial is solely responsible for determining whether the trial and its results are subject to 
the 
requirements 
for 
submission 
to 
http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries.  Merck, as Sponsor of this trial, will 
review this protocol and submit the information necessary to fulfill these requirements. 
Merck entries are not limited to FDAAA or the EMA clinical trial directive mandated trials.  
 
 
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Information posted will allow subjects to identify potentially appropriate trials for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate trial locations and trial site contact information.  
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this trial or its results to those 
registries.
Quality Management System
By signing this protocol, the Sponsor agrees to be responsible for implementing and 
maintaining a quality management system with written development procedures and 
functional area standard operating procedures (SOPs) to ensure that trials are conducted and 
data are generated, documented, and reported in compliance with the protocol, accepted 
standards of Good Clinical Practice, and all applicable federal, state, and local laws, rules and 
regulations relating to the conduct of the clinical trial.
Data Management
The investigator or qualified designee is responsible for recording and verifying the accuracy 
of subject data.  By signing this protocol, the investigator acknowledges that his/her 
electronic signature is the legally binding equivalent of a written signature.  By entering 
his/her electronic signature, the investigator confirms that all recorded data have been 
verified as accurate.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
Publications
This trial is intended for publication, even if terminated prematurely. Publication may include 
any or all of the following: posting of a synopsis online, abstract and/or presentation at a 
scientific conference, or publication of a full manuscript.  The Sponsor will work with the 
authors to submit a manuscript describing trial results within 12 months after the last data 
become available, which may take up to several months after the last subject visit in some 
cases such as vaccine trials.  However, manuscript submission timelines may be extended on 
OTC trials.  For trials intended for pediatric-related regulatory filings, the investigator agrees 
to delay publication of the trial results until the Sponsor notifies the investigator that all 
relevant regulatory authority decisions on the trial drug have been made with regard to 
pediatric-related regulatory filings. Merck will post a synopsis of trial results for approved 
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 
 
 
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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.
11.0 LIST OF REFERENCES
1. Ji, Y., Liu, P., Li, Y., & Bekele, B. N. (2010). A modified toxicity probability interval 
method for dose-finding trials. Clinical Trials (London, England), 7(6), 653–63
2. Disis ML. Immune regulation of cancer. J Clin Oncol 2010; 28(29):4531-8.
3. 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.  
 
 
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4. Sharpe AH, Freeman GJ. The B7-CD28 superfamily. Nature 2002;2:116-26.
5. 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.  
6. Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity. 
Immunol Rev 2010;236:219-42.
7. 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.  
8. Talmadge JE, Donkor M, Scholar E. Inflammatory cell infiltration of tumors: Jekyll or 
Hyde. Cancer Metastasis Rev 2007;26:373-400.
9. 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.
10. Al-Shibli KI, Donnem T, Al-Saad S, Persson M, Bremnes RM, Busund L-T. Prognostic 
effect of epithelial and stromal symphocyte infiltration in non-small cell lung cancer. Clin 
Cancer Res 2008;14(16):5220-7.
11. 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.
12. 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.
13. 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.
14. Hiraoka N. Tumor-infiltrating lymphocytes and hepatocellular carcinoma: molecular 
biology. Int J Clin Oncol 2010;15:544-51.
15. 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.
16. Hodi FS, Dranoff G. The biologic importance of tumor-infiltrating lymphocytes. J Cutan 
Pathol 2010;37(Suppl 1):48-53.
 
 
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17. Kloor M. Lymphocyte infiltration and prognosis in colorectal cancer. Lancet 
2009;10:840-841.
18. 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.
19. 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.
20. 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.
21. 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.
22. 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.
23. Bass, AJ et.al, Comprehensive molecular characterization of gastric adenocarcinoma. 
Nature 513:202-209, 2014.
24. 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.
25. 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.
26. 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.
27. Pölcher M, Braun M, Friedrichs N, Rudlowski C, Bercht E, Fimmers R, et al. Foxp3+ 
cell infiltration and granzyme B+/Foxp3+ cell ratio are associated with outcome in 
neoadjuvant chemotherapy-treated ovarian carcinoma. Cancer Immunol Immunother 
2010;59:909-19.
28. 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.
 
 
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29. Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Annu Rev Immunol 
2005;23:515-48
30. Muro K, et al. A Phase Ib Study of MK-3475 in Patients with Gastric Cancer. Ann Oncol. 
2014;25(Suppl 4)
31. Van Cutsem E, Kang Y, Chung H, Shen L, Sawaki S, Lordick F, et al.  Efficacy results 
from the ToGA trial: A phase III study of trastuzumab added to standard chemotherapy 
(CT) in first-line human epidermal growth factor receptor 2 (HER2)-positive advanced 
gastric cancer (GC).  J Clin Oncol.  2009;27(18S):Abstract LBA4509
32. Rivera F, Vega-Villegas ME, López-Brea MF.  Chemotherapy of advanced gastric 
cancer.  Cancer Treat Rev.  2007;33(4):315-324.
33. Wöhrer SS, Raderer M, Hejna M.  Palliative chemotherapy for advanced gastric cancer.  
Ann Oncol.  2004;15(11):1585-1595
34. Van Cutsem E, Moiseyenko VM, Tjulandin S, Majlis A, Constenla M, Boni C, et al.  
Phase III study of docetaxel and cisplatin+ fluorouracil compared with cisplatin and 
fluorouracil as first-line therapy for advanced gastric cancer: A report of the V325 Study 
Group.  J Clin Oncol. 2006;24:4991-4997
35. Cunningham D, Starling N, Rao S, Iveson T, Nicolson M, Coxon F, et al.  Capecitabine 
and oxaliplatin for advanced esophagogastric cancer.  N Engl J Med.  2008;358:36-46.
36. Kang YK, Kang WK, Shin DB, Chen J, Xiong J, Wang J, et al.  Capecitabine/cisplatin 
versus 5-fluorouracil/cisplatin as first-line therapy in patients with advanced gastric 
cancer: a randomised phase III noninferiority trial.  Ann Oncol.  2009;20(4):666-673
37. Koizumi W, Narahara H, Hara T, Takagane A, Akiya T, Takagi M, et al.  S-1 plus 
cisplatin versus S-1 alone for first-line treatment of advanced gastric cancer (SPIRITS 
trial): a phase III trial.  Lancet Oncol.  2008;9(3):215-221
38. Ajani JA, Rodriguez W, Bodoky G, Moiseyenko V, Lichinitser M, Gorbunova V, et al. 
Multicenter phase III comparison of cisplatin/S-1 (CS) with cisplatin/5-FU (CF) as first-
line therapy in patients with advanced gastric cancer (FLAGS). Am Soc Clin Oncol.  
2009; Gastrointestinal Cancers Symposium.  Abstract #8
39. 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
40. Finkelstein DM (1986). A proportional hazards model for interval-censored failure time 
data. Biometrics 42, 845-54.
41. Uno, H., et al. Moving Beyond the Hazard Ratio in Quantifying the Between-Group 
Difference in Survival Analysis. J Clin Oncol. 2014; 32 (22): 2380-2385.
 
 
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42. Odell P.M., Anderson K.M., Kannel B.W. New models for predicting cardiovascular 
events. Journal of Clinical Epidemiology 1994; 47(6): 583-592.
43. Robins, J.M., Tsiatis, A.A. Correcting for non-compliance in randomized trials using 
rank preserving structural failure time models. Communications in Statistics-Theory and 
Methods, 1991;20 (8): 2609-2631.
44. Maurer W, Bretz F. Multiple Testing in Group Sequential Trials using Graphical 
Approaches. Statistics in Biopharmaceutical Research 2013; 5(4): 311-320.
45. Bang, Y., VanCutsem, E., Feyereislova, A., et al. Trastuzumab in combination with 
chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced 
gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomized 
controlled trial. Lancet, 2010:376:687-97.
46. Ohtsu, A., Shah, M.A., VanCutsem, E., et al. Bevacizumab in combination with 
chemotherapy as first-line therapy in advanced gastric cancer: a randomized double-
blind, placebo-controlled phase III study. J Clin Oncol. 2011;29:3968-3976.
47. 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.
48. Ferris, R.L., et al. Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and
Neck. N Engl J Med 2016; 375:1856-1867.
49. Borghaei, H., et al. Nivolumab versus Docetaxel in Advanced Nonsquamous Non–Small-
Cell Lung Cancer. N Engl J Med 2015; 373:1627-1639.
50. Bellmunt J., et al. Pembrolizumab as Second-Line Therapy for Advanced Urothelial
Carcinoma. N Eng J Med: February 17, 2017DOI: 10.1056/NEJM.
51. Nishino, M. et al, “Developing a Common Language for Tumor Response to 
Immunotherapy: Immune-Related Criteria Using Unidimensional Measurements”. Clin 
Cancer Res; 19: 3936-43 (2013).
52. Guidance for Industry: Non-Inferiority Clinical Trials to Establish Effectiveness (2016).
53. Wagner, A. D. et. al. ‘Chemotherapy in Advanced Gastric Cancer: A Systematic Review 
and Meta-Analysis Based on Aggregate Data”. Journal of Clinical Oncology; Vol 24: 
Number 18;2903-2908.
 
 
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12.0
APPENDICES
Merck Code of Conduct for Clinical Trials
Merck*
Code of Conduct for Clinical Trials
I.
Introduction
A. Purpose
Merck, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing and reporting these trials in 
compliance with the highest ethical and scientific standards. Protection of subject safety is the overriding concern in 
the design of clinical trials. In all cases, Merck clinical trials will be conducted in compliance with local and/or 
national regulations and in accordance with the ethical principles that have their origin in the Declaration of Helsinki. 
B. Scope
Such standards shall be endorsed for all clinical interventional investigations sponsored by Merck irrespective of the 
party (parties) employed for their execution (e.g., contract research organizations, collaborative research efforts). This 
Code is not intended to apply to trials which are observational in nature, or which are retrospective. Further, this Code 
does not apply to investigator-initiated trials which are not under the control of Merck.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of Merck or comparator products.  Alternatively, Merck may 
conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to determine 
subject preferences, etc.  
The design (i.e., subject population, duration, statistical power) must be adequate to address the specific purpose 
of the trial.  Research subjects must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
Merck selects investigative sites based on medical expertise, access to appropriate subjects, adequacy of facilities 
and staff, previous performance in Merck trials, as well as budgetary considerations.  Prior to trial initiation, sites 
are evaluated by Merck personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Trial sites are monitored to assess compliance with the trial protocol and general principles of Good Clinical 
Practice.  Merck reviews clinical data for accuracy, completeness and consistency. Data are verified versus source 
documentation according to standard operating procedures.  Per Merck policies and procedures, if fraud, 
misconduct or serious GCP-non-Compliance are suspected, the issues are promptly investigated. When necessary, 
the clinical site will be closed, the responsible regulatory authorities and ethics review committees notified and 
data disclosed accordingly. 
B. Publication and Authorship
To the extent scientifically appropriate, Merck seeks to publish the results of trials it conducts.  Some early phase or 
pilot trials are intended to be hypothesis-generating rather than hypothesis testing.  In such cases, publication of 
results may not be appropriate since the trial may be underpowered and the analyses complicated by statistical issues 
of multiplicity.
Merck’s policy on authorship is consistent with the requirements outlined in the ICH-Good Clinical Practice 
guidelines. In summary, authorship should reflect significant contribution to the design and conduct of the trial, 
performance or interpretation of the analysis, and/or writing of the manuscript.  All named authors must be able to 
defend the trial results and conclusions.  Merck funding of a trial will be acknowledged in publications. 
 
 
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III. Subject Protection
A. IRB/ERC review
All clinical trials will be reviewed and approved by an independent IRB/ERC before being initiated at each site.  
Significant changes or revisions to the protocol will be approved by the IRB/ERC prior to implementation, except that 
changes required urgently to protect subject safety and well-being may be enacted in anticipation of IRB/ERC 
approval. For each site, the IRB/ERC and Merck will approve the subject informed consent form. 
B. Safety
The guiding principle in decision-making in clinical trials is that subject welfare is of primary importance.  Potential 
subjects will be informed of the risks and benefits of, as well as alternatives to, trial participation. At a minimum, trial
designs will take into account the local standard of care.  Subjects are never denied access to appropriate medical care 
based on participation in a Merck clinical trial. 
All participation in Merck clinical trials is voluntary.  Subjects are enrolled only after providing informed consent for 
participation.  Subjects may withdraw from a Merck trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
Merck is committed to safeguarding subject confidentiality, to the greatest extent possible. Unless required by law, 
only the investigator, sponsor (or representative) and/or regulatory authorities will have access to confidential medical 
records that might identify the research subject by name.  
D. Genomic Research
Genomic Research will only be conducted in accordance with informed consent and/or as specifically authorized by 
an Ethics Committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive.  It is Merck’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of Merck trials.   Merck does not pay incentives to 
enroll subjects in its trials.  However, when enrollment is particularly challenging, additional payments may be made 
to compensate for the time spent in extra recruiting efforts.
Merck does not pay for subject referrals.  However, Merck may compensate referring physicians for time spent on 
chart review to identify potentially eligible subjects.
B. Clinical Research Funding 
Informed consent forms will disclose that the trial is sponsored by Merck, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial.  However, the local IRB/ERC may wish to alter 
the wording of the disclosure statement to be consistent with financial practices at that institution.  As noted above, 
publications resulting from Merck trials will indicate Merck as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices including, in the U.S., those established by the American Medical 
Association (AMA). 
V. Investigator Commitment
Investigators will be expected to review Merck’s Code of Conduct as an appendix to the trial protocol, and in signing 
the protocol, agree to support these ethical and scientific standards.
* In this document, "Merck" refers to Merck Sharp & Dohme Corp. and Schering Corporation, each of which is a 
subsidiary of Merck & Co., Inc.  Merck is known as MSD outside of the United States and Canada.  As warranted by 
context, Merck also includes affiliates and subsidiaries of Merck & Co., Inc."
 
 
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Collection and Management of Specimens for Future Biomedical Research
1. Definitions
a.
Biomarker:  A biological molecule found in blood, other body fluids, or tissues that is 
a sign of a normal or abnormal process or of a condition or disease.  A biomarker may 
be used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics:  The investigation of variations of DNA and RNA characteristics 
as related to drug/vaccine response.2
c.
Pharmacogenetics:  A subset of pharmacogenomics, pharmacogenetics is the 
influence of variations in DNA sequence on drug/vaccine response.2
d. DNA:  Deoxyribonucleic acid.
e.
RNA:  Ribonucleic acid.
2. Scope of Future Biomedical Research
The specimens collected in this trial as outlined in Section 7.1.3.3 – 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 the 
Future Biomedical Research sub-trial.
b. Informed Consent
Informed consent for specimens (i.e., DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all subjects or legal guardians, at a trial 
visit by the investigator or his or her designate.  Informed consent for Future 
Biomedical Research should be presented to the subjects on Visit 1.  If delayed, 
present consent at next possible Subject Visit. Informed consent must be obtained 
prior to collection of all Future Biomedical Research specimens.  Consent forms 
signed by the subject will be kept at the clinical trial site under secure storage for 
regulatory reasons.  Information contained on the consent form alone cannot be traced 
 
 
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to any specimens, test results, or medical information once the specimens have been 
rendered de-identified
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 this sub-trial.  Future Biomedical Research 
specimens remaining with the third party after the specific analysis is performed will be 
 
 
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returned to the sponsor or destroyed and documentation of destruction will be reported to 
Merck.
6. Withdrawal From Future Biomedical Research 
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   Subjects may withdraw consent at any time by 
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. No additional 
risks to the subject have been identified as no additional specimens are being collected 
for Future Biomedical Research (ie, only leftover samples are being retained
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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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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ECOG Performance Status
GRADE ECOG PERFORMANCE STATUS
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light or sedentary nature, eg, light house work, office work
2
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
Capable of only limited self-care; confined to bed or chair more than 50% of 
waking hours
4
Completely disabled; cannot carry on any self-care; totally confined to bed or 
chair
5
Dead
*Oken M, Creech R, Tormey D, et al. Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol. 1982;5:649-655
http://ecog-acrin.org/resources/ecog-performance-status
 
 
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Common Terminology Criteria for Adverse Events V4.0 (CTCAE)
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0 will be utilized for AE
reporting. 
(http://ctep.cancer.gov/reporting/ctc.html).
 
 
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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 [46].
 
 
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Dose Modification Table (based on modified Toxicity Profile Interval [33]
Sample size = 40a; 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 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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List of Abbreviations
Abbreviation/Term
Definition
1L
First Line
2L
Second Line
5-FU
5-fluorouracil
AE
Adverse Event
ADA
Anti-Drug Antibodies
ALT
Alanine Aminotransferase
ANC
Absolute Neutrophil Count
AP
Alkaline Phosphatase
ASaT
All Subjects as Treated
aPTT
Activated Partial Thromboplastin Time
ASCO
American Society of Clinical Oncology
AST
Aspartate Aminotransferase
AUC
Area Under the Curve
BICR
Blinded Independent Central Review
BID
Twice a Day
ß-HCG
Beta Human Chorionic Gonadotropin
BSA
Body Surface Area
CBC
Complete Blood Count
CI
Confidence Interval
CNS
Central Nervous System
CPS
Combined Positive Score 
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
DCR
Disease Control Rate
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic acid
DOR
Duration of Response
DR
Drug Related
ECI
Events of Clinical Interest
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eDMC
external Data Monitoring Committee
EOC
Executive Oversight Committee
EORTC
European Organization for Research and Treatment of Cancer
ePRO
Electronic Patient Reported Outcomes
ERC
Ethics Review Committee
FA
Final Analysis
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
FNA
Fine Needle Aspirate
 
 
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Abbreviation/Term
Definition
FP
Cisplatin + 5-fluoruracil
GCP
Good Clinical Practice
GEJ
Gastroesophageal Junction
5-FU
5-fluoruracil 
GFR
Glomerular Filtration Rate
HBsAg
Hepatitis B surface Antigen
HCV
Hepatitis C Virus
HER2/neu
Human Epidermal Growth Factor Receptor 2
HIV
Human Immunodeficiency Virus
HNSCC
Head and Neck Squamous Cell Carcinoma
HPV
Human Papillomavirus
HRQoL
Health Related Quality of Life
IA
Interim Analysis
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IHC
Immunohistochemistry
INR
International Normalized Ratio
irAEs
Immune-related Adverse Events
irRECIST
Modification of RECIST 1.1
IRB
Institutional Review Board
ITIM
Immunoreceptor Tyrosine-based Inhibition Motif
ITSM
Immunoreceptor Tyrosine-based Switch Motif
ITT
Intention To Treat
IV
Intravenous
IVRS
Interactive Voice Response System
IWRS
Integrated Web Response System
Kg
Kilogram
KN
KEYNOTE
LDH
Lactate Dehydrogenase
mAb
Monoclonal Antibody
mcL
Microliters
MEL
Melanoma 
Mg
Milligram
Mg/kg
Milligram per Kilogram
mL
milliliter
MRI
Magnetic Resonance Imaging
MSD
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
MTD
Maximum Tolerated Dose
NA or N/A
Not Applicable
NCI
National Cancer Institute
NSAID
Non-Steroidal Anti-inflammatory Drug
NSCLC
Non-Small Cell Lung Cancer
ORR
Overall Response Rate
OS
Overall Survival
OTC
Over-the-counter
PD
Progressive Disease
PD-1
Programmed Death-1
PD-L1
Programmed Death-Ligand 1
PFS
Progression Free Survival
 
 
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Abbreviation/Term
Definition
PGt
Pharmacogenetic
PIN
Personal Identification Number
PK
Pharmacokinetic
PK/PD
Pharmacokinetic/Pharmacodynamic
PO
Oral Administration
PR
Partial Response
PRO
Patient Reported Outcomes
PT
Prothrombin Time
PS
Performance Status
QoL
Quality of Life
R/M
Recurrent or Metastatic
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
Ribonucleic Acid
RR
Response Rate
QoL
Quality of Life
Q2W
Every 2 Weeks
Q3W
Every 3 Weeks
SAC
Scientific Advisory Committee
SAE
Serious Adverse Events
SAP
Statistical Analysis Plan
SD
Stable disease 
SFU
Survival Follow-Up
SGOT
Serum Glutamic Oxaloacetic Transaminase
SGPT
Serum Glutamic Pyruvic Transaminase
siDMC
Standing Internal Data Monitoring Committee
SIM
Site Imaging Manual 
SOC
Standard of Care
SOP
Standard Operating Procedures
T1DM
Type 1 Diabetes Mellitus
TIL
Tumor Infiltrating Lymphocytes
TSH
Thyroid Stimulating Hormone
ULN
Upper Limit of Normal
WBC
White Blood Cell
 
 
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13.0 SIGNATURES
Sponsor's Representative
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
Investigator
I agree to conduct this clinical trial in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol (including other manuals and documents 
referenced from this protocol).  I agree to conduct the trial in accordance with generally 
accepted standards of Good Clinical Practice.  I also agree to report all information or data in 
accordance with the protocol and, in particular, I agree to report any serious adverse events 
as defined in Section 7.0 – 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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