Clinical trial NCT03019588
Conditions: Gastric Neoplasms Gastroesophageal Junction Adenocarcinoma
Keywords: Programmed Cell Death-1 (PD1, PD-1) Programmed Cell Death 1 Ligand 1 (PDL1, PD-L1) Programmed Cell Death 1 Ligand 2 (PDL2, PD-L2)
Sponsor: Merck Sharp & Dohme LLC
Start date: 2017-02-16; Completion date: 2021-06-29
Enrollment: 94 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The study will compare the efficacy and safety of treatment with pembrolizumab (MK-3475) versus paclitaxel in Asian, programmed death-ligand 1 (PD-L1) positive participants with advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma who have progressed after failure of any combination chemotherapy containing a platinum and a fluoropyrimidine agent.

The primary study hypotheses are that pembrolizumab prolongs Overall Survival (OS) compared to paclitaxel and that pembrolizumab prolongs Progression-free Survival (PFS) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) assessed by blinded central radiologists' review compared to paclitaxel.

Detailed description:
Once the participant has achieved the study objective or the study has ended, the participant will be discontinued from the study and may be enrolled in an extension study to continue protocol-defined assessments and treatment. Enrollment in the extension study will be conditional on participant consent. Treatment with pembrolizumab or paclitaxel will continue until documented disease progression, unacceptable adverse event(s), intercurrent illness that prevents further administration of treatment, investigator's decision to discontinue the participant, participant withdraws consent, pregnancy of the participant, participant receives 35 administrations (approximately 2 years) of pembrolizumab, or administrative reasons requiring cessation of treatment.

Arms: arm 1: Participants receive pembrolizumab 200 mg intravenous (IV) infusion on Day 1 of each 3-week cycle for up to 35 cycles (up to approximately 2 years). arm 2: Participants receive paclitaxel 80 mg/m\^2 IV infusion on Days 1, 8 and 15 of each 4-week cycle for up to approximately 2 years.
Interventions: intervention 1: Pembrolizumab intervention 2: Paclitaxel
Intervention descriptions: intervention 1: IV infusion intervention 2: IV infusion

Protocol documents:
Prot_000.pdf: 
Official Protocol Title: 
NCT number: 
Document Date: 
A Phase III, Randomized, Open-label Clinical Trial of 
Pembrolizumab (MK-3475) versus Paclitaxel in Asian Subjects 
with Advanced Gastric or Gastroesophageal Junction
Adenocarcinoma who Progressed after First-Line Therapy with 
Platinum and Fluoropyrimidine
22-Apr-2020
NCT03019588


Product:  MK-3475 
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Protocol/Amendment No.: 063-03 
MK-3475-063-03 Final Protocol
22-Apr-2020
Confidential
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., 
WHITEHOUSE STATION, NJ, U.S.A.
SPONSOR:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. 
(hereafter referred to as the Sponsor or Merck)
One Merck Drive
P.O. Box 100
Whitehouse Station, New Jersey, 08889-0100, U.S.A.
Protocol-specific Sponsor Contact information can be found in the Investigator Trial File 
Binder (or equivalent).
TITLE:
A Phase III, Randomized, Open-label Clinical Trial of Pembrolizumab (MK-3475) versus 
Paclitaxel in Asian Subjects with Advanced Gastric or Gastroesophageal Junction 
Adenocarcinoma 
who 
Progressed 
after 
First-Line 
Therapy 
with 
Platinum 
and 
Fluoropyrimidine
EudraCT NUMBER:  [Not Applicable]
 
 
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TABLE OF CONTENTS
DOCUMENT HISTORY ..................................................................................................... 11
SUMMARY OF CHANGES................................................................................................ 12
1.0
TRIAL SUMMARY.................................................................................................. 17
2.0
TRIAL DESIGN........................................................................................................ 18
Trial Design ........................................................................................................... 18
Trial Diagram........................................................................................................ 20
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 20
Primary Objective(s) & Hypothesis(es).............................................................. 21
Secondary Objective(s) & Hypothesis(es)........................................................... 21
Exploratory Objectives......................................................................................... 21
4.0
BACKGROUND & RATIONALE.......................................................................... 21
Background ........................................................................................................... 21
Pharmaceutical and Therapeutic Background .................................................... 22
Gastric cancer Worldwide and in Asia/China.............................................. 22
Anti-PD-1 Blockage for Malignancy........................................................... 22
Anti PD-1 Antibody, Pembrolizumab.......................................................... 23
Pre-clinical Studies of Pembrolizumab............................................................... 23
Ongoing Clinical Trials....................................................................................... 24
Ongoing Clinical Trials in Gastric Cancer................................................... 24
Rationale................................................................................................................ 25
Rationale for the Trial and Selected Subject Population .................................... 25
Rationale for Dose Selection/Regimen/Modification......................................... 26
Rationale for Paclitaxel as the Comparator ................................................. 27
Rationale for Endpoints ...................................................................................... 27
Efficacy Endpoints....................................................................................... 27
Secondary Efficacy Endpoints..................................................................... 28
Safety Endpoints.......................................................................................... 28
Exploratory Endpoints ................................................................................. 28
 
 
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4.2.3.4.1
Exploratory Efficacy Endpoints............................................................ 28
4.2.3.4.2
Patient Reported Outcomes .................................................................. 29
4.2.3.4.3
Exploratory Biomarkers........................................................................ 30
Future Biomedical Research........................................................................ 31
Benefit/Risk ........................................................................................................... 31
5.0
METHODOLOGY ................................................................................................... 32
Entry Criteria........................................................................................................ 32
Diagnosis/Condition for Entry into the Trial...................................................... 32
Subject Inclusion Criteria.................................................................................... 32
Subject Exclusion Criteria .................................................................................. 34
Trial Treatment(s) ................................................................................................ 36
Dose Selection/Modification .............................................................................. 37
Dose Selection (Preparation) ....................................................................... 37
Dose Modification (Escalation/Titration/Other).......................................... 37
5.2.1.2.1
Dose Modification and Toxicity Management Guidelines for 
Pembrolizumab..................................................................................... 37
5.2.1.2.2
Dose Modification for Paclitaxel.......................................................... 42
Timing of Dose Administration.......................................................................... 44
Pembrolizumab ............................................................................................ 44
Paclitaxel...................................................................................................... 44
Trial Blinding...................................................................................................... 45
Randomization or Treatment Allocation............................................................ 45
Stratification.......................................................................................................... 45
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 45
Acceptable Concomitant Medications ................................................................ 45
Prohibited Concomitant Medication................................................................... 46
Rescue Medications & Supportive Care............................................................. 47
Supportive Care Guidelines for Pembrolizumab ................................................ 47
Supportive Care Guidelines for Paclitaxel.......................................................... 47
Diet/Activity/Other Considerations..................................................................... 48
Diet...................................................................................................................... 48
Contraception...................................................................................................... 48
 
 
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Use in Pregnancy ................................................................................................ 49
Use in Nursing Women....................................................................................... 49
Subject Withdrawal/Discontinuation Criteria................................................... 49
Discontinuation of Treatment ............................................................................. 49
Withdrawal from the Trial .................................................................................. 51
Subject Replacement Strategy............................................................................. 52
Beginning and End of the Trial ........................................................................... 52
Clinical Criteria for Early Trial Termination ................................................... 52
6.0
TRIAL FLOW CHART ........................................................................................... 53
Trial Flow Chart – Initial Treatment Phase for Pembrolizumab Arm........... 53
Trial Flow Chart – Initial Treatment Phase for Paclitaxel Arm...................... 57
Second Course Phase (Retreatment with Pembrolizumab).............................. 61
7.0
TRIAL PROCEDURES ........................................................................................... 63
Trial Procedures ................................................................................................... 63
Administrative Procedures.................................................................................. 63
Informed Consent......................................................................................... 63
7.1.1.1.1
General Informed Consent.................................................................... 63
7.1.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research................................................................................................ 64
Inclusion/Exclusion Criteria ........................................................................ 64
Subject Identification Card .......................................................................... 64
Medical History ........................................................................................... 64
7.1.1.4.1
Disease Details...................................................................................... 64
Prior and Concomitant Medications Review............................................... 65
7.1.1.5.1
Prior Medications.................................................................................. 65
7.1.1.5.2
Concomitant Medications..................................................................... 65
Assignment of Screening Number............................................................... 65
Assignment of Treatment/Randomization Number..................................... 65
Trial Compliance (Medication/Diet/Activity/Other)................................... 65
Clinical Procedures/Assessments........................................................................ 66
Adverse Event (AE) Monitoring.................................................................. 66
Physical Exam.............................................................................................. 66
 
 
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7.1.2.2.1
Full Physical Exam ............................................................................... 66
7.1.2.2.2
Directed Physical Exam........................................................................ 66
Vital Signs.................................................................................................... 66
12-Lead Electrocardiogram ......................................................................... 66
Eastern Cooperative Oncology Group (ECOG) Performance Status .......... 67
Tumor Imaging and Assessment of Disease................................................ 67
7.1.2.6.1
Initial Tumor Imaging........................................................................... 67
7.1.2.6.2
Tumor Imaging During Trial ................................................................ 67
7.1.2.6.3
Second Course (Retreatment Tumor Imaging)..................................... 68
7.1.2.6.4
RECIST 1.1 Assessment of Disease..................................................... 68
7.1.2.6.5
irRECIST Assessment of Disease......................................................... 69
Tumor Tissue Collection and Correlative Blood Sampling......................... 73
Blood Collections – Samples for Correlative and Genetic Analyses .......... 73
Patient Reported Outcomes (PRO).............................................................. 74
Laboratory Procedures/Assessments .................................................................. 74
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) .. 74
Serum/Urine β-hCG..................................................................................... 75
Pharmacokinetic/Pharmacodynamic Evaluations........................................ 75
7.1.3.3.1
Blood Collection for Serum MK-3475 ................................................. 75
7.1.3.3.2
Blood Collection for Anti-pembrolizumab Antibodies ........................ 75
Planned Genetic Analysis Sample Collection.............................................. 76
Future Biomedical Research Samples ......................................................... 76
Other Procedures................................................................................................. 76
Withdrawal/Discontinuation........................................................................ 76
7.1.4.1.1
Withdrawal From Future Biomedical Research ................................... 76
Subject Blinding/Unblinding ....................................................................... 77
Calibration of Critical Equipment................................................................ 77
Visit Requirements.............................................................................................. 77
Screening...................................................................................................... 77
7.1.5.1.1
Pre-screening Period............................................................................. 77
7.1.5.1.2
Screening Period................................................................................... 78
Treatment Period.......................................................................................... 78
 
 
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Discontinued Subjects Continuing to be Monitored in the Trial................. 78
Post-Treatment............................................................................................. 79
7.1.5.4.1
Safety Follow-up................................................................................... 79
7.1.5.4.2
Follow-up Visits ................................................................................... 79
7.1.5.4.3
Survival Follow-up ............................................................................... 79
7.1.5.4.4
Survival Status...................................................................................... 79
Second Course Phase (Retreatment Period) ................................................ 80
Assessing and Recording Adverse Events .......................................................... 81
Definition of an Overdose for This Protocol and Reporting of Overdose to 
the Sponsor.......................................................................................................... 82
Reporting of Pregnancy and Lactation to the Sponsor ....................................... 82
Immediate Reporting of Adverse Events to the Sponsor.................................... 83
Serious Adverse Events ............................................................................... 83
Events of Clinical Interest............................................................................ 84
Protocol-Specific Exceptions to Serious Adverse Event Reporting............ 85
Evaluating Adverse Events................................................................................. 85
Sponsor Responsibility for Reporting Adverse Events ...................................... 88
TRIAL GOVERNANCE AND OVERSIGHT................................................... 88
Scientific Advisory Committee........................................................................... 88
Executive Oversight Committee......................................................................... 88
Data Monitoring Committee............................................................................... 88
8.0
STATISTICAL ANALYSIS PLAN ........................................................................ 89
Statistical Analysis Plan Summary ..................................................................... 89
Responsibility for Analyses/In-House Blinding ................................................. 90
Hypotheses/Estimation ......................................................................................... 91
Analysis Endpoints ............................................................................................... 91
Efficacy Endpoints.............................................................................................. 91
Safety Endpoints ................................................................................................. 91
Analysis Populations............................................................................................. 92
Efficacy Analysis Populations ............................................................................ 92
Safety Analysis Populations ............................................................................... 92
Statistical Methods................................................................................................ 92
 
 
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Statistical Methods for Efficacy Analyses.......................................................... 92
Overall Survival (OS) .................................................................................. 92
Progression-Free Survival (PFS) ................................................................. 93
Objective Response Rate (ORR) ................................................................. 94
Statistical Methods for Safety Analyses ............................................................. 95
Summaries of Demographic and Baseline Characteristics ................................. 97
Interim Analyses ................................................................................................... 97
Multiplicity ............................................................................................................ 99
Sample Size and Power Calculations .................................................................. 99
Subgroup Analyses and Effect of Baseline Factors ......................................... 100
Compliance (Medication Adherence)................................................................ 100
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ............................................................................................................... 101
Investigational Product ...................................................................................... 101
Packaging and Labeling Information ............................................................... 101
Clinical Supplies Disclosure............................................................................... 102
Storage and Handling Requirements................................................................ 102
Discard/Destruction/Returns and Reconciliation ............................................ 102
Standard Policies................................................................................................. 102
10.0
ADMINISTRATIVE AND REGULATORY DETAILS..................................... 102
Confidentiality..................................................................................................... 102
Confidentiality of Data ..................................................................................... 102
Confidentiality of Subject Records................................................................... 103
Confidentiality of Investigator Information...................................................... 103
Confidentiality of IRB/IEC Information........................................................... 103
Compliance with Financial Disclosure Requirements..................................... 104
Compliance with Law, Audit and Debarment ................................................. 104
Compliance with Trial Registration and Results Posting Requirements ...... 106
Quality Management System............................................................................. 106
Data Management............................................................................................... 106
Publications ......................................................................................................... 107
11.0
LIST OF REFERENCES....................................................................................... 108
 
 
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12.0
APPENDICES......................................................................................................... 113
Merck Code of Conduct for Clinical Trials...................................................... 113
Collection and Management of Specimens for Future Biomedical 
Research............................................................................................................... 115
Understanding the Intent, Scope and Public Health Benefits of 
Exploratory Biomarker Research: A Guide for IRBs/IECs and 
Investigational Site Staff .................................................................................... 119
ECOG Performance Status................................................................................ 130
Common Terminology Criteria for Adverse Events V4.0 (CTCAE)............. 131
List of Abbreviations .......................................................................................... 132
13.0
SIGNATURES......................................................................................................... 135
Sponsor's Representative ................................................................................... 135
Investigator.......................................................................................................... 135
 
 
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LIST OF TABLES
    
Table 1
Adequate Organ Function Laboratory Values ................................................ 34
Table 2
Trial Treatment ............................................................................................... 36
Table 3
Dose Modification and Toxicity Management Guidelines for 
Immune-related AEs Associated with Pembrolizumab.................................. 38
Table 4
Pembrolizumab Infusion Reaction Dose Modification and 
Treatment Guidelines...................................................................................... 41
Table 5
Criteria for Paclitaxel Treatment on Each Cycle............................................ 43
Table 6
Guidelines for Hypersensitivity Reactions in Paclitaxel Arm........................ 43
Table 7
Imaging and Treatment after First Radiologic Evidence of 
Progressive Disease (PD)................................................................................ 71
Table 8
Laboratory Tests ............................................................................................. 74
Table 9
Evaluating Adverse Events............................................................................. 86
Table 10
Censoring rules for Primary and Sensitivity Analyses of PFS ....................... 94
Table 11
Analysis Strategy for Key Efficacy Endpoints............................................... 95
Table 12
Analysis Strategy for Safety Parameters......................................................... 97
Table 13
Summary of Timing, Sample Size and Decision Guidance of 
Interim Analysis and Final analysis................................................................ 98
Table 14
Product Descriptions..................................................................................... 101
 
 
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LIST OF FIGURES
          
Figure 1
Trial Design Schematic....................................................................................... 20
Figure 2
Imaging and Treatment for Clinically Stable Subjects Treated with 
Pembrolizumab after First Radiologic Evidence of PD Assessed by 
the Site ............................................................................................................... 72
Figure 3
Multiplicity Strategy........................................................................................... 99
 
 
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
3475-063-03
22-APR-2020
Added standard extension study language
3475-063-02
17-NOV-2017
Changes made to update dose modification and toxicity management guidelines for 
pembrolizumab to align with the USPI and SMPC; additional changes made to allow 
flexibility in the entire follow-up period
3475-063-01
29-MAR-2017
Changes made to exclusion criteria and trial flow chart to be consistent with other 
pembrolizumab China/Asia pacific studies (except HCC)
3475-063-00 
07-JUN-2016
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
1.0
Trial Summary/Duration of 
Participation
Added: Once the participant has achieved the 
study objective or the study has ended, the 
participant is discontinued from the study and 
may be enrolled in an extension study to 
continue 
protocol-defined 
assessments 
and 
treatment.
To include extension study
2.2
Trial Diagram
Added: Study Completion and Pembrolizumab 
Extension Study
5.10
Beginning and End of the 
Trial
Added: Upon study completion, participants are 
discontinued and may be
enrolled in a 
pembrolizumab extension study. Enrollment in 
the extension study is conditional on subject 
consent.
 
 
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ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
Section 
Number (s)
Section Title (s)
Description of Change (s)
Rationale
1.0 
Trial Summary: Duration of 
Participation
Replaced 
word 
“withdraw” 
with 
“discontinue”: 
Treatment 
with 
pembrolizumab or paclitaxel will continue 
until 
documented 
disease 
progression, 
unacceptable adverse event(s), intercurrent 
illness that prevents further administration of 
treatment, investigator’s decision to withdraw
discontinue the subject, subject withdraws 
consent, pregnancy of the subject, subject 
receives 35 administrations (approximately 2 
years) of pembrolizumab, or administrative 
reasons requiring cessation of treatment.
To 
align 
with 
current 
pembrolizumab program
1.0
2.1
5.8.1
Trial Summary: Duration of 
Participation
Trial Design
Discontinuation of Treatment
Removed: 
Noncompliance 
with 
study 
treatment or procedure requirements
To 
align 
with 
current 
pembrolizumab 
program. 
The 
current wording of noncompliance 
with study treatment or procedure 
requirements created a protocol 
deviation when a participant remains 
on study
4.2.3.5
Future Biomedical Research
Statement updated to: The details of this
Future Biomedical Research sub-trial are 
presented in Section 12.2.
Due to EU CTR changes that will 
require FBR results to be reported if 
FBR is indicated as a sub-study to 
the clinical protocol.
 
 
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Section 
Number (s)
Section Title (s)
Description of Change (s)
Rationale
5.5.2
Prohibited 
Concomitant 
Medication
Systemic glucocorticoids for any purpose 
other than to modulate symptoms from an 
event of clinical interest AE that is suspected 
to have an immunologic etiology.  The use of 
physiologic doses of corticosteroids may be 
approved after consultation with the Sponsor 
(e.g., for control of acute asthma symptoms).
Event of clinical interest changed to 
AE since AEs with immunologic 
etiology are no longer routinely 
collected as ECIS
6.3
Second 
Course 
Phase 
(Retreatment 
with 
Pembrolizumab)
Footnote n: Added “See Section 7.1.2.6.3.”
To clarify tumor imaging procedures 
during Second Course Phase
7.1.1.1.2
Consent and Collection of 
Specimen 
for 
Future 
Biomedical Research
Statement updated to: The investigator or 
qualified designee will explain the Future 
Biomedical 
Research
consent 
to 
the 
participant, answer all of his/her questions, 
and obtain written informed consent before 
performing any procedure related to the
Future Biomedical Research sub-trial.  A 
copy of the informed consent will be given to 
the participant.
Due to EU CTR changes that will 
require FBR results to be reported if 
FBR is indicated as a sub-study to 
the clinical protocol.
7.1.1.8
Trial 
Compliance 
(Medication/Diet/Activity/Ot
her)
Changed 
the 
word 
“witnessed” 
to 
“monitored”
To appropriately describe the work 
being done by the investigator 
and/or trial staff.
7.1.2.6.3 
(Added)
Second Course (Retreatment) 
Tumor Imaging
Added Section and text describing Second 
Course Tumor imaging including timing and 
activities 
To clarify tumor imaging procedures 
during Second Course Phase.
 
 
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Section 
Number (s)
Section Title (s)
Description of Change (s)
Rationale
7.1.2.6.4
RECIST 1.1 Assessment of 
Disease
Originally Section 7.1.2.6.3 but moved to 
7.1.2.6.4. Therefore, all references to RECIST 
1.1 Assessment of Disease were updated to 
7.1.2.6.4.
Due to the addition of Second 
Course 
(Retreatment) 
Tumor 
Imaging 
(Section 
7.1.2.6.3), 
RECIST 1.1 Assessment of Disease 
was moved to Section 7.1.2.6.4.
7.1.2.6.5
irRECIST 
Assessment 
of 
Disease
Originally Section 7.1.2.6.4 but moved to 
7.1.2.6.5. 
Therefore, 
all 
reference 
to 
irRECIST Assessment of Disease were
updated to 7.1.2.6.5
Due to the addition of Second 
Course 
(Retreatment) 
Tumor 
Imaging 
(Section 
7.1.2.6.3), 
irRECIST Assessment of Disease 
was moved to Section 7.1.2.6.5.
7.1.5.4.1
Safety Follow-up
Removal of “All AEs that occur prior to the 
30-Day Safety Follow-up Visit should be 
recorded. Subjects with an AE of Grade > 1 
will be followed until the resolution of the AE 
to Grade 0-1 or until the beginning of a new 
anti-cancer therapy, whichever occurs first. 
SAEs will be collected for 90 days after the 
end of the treatment of 30 days following last 
dose of trial treatment if the subject initiates 
new anti-cancer therapy, whichever occurs 
first.”
To 
align 
with 
current 
pembrolizumab program. Original 
wording introduced conflict for 
reporting AEs.
 
 
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Section 
Number (s)
Section Title (s)
Description of Change (s)
Rationale
12.2
Collection and Management 
of Specimens for Future 
Biomedical Research
Updated content under:
3. Summary of Procedures for Future 
Biomedical Research
a. Subjects for Enrollment
All subjects enrolled in the clinical trial will 
be considered for enrollment in the Future 
Biomedical Research sub-trial.
Due to EU CTR changes that will 
require FBR results to be reported if 
FBR is indicated as a sub-study to 
the clinical protocol.
12.2
Collection and Management 
of Specimens for Future 
Biomedical Research
Updated content under
5. Biorepository Specimen Usage
Any contracted third-party analyses will 
conform to the specific scope of analysis 
outlined in future biomedical research 
protocol and consent this sub-trial.  Future 
Biomedical Research specimens remaining 
with the third party after the specific analysis 
is performed will be reported to the Sponsor.
Due to EU CTR changes that will 
require FBR results to be reported if 
FBR is indicated as a sub-study to 
the clinical protocol.
Throughout
Throughout 
Miscellaneous formatting and edits have been 
corrected
 
 
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1.0 TRIAL SUMMARY
Abbreviated Title
Pembrolizumab (MK-3475) vs Paclitaxel in 2L Asian Subjects with 
Advanced Gastric Adenocarcinoma
Sponsor Product Identifiers
MK-3475
Pembrolizumab
Trial Phase
III
Clinical Indication
Advanced Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma
Trial Type
Interventional
Type of control
Active control without placebo
Route of administration
Intravenous
Trial Blinding
Unblinded Open-label
Treatment Groups
Arm 1: Pembrolizumab (MK-3475) 200 mg every 3 weeks (Q3W)
Arm 2: Paclitaxel 80 mg/m2 on Days 1, 8, and 15 of every 28 day (4-
week) cycle
Number of trial subjects
Approximately 360 subjects will be enrolled.
Estimated duration of trial
The Sponsor estimates that the trial will require approximately 36 months 
from the time the first subject signs the informed consent until the last 
subject’s last study-related phone call or visit.
Duration of Participation
Each subject will participate in the trial from the time the subject signs 
the Informed Consent Form (ICF) through the final contact. After a 
screening phase of up to 28 days, eligible subjects will receive treatment 
beginning on Day 1 of each 3-week dosing cycle for pembrolizumab or 3 
weeks on, 1-week off dosing cycle for paclitaxel. 
Treatment with pembrolizumab or paclitaxel will continue until 
documented 
disease 
progression, 
unacceptable 
adverse 
event(s), 
intercurrent illness that prevents further administration of treatment, 
investigator’s decision to discontinue the subject, subject withdraws 
consent, pregnancy of the subject, subject receives 35 administrations 
(approximately 2 years) of pembrolizumab, or administrative reasons 
requiring cessation of treatment. After the end of treatment, each subject 
will be followed for 30 days for adverse event and events of clinical 
interest monitoring (serious adverse events 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 within the pembrolizumab arm who discontinue after 35 
administrations (approximately 2 years) of therapy for reasons other than 
disease progression or intolerability or who discontinue after attaining a 
CR may be eligible for up to one year of retreatment after they have 
experienced radiographic disease progression.
Subjects who discontinue for reasons other than disease progression will 
have post-treatment follow-up for disease status until disease progression, 
initiating a non-study cancer treatment, withdrawing consent, or 
becoming lost to follow-up. All subjects will be followed by telephone 
for overall survival until death, withdrawal of consent, or the end of the 
study.
 
 
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Once the participant has achieved the study objective or the study has 
ended, the participant is discontinued from the study and may be enrolled 
in an extension study to continue protocol-defined assessments and 
treatment. 
A list of abbreviations used in this document can be found in Section 12.6.
2.0 TRIAL DESIGN
Trial Design
This is a randomized, multi-center, open-label trial of pembrolizumab (MK-3475) versus 
paclitaxel in Asian, programmed death-ligand 1 (PD-L1) positive subjects with advanced 
gastric or gastroesophageal junction (GEJ) adenocarcinoma who have progressed after failure 
of any combination chemotherapy containing a platinum and a fluoropyrimidine agent. 
In this trial, approximately 360 subjects (approximately 70%-80% of total population from 
China) will be randomized to compare the efficacy and safety of pembrolizumab versus 
paclitaxel. Subjects will be randomized in a 1:1 ratio to receive pembrolizumab or paclitaxel 
and stratified by time to progression on first line therapy (< 6 months vs. ≥6 months) and 
Eastern Cooperative Oncology Group (ECOG) Performance Scale (0 vs. 1). 
Subjects will be required to provide tissue of a tumor lesion to be evaluated at a central 
laboratory for expression status of PD-L1. Only subjects whose tumors express PD-L1 (are 
PD-L1+) as determined by the central laboratory facility will be eligible for randomization in 
this study.
All study subjects will be evaluated every 6 weeks (+/- 7 days) following the date of 
randomization until progression of disease is documented with radiologic imaging (computed 
tomography or magnetic resonance imaging). 
The primary efficacy endpoints are overall survival (OS) and progression-free survival 
(PFS). The primary PFS analysis will be based on RECIST 1.1 by blinded central 
radiologists’ review. RECIST 1.1 will also be used by the local site for treatment decisions.  
However, because of the unique tumor responses typical with pembrolizumab, RECIST 1.1 
[1] has been modified as described in Section 7.1.2.6.5 to allow for continued treatment and a 
repeat confirmatory scan in subjects with initial evidence of progressive disease (PD) by 
standard RECIST 1.1 (hereafter referred to irRECIST). If a subject has progression of disease 
by RECIST 1.1, it is recommended that the subject be discontinued from the study treatment 
unless, in the investigator’s opinion, the subject is deriving benefit from treatment.  Clinically 
stable subjects, as defined in Section 7.1.2.6.5, may continue to receive trial therapy at the 
discretion of the investigator.  If a repeat scan confirms progression of disease and the subject 
remains clinically stable, the subject may continue treatment after consultation with the 
Sponsor. 
Adverse events will be monitored throughout the trial and graded in severity according to the 
guidelines outlined in the NCI Common Terminology Criteria for Adverse Events (CTCAE) 
version 4.0. 
Randomization Ratio
1:1
 
 
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Except as noted above, treatment with pembrolizumab or paclitaxel will continue until 
documented disease progression, unacceptable adverse event(s), intercurrent illness that 
prevents further administration of treatment, investigator’s decision to withdraw the subject, 
subject withdraws consent, pregnancy of the subject, completion of 35 administrations 
(approximately 2 years) of pembrolizumab, or administrative reasons requiring the cessation 
of treatment.  
Subjects on the pembrolizumab arm, who attain an investigator-determined confirmed 
complete response (CR), may consider stopping trial treatment after receiving at least 24 
weeks of treatment with pembrolizumab. Subjects who discontinue after 35 administrations 
(approximately 2 years) of pembrolizumab for reasons other than disease progression or 
intolerability or who discontinue after attaining a CR may be eligible for up to one year of 
retreatment after they have experienced radiographic disease progression.  The decision to 
retreat will be at the discretion of the investigator only if no cancer treatment was 
administered since the last dose of pembrolizumab, the subject still meets the safety 
parameters listed in the Inclusion/Exclusion criteria and the trial remains open (refer to 
Section 7.1.5.5 for further details). Subjects within the paclitaxel arm will continue on 
treatment until disease progression or unacceptable toxicity. A cross-over of treatment 
groups after documented disease progression on the study treatment will not be allowed. 
After the end of treatment, each subject will be followed for 30 days for adverse event and 
events of clinical interest monitoring (serious adverse events will be collected for 90 days 
after the end of treatment or 30 days after the end of treatment if the subject initiates new 
anticancer therapy, whichever is earlier). Subjects who discontinue treatment for reasons 
other than disease progression will have post-treatment follow-up for disease status until 
disease progression, initiating a non-study cancer treatment, withdrawing consent, or 
becoming lost to follow-up. All subjects will be followed by telephone contact for overall 
survival until death, withdrawal of consent or the end of the study, 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 an independent, external Data Monitoring Committee (eDMC) to monitor 
safety and efficacy. The role of the eDMC will be clearly elucidated in the eDMC Charter. 
There will be one formal interim analysis for OS and no interim analysis for PFS. For further 
details, please refer to Section 8 of the protocol.
 
 
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Trial Diagram
The trial design is depicted in Figure 1
Figure 1
Trial Design Schematic
3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
In PD-L1 positive subjects with advanced gastric or GEJ adenocarcinoma who have 
progressed on one previous line of therapy.
 
 
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Primary Objective(s) & Hypothesis(es)
(1) Objective: To compare OS.
Hypothesis: Pembrolizumab prolongs OS compared to paclitaxel.
(2) Objective: To compare PFS per RECIST 1.1 by blinded central radiologists’ review.
Hypotheses: Pembrolizumab prolongs PFS per RECIST 1.1 by blinded central 
radiologists’ review compared to paclitaxel.
The study is considered to have met its primary objective if pembrolizumab is superior to 
paclitaxel either in OS (interim or final analysis) or in the final PFS analysis.
Secondary Objective(s) & Hypothesis(es)
(1) To evaluate the Objective Response Rate (ORR) per RECIST 1.1 assessed by blinded 
central radiologists’ review.
Hypotheses: Pembrolizumab improves ORR per RECIST 1.1 assessed by blinded central 
radiologists’ review compared to paclitaxel.
(2) Objective: Evaluate the safety and tolerability profile of pembrolizumab compared to 
paclitaxel.
Exploratory Objectives
(1) Objective: To evaluate PFS per immune-related RECIST (irRECIST) by blinded central 
radiologists’ review among subjects when treated with pembrolizumab compared to 
paclitaxel.
(2) Objective: To evaluate the Time to Progression (TTP) and Duration of Response (DOR) 
per RECIST 1.1 by blinded central radiologists’ review among subjects when treated 
with pembrolizumab compared to paclitaxel.
(3) Objective: To evaluate score change of health related quality of Life using the EORTC 
QLQ-C30 and the EORTC QLQ-STO22 from baseline among subjects when treated with 
pembrolizumab compared to paclitaxel.  
(4) Objective: To characterize utilities using EuroQol EQ-5D among subjects when treated 
with pembrolizumab compared to paclitaxel. 
(5) Objective: To explore the relationship between genetic variation and response to the 
treatment(s) administered. Genomic variability will be analyzed for association with 
clinical data collected in this study.
4.0 BACKGROUND & RATIONALE
Background
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background 
information on MK-3475.
 
 
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Pharmaceutical and Therapeutic Background
Gastric cancer Worldwide and in Asia/China
Gastric cancer is the fifth most commonly diagnosed cancer and the third most common 
cause of cancer-related deaths worldwide [2]. In China, gastric cancer is one of the most 
common malignancies, ranking second in incidence and third in mortality [3]. In 2012, there 
were approximately 952,000 new cases (half the world total occurs in Eastern Asia) of 
gastric cancer and 723,000 deaths worldwide; of these, approximately 405,000 new cases 
(43%) and 325,000 deaths (45%) occurred in China [3]. 
To date, surgery is still the only curative treatment for patients with gastric cancer, but this is 
only an option for patients with early or locally advanced gastric cancer. At present, the 
early-stage diagnosis rate is low in China, and as a result, most patients have advanced or 
metastatic gastric cancer at diagnosis; as reported by Chinese Society of Clinical Oncology
(CSCO), 31.2% and 39.8% were stage IV and stage III at diagnosis (CSCO gastric cancer 
survey, 2011). The only treatment option for patients with advanced gastric cancer is 
chemotherapy, although the efficacy of such treatment is limited [4-6]. Many patients 
initially respond to chemotherapy, but treatment is not curative, and patients experience 
progression. Second-line once-per-week paclitaxel is widely used in this setting in Asian
countries, with median OS of 151 days to 9.5 months and PFS of 2.6 to 3.6 months [7-9].
Anti-PD-1 Blockage for Malignancy
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades [10]. Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies [11-15]. In particular, the presence of cluster of differentiation (CD)8+ 
T-cells and the ratio of CD8+ effector T-cells/FoxP3+ regulatory T-cells seems to correlate 
with improved prognosis and long-term survival in many solid tumors.
The programmed cell death 1 (PD-1) receptor-ligand interaction is a major pathway hijacked 
by tumors to suppress immune control. The normal function of PD-1, expressed on the cell 
surface of activated T-cells under healthy conditions, is to down-modulate unwanted or 
excessive immune responses, including autoimmune reactions.  PD-1 (encoded by the gene 
Pdcd1) is an Ig superfamily member related to CD28 and cytotoxic T-lymphocyte-associated 
antigen-4 (CTLA-4) that has been shown to negatively regulate antigen receptor signaling 
upon engagement of its ligands (PD-L1 and/or programmed death-ligand 2 [PD-L2]) [16,
17]. The structure of murine PD-1 has been resolved [18]. 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 
signaling molecules. The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling 
motifs, an immunoreceptor tyrosine-based inhibition motif (ITIM) and an immunoreceptor 
tyrosine-based switch motif (ITSM). Following T-cell stimulation, PD-1 recruits the tyrosine 
phosphatases SHP-1 and SHP-2 to the ITSM motif within its cytoplasmic tail, leading to the 
dephosphorylation of effector molecules such as CD3ζ, PKCθ, and ZAP70 which are 
involved in the CD3 T-cell signaling cascade [16, 19-21]. The mechanism by which PD-1
 
 
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down modulates T-cell responses is similar to, but distinct from that of CTLA-4 as both 
molecules regulate an overlapping set of signaling proteins [22, 23]. 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 [24, 25]. Expression has also been shown during thymic 
development on CD4-CD8- (double negative) T-cells as well as subsets of macrophages and 
dendritic cells [26]. The ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed 
or can be induced in a variety of cell types, including non-hematopoietic tissues as well as in 
various tumors [22, 27-29]. Both ligands are type I transmembrane receptors containing both 
IgV- and IgC-like domains in the extracellular region and contain short cytoplasmic regions 
with no known signaling motifs. Binding of either PD-1 ligand to PD-1 inhibits T-cell 
activation triggered through the T-cell receptor. PD-L1 is expressed at low levels on various 
non-hematopoietic tissues, most notably on vascular endothelium, whereas PD-L2 protein is 
only detectably expressed on antigen-presenting cells found in lymphoid tissue or chronic 
inflammatory environments. 
PD-L2 is thought to control immune T-cell activation in 
lymphoid organs, whereas PD-L1 serves to dampen unwarranted T-cell function in peripheral 
tissues [22]. Although healthy organs express little (if any) PD-L1, a variety of cancers were 
demonstrated to express abundant levels of this T-cell inhibitor. PD-1 has been suggested to 
regulate tumor-specific T-cell expansion in patients with melanoma [30]. 
In gastric cancer PD-L1 and PD-L2 overexpression have recently been associated with EBV-
positive tumors [31]. This suggests that the PD-1/PD-L1 pathway plays a critical role in 
tumor immune evasion and should be considered as an attractive target for therapeutic 
intervention.
Anti PD-1 Antibody, Pembrolizumab
Pembrolizumab (MK-3475) is a potent and highly selective humanized monoclonal antibody 
(mAb) of the IgG4/kappa isotype designed to directly block the interaction between PD-1 
and its ligands, PD-L1 and PD-L2. Keytruda® (pembrolizumab) has recently been approved 
in the United States for the treatment of patients with unresectable or metastatic melanoma 
and disease progression following ipilumumab and, if BRAF V600 mutation positive, a 
BRAF inhibitor.
Pre-clinical Studies of Pembrolizumab
Therapeutic studies in mouse models have shown that administration of antibodies blocking 
PD-1/PD-L1 interaction enhances infiltration of tumor-specific CD8+ T-cells and leads 
ultimately to tumor rejection, either as a mono-therapy or in combination with other 
treatment modalities. Anti-mouse PD-1 or anti-mouse PD-L1 antibodies have demonstrated 
anti-tumor responses as a mono-therapy in models of squamous cell carcinoma, pancreatic 
carcinoma, MEL and colorectal carcinoma. Blockade of the PD-1 pathway effectively 
promoted CD8+ T-cell infiltration into the tumor and the presence of IFN-, granzyme B and 
perforin, indicating that the mechanism of action involved local infiltration and activation of 
effector T-cell function in vivo [32-37]. Experiments have confirmed the in vivo efficacy of 
PD-1 blockade as a mono-therapy as well as in combination with chemotherapy in syngeneic 
mouse tumor models (see the IB).
 
 
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Clinical trials have demonstrated efficacy in subjects with advanced melanoma, non-small 
cell lung cancer (NSCLC), head and neck cancer, bladder cancer, Hodgkin’s lymphoma, 
triple negative breast cancer, and gastric adenocarcinoma.
Ongoing Clinical Trials
Ongoing clinical trials are being conducted in advanced melanoma, NSCLC, a number of 
advanced solid tumor indications, and hematologic malignancies.  For study details, please 
refer to the IB.
Ongoing Clinical Trials in Gastric Cancer
Preliminary interim data is available from a cohort of gastric adenocarcinoma subjects 
studied in trial KEYNOTE 012 (KN012) [38]. Thirty-nine subjects (19 from clinical trial 
sites in Asia and 20 from trial sites outside Asia) who had metastatic gastric or GEJ 
adenocarcinoma, ECOG performance status of 0 or 1, and tumor positive for PD-L1 by 
immunohistochemistry (defined as staining in ≥1% of tumor cells or any stroma cells using a 
prototype assay) received single agent pembrolizumab at a dose of 10 mg/kg every 2 weeks. 
The number of prior systemic treatments for metastatic disease ranged from zero to greater 
than 4. The primary efficacy endpoint was overall response rate (ORR). Overall, the interim 
ORR is 30.8% (95% confidence interval [CI] [17.0%, 47.6%]; all partial responses), while 
the interim disease control rate (DCR) is 43.6% (95% CI [27.8%, 60.4%]). 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. It should be noted that in the non-
Asia group, subjects had less prior therapy relative to the Asian subjects, and that ORR in 
later line subjects (≥3L) was higher in the Asian group (1 partial response [PR]/7 subjects in 
the non-Asia group, 4 PR/13 subjects in the Asia group). As of the data cutoff (06 Aug 
2014), the overall median duration of follow-up is 6-months, and 11/12 subjects who 
responded are still continuing.  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 every 2 
weeks was generally well tolerated, with the type, severity, and frequency of adverse events 
similar to that observed in other indications (see the IB for information about adverse events 
in other indications). There was 1 death reported in the gastric cancer cohort. This was a 
subject who had adverse events of tracheomalacia (Grade 3) and hypoxia (Grade 5). The 
investigator considered the Grade 5 hypoxia related to the study treatment.
KN059 is a non-randomized, multi-site, open-label trial of pembrolizumab in subjects with 
gastric or gastroesophageal junction adenocarcinoma. Approximately 223 subjects may be 
enrolled across three cohorts to examine the safety and efficacy of pembrolizumab: Cohort 1) 
subjects who have progressed on at least 2 prior systemic treatments for advanced disease 
(3L+ subjects) that will receive pembrolizumab as monotherapy; Cohort 2) subjects who 
have not previously received systemic therapy for advanced disease (1L subjects) who will 
receive pembrolizumab in combination with cisplatin and 5-FU. Sites in Japan will also 
administer pembrolizumab in combination with cisplatin and capecitabine; and Cohort 3) 
PD-L1 positive subjects who have not previously received systemic therapy for advanced 
 
 
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disease (1L subjects) who will receive pembrolizumab as monotherapy. 
The primary 
objectives of the trial are to determine the safety, tolerability, and ORR of pembrolizumab 
(200 mg fixed dose every 3 weeks [Q3W]) given as first and third line monotherapy to 
subjects with gastric or gastroesophageal junction adenocarcinoma whose tumors express 
PD-L1, and to determine the safety and tolerability of pembrolizumab administered in 
combination with cisplatin and 5-FU as first line therapy in subjects with gastric or 
gastroesophageal junction adenocarcinoma. 
KN061 is a randomized, multi-center, open-label trial of pembrolizumab versus paclitaxel in 
subjects with advanced gastric or gastroesophageal junction adenocarcinoma who have 
progressed after failure of any combination chemotherapy containing a platinum and a 
fluoropyrimidine agent. Up to 720 subjects will be randomized; the enrollment will include 
all subjects without regard for PD-L1 expression status. The overall study enrollment will be 
driven by the number of subjects with PD-L1 positive expression on their tumor (n = 360). 
That is, enrollment will stop when approximately 360 subjects with PD-L1 positive 
expression on their tumor have been randomized. Additionally, there will be a cap on 
enrollment (30% of total) for subjects residing in the Asia Pacific region for this study. The 
primary efficacy endpoints are PFS and overall survival (OS). The primary PFS analysis will 
be based on RECIST 1.1 by blinded central radiologists’ review. RECIST 1.1 will also be 
used by the local site for treatment decisions.
KN062 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 PD-L1 positive, 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. Subjects will be randomized in 
a 1:1:1 ratio among the three treatment arms, stratified by geographic region, disease status, 
and fluoropyrimidine treatment. There will be one interim PFS/OS analysis, one planned 
interim safety analysis, and quarterly safety monitoring.
Rationale
Rationale for the Trial and Selected Subject Population
Trials evaluating pembrolizumab in gastric cancer have demonstrated clinical activity in 
subjects with 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). This 
study is designed to investigate if pembrolizumab monotherapy in second line gastric cancer 
subjects improves OS and PFS. 
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.
 
 
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Rationale for Dose Selection/Regimen/Modification
The planned dose of pembrolizumab for this trial is 200 mg Q3W. Based on the totality of 
data generated in the pembrolizumab development program, 200 mg Q3W is the appropriate 
dose of pembrolizumab across all indications and regardless of tumor type. As outlined 
below, this dose is justified by: 

Clinical data from 8 randomized studies demonstrating flat dose- and exposure-
efficacy relationships from 2 mg/kg Q3W to 10 mg/kg every 2 weeks (Q2W),

Clinical data showing meaningful improvement in benefit-risk, including overall 
survival at 200 mg Q3W across multiple indications, and

Pharmacology data showing full target saturation in both systemic circulation 
(inferred from pharmacokinetic [PK] data) and tumor (inferred from physiologically 
based PK analysis) at 200 mg Q3W
Among the 8 randomized dose-comparison studies, a total of 2262 subjects were enrolled 
with melanoma and NSCLC, covering different disease settings (treatment naïve, previously 
treated, PD-L1 enriched and all-comers) and different treatment settings (monotherapy and in 
combination with chemotherapy). Five studies compared 2 mg/kg Q3W vs. 10 mg/kg Q3W 
(KN001 B2, KN001 D, KN002, KN010, and KN021), and 3 studies compared 10 mg/kg 
Q3W vs. 10 mg/kg Q2W (KN001 B3, KN001 F2, and KN006). All of these studies 
demonstrated flat dose- and exposure-response relationships across the doses studied,
representing an approximate 5- to 7.5-fold difference in exposure. The 2 mg/kg (or 200 mg 
fixed-dose) Q3W dose provided similar responses to the highest doses studied. Subsequently, 
flat dose-/exposure-response relationships were also observed in other tumor types, including 
head and neck cancer, bladder cancer, gastric cancer, and classical Hodgkin’s Lymphoma, 
confirming 200 mg Q3W as the appropriate dose independent of the tumor type. These 
findings are consistent with the mechanism of action of pembrolizumab, which acts by 
interaction with immune cells, and not via direct binding to cancer cells.
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W. First, PK 
data in KN001 evaluating target-mediated drug disposition conclusively demonstrated 
saturation of PD-1 in systemic circulation at doses much lower than 200 mg Q3W. Secondly, 
a physiologically based pharmacokinetic analysis was conducted to predict tumor PD-1 
saturation over a wide range of tumor penetration and PD-1 expression. This evaluation 
concluded that pembrolizumab at 200 mg Q3W achieves full PD-1 saturation in both blood 
and tumor.
Finally, population PK analysis of pembrolizumab, which characterized the influence of 
body weight and other subject covariates on exposure, has shown that fixed dosing provides 
similar control of PK variability as weight-based dosing, with considerable overlap in the 
distribution of exposures from the 200 mg Q3W fixed dose and 2 mg/kg Q3W dose. 
Supported by these PK characteristics, and given that the fixed dose has advantages of 
reduced dosing complexity and reduced potential of dosing errors, the 200 mg Q3W fixed
dose was selected for evaluation across all pembrolizumab protocols.
 
 
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Rationale for Paclitaxel as the Comparator
The use of paclitaxel at a dose of 80 mg/m2 intravenously administered on Days 1, 8, and 15 
of a 28-day (4 week) cycle has become a common practice in the second-line treatment of 
metastatic gastric cancer globally and this regimen was used as a chemotherapy backbone 
and control in the RAINBOW study and the TyTAN study [39, 40].
Ramucirumab, an anti-vascular endothelial growth factor receptor 2 antibody (VEGFR2), 
was approved by the US FDA as monotherapy for second line gastric cancer in April 2014, 
based on the results from the REGARD study [41]. The REGARD study was a Phase 3 study 
comparing ramucirumab monotherapy (8 mg/kg intravenous infusion on days 1 and 15 every 
4 weeks), versus best supportive care (BSC) in subjects refractory to previous 
fluoropyrimidine treatment (with or without platinum). Ramucirumab significantly improved 
OS (5.2 mo vs 3.8 mo with BSC, HR = 0.776, P = 0.047) and PFS (2.1 mo vs 1.3 mo with 
BSC, HR 0.483, P < 0.0001)
The combination of ramucirumab plus paclitaxel was approved for second line gastric cancer 
by the US FDA in November, 2014, based on results from the RAINBOW study [39].  
RAINBOW was a Phase 3 study testing paclitaxel (80 mg/m2 on days 1, 8, and 15, of a 28 
day cycle) with or without ramucirumab (8 mg/kg intra-venous infusion on days 1 and 15 of 
a 28 day cycle) in subjects with metastatic gastric cancer refractory or progressive after first-
line therapy with a platinum and a fluoropyrimidine. Median overall survival was 9.6 months 
for the combination and 7.4 months for paclitaxel alone with a HR 0.807(P = 0.0169) 
favoring the group receiving ramucirumab. Median progression-free survival was 4.4 months 
and 2.9 months, respectively, with a HR of 0.635 (P < 0.0001). Adverse events of grade ≥ 3 
were somewhat greater with combination treatment and included neutropenia (40.7% vs 
18.8%), leukopenia (17.4% vs 6.7%), hypertension (14.1% vs 2.4%) and fatigue (7.0% vs 
4.0%).
Although ramucirumab was approved as monotherapy and combination with paclitaxel in the 
US, ramucirumab containing regimens are not considered current standard of care for second 
line treatment globally; the paclitaxel regimen (given on Days 1, 8, and 15 of a 28 day (4-
week) cycle [3-weeks on, 1-week off dosing cycle]) remains a standard therapy for second-
line treatment of gastric cancer globally.
Rationale for Endpoints
Efficacy Endpoints
This trial will use overall survival (OS) and progression free survival (PFS) as a dual primary 
endpoint. The endpoint of OS is the standard for demonstrating superiority of antineoplastic 
therapy in clinical studies in the area of oncology. Additionally, 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 progression, as this 
methodology is uniformly accepted by regulatory authorities. Because the treatment 
assignment is unblinded for pembrolizumab monotherapy, images will be read by central 
 
 
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radiologists blinded to treatment assignment to minimize bias in the assessment of 
progression.
RECIST 1.1 will also be used by the local site for treatment decisions for both arms of the 
study.  However RECIST 1.1 will be adapted to account for the unique tumor response 
profile seen with immunotherapies such as pembrolizumab. Immunotherapeutic agents such 
as pembrolizumab may produce antitumor effects by potentiating endogenous cancer-specific 
immune responses which may be functionally anergic. The response patterns seen with such 
an approach may extend beyond the typical time course of responses seen with cytotoxic 
agents, and can manifest a clinical response after an initial increase in tumor burden or even 
the appearance of new lesions. Standard RECIST criteria may not provide a complete 
response assessment of immunotherapeutic agents such as pembrolizumab. 
Therefore, 
RECIST 1.1 will be used with the following adaptation, outlined in Section 7.1.2.6.5, termed 
irRECIST.
When feasible, subjects within the pembrolizumab arm should not be discontinued until 
progression is confirmed. This allowance to continue treatment despite initial radiologic 
progression takes into account the observation that some subjects can have a transient tumor 
flare in the first few months after the start of immunotherapy, but with subsequent disease 
response.
Secondary Efficacy Endpoints
The secondary efficacy endpoint of this study is ORR per RECIST 1.1 assessed by blinded 
central radiologists’ review.
Safety Endpoints
The primary safety objective of this trial is to characterize the safety and tolerability of 
pembrolizumab in subjects with metastatic gastric cancer. The primary safety analysis will be 
based on subjects who experienced toxicities as defined by CTCAE criteria. Safety will be 
assessed by quantifying the toxicities and grades experienced by subjects who have received 
pembrolizumab compared to paclitaxel including serious adverse events (SAEs) and events 
of clinical interest (ECIs).
Safety will be assessed by reported adverse experiences using CTCAE, Version 4.0. The 
attribution to drug, time-of-onset, duration of the event, its resolution, and any concomitant 
medications administered will be recorded. Adverse Events (AEs) will be analyzed including 
but not limited to all AEs, SAEs, fatal AEs, and laboratory changes.
Exploratory Endpoints
4.2.3.4.1 Exploratory Efficacy Endpoints
The exploratory endpoints of this study includes efficacy endpoints to evaluate PFS per 
irRECIST by blinded central radiologists’ review, and the Time to Progression (TTP) and 
Duration of Response (DOR) per RECIST 1.1 by blinded central radiologists’ review among 
subjects when treated with pembrolizumab compared to paclitaxel.
 
 
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4.2.3.4.2 Patient Reported Outcomes
As part of the exploratory analyses, subjects will provide information regarding their health-
related quality of life (HRQoL) via the following assessment tools: EORTC QLQ-C30 and 
QLQ-STO22, and EuroQol-5D (EQ-5D) questionnaires. These measures are not pure 
efficacy or safety endpoints because they are affected by both disease progression and 
treatment tolerability.
EORTC QLQ-C30 and EORTC QLQ-STO22
The EORTC-QLQC30 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, diarrhea, and financial impact), and a 
global health and quality of life scale [42]. 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 
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 study Flow Chart, beginning with Cycle 1 until 30 days post-treatment 
discontinuation.
EuroQoL-5D 
The EuroQol-5D (EQ-5D) is a standardized instrument for use as a measure of health 
outcome. The EQ-5D 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 [43]. Each dimension is rated on a three point scale 
from 1 (extreme problem) to 3 (no problem). The EQ-5D 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 EQ-5D 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 study Flow Chart, beginning with Cycle 1 until 30 days post-
treatment discontinuation.
 
 
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4.2.3.4.3 Exploratory Biomarkers
Introduction: Cancer immunotherapies represent an important and novel class of anti-tumor 
agents.  However, the mechanism of action of these exciting new therapies is not completely 
understood and much remains to be learned regarding how best to leverage these new drugs 
in treating patients. Thus, to aid future patients, it is important to investigate the determinants 
of response or resistance to cancer immunotherapy as well as determinants of adverse events 
in 
the 
course 
of 
our
clinical 
trials. 
These 
efforts 
will 
identify 
novel 
predictive/pharmacodynamic biomarkers and generate information that will better guide 
single-agent and combination therapy with immuno-oncology drugs. To identify novel 
biomarkers, we will collect biospecimens (blood components, tumor material, etc.) to support 
analyses of cellular components (e.g., protein, DNA, RNA, metabolites) and other circulating 
molecules. Investigations may include but are not limited to:
Germline (blood) genetic analyses (e.g., SNP analyses, whole exome sequencing, whole 
genome sequencing): This research will evaluate whether genetic variation within a clinical 
trial population correlates with response to the treatment(s) under evaluation. If genetic 
variation is found to predict efficacy or adverse events, the data might inform optimal use of 
therapies in the patient population. Furthermore, it is important to evaluate germline DNA 
variation across the genome in order to interpret tumor-specific DNA mutations. Finally, 
microsatellite instability (MSI) may be evaluated as this is an important biomarker for some 
cancers (i.e., colorectal cancer).
Genetic (DNA) analyses from tumor: The application of new technologies, such as next 
generation sequencing, has provided scientists the opportunity to identify tumor-specific 
DNA changes (i.e., mutations, methylation status, microsatellite instability etc). Key 
molecular changes of interest to immune-oncology drug development include (for example) 
the mutational burden of tumors and the clonality of T-cells in the tumor microenvironment.  
Increased mutational burden (sometimes referred to as a ‘hyper-mutated’ state) may generate 
neo-antigen presentation in the tumor microenvironment. To conduct this type of research, it 
is important to identify tumor-specific mutations that occur across all genes in the tumor 
genome. Thus, genome wide approaches may be used for this effort. Note that in order to 
understand tumor-specific mutations; it is necessary to compare the tumor genome with the 
germline genome. Microsatellite instability (MSI) may also be evaluated as this is an 
important biomarker for some cancers (i.e., colorectal cancer).
Tumor and blood RNA analyses: Both genome-wide and targeted messenger RNA (mRNA) 
expression profiling and sequencing in tumor tissue and in blood may be performed to define 
gene signatures that correlate to clinical response to treatment with pembrolizumab or other 
immunotherapies. Pembrolizumab induces a response in tumors that likely reflects an 
inflamed/ immune phenotype. Specific immune-related gene sets (such as those capturing 
interferon-gamma transcriptional pathways) may be evaluated and new signatures may be 
identified. Individual genes related to the immune system may also be evaluated (e.g., IL-10).  
MicroRNA profiling may also be pursued.
Proteomics and immunohistochemistry (IHC) using blood or tumor: Tumor and blood 
samples from this study may undergo proteomic analyses (e.g., PD-L1 IHC). PD-L1 protein 
 
 
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level in tumor sections, assessed by IHC, has been shown to correlate with response to 
pembrolizumab in patients with NSCLC, and an IVD device has been developed for use with 
pembrolizumab in NSCLC. Preliminary data indicate that this association may also be true in 
additional cancer types (i.e., triple-negative breast cancer, head and neck, and gastric). 
Additional tumor or blood-derived proteins may also correlate with response to 
pembrolizumab.  Therefore, tumor tissue may be subjected to proteomic analyses using a 
variety of platforms that could include but are not limited to immunoassays, liquid 
chromatography/mass spectrometry. This approach could identify novel protein biomarkers 
that could aid in patient selection for pembrolizumab (MK-3475) therapy.
Other blood derived biomarkers: In addition to expression on the tumor tissue, PD-L1 and 
other tumor derived proteins can be shed from tumor and released into the blood. Assays 
such as enzyme-linked immunoassay measure such proteins in serum. Correlation of 
expression with response to pembrolizumab therapy may identify new approaches for 
predictive biomarkers in blood, representing a major advance from today’s reliance on 
assessing tumor biomarkers. This research would serve to develop such assays for future 
clinical use.
Details regarding time points for blood collection are outlined in the Trial Flow Chart –
Section 6.1 and within the Procedures Manual.
Future Biomedical Research
The Sponsor will conduct Future Biomedical Research on specimens consented for future 
biomedical research during this clinical trial.  This research may include genetic analyses 
(DNA), gene expression profiling (RNA), proteomics, metabolomics (serum, plasma) and/or 
the measurement of other analytes, depending on which specimens are consented for future 
biomedical research.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main trial) and will only be conducted on specimens from 
appropriately consented subjects. The objective of collecting/retaining specimens for Future 
Biomedical Research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. The overarching goal is to use 
such information to develop safer, more effective drugs/vaccines, and/or to ensure that 
subjects receive the correct dose of the correct drug/vaccine at the correct time.  The details 
of Future Biomedical Research are presented in Section 12.2 - 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.
 
 
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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.
5.0 METHODOLOGY
Entry Criteria
Diagnosis/Condition for Entry into the Trial
Male/Female Asian subjects with advanced 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 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 histologically or cytologically
confirmed diagnosis of gastric or GEJ 
adenocarcinoma. 
4.
Have metastatic disease or locally advanced, unresectable disease.
5.
Have measurable disease as defined by RECIST 1.1 as determined by investigator.  
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.
6.
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 study therapy.
7.
Has experienced documented objective radiographic or clinical disease progression 
during or after first-line therapy containing any platinum/fluoropyrimidine doublet.  
a.
To be considered as second-line, the subject needs to have the documentation of 
disease progression on first-line treatment. The disease progression can be 
confirmed by CT scan or by clinical evidence (such as cytology report from newly 
developed ascites and plural effusion).
b. Any new or worsening malignant effusion (documented by ultrasound) may be 
confirmed by pathologic criteria (histology and/or cytology) if appropriate.
c.
A subject experiencing clinical disease progression during or within 6 months 
following the last dose of adjuvant or neo-adjuvant therapy will be eligible for 
enrollment provided they received a platinum/fluoropyrimidine doublet as required.
 
 
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d. To be eligible, the subject is required to have received at least one dose of platinum 
and fluoropyrimidine therapy. The dose reduction and discontinuation of one of 
these drugs, switching to/adding new drugs on the first-line treatment is allowed; 
however, the documentation of disease progression on/after the first-line treatment 
is required. Therefore, subjects with discontinuation due to adverse events on first-
line treatment prior to disease progression are not eligible until disease progression 
is confirmed by documentation.
8.
Be willing to provide tissue for PD-L1 biomarker analysis and, based on the adequacy 
of the tissue sample quality for assessment of PD-L1 status, receives notification of 
adequate sample from the core lab. Repeat samples may be required if adequate tissue 
is not provided. Newly obtained biopsy specimens are preferred to archived samples 
and formalin-fixed, paraffin-embedded (FFPE) block specimens are preferred to slides.
a. Newly obtained is defined as a specimen obtained up to 6 weeks (42 days) prior to 
initiation of treatment on Day 1. Subjects for whom newly obtained endoscopic 
samples cannot be provided (e.g., inaccessible or subject safety concern) may 
submit an archived specimen.
9.
Have tumor express PD-L1 positive (based on analysis of sample provided to core lab).
10.
Subjects with HER-2/neu negative tumors are eligible.  For subjects with HER2/neu 
positive tumors or have an unknown tumor status, need to match the following:
a.
If HER2/neu positive, subject must have documentation of disease progression on 
treatment containing trastuzumab. 
b. Subjects with unknown status must have their HER2/neu status determined locally.  
If HER2/neu negative, the subject will be eligible.  If HER2/neu positive, the 
subject must have documentation of disease progression on treatment containing 
trastuzumab.
11.
Female subjects of childbearing potential should be willing to use 2 methods of birth 
control or be surgically sterile, or abstain from heterosexual activity for the course of 
the study through 120 days after the last dose of study treatment for the pembrolizumab 
arm and through 180 days after the last dose of study treatment for the paclitaxel arm
(Section 5.7.2). Subjects of childbearing potential are those who have not been 
surgically sterilized or have not been free from menses for > 1 year. 
Male subjects should agree to use an adequate method of contraception starting with the 
first dose of study therapy through 120 days after the last dose of study treatment for 
the pembrolizumab arm and through 180 days after the last dose of study treatment for 
the paclitaxel arm.
12.
Demonstrate adequate organ function as defined in Table 1. All screening labs should 
be performed within 10 days of trail treatment initiation.
 
 
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Table 1
Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
≥1,500 /mcL
Platelets
≥100,000 / mcL
Hemoglobin
≥9 g/dL or ≥5.6 mmol/L without transfusion or EPO 
dependency within 7 days.
Renal
Creatinine OR
Measured or calculated creatinine clearance
(GFR can also be used in place of creatinine 
or CrCl)
≤1.5 X upper limit of normal (ULN) OR
≥60 mL/min for subject with creatinine levels > 1.5 X 
institutional ULN
Note:  Creatinine clearance should be calculated per 
institutional standard
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
13.
Female subjects of childbearing potential should have a negative urine or serum 
pregnancy test within 72 hours prior to receiving the first dose of study therapy. If the 
urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be 
required.
Subject Exclusion Criteria
The subject must be excluded from participating in the trial if the subject:
1.
Is currently participating and receiving study therapy or has participated in a study of 
an investigational agent and received study therapy or used an investigation device
within 4 weeks of the first dose of treatment.
2.
Has squamous cell or undifferentiated gastric cancer.
3.
Has active autoimmune disease that has required systemic treatment in past 2 years (i.e. 
with use of disease modifying agents, corticosteroids or immunosuppressive drugs). 
Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement 
 
 
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therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic 
treatment.
4.
Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any 
other form of immunosuppressive therapy within 7 days prior to the first dose of trial 
treatment. The use of physiologic doses of corticosteroids may be approved after 
consultation with the Sponsor.
5.
Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to the 
first dose of trial treatment or who has not recovered (i.e., ≤ Grade 1 or at baseline) 
from adverse events due to agents administered more than 4 weeks earlier.
6.
Has had prior chemotherapy, targeted small molecule therapy, radiation therapy, or any 
other agents used as systemic treatment for cancer, within 2 weeks prior to the first 
dose of trial treatment or who has not recovered (i.e., ≤ Grade 1 or at baseline) from 
adverse events due to a previously administered agent. Note: Subjects with ≤ Grade 2 
neuropathy or ≤ Grade 2 alopecia are an exception to this criterion and may qualify for 
the study.
a. If subject received major surgery, they must have recovered adequately from the 
toxicity and/or complications from the intervention prior to starting therapy.
7.
Has a known additional malignancy that is progressing or has required active treatment
within the past 5 years. Exceptions include basal cell carcinoma of the skin, squamous 
cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially 
curative therapy.
Note:  Subjects with basal cell carcinoma of the skin, squamous cell carcinoma of the 
skin, or carcinoma in situ (e.g. breast carcinoma, cervical cancer in situ) that have 
undergone potentially curative therapy are not excluded.
8.
Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis. Subjects with previously treated brain metastases may participate provided 
they are radiologically stable, i.e. without evidence of progression for at least 4 weeks
by repeat imaging (note that the repeat imaging should be performed during study 
screening), clinically stable and without requirement of steroid treatment for at least 14 
days prior to first dose of trial treatment.
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, 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 
 
 
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the last dose of study treatment for the pembrolizumab arm and through 180 days after 
the last dose of study treatment for the paclitaxel arm.
14.
Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with 
an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, 
OX-40, CD137).
15.
Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
16.
Has known active Hepatitis B or C. Active Hepatitis B is defined as a known positive 
HBsAg result. Active Hepatitis C is defined by a known positive Hepatitis C Ab result 
or known quantitative HCV RNA results greater than the lower limits of detection of 
the assay.
17.
Has received a live vaccine within 30 days of planned start of study therapy.
a. Note: Seasonal influenza vaccines for injection are generally inactivated flu 
vaccines and are allowed; however intranasal influenza vaccines (e.g., FluMist®) 
are live attenuated vaccines, and are not allowed.
18.
Known allergy or hypersensitivity to paclitaxel or any components used in the 
paclitaxel preparation or other contraindication for taxane therapy.
Trial Treatment(s)
The treatments to be used in this trial are outlined below in Table 2.
Table 2
Trial Treatment
Drug
Dose/
Potency
Dose Frequency
Route of 
Administration
Regimen/
Treatment Period
Use
Pembrolizumab
200 mg
Every 3 weeks
IV infusion
Day 1 of each 
3-week cycle
Experimental
Paclitaxel
80 mg/m2
3 weeks on, 
1 week off
IV infusion
Days 1, 8, and 15 of 
each 28-day 
(4-week) cycle
Comparator 
Regimen
Trial Treatment should begin within 3 days of randomization. However, every effort should 
be made to begin trial treatment on day of randomization.
All supplies indicated in Table 2 above will be provided centrally by the Sponsor or locally 
by the trial site, subsidiary or designee, depending on local country operational or regulatory 
requirements.
For any commercially available product that is provided by the trial site, subsidiary or 
designee every attempt will be made to source these supplies from a single lot/batch number. 
The trial site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product as per local guidelines unless otherwise instructed by the 
Sponsor.
 
 
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The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of trial 
treatments in accordance with the protocol and any applicable laws and regulations.
Dose Selection/Modification
Dose Selection (Preparation)
The rationale for selection of the dose of pembrolizumab to be used in this trial is provided in 
Section 4.0, Background and Rationale. Details on preparation and administration of study 
drug are provided in the Pharmacy Manual.
Preparation and administration of paclitaxel should be completed as per the approved product 
label. Body surface area (BSA) in m2 should be calculated per local guidance.
Dose Modification (Escalation/Titration/Other)
5.2.1.2.1 Dose Modification and Toxicity Management Guidelines for Pembrolizumab
Dose modification and toxicity management for immune-related AEs associated with 
pembrolizumab
Adverse events associated with pembrolizumab exposure may represent an immunologic 
etiology. These immune-related AEs (irAEs) may occur shortly after the first dose or several 
months after the last dose of pembrolizumab treatment and may affect more than one body 
system simultaneously. Therefore, early recognition and initiation of treatment is critical to 
reduce complications.  Based on existing clinical trial data, most irAEs were reversible and 
could be managed with interruptions of pembrolizumab, administration of corticosteroids,
and/or other supportive care. For suspected irAEs, ensure adequate evaluation to confirm 
etiology or exclude other causes. Additional procedures or tests such as bronchoscopy, 
endoscopy, or skin biopsy may be included as part of the evaluation. Based on the severity 
of irAEs, withhold or permanently discontinue pembrolizumab and administer 
corticosteroids. Dose modification and toxicity management guidelines for irAEs associated 
with pembrolizumab are provided in Table 3. 
 
 
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Table 3
Dose Modification and Toxicity Management Guidelines for Immune-related AEs Associated with Pembrolizumab
General instructions:
1.
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks.
2.
For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and corticosteroid 
has been tapered. Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids cannot 
be reduced to ≤ 10 mg prednisone or equivalent per day within 12 weeks. 
3.
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive treatment should 
be initiated if irAEs cannot be controlled by corticosteroids.
Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with corticosteroid 
and/or other therapies 
Monitor and follow-up 
Pneumonitis 
Grade 2
Withhold 

Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper
Monitor participants for signs and symptoms 
of pneumonitis
Evaluate participants with suspected 
pneumonitis with radiographic imaging and 
initiate corticosteroid treatment
Add prophylactic antibiotics for opportunistic 
infections
Grade 3 or 4, or 
recurrent Grade 2
Permanently 
discontinue
Diarrhea / colitis 
Grade 2 or 3
Withhold

Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper
Monitor participants for signs and symptoms 
of enterocolitis (i.e., diarrhea, abdominal pain, 
blood or mucus in stool with or without fever) 
and of bowel perforation (i.e., peritoneal signs 
and ileus).
Participants with ≥ Grade 2 diarrhea 
suspecting colitis should consider GI 
consultation and performing endoscopy to 
rule out colitis. 
Participants with diarrhea/colitis should be 
advised to drink liberal quantities of clear 
fluids.  If sufficient oral fluid intake is not 
feasible, fluid and electrolytes should be 
substituted via IV infusion.
Grade 4
Permanently 
discontinue
 
 
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Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with corticosteroid 
and/or other therapies 
Monitor and follow-up 
AST / ALT 
elevation or 
Increased 
bilirubin
Grade 2
Withhold

Administer corticosteroids (initial 
dose of 0.5-1 mg/kg prednisone or 
equivalent) followed by taper
Monitor with liver function tests (consider 
weekly or more frequently until liver enzyme 
value returned to baseline or is stable
Grade 3 or 4 
Permanently 
discontinue

Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper
Type 1 diabetes 
mellitus (T1DM) 
or Hyperglycemia
Newly onset 
T1DM or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -cell 
failure
Withhold

Initiate insulin replacement therapy 
for participants with T1DM 

Administer anti-hyperglycemic in 
participants with hyperglycemia 
Monitor participants for hyperglycemia or 
other signs and symptoms of diabetes.
Hypophysitis
Grade 2
Withhold

Administer corticosteroids and 
initiate hormonal replacements as 
clinically indicated
Monitor for signs and symptoms of 
hypophysitis (including hypopituitarism and 
adrenal insufficiency) 
Grade 3 or 4 
Withhold or 
permanently 
discontinue1
Hyperthyroidism 
Grade 2
Continue 

Treat with non-selective beta-
blockers (e.g., propranolol) or 
thionamides as appropriate 
Monitor for signs and symptoms of thyroid 
disorders
Grade 3 or 4 
Withhold or 
permanently 
discontinue1
Hypothyroidism
Grade 2-4
Continue 

Initiate thyroid replacement 
hormones (e.g., levothyroxine or 
liothyronine) per standard of care
Monitor for signs and symptoms of thyroid 
disorders
Nephritis and 
renal dysfunction
Grade 2
Withhold 

Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by taper.
Monitor changes of renal function
Grade 3 or 4 
Permanently 
discontinue
 
 
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Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with corticosteroid 
and/or other therapies 
Monitor and follow-up 
Myocarditis
Grade 1 or 2
Withhold

Based on severity of AE administer 
corticosteroids
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes
Grade 3 or 4
Permanently 
discontinue
All Other 
immune-related 
AEs
Intolerable/ 
Persistent Grade 2
Withhold

Based on type and severity of AE 
administer corticosteroids 
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes
Grade 3
Withhold or 
discontinue based 
on the type of event.  
Events that require 
discontinuation 
include and not 
limited to:  GBS 
(Guillain-Barre 
Syndrome), SOTR 
(solid organ 
transplant rejection), 
encephalitis
Grade 4 or 
recurrent Grade 3 
Permanently 
discontinue
1.
Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.  
NOTE: 
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may be resumed when 
AE resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM).  
 
 
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Dose modification and toxicity management of infusion-reactions related to 
pembrolizumab
Pembrolizumab may cause severe or life threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion. 
Dose modification and toxicity management guidelines on pembrolizumab associated 
infusion reaction are provided in Table 4. 
Table 4
Pembrolizumab Infusion Reaction Dose Modification and Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at 
Subsequent Dosing
Grade 1
Mild reaction; infusion 
interruption not 
indicated; intervention 
not indicated
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator.
None
Grade 2
Requires therapy or 
infusion interruption but 
responds promptly to 
symptomatic treatment 
(e.g., antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated 
for ≤24 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 (e.g., from 100 
mL/hr to 50 mL/hr).  Otherwise dosing will be 
held until symptoms resolve and the subject 
should be premedicated for the next scheduled 
dose.
Subjects who develop Grade 2 toxicity despite 
adequate premedication should be permanently 
discontinued from further study drug treatment
Subject may be premedicated 
1.5h (± 30 minutes) prior to 
infusion of pembrolizumab 
(MK-3475) with:
Diphenhydramine 50 mg po 
(or equivalent dose of 
antihistamine).
Acetaminophen 500-1000 mg 
po (or equivalent dose of
analgesic).
 
 
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NCI CTCAE Grade
Treatment
Premedication at 
Subsequent Dosing
Grades 3 or 4
Grade 3:
Prolonged (i.e., not 
rapidly responsive to 
symptomatic medication 
and/or brief interruption 
of infusion); recurrence 
of symptoms following 
initial improvement; 
hospitalization indicated 
for other clinical 
sequelae (e.g., renal 
impairment, pulmonary 
infiltrates)
Grade 4:
Life-threatening; 
pressor or ventilatory 
support indicated
Stop Infusion.
Additional appropriate medical therapy may 
include but is not limited to:
Epinephrine**
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator.
Hospitalization may be indicated.
**In cases of anaphylaxis, epinephrine should 
be used immediately.
Subject is permanently discontinued from 
further study drug treatment.
No subsequent dosing
Appropriate resuscitation equipment should be available at the bedside and a physician readily available 
during the period of drug administration.
For further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) 
at http://ctep.cancer.gov
Other allowed dose interruption for pembrolizumab 
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as 
medical / surgical events or logistical reasons not related to study therapy.  Subjects should 
be placed back on study therapy within 3 weeks of the scheduled interruption, unless 
otherwise discussed with the Sponsor.  The reason for interruption should be documented in 
the patient's study record.
5.2.1.2.2 Dose Modification for Paclitaxel
Prior to each administration of study therapy, hematology and liver function must be 
adequate (see Table 5), and all toxicities must have resolved to Grade < 2 or baseline.  
Otherwise, hold study treatment until resolution. Pre-infusion laboratory data may not be 
older than 48 hours.
The paclitaxel dose will be reduced by 10 mg/m2 when NCI-CTCAE (Version 4.0) Grade 4 
hematological toxicity or Grade 3 paclitaxel-related non-hematological toxicity is observed.  
If the dose of paclitaxel is reduced because of potentially related AEs, subsequent dose 
increases are not permitted. Paclitaxel will be permanently discontinued if dose reduction to 
less than 60 mg/m2 would be required, or in case of any paclitaxel-related event that is 
deemed life-threatening, regardless of grade. Any proposed variations to the dosing 
 
 
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medication guidelines may be approved after being discussed with a medically qualified 
Sponsor representative. 
Table 5
Criteria for Paclitaxel Treatment on Each Cycle
Parameter
Criterion
Absolute neutrophil count
≥ 1.0 × 109/L
Platelet count
≥ 75 × 109/L
Bilirubin
≤ 1.5 × ULN
AST/ALT
≤ 3 × ULN, or < 5 × ULN if the aminotransferase elevation is due to 
liver metastases
Paclitaxel-related toxicities/AEs
NCI-CTCAE Version 4.00 Grade < 2 or baseline (except for alopecia)
In each case of hypersensitivity reaction associated with paclitaxel (see Table 6), the 
investigator should institute treatment measures according to the best available medical 
practice. 
Table 6
Guidelines for Hypersensitivity Reactions in Paclitaxel Arm
Severity
Action Taken with 
Paclitaxel at onset of AE
Supportive Care
Discontinue Paclitaxel
Grade 1
No Action 
Supervise at bedside
NA
Grade 2
Stop Infusion
Administer diphenhydramine 25 to 
50 mg I.V. and dexamethasone 8-
20 mg I.V. (or equivalent, per 
institutional guidelines).  Resume 
the paclitaxel infusion after 
recovery of symptoms at a reduced 
rate (20 mL/hour for 15 minutes).  
The infusion rate may then be 
increased to 40 mL/hour for 15 
minutes, and subsequently at the 
full rate if symptoms do not recur
If symptoms recur.
Grade 3/4
Stop Infusion
Give I.V. diphenhydramine and 
dexamethasone (per institutional
guidelines).  Add epinephrine or 
bronchodilators if indicated.  The 
subject should be removed from 
paclitaxel treatment.
At first occurrence
In addition, investigators may withdraw a subject from paclitaxel therapy for any of the 
following reasons:

An unacceptable adverse event/toxicity (e.g., a persistent moderate toxicity that is 
intolerable to the subject) and is, in the opinion of the investigator, clearly attributed 
to paclitaxel 
 
 
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
Any event which would warrant paclitaxel therapy to be modified by more than two 
dose reductions or to be held for more than 4 weeks from the last administered dose, 
and is clearly attributed to paclitaxel (i.e. recurrent or persistent neuropathy).
Dosing interruptions are permitted in the case of medical/surgical events or logistical reasons 
not related to study therapy (e.g., elective surgery, unrelated medical events, patient vacation, 
and/or holidays). 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 patient's study record.
Timing of Dose Administration
Trial treatment of pembrolizumab may be administered up to 3 days before or after the 
scheduled Day 1 of each cycle due to administrative reasons (up to 3 days after subject is 
randomization is permitted).  Trial treatment of paclitaxel may be administered up to 3 days 
after the scheduled dosing visits of each cycle due to administrative reasons.  If dosing is 
delayed due to administrative reasons, the subsequent dosing visit should be re-calculated to 
account for the weekly dosing visits.
Pembrolizumab
Pembrolizumab should be administered on Day 1 of each three week cycle (Q3W) after all 
procedures/assessments have been completed as detailed on the Trial Flow Chart (Section 
6.0). Trial treatment may be administered up to 3 days before or after the scheduled Day 1 of 
each cycle due to administrative reasons.
Pembrolizumab 200 mg will be administered as a 30 minute IV infusion Q3W.  Sites should 
make every effort to target infusion timing to be as close to 30 minutes as possible. However, 
given the variability of infusion pumps from site to site, a window of -5 minutes and +10 
minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min).
The Pharmacy Manual contains specific instructions for the preparation of the 
pembrolizumab infusion fluid and administration of infusion solution.
Paclitaxel
Paclitaxel should be administered on Day 1, 8, and 15 of each four week cycle after all 
procedures/assessments have been completed as detailed on the Trial Flow Chart (Section 
6.0). Paclitaxel should be administered intravenously over approximately 1 hour according to 
manufacturer standards, at a dose of 80 mg/m2. The first dose of paclitaxel is dependent upon 
the subject’s baseline body surface area. Subsequent doses of paclitaxel must be recalculated 
if there is a ≥ 10% change (increase or decrease) in body surface area from baseline; 
subsequent doses may be recalculated if there is a < 10% change (increase or decrease) in 
body surface area from baseline.
Premedication is recommended prior to infusion of paclitaxel according to the 
manufacturer’s instructions and local standards. Premedication will consist of an oral steroid 
(such as dexamethasone 8-20 mg or equivalent administered [PO] 12 and 6 hours or [IV] 
 
 
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30-60 minutes before paclitaxel), an antihistamine (H1 antagonist) such as diphenhydramine 
hydrochloride 50 mg I.V. (or equivalent), cimetidine (H2 antagonist) 300 mg I.V. or 
equivalent, and an antiemetic (such as ondansetron 8 mg dose PO or 0.15 mg/kg I.V. as per 
ondansetron prescribing information), administered 30 to 120 minutes before paclitaxel.  
Premedication may be provided per local guidance and all medications should be captured on 
the appropriate case report form.
Trial Blinding 
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered.
Imaging data for the primary analysis will be centrally reviewed by independent 
radiologist(s) without knowledge of subject treatment assignment.
Randomization or Treatment Allocation
Treatment allocation/randomization will occur centrally using an interactive voice response 
system / integrated web response system (IVRS/IWRS).
There are 2 treatment arms.  
Subjects will be assigned randomly in a 1:1 ratio to pembrolizumab or paclitaxel.
Stratification
Treatment allocation/randomization will be stratified according to the following factors:
1.
Time to progression from the first dose of first-line therapy (< 6 months vs. ≥ 6 
months)
2.
Eastern Cooperative Oncology Group (ECOG) Performance Status (0 vs. 1)
Concomitant Medications/Vaccinations (Allowed & Prohibited)
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for any medication or vaccination 
specifically prohibited during the trial, discontinuation from trial therapy or vaccination may 
be required.  The investigator should discuss any questions regarding this with the Sponsor 
Clinical Director.  The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the subject's primary physician.  However, the decision to continue the 
subject on trial therapy or vaccination schedule requires the mutual agreement of the 
investigator, the Sponsor and the subject.
Acceptable Concomitant Medications
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care. All concomitant medication will be recorded on the case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications 
and fluids.  If changes occur during the trial period, documentation of drug dosage, regimen, 
route, and date may also be included on the CRF.
 
 
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All concomitant medications received within 30 days before the first dose of trial treatment 
and 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 as defined in Section 7.2.
Prohibited Concomitant Medication
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-complete response relapse) of this trial:

Antineoplastic systemic chemotherapy or biological therapy 

Immunotherapy not specified in this protocol

Chemotherapy not specified in this protocol

Investigational agents other than pembrolizumab

Radiation therapy
o
Note: Radiation therapy to a symptomatic solitary lesion or to the brain may be 
allowed after consultation with Sponsor.  

Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, 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 (e.g. 
FluMist®) are not allowed.

Pembrolizumab arm only: Systemic glucocorticoids for any purpose other than to 
modulate symptoms from an AE that is suspected to have an immunologic etiology.  
The use of physiologic doses of corticosteroids may be approved after consultation 
with the Sponsor (e.g., for control of acute asthma symptoms).
Note: for urgent medical condition, systemic glucocorticoids can be used before the 
consultation with the Sponsor; the investigators will subsequently provide detailed 
documentation for the sponsor regarding the case.
Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial.  
Subjects may receive other medications that the investigator deems to be medically 
necessary.
The Exclusion Criteria describes other medications which are prohibited in this trial.
There are no prohibited therapies during the Post-Treatment Follow-up Phase; however, 
participants must be discontinued from the safety follow-up phase if they begin a non-trial 
treatment.
For those participants randomized to the paclitaxel arm of the study, pre-medication with 
steroids is acceptable.
 
 
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Rescue Medications & Supportive Care
Supportive Care Guidelines for Pembrolizumab
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of AEs with 
potential immunologic etiology are outlined along with the dose modification guidelines in 
Section 5.2.1.2.1.  Where appropriate, these guidelines include the use of oral or IV treatment 
with corticosteroids, as well as additional anti-inflammatory agents if symptoms do not 
improve with administration of corticosteroids.  Note that several courses of steroid tapering 
may be necessary as symptoms may worsen when the steroid dose is decreased.  For each 
disorder, attempts should be made to rule out other causes such as metastatic disease or 
bacterial or viral infection, which might require additional supportive care.  The treatment 
guidelines are intended to be applied when the investigator determines the events to be 
related to pembrolizumab. 
Note: If after the evaluation of the event, it is determined not to be related to pembrolizumab, 
the investigator does not need to follow the treatment guidance.  Refer to Table 3 in Section 
5.2.1.2.1 for guidelines regarding dose modification and supportive care. 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event.
Supportive Care Guidelines for Paclitaxel
Palliative and supportive care for other disease-related symptoms and for toxicity associated 
with treatment will be offered to subjects within the paclitaxel arm of this trial. Supportive 
care measures may include but are not limited to antidiarrheal agents, antiemetic agents, 
opiate and nonopiate analgesic agents, appetite stimulants, and granulocyte and erythroid 
growth factors. 
Non-drug supportive care procedures may be performed as medically 
necessary and appropriate in the opinion of the investigator.  Details of interventions, 
procedures, or blood products (e.g., blood cells, platelets, or fresh frozen plasma 
transfusions) should be recorded on the eCRF. Appropriate management of hypersensitivity 
reactions is described in Section 5.2.1.2.2 and Table 6. The uses of other specific supportive 
care agents are presented below.

Diarrhea:
o
In the event of Grade 3 or 4 diarrhea, supportive measures may include hydration, 
loperamide, octreotide, and antidiarrheals.
o
If diarrhea is severe (i.e., requires intravenous hydration) and associated with fever or 
severe (Grade 3 or 4) neutropenia, broad-spectrum antibiotics may be prescribed.
o
Subjects with severe diarrhea or any diarrhea associated with severe nausea or 
vomiting must be hospitalized for intravenous hydration and correction of electrolyte 
imbalance.

Nausea/Vomiting:
o
The use of antiemetic agents is permitted at the discretion of the investigator.
 
 
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Additional Supportive Care Guidelines:

Analgesic Agents:
The use of analgesic agents is permitted at the discretion of the investigator. The chronic use 
of non-steroidal anti-inflammatory drugs (NSAIDs) with a high risk of bleeding (e.g., 
indomethacin, ibuprofen, naproxen, or similar agents) is strongly discouraged unless at the 
discretion and responsibility of the investigator after careful assessment of the individual 
bleeding risk of the subject. Chronic use of analgesic agents with no or low bleeding risk 
(e.g., paracetamol/acetaminophen, metamizole, dipyrone, propyphenazone) is acceptable.

Granulocyte-Colony Stimulating Factors:
The use of granulocyte-colony stimulating factors (G-CSF) is permitted during 
investigational therapy at the discretion of the investigator. G-CSF or similar agents are 
strongly recommended following Grade 3 or 4 neutropenia of duration > 5 days or following 
any incidence of febrile neutropenia (ANC < 1.0 × 109/L with temperature ≥ 38.5°C). 

Erythroid Growth Factors:
The use of erythroid-stimulating factors (eg, erythropoietin) is permitted at the discretion of 
the investigator based on American Society of Clinical Oncology and Food and Drug 
Administration (FDA) guidelines, or according to local guidelines [44].
Please refer to the product label or local standards of care for additional paclitaxel supportive 
measures.
Diet/Activity/Other Considerations
Diet
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting.
Contraception
Pembrolizumab and paclitaxel may have adverse effects on a fetus in utero. Furthermore, it is 
not known if pembrolizumab or paclitaxel has transient adverse effects on the composition of 
sperm. Therefore, non-pregnant, non-breast-feeding women may only be enrolled if they are 
willing to use 2 methods of birth control or are considered highly unlikely to conceive.  
Highly unlikely to conceive is defined as 1) surgically sterilized, or 2) postmenopausal (a 
woman who is ≥ 45 years of age and has not had menses for greater than 1 year will be
considered postmenopausal), or 3) not heterosexually active for the duration of the study.  
The two birth control methods can either be two barrier methods or a barrier method plus a 
hormonal method to prevent pregnancy. Subjects within the pembrolizumab arm of the study 
should start using birth control from study Visit 1 throughout the study period up to 120 days 
after the last dose of study treatment. Subjects within the paclitaxel arm of the study should 
start using birth control from study Visit 1 throughout the study period up to 180 days after 
the last dose of study treatment.
 
 
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The following are considered adequate barrier methods of contraception: diaphragm, condom 
(by the partner), copper intrauterine device, sponge, or spermicide as per local regulations or 
guidelines. Appropriate hormonal contraceptives will include any registered and marketed 
contraceptive agent that contains an estrogen and/or a progestational agent (including oral, 
subcutaneous, intrauterine, or intramuscular agents).
Abstinence is acceptable if this is the established and preferred contraception for the subject.
Subjects should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study. In order to participate in 
the study they must adhere to the contraception requirement (described above) for the 
duration of the study and during the follow-up period defined in Section 7.2.2, Reporting of 
Pregnancy and Lactation to the Sponsor. If there is any question that a subject will not 
reliably comply with the requirements for contraception, that subject should not be entered 
into the study.
Use in Pregnancy
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab or 
paclitaxel, the subject will immediately be removed from the study. The site will contact the 
subject at least monthly and document the subject’s status until the pregnancy has been 
completed or terminated. The outcome of the pregnancy will be reported to the Sponsor 
without delay and within 24 hours if the outcome is a serious adverse experience (e.g., death, 
abortion, congenital anomaly, or other disabling or life-threatening complication to the 
mother or newborn). The study investigator will make every effort to obtain permission to 
follow the outcome of the pregnancy and report the condition of the fetus or newborn to the 
Sponsor. If a male subject impregnates his female partner the study personnel at the site must 
be informed immediately and the pregnancy reported to the Sponsor and followed as 
described above and in Section 7.2.2.
Use in Nursing Women
It is unknown whether pembrolizumab or paclitaxel are excreted in human milk, and because 
of the potential for serious adverse reactions in the nursing infant, subjects who are breast-
feeding are not eligible for enrollment. Specific additional information follows for individual 
agents used in this trial.
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 treatment will still continue to participate in the trial as specified in 
 
 
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Section 6.0 - Trial Flow Chart and Section 7.1.5.3 – Discontinued Subjects Continuing to be 
Monitored in the Trial.
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:
o
The subject or subject’s legally acceptable representative requests to discontinue 
treatment.
o
Confirmed radiographic disease progression outlined in Section 7.1.2.6.4 and Section 
7.1.2.6.5 (exception if the Sponsor approves treatment continuation)
o
Unacceptable adverse experiences as described in Section 5.2.1.2
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
Investigator’s decision to withdraw the subject
o
Completion of 35 treatments (approximately 2 years) with pembrolizumab
Note: The number of treatments is calculated starting with the first dose.  Subjects who 
stop after receiving 35 doses may be eligible for retreatment if they progress after 
stopping trial treatment provided they meet the requirements detailed in Section 7.1.5.5. 
Subjects may be retreated in the Second Course Phase (Retreatment) for up to an 
additional 17 cycles (approximately 1 year).
o
Discontinuation of treatment may be considered for subjects who have attained a 
confirmed CR and have been treated for at least 8 cycles (at least 24 weeks), receiving at 
least 2 doses of pembrolizumab beyond the date when the initial CR was declared. 
o
Subjects who stop pembrolizumab with stable disease (SD), PR, or CR, may be eligible 
for up to 1 year (17 cycles) of pembrolizumab if they experience disease progression after 
stopping pembrolizumab.  This retreatment is termed the Second Course Phase 
(Retreatment) and is described in detail in Section 7.1.5.5.
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 
 
 
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will be followed for 30 days for adverse event monitoring (serious adverse events will be 
collected for 90 days after the end of treatment or 30 days after the end of treatment if the 
subject initiates new anticancer therapy, whichever is earlier, as described in Section 7.2.3.1). 
Subjects who discontinue for reasons other than progressive disease will have post-treatment 
follow-up for disease status until disease progression, initiating a non-study cancer treatment, 
withdrawing consent or becoming lost to follow-up. After documented disease progression,
each subject will be followed by telephone for overall survival until death, withdrawal of 
consent, or the end of the study, whichever occurs first. 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.
Discontinuation of Study Therapy after CR
Discontinuation of treatment may be considered for subjects who have attained a confirmed 
CR that have been treated for at least 24 weeks with pembrolizumab and had at least two 
treatments with pembrolizumab beyond the date when the initial CR was declared. Subjects 
who then experience radiographic disease progression may be eligible for up to one year of 
additional treatment with pembrolizumab via the Second Course Phase at the discretion of 
the investigator if no cancer treatment was administered since the last dose of 
pembrolizumab, the subject meets the safety parameters listed in the Inclusion/Exclusion 
criteria, and the trial is open. Subjects will resume therapy at the same dose and schedule at 
the time of initial discontinuation. Additional details are provided in Section 7.1.5.5.
For subjects who are discontinued from treatment but continue to be monitored in the trial, 
see Section 6.0 – Trial Flow Chart, and Section 7.1.5.3 – Discontinued Subjects Continuing 
to be Monitored in the Trial for those procedures to be completed at each specified visit.
Subjects may be allowed to begin treatment again if deemed medically appropriate, unless 
the subject’s treatment assignment has been unblinded by the investigator/delegate and/or 
non-study treating physician.
Withdrawal from the Trial
Subjects may withdraw from the trial at any time for any reason.  If a subject withdraws from 
the trial, they will no longer receive treatment or be followed at scheduled protocol visits.
A subject must be withdrawn from the trial if:
○
The subject or subject’s legally acceptable representative withdraws consent from the 
trial.
○
The subject is lost to follow-up.
Specific details regarding procedures to be performed at the time of withdrawal from the trial 
including specific details regarding withdrawal from Future Biomedical Research are 
outlined in Section 7.1.4 – Other Procedures.
 
 
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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.  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). Upon study completion, participants are discontinued and may be enrolled in a 
pembrolizumab extension study. Enrollment in the extension study is conditional on subject 
consent.
Clinical Criteria for Early Trial Termination
The clinical trial may be terminated early if the extent (incidence and/or severity) of 
emerging effects/clinical endpoints is such that the risk/benefit ratio to the trial population as 
a whole is unacceptable.  In addition, further recruitment in the trial or at (a) particular trial 
site(s) may be stopped due to insufficient compliance with the protocol, GCP and/or other 
applicable regulatory requirements, procedure-related problems or the number of 
discontinuations for administrative reasons is too high.
Early trial termination will be the result of the criteria specified below:
1. Quality or quantity of data recording is inaccurate or incomplete
2. Poor adherence to protocol and regulatory requirements
3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential 
health hazard to subjects
4. Plans to modify or discontinue the development of the study drug
In the event of Sponsor decision to no longer supply study drug, ample notification will be 
provided so that appropriate adjustments to subject treatment can be made.
 
 
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Product:  MK-3475 
53
Protocol/Amendment No.: 063-03 
MK-3475-063-03 Final Protocol
22-Apr-2020
Confidential
6.0 TRIAL FLOW CHART
Trial Flow Chart – Initial Treatment Phase for Pembrolizumab Arm
Trial Period:
Screening 
Phase
Treatment Cyclesa
End of Treatment
Post-Treatment
Treatment Cycle/Title:
Screening 
(Visit 1)
1
2
3
4
To be repeated 
beyond 6 cycles
Discon
Safety 
Follow-up
Follow Up 
Visitsb
Survival 
Follow-upc
5
6
At time of discon
30 days
post discon
Every 6 
weeks
post discon
Every 12 
weeks
Scheduling Window (Days)d:
-28 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
PROs (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
Height, Weight, and Vital Signs (T, P, RR, 
BP)j
X
X
X
X
X
X
X
X
ECOG Performance Status
Xk
X
X
X
X
X
X
X
Post-study Anticancer Therapy Status
X
X
X
Survival Statusc
X
Trial Treatment Administration
Pembrolizumabl
X
X
X
X
X
X
Laboratory Procedures/Assessments:  
Analysis performed by LOCAL laboratory
Pregnancy Test – Urine or Serum β-HCGm
X
PT/INR and aPTTn
X
CBC with Differentialo
X
X
X
X
X
Xo
X
Xo
Chemistry Panelo
X
X
X
X
X
Xo
X
Xo
 
 
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Product:  MK-3475 
54
Protocol/Amendment No.: 063-03 
MK-3475-063-03 Final Protocol
22-Apr-2020
Confidential
Trial Period:
Screening 
Phase
Treatment Cyclesa
End of Treatment
Post-Treatment
Treatment Cycle/Title:
Screening 
(Visit 1)
1
2
3
4
To be repeated 
beyond 6 cycles
Discon
Safety 
Follow-up
Follow Up 
Visitsb
Survival 
Follow-upc
5
6
At time of discon
30 days
post discon
Every 6 
weeks
post discon
Every 12 
weeks
Urinalysiso
X
T3, FT4 and TSH
X o
X
X
X
X
Serum carcinoembryonic antigen (CEA)p
X
X
X
Serum CA 19-9p
X
X
X
HBsAg
X q
Hep C Ab and HCV RNA
X q
Laboratory Procedures/Assessments: 
Analysis performed by CENTRAL 
laboratory
Pharmacokineticsr
X
X
X
Xr
Anti-Drug Antibodies (ADA)r
X
X
X
Xr
Blood for Genetic Analysess
X
Correlative Blood Samples (RNA)t
X
X
X
X
Correlative Blood Samples (plasma)t
X
X
X
Correlative Blood Samples (serum)t
X
X
X
Efficacy Measurements
Tumor Imagingu
X
X
X
Xv
X
Tumor Tissue Collection
Archival and/or Newly-Obtained Tissue 
Collection 
Xw
---------------------------Xw------------------------------------
Xw
a.
Unless otherwise specified, assessments/procedures are to be performed on Day 1 and prior to the first dose of treatment for each cycle.
b.
In subjects who discontinued 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 blinded central radiologists’ 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 blinded central radiologists’ vendor, the subject should be contacted by telephone 
approximately every 12 weeks to assess for survival status.  Updated survival status may be requested by the Sponsor at any time during the course of the study. Upon 
Sponsor notification, all participants who do not/will not have a scheduled study visit or study contact during the Sponsor-defined time period will be contacted for their 
survival status (excluding participants that have a death event previously recorded).
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 (e.g., within 28 days prior to the first dose of trial treatment).  Pre-
screening informed consent may be signed prior to the Screening Period specified above in the Trial Flow Chart (-28 to -1 days) to allow the submission of archive tumor 
tissue sample for determination of PD-L1 status and is expected to comply with all IRB/EC requirements.
 
 
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07ZNRX


Product:  MK-3475 
55
Protocol/Amendment No.: 063-03 
MK-3475-063-03 Final Protocol
22-Apr-2020
Confidential
Trial Period:
Screening 
Phase
Treatment Cyclesa
End of Treatment
Post-Treatment
Treatment Cycle/Title:
Screening 
(Visit 1)
1
2
3
4
To be repeated 
beyond 6 cycles
Discon
Safety 
Follow-up
Follow Up 
Visitsb
Survival 
Follow-upc
5
6
At time of discon
30 days
post discon
Every 6 
weeks
post discon
Every 12 
weeks
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.
g.
Prior medications – Record all medications taken within 30 days of screening visit.  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 and ECIs occurring within 30 days after the last dose of trial treatment.  Report all SAEs (related and unrelated to trial treatment) occurring up until 90 days 
after the last dose of trial treatment or 30 days following last dose of trial treatment if the subject initiates new anticancer therapy, whichever comes first.  Afterwards, report 
only SAEs and ECIs that are related to trial treatment.
i.
It is most relevant and strongly recommended that Patient Reported Outcomes (PROs) are administered prior to drug administration, adverse event evaluation and disease 
status notification starting with the EQ-5D, followed by EORTC QLQ-C30 and EORTC QLQ-ST022; an exception to this recommendation may occur at the treatment 
discontinuation visit where patients may have already been notified of their disease status or an AE evaluation is known prior to them arriving to the clinic. All PROs are to
be performed at Cycle 1, Cycle 2, Cycle 3, Cycle 4, Cycle 5, Cycle 7, and Cycle 9.  After Week 24, PROs are to be performed every 6 weeks (conducted at corresponding 
study visit) 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 PROs, 
the MISS_MODE form must be completed to capture the reason the assessment was not performed.
j.
Height will be measured at Visit 1 only.  Vitals Signs include temperature, pulse, respiratory rate, and blood pressure.
k.
ECOG PS should be assessed within 3 days prior to the first dose of trial treatment.
l.
Pembrolizumab should be administered on Day 1 of each 3-week cycle after all procedures/assessments have been completed. 
m.
Female subjects of childbearing potential should have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study therapy. If the urine 
test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
n.
Coagulation factors (PT/INR and aPTT) should be tested as part of the screening procedures for all subjects.
o.
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 and Chemistry panel are to be repeated every 2 cycles after Cycle 6 
(e.g., Cycle 8-Day 1, Cycle 10-Day 1).  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.  
p.
Serum CEA and CA 19-9 should be collected at screening (baseline) and every 6 weeks (conducted at corresponding study visits) until study treatment discontinuation.
q.
Tests will be performed by a central laboratory only if the local laboratory is unable to perform this service.  The need for additional testing due to positive test results will be 
at the discretion of the investigator.
r.
PK and anti-pembrolizumab antibody will be collected for all subjects who receive pembrolizumab monotherapy.  Pre-dose trough PK and anti-pembrolizumab antibody 
samples will be collected at Cycles 1, 2, 4, 6, and 8 and every 4 cycles thereafter.  All pre-dose trough samples should be drawn within 24 hours before infusion of 
pembrolizumab.
s.
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.  If the planned genetic analysis is not approved, but FBR is approved and consent is given, this sample will be collected for the 
purpose of FBR.  Detailed instructions for the collection and management of specimens are provided in the Procedures Manual and Section 12.2.
t.
Whole blood sample for correlative studies should be collected pre-dose on Day 1 of Cycle 1, 2, and 5, or at time of discontinuation.  Blood for serum and blood for plasma to 
 
 
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07ZNRX


Product:  MK-3475 
56
Protocol/Amendment No.: 063-03 
MK-3475-063-03 Final Protocol
22-Apr-2020
Confidential
Trial Period:
Screening 
Phase
Treatment Cyclesa
End of Treatment
Post-Treatment
Treatment Cycle/Title:
Screening 
(Visit 1)
1
2
3
4
To be repeated 
beyond 6 cycles
Discon
Safety 
Follow-up
Follow Up 
Visitsb
Survival 
Follow-upc
5
6
At time of discon
30 days
post discon
Every 6 
weeks
post discon
Every 12 
weeks
be collected pre-dose on Day 1 of Cycle 1, 2, or at time of discontinuation. Leftover RNA, plasma and serum will be stored at the end of the study for future biomedical 
research if the subject consents to future biomedical research. See Procedures Manual.
u.
Baseline tumor imaging will be performed within 14 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) or earlier if clinically indicated and will continue 
to be performed every 6 weeks (± 7 days) regardless of any treatment delays.  Imaging timing should follow calendar days.  On-study scans should be submitted immediately 
to the blinded central radiologists’ vendor.  
v.
In subjects who discontinue study therapy without centrally verified disease progression, a radiologic evaluation should be performed at the time of treatment discontinuation 
(i.e., 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.
w.
Baseline tumor 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. An optional newly obtained core or excisional biopsy (FNA not adequate) is requested at any post-
treatment time point during the study (preference would be as close to dosing at Week 12 as possible).  A biopsy is also requested at the time of discontinuation for PD, but 
will not be required.  Endoscopic biopsies are permitted. Any leftover tumor will be stored for future biomedical research if the subject signs the FBR consent.
 
 
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Product:  MK-3475 
57
Protocol/Amendment No.: 063-03 
MK-3475-063-03 Final Protocol
22-Apr-2020
Confidential
Trial Flow Chart – Initial Treatment Phase for Paclitaxel Arm
Trial Period:
Screening 
Phase
Treatment Cyclesa
End of 
Treatment
Post-Treatment
Continue to Repeat Cycles 1 and 2 until Discon
Treatment Cycle/Title:
Screening 
(Visit 1)
Cycle 1 
Day 1
Cycle 1
Day 8
Cycle 1 
Day 15
Cycle 2 
Day 1
Cycle 2
Day 8
Cycle 2 
Day 15
Discon
Safety 
Follow-up
Follow Up 
Visits b
Survival 
Follow-up c
At time of 
discon
30 days
post discon
Every 6 
weeks
post discon
Every 12 
weeks
Scheduling Window (Days) d:
-28 to -1
± 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 Review g
X
X
X
X
X
X
X
X
X
Clinical Procedures/Assessments
Review Adverse Events h
X
X
X
X
X
X
X
X
X
X
PROs (HRQoL Measures) i
X
X
X
X
X
12-Lead ECG (Local)
X
Full Physical Examination
X
X
Directed Physical Examination
X
X
X
X
X
X
Height, Weight, and Vital Signs (T, P, RR, 
BP)j
X
X
X
X
X
X
X
X
ECOG Performance Status
Xk
X
X
X
X
X
X
X
Post-study Anticancer Therapy Status
X
X
X
Survival Statusc
X
Trial Treatment Administration
Paclitaxell
X
X
X
X
X
X
Laboratory Procedures/Assessments:  
Analysis performed by LOCAL laboratory
Pregnancy Test – Urine or Serum β-HCGm
X
PT/INR and aPTT n
X
CBC with Differentialo
X
X
X
X
X
X
X
X
Chemistry Panelo
X
X
X
X
X
X
X
X
Urinalysis o
X
T3, FT4 and TSH
Xo
X
X
X
 
 
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05GVHK
07ZNRX


Product:  MK-3475 
58
Protocol/Amendment No.: 063-03 
MK-3475-063-03 Final Protocol
22-Apr-2020
Confidential
Trial Period:
Screening 
Phase
Treatment Cyclesa
End of 
Treatment
Post-Treatment
Continue to Repeat Cycles 1 and 2 until Discon
Treatment Cycle/Title:
Screening 
(Visit 1)
Cycle 1 
Day 1
Cycle 1
Day 8
Cycle 1 
Day 15
Cycle 2 
Day 1
Cycle 2
Day 8
Cycle 2 
Day 15
Discon
Safety 
Follow-up
Follow Up 
Visits b
Survival 
Follow-up c
At time of 
discon
30 days
post discon
Every 6 
weeks
post discon
Every 12 
weeks
Serum carcinoembryonic antigenp
X
X
Serum CA19-9p
X
X
HBsAg
X q
Hep C Ab and HCV RNA
X q
Laboratory Procedures/Assessments: 
Analysis performed by CENTRAL 
laboratory
Blood for Genetic Analysesr
X
Correlative Blood Samples (RNA)s
X
X
X
Correlative Blood Samples (plasma)s
X
X
X
Correlative Blood Samples (serum)s
X
X
X
Efficacy Measurements
Tumor Imagingt
X
Xt
Xu
X
Tumor Tissue Collection
Archival and/or Newly-Obtained Tissue 
Collection 
Xv
---------------------------Xv------------------------------------
Xv
a.
Unless otherwise specified, assessments/procedures are to be performed on Day 1 and prior to the first dose of treatment for each cycle.
b.
In subjects who discontinued 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 blinded central radiologists’ 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 blinded central radiologists’ vendor, the subject should be contacted by telephone 
approximately every 12 weeks to assess for survival status.  Updated survival status may be requested by the Sponsor at any time during the course of the study. Upon 
Sponsor notification, all participants who do not/will not have a scheduled study visit or study contact during the Sponsor-defined time period will be contacted for their 
survival status (excluding participants that have a death event previously recorded).
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 from (e.g., within 28 days prior to the first dose of trial treatment). Pre-
screening informed consent may be signed prior to the Screening Period specified above in the Trial Flow Chart (-28 to -1 days) to allow the submission of archive tumor 
tissue sample for determination of PD-L1 status and is expected to comply with all IRB/EC requirements.
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 
provide the Procedures Manual.
g.
Prior medications – Record all medications taken within 30 days of screening visit.  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. 
 
 
05GVHK
05GVHK
07ZNRX


Product:  MK-3475 
59
Protocol/Amendment No.: 063-03 
MK-3475-063-03 Final Protocol
22-Apr-2020
Confidential
Trial Period:
Screening 
Phase
Treatment Cyclesa
End of 
Treatment
Post-Treatment
Continue to Repeat Cycles 1 and 2 until Discon
Treatment Cycle/Title:
Screening 
(Visit 1)
Cycle 1 
Day 1
Cycle 1
Day 8
Cycle 1 
Day 15
Cycle 2 
Day 1
Cycle 2
Day 8
Cycle 2 
Day 15
Discon
Safety 
Follow-up
Follow Up 
Visits b
Survival 
Follow-up c
At time of 
discon
30 days
post discon
Every 6 
weeks
post discon
Every 12 
weeks
h.
Record all AEs and ECIs occurring within 30 days after the last dose of trial treatment.  Report all SAEs (related and unrelated to trial treatment) occurring up until 90 days 
after the last dose of trial treatment or 30 days following last dose of trial treatment if the subject initiates new anticancer therapy, whichever comes first.  Afterwards, report 
only SAEs and ECIs that are related to trial treatment.
i.
It is most relevant and strongly recommended that Patient Reported Outcomes (PROs) are administered prior to drug administration, adverse event evaluation and disease 
status notification starting with the EQ-5D, followed by EORTC QLQ-C30, EORTC QLQ-ST022 an exception to this recommendation may occur at the treatment 
discontinuation visit where patients may have already been notified of their disease status or an AE evaluation is known prior to them arriving to the clinic.  All PROs are to 
be performed prior to Cycle 1-Day 1, Cycle 2-Day 1, Cycle 2-Day 15, Cycle 3-Day 8, Cycle 4-Day 1 and every 6 weeks thereafter (conducted at corresponding study visit) 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 PROs, the 
MISS_MODE form must be completed to capture the reason the assessment was not performed. 
j.
Height will be measured at Visit 1 only.  Vitals Signs include temperature, pulse, respiratory rate, and blood pressure.
k.
ECOG PS should be assessed within 3 days prior to the first dose of trial treatment.
l.
Paclitaxel should be administered on Day 1, 8, and 15 of each 28-day (4-week) cycle after all procedures/assessments have been completed.   
m.
Female subjects of childbearing potential should have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study therapy. If the urine 
test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
n.
Coagulation factors (PT/INR and aPTT) should be tested as part of the screening procedures for all subjects.
o.
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 must be collected within 48 hours prior to the scheduled dose administration of paclitaxel.  CBC with differential and chemistry panel should be completed at 
every study visit, except for unscheduled visits (unless clinically indicated). 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.
p.
Serum CEA and CA19-9 should be collected at screening (baseline) and every 6 weeks (conducted at corresponding study visits) until study treatment discontinuation.
q.
Tests will be performed by a central laboratory only if the local laboratory is unable to perform this service. The need for additional testing due to positive test results will be 
at the discretion of the investigator.
r.
This sample should be drawn for planned analysis of the association between genetic variants in DNA and drug response. If there is either a documented law or regulation 
prohibiting collection, or if the IRB/IEC does not approve the collection of the sample for these purposes, then this sample will not be collected at that site. If the sample is 
collected, leftover extracted DNA will be stored for future biomedical research if the subject signs the FBR consent. If the planned genetic analysis is not approved, but FBR 
is approved and consent is given, this sample will be collected for the purpose of FBR. 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 pre-dose on Day 1 of Cycle 1, 2, and 5, or at time of discontinuation.  Blood for serum and blood for plasma to 
be collected pre-dose on Day 1 of Cycle 1, 2, or at time of discontinuation. Leftover RNA, plasma and serum will be stored at the end of the study for future biomedical 
research if the subject consents to future biomedical research.  See Procedures Manual.
t.
Baseline tumor imaging will be performed within 14 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) or earlier if clinically indicated and will continue 
to be performed every 6 weeks (± 7 days) regardless of any treatment delays.  Imaging timing should follow calendar days.  On-study scans should be submitted immediately 
 
 
05GVHK
05GVHK
07ZNRX


Product:  MK-3475 
60
Protocol/Amendment No.: 063-03 
MK-3475-063-03 Final Protocol
22-Apr-2020
Confidential
Trial Period:
Screening 
Phase
Treatment Cyclesa
End of 
Treatment
Post-Treatment
Continue to Repeat Cycles 1 and 2 until Discon
Treatment Cycle/Title:
Screening 
(Visit 1)
Cycle 1 
Day 1
Cycle 1
Day 8
Cycle 1 
Day 15
Cycle 2 
Day 1
Cycle 2
Day 8
Cycle 2 
Day 15
Discon
Safety 
Follow-up
Follow Up 
Visits b
Survival 
Follow-up c
At time of 
discon
30 days
post discon
Every 6 
weeks
post discon
Every 12 
weeks
to the blinded central radiologists’ vendor.  
u.
In subjects who discontinue study therapy without centrally verified disease progression, a radiologic evaluation should be performed at the time of treatment discontinuation 
(i.e., 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.
v.
Baseline tumor 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. An optional newly obtained core or excisional biopsy (FNA not adequate) is requested at any post-
treatment time point during the study (preference would be as close to dosing at Week 12 as possible).  A biopsy is also requested at the time of discontinuation for PD, but 
will not be required.  Endoscopic biopsies are permitted. Any leftover tumor will be stored for future biomedical research if the subject signs the FBR consent.
 
 
05GVHK
05GVHK
07ZNRX


Product:  MK-3475 
61
Protocol/Amendment No.: 063-03 
MK-3475-063-03 Final Protocol
22-Apr-2020
Confidential
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
Discon
Safety 
Follow-up
Follow Up 
Visitsb
Survival 
Follow-upc
At time of discon
30 days post 
discon
Every 6 
weeks post 
discon
Every 12 
weeks
Scheduling Window (Days)d:
± 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
ECOG Performance Status
Xi
X
X
X
X
X
X
Pembrolizumab Administrationj
X
X
X
X
X
X
Post-study Anticancer Therapy Status
X
X
X
Survival Statusc
X
Laboratory Procedures/Assessments:  Analysis 
performed by LOCAL laboratory
Pregnancy Test – Urine or Serum β-HCGk
X
PT/INR and aPTTl
X
CBC with Differentialm
X
X
X
X
X
Xm
X
X
Chemistry Panelm
X
X
X
X
X
Xm
X
X
Urinalysism
X
T3, FT4 and TSHm
X
X
X
X
Efficacy Measurements
Tumor Imagingn
X
X
X
Xo
X
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 ± 3 days) until (1) the start of new anti-cancer treatment, (2) disease progression as assessed by the blinded central radiologists’ 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 blinded central radiologists’ vendor, the subject should be contacted by telephone 
approximately every 12 weeks to assess for survival status.  Updated survival status may be requested by the Sponsor at any time during the course of the study. Upon 
Sponsor notification, all participants who do not/will not have a scheduled study visit or study contact during the Sponsor-defined time period will be contacted for their 
 
 
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Trial Period:
Treatment Cyclesa
End of Treatment
Post-Treatment
Treatment Cycle:
1
2
3
4
5
Cycle 6 
and 
beyond
Discon
Safety 
Follow-up
Follow Up 
Visitsb
Survival 
Follow-upc
At time of discon
30 days post 
discon
Every 6 
weeks post 
discon
Every 12 
weeks
Scheduling Window (Days)d:
± 3
± 3
± 3
± 3
± 3
± 3
± 7
± 7
± 7
survival status (excluding participants that have a death event previously recorded).
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 (~ 2 years) on pembrolizumab for reasons other than disease 
progression or intolerability may restart trial treatment if they meet the criteria specified in Section 7.1.5.5.  
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 and ECIs occurring within 30 days after the last dose of trial treatment.  Report all SAEs (related and unrelated to trial treatment) occurring up until 90 days 
after the last dose of trial treatment or 30 days following last dose of trial treatment if the subject initiates new anti-cancer therapy, whichever comes 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.
ECOG PS should be assessed within 3 days prior to the first dose of trial treatment in Second Course Phase.
j.
Subjects who restart treatment should resume at the same dose and schedule which they were receiving prior to discontinuation.
k.
Female subjects of childbearing potential should have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study therapy. If the urine 
test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
l.
Coagulation factors (PT/INR and aPTT) should be tested as part of the screening procedures for all subjects.
m.
Laboratory tests for determining eligibility for retreatment are to be performed within 10 days prior to the first retreatment dose of pembrolizumab.  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 6.  
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.
n.
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 treatment or more frequently if clinically indicated.  Imaging timing should follow calendar days and should not be adjusted for any dose modifications.  The 
exact same image acquisition and processing parameters should be used throughout the study.  See Section 7.1.2.6.3
o.
In subjects who discontinue study therapy without confirmed disease progression, a radiologic evaluation should be performed at the time of treatment discontinuation (i.e., 
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.
 
 
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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
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. If there are changes to the subject’s status during the 
trial (e.g., health or age of majority requirements), the investigator or qualified designee must 
ensure the appropriate consent is in place. 
7.1.1.1.1 General Informed Consent
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion. 
A copy of the signed and dated consent form should be given to the subject before 
participation in the trial.
The initial informed consent form, any subsequent revised written informed consent form 
and any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The subject or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the trial.  The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the subject’s dated signature or 
by the subject’s legally acceptable representative’s dated signature.
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.  
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements.
 
 
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7.1.1.1.2 Consent and Collection of Specimens for Future Biomedical Research
The investigator or qualified designee will explain the Future Biomedical Research consent 
to the subject, answer all of his/her questions, and obtain written informed consent before 
performing any procedure related to Future Biomedical Research. A copy of the informed 
consent will be given to the subject.
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.
Subject Identification Card
All subjects will be given a Subject Identification Card identifying them as participants in a 
research trial. The card will contain trial site contact information (including direct telephone 
numbers) to be utilized in the event of an emergency. The investigator or qualified designee 
will provide the subject with a Subject Identification Card immediately after the subject 
provides written informed consent. At the time of treatment allocation/randomization, site 
personnel will add the treatment/randomization number to the Subject Identification Card.
The subject identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about trial 
medication/vaccination in emergency situations where the investigator is not available.
Medical History
A medical history will be obtained by the investigator or qualified designee. Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
are considered to be clinical significant by the investigator. Details regarding the subject’s 
gastric or GEJ adenocarcinoma will be recorded separately and not listed as medical history.
Please note that if the patient has lost at least 6.8 kg (15 lbs.) over the three months prior to 
screening, “weight loss” should be entered as an active condition on the Medical History. As 
well, any autoimmune disorders, regardless of onset date, should be recorded.
7.1.1.4.1 Disease Details
The investigator or qualified designee will obtain prior and current details regarding the 
subject’s gastric or GEJ adenocarcinoma.
 
 
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Prior and Concomitant Medications Review
7.1.1.5.1 Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject 
within 30 days before starting the trial. Details regarding the subject’s gastric or GEJ 
adenocarcinoma medications will be recorded separately and not listed as prior medications.
7.1.1.5.2 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 form until the Safety Follow-
up Visit. All medications related to reportable SAEs and ECIs should be recorded as defined 
in Section 7.2.
Assignment of Screening Number
All consented subjects will be given a unique screening number that will be used to identify 
the subject for all procedures that occur prior to randomization or treatment allocation.  Each 
subject will be assigned only one screening number.  Screening numbers must not be re-used 
for different subjects.
Any subject who is screened multiple times will retain the original screening number 
assigned at the initial screening visit.
Specific details on the screening visit requirements (screening/rescreening) are provided in 
Section 7.1.5.1.  
Assignment of Treatment/Randomization Number
All eligible subjects will be randomly allocated and will receive a treatment/randomization 
number.  The treatment/randomization number identifies the subject for all procedures 
occurring after treatment allocation/randomization.  Once a treatment/randomization number 
is assigned to a subject, it can never be re-assigned to another subject.
A single subject cannot be assigned more than 1 treatment/randomization number.
Drug administration should occur within 3 days from assignment of a randomization number.
Trial Compliance (Medication/Diet/Activity/Other)
Interruptions from the protocol specified treatment plan for greater than 12 weeks between 
pembrolizumab dose require consultation between the investigator and the Sponsor and 
written documentation of the collaborative decision on subject management.
Administration of trial medication will be monitored by the investigator and/or trial staff.
 
 
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Clinical Procedures/Assessments
Adverse Event (AE) Monitoring
The investigator or qualified designee will assess each subject to evaluate for potential new 
or worsening AEs as specified in the Trial Flow Chart and more frequently if clinically 
indicated.  Adverse events will be graded and recorded throughout the study and during the 
follow-up period according to NCI CTCAE Version 4.0 (see Section 12.5). Toxicities will be 
characterized in terms regarding seriousness, causality, toxicity grading, and action taken 
with regard to trial treatment.  
All AEs of unknown etiology associated with study treatment exposure should be evaluated 
to determine if it is possibly an event of a potentially immunologic etiology; see Section 
5.6.1.
Please refer to Section 7.2 for detailed information regarding the assessment and recording of 
AEs.
Physical Exam
7.1.2.2.1 Full Physical Exam
The investigator or clinical designee will perform a complete physical exam during the 
screening period. Clinically significant abnormal findings should be recorded as medical 
history. A full physical exam should be performed as specified in the Trial Flow Chart. After 
the first dose of trial treatment new clinically significant abnormal findings should be 
recorded as AEs.
7.1.2.2.2 Directed Physical Exam
For cycles/visits that do not require a full physical exam per the Trial Flow Chart, the 
investigator or qualified designee will perform a directed physical exam as clinically 
indicated prior to dosing on Day 1 of each treatment cycle for the pembrolizumab arm and on 
Days 1, 8, and 15 of each treatment cycle for the paclitaxel arm. New clinically significant 
abnormal findings should be recorded as AEs.
Vital Signs
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment and at treatment discontinuation as specified in 
the Trial Flow Chart. Vital signs should include temperature, pulse, respiratory rate, weight 
and blood pressure.  Height will be measured at screening only.
12-Lead Electrocardiogram
A standard 12-lead ECG will be performed using local standard procedures once at 
screening. Clinically significant abnormal findings should be recorded as medical history. 
Additional time points may be performed as clinically necessary.
 
 
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Eastern Cooperative Oncology Group (ECOG) Performance Status
The investigator or qualified designee will assess ECOG performance status (see 
Section 12.4) at screening, prior to dosing of trial treatment, and at discontinuation of trial 
treatment for both treatment arms, as specified in the Trial Flow Chart.
Tumor Imaging and Assessment of Disease
Processes for image collection and transmission to the central vendor can be found in the 
Procedure Manual. The Site Imaging Manual will provide details on acquisition parameters 
and image transmission practices required for this trial. 
7.1.2.6.1 Initial Tumor Imaging
To meet screening criteria, initial tumor imaging must be performed within 14 days prior to 
randomization. This scan will be considered the baseline assessment for the study. The site 
study team must review pre-trial images to confirm the subject has at least one target lesion 
per standard RECIST 1.1.
Scans performed as part of routine clinical management are acceptable for use as the baseline 
scan if they are of diagnostic quality and performed within 14 days prior to randomization.
7.1.2.6.2 Tumor Imaging During Trial
The first on-study imaging assessment should be performed at 6 weeks (42 days ± 7 days) 
from the date of randomization.  Subsequent imaging should be performed every 6 weeks (42 
days ± 7 days) or more frequently if clinically indicated. Imaging timing should follow 
calendar days and should not be adjusted for delays in cycle starts.  Imaging should continue 
to be performed until disease progression verified by the central imaging vendor (unless the 
site principal investigator elects to continue treatment and follow irRECIST), the start of new 
anticancer treatment, withdrawal of consent, or death, whichever occurs first.  All 
supplemental imaging must be submitted to the central imaging vendor.
Note: The exact same image acquisition and processing parameters should be used 
throughout the study.
Per RECIST 1.1, PR and CR should be confirmed by a repeat tumor imaging assessment 
obtained 4 weeks or longer from the date the response was first documented.  The tumor 
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 (i.e., 6 weeks later), whichever is 
clinically indicated.  Subjects will then return to regular scheduled imaging every 6 weeks, 
starting with the next scheduled imaging time point.  Subjects who obtain a confirmation 
scan do not need to undergo the next scheduled tumor imaging if it is <4 weeks later; tumor 
imaging may resume at the subsequent scheduled imaging time point.
At the time of the initial PD by RECIST 1.1 imaging scans should be sent to the central 
vendor to verify PD. If PD is verified, the investigator may choose to continue treatment if 
 
 
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the patient is clinically stable and repeat imaging at least 4 weeks after the first tumor 
imaging indicating PD to confirm PD (by the site) and then follow irRECIST.
Per irRECIST (Section 7.1.2.6.5), disease progression on subjects treated with 
pembrolizumab should be 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 7.1.2.6.5.  Subjects who obtain a confirmation scan do not need to 
undergo the next scheduled tumor imaging if it is <4 weeks later; tumor imaging may resume 
at the subsequent scheduled imaging time point if clinically stable.  Subjects who have 
confirmed disease progression, as assessed by the site, will discontinue trial treatment.  
Exceptions are detailed in Section 7.1.2.6.5.
7.1.2.6.3 Second Course (Retreatment Tumor Imaging)
Tumor imaging must be performed within 21 days prior to restarting treatment with 
pembrolizumab. Imaging should continue to be performed every 6 weeks (42 days ± 7 days) 
after the restart of treatment or more frequently, if clinically indicated. Imaging timing 
should follow calendar days and should not be adjusted for any dose modifications. The 
exact same image acquisition and processing parameters should be used throughout the 
study. Local reading (investigator assessment with site radiology reading) will be used to 
determine eligibility. All Second Course imaging should be submitted to the imaging Contract 
Research Organization (iCRO) for quality control, storage, and possible retrospective review.
For participants who discontinue Second Course study intervention, tumor imaging should be 
performed at the time of intervention discontinuation (±4-week window). If previous imaging 
was obtained within 4 weeks prior to the date of discontinuation, then imaging at intervention 
discontinuation is not mandatory. For participants who discontinue study intervention due to 
documented disease progression, this is the final required tumor imaging.
For participants who discontinue Second Course study intervention without documented disease 
progression, every effort should be made to continue monitoring their disease status by radiologic
imaging every 6 weeks (42 days ±7 days) until either the start of a new anticancer treatment, 
disease progression, death, or the end of the study, whichever occurs first.
7.1.2.6.4 RECIST 1.1 Assessment of Disease
RECIST 1.1 will be used by blinded independent central review (BICR) as the primary 
measure for assessment of tumor response, date of disease progression, and as a basis for all 
protocol guidelines related to disease status (e.g., 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 target lesions in total and 5 per organ, if clinically relevant, to 
enable a broader sampling of tumor burden.  Initial tumor 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 2 illustrates the imaging flow involving verification of PD for 
clinically stable subjects.
 
 
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7.1.2.6.5 irRECIST Assessment of Disease
irRECIST is RECIST 1.1 adapted as described below to account for the unique tumor 
response seen with immunotherapeutic drugs. irRECIST will be used by the site 
investigator/local radiology reviewers to assess tumor response and progression, and to make 
treatment decisions.  These 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 tumor 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 tumor imaging for confirmation of PD.  
Tumor flare includes any of the following scenarios:

Worsening of existing target lesion(s)

Worsening of existing nontarget 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 
principal investigator whether to continue a subject on trial medication until repeat imaging 
is obtained (using irRECIST for subject management (see Table 7 and Figure 2). 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 tumor 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 tumor at critical anatomical sites (e.g., 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 tumor burden has increased or decreased per irRECIST, 
the local site investigator should consider all target and nontarget lesions, as well as any 
incremental new lesion(s).
 
 
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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

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 (i.e., 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 tumor burden at the confirmatory tumor 
imaging, an exception to continue treatment may be considered following consultation with 
the Sponsor.  In this case, if treatment is continued, tumor 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.
 
 
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Table 7
Imaging and Treatment after First Radiologic Evidence of Progressive Disease 
(PD)
Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
First radiologic 
evidence of PD,
which has been 
verified by the 
central imaging 
vendor
Repeat imaging at 
site at 4 weeks 
to confirm PD
May continue trial 
treatment at the 
local site 
investigator’s 
discretion while 
awaiting 
confirmatory 
tumor imaging by 
site by irRECIST
Repeat imaging at 
4 weeks to 
confirm PD per 
physician 
discretion only
Discontinue 
treatment
Repeat tumor 
imaging
confirms PD by 
irRECIST at the 
local site
No additional 
imaging required
Discontinue 
treatment 
(exception is 
possible upon 
consultation with 
Sponsor).
No additional 
imaging required
Not applicable
Repeat tumor 
imaging shows 
SD, PR, or CR
by irRECIST at 
the local site
Continue 
regularly 
scheduled 
imaging 
assessments every 
6 weeks
Continue trial
treatment at the 
local site 
investigator’s 
discretion
Continue 
regularly 
scheduled 
imaging 
assessments every 
6 weeks 
May restart trial 
treatment if 
condition has 
improved 
and/or clinically 
stable per 
investigator’s
discretion.  
Next tumor 
image should 
occur according 
to the regular 
imaging 
schedule.
 
 
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Figure 2
Imaging and Treatment for Clinically Stable Subjects Treated with 
Pembrolizumab after First Radiologic Evidence of PD Assessed by the Site
 
 
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Tumor Tissue Collection and Correlative Blood Sampling
Participation in this trial will be dependent upon supplying a tumor tissue specimen. Newly 
obtained endoscopic biopsy specimens are preferred to archived samples and formalin-fixed, 
paraffin-embedded (FFPE) block specimens are preferred to slides. The specimen will be 
evaluated at a central laboratory facility for expression status of PD-L1, and only PD-L1 
positive subjects will be eligible for this trial.
Note: A fine needle aspirate (FNA) or cytologic specimen will not be acceptable. Newly 
obtained endoscopic biopsy specimen or archived tissue should be submitted in the condition 
described in the Procedure Manual. If there is an existing specimen obtained with surgical 
resection or core needle biopsy, these can be submitted. Newly-obtained specimens are 
defined as FFPE-preserved blocks of tissue collected up to 6 weeks (42 days) prior to Day 1.
Collection of an archived tissue sample will also be requested (where available) to support 
evaluation of the clinical utility of PD-L1 assessment in newly obtained vs. archived tissue 
samples; however, a subject will not be precluded from participating in the study if an 
archived tissue sample is not available for collection or is otherwise insufficient for analysis.
If the subject signs the Future Biomedical Research (FBR) consent, any leftover tissue that 
would ordinarily be discarded at the end of the main study will be retained for FBR. Details 
regarding time points for collection of tumor tissue are outlined in the Trial Flow Chart –
Section 6.1.
Detailed instructions for tissue collection, processing and shipment are provided in the 
Procedures Manual.
Blood Collections – Samples for Correlative and Genetic Analyses
Additional biomarker research to identify factors important for pembrolizumab therapy may 
also be pursued. For example, tumor and blood samples (including serum and plasma) from 
this study may undergo proteomic, genomic, metabolomics, and transcriptional analyses.  
Additional research may evaluate factors important for predicting responsiveness or 
resistance to pembrolizumab therapy and other immunologic targets.
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.
Any leftover specimens may be used for future biomedical research provided the subject has 
provided the relevant informed consent.
Details regarding time points for blood collection are outlined in the Trial Flow Chart –
Section 6.1. Further details can also be found in Section 4.2.3.4.3 and further detailed 
instructions for tissue collection, processing and shipment are provided in the Procedures 
Manual.
 
 
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Patient Reported Outcomes (PRO)
The EuroQol EQ-5D, EORTC QLQ-C30, and EORTC QLQ-STO22 questionnaires will be 
administered by trained study site personnel and completed by subjects. It is strongly 
recommended that the EORTC QLQ-C30, EORTC QLQ-STO22 and EuroQol EQ-5D is 
completed by the patient prior to drug administration, adverse event evaluation and disease 
status notification; an exception to this recommendation may occur at the treatment 
discontinuation visit. PROs will be administrated in the following order: EuroQol EQ-5D 
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 Procedure Manual.
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
Laboratory tests for hematology, chemistry, and urinalysis are specified in Table 8.
Table 8
Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Hematocrit
Albumin
Blood
Serum β-human chorionic 
gonadotropin (β-hCG)a
Hemoglobin
Alkaline phosphatase
Glucose
PT (INR)
Platelet count
Alanine aminotransferase 
(ALT)
Protein
aPTT
WBC (total and 
differential)
Aspartate aminotransferase 
(AST)
Specific gravity 
Total triiodothyronine (T3) 
or Free T3
Red Blood Cell Count
Calcium
Microscopic exam, if 
abnormal results are 
noted 
Free thyroxine (T4)
Absolute Neutrophil 
Count
Chloride
Urine pregnancy testa
Thyroid stimulating 
hormone (TSH)
Absolute Lymphocyte 
Count
Creatinine
Glucose
Phosphorus
Potassium
Sodium
Total Bilirubin  
Direct Bilirubin, if total 
bilirubin is elevated above 
the upper limit of normal
Total protein
Carbon dioxide (CO2) or 
bicarbonateb
Uric acid
Blood Urea Nitrogen/Ureac
 
 
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Hematology
Chemistry
Urinalysis
Other
a.
Perform on women of childbearing potential only.  Serum pregnancy test is preferred but urine test can be considered 
if serum not appropriate.
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.
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 for both arms of the study. After Cycle 1, pre-dose laboratory procedures can 
be conducted up to 72 hours prior to dosing for the pembrolizumab arm. For subjects within 
the paclitaxel arm, after Cycle 1 Day 1, the pre-infusion data may not be older than 48 hours. 
Results must be reviewed by the investigator or qualified designee and found to demonstrate
adequate organ functions prior to each dose of trial treatment.
There may be instances when sites are unable to obtain the thyroid function testing results 
prior to scheduled dosing.  After Cycle 1, review of thyroid function tests (FT3, FT4 and 
TSH) results after dosing is acceptable.
Serum/Urine β-hCG 
All women who are being considered for participation in the trial, and who are not surgically 
sterilized or postmenopausal, will be tested for pregnancy within 72 hours of receiving the 
first dose of study therapy, and must be excluded in the event of a positive or borderline-
positive test result. If a urine test is positive or borderline a serum β-HCG test will be 
required.
Pharmacokinetic/Pharmacodynamic Evaluations
To evaluate the immunogenicity and exposure of pembrolizumab in this indication, sample 
collections for analysis of anti-pembrolizumab antibodies (ADA) and PK are currently 
planned as shown in the Trial Flow Chart (Section 6.1). Further analysis may be performed,
if required. If ongoing PK and/or ADA sampling is deemed to be unnecessary by the 
Sponsor, it may be reduced or discontinued. 
7.1.3.3.1 Blood Collection for Serum MK-3475
Sample collection, storage and shipment instructions for serum PK samples will be provided 
in the Procedures Manual. PK samples should be drawn according to the PK collection 
schedule for subjects who receive pembrolizumab. 
7.1.3.3.2 Blood Collection for Anti-pembrolizumab Antibodies
Sample collection, storage and shipment instructions for anti- pembrolizumab antibody 
samples will be provided in the Procedures Manual. Anti- pembrolizumab antibody samples 
should be drawn according to the ADA collection schedule for subjects who receive 
pembrolizumab.  Simultaneous PK sampling is required for interpretation of ADA analysis.
 
 
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Planned Genetic Analysis Sample Collection
Sample collection, storage and shipment instructions for Planned Genetic Analysis samples 
will be provided in the Procedure Manual.
Future Biomedical Research Samples
The following specimens are to be obtained as part of Future Biomedical Research:

Leftover DNA

Leftover RNA

Leftover plasma and serum from biomarker studies

Leftover tumor tissue
Other Procedures
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 arm who a) attain a CR or b) 
complete 35 administrations (approximately 2 years) of treatment with pembrolizumab may 
discontinue treatment with the option of restarting treatment if they meet the criteria 
specified in Section 7.1.5.5. After discontinuing treatment following assessment of CR or 35 
administrations (~ 2 years) of treatment, these subjects should return to the site for a Safety 
Follow-up Visit (described in Section 7.1.5.4.1) and then proceed to the Follow-up Period of 
the study (described in Section 7.1.5.4.2).
7.1.4.1.1 Withdrawal From Future Biomedical Research
Subjects may withdraw their consent for Future Biomedical Research.  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).  Subsequently, 
the subject's consent for Future Biomedical Research will be withdrawn.  A letter will be sent 
from the Sponsor to the investigator confirming the withdrawal. It is the responsibility of the 
investigator to inform the subject of completion of withdrawal.  Any analyses in progress at 
the time of request for withdrawal or already performed prior to the request being received 
by the Sponsor will continue to be used as part of the overall research trial data and results.  
No new analyses would be generated after the request is received.
 
 
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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 withdrawal cannot be processed.
Subject Blinding/Unblinding
This is an open label trial; there is no blinding for this trial.
Calibration of Critical Equipment
The investigator or qualified designee has the responsibility to ensure that any critical device
or instrument used for a clinical evaluation/test during a clinical trial that provides important 
information about inclusion/exclusion criteria and/or safety or efficacy parameters shall be 
suitably calibrated and maintained to ensure that the data obtained is reliable and/or 
reproducible.  Documentation of equipment calibration must be retained as source 
documentation at the trial site.
Critical Equipment for this trial includes:

Laboratory equipment – as required for inclusion labs and trial assessments

Imaging equipment – as required for study objective
See protocol-specified guidance in the Administrative Binder, Procedures Manual, Site 
Imaging Manual (SIM) and irRECIST Tip Sheet.
Visit Requirements
Visit requirements are outlined in Section 6.0 - Trial Flow Chart. Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures.
Screening
7.1.5.1.1 Pre-screening Period
The Pre-screening period may be utilized by subjects to determine biomarker eligibility 
based on PD-L1 status using an archival tumor biopsy sample.  After providing a pre-
screening consent, subjects will be assigned a screening number. Characterization of PD-L1 
status will be performed at a pre-screening visit for subjects with an available archival tumor 
biopsy sample.  
Subjects that do not have an archival tumor biopsy sample available must provide written 
consent for the main study before the tumor biopsy or any other protocol-specified 
procedures can occur.  These subjects will not enter the pre-screening period as eligibility 
based on PD-L1 expression will be determined in the main study screening period.
 
 
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7.1.5.1.2 Screening Period
Approximately 28 days prior to randomization, potential subjects will be evaluated to 
determine that they fulfill the entry requirements as set forth in Section 5.1. Screening 
procedures may be repeated after consultation with the Sponsor. Visit requirements are 
outlined in Section 6.0 – Trial Flow Chart.
Results of a test performed prior to the subject signing consent as part of routine clinical 
management are acceptable in lieu of a screening test if performed within the specified time 
frame. Screening procedures are to be completed within 28 days prior to the first dose trial 
treatment except for the following:

Laboratory tests are to be performed within 10 days prior to the first dose of trial 
treatment; ECOG PS should be assessed within 3 days prior to the first dose of trial 
treatment.

For women of reproductive potential, a serum pregnancy test will be performed 
within 72 hours prior to the first dose of trial treatment.  A urine test may be 
considered if serum test is not appropriate.

Baseline tumor imaging will be performed within 14 days prior to randomization for 
all subjects.  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.
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.
Treatment Period
Visit requirements are outlined in Section 6.0 – Trial Flow Chart. Specific procedure-related 
details are provided above in Section 7.1 – Trial Procedures.
Discontinued Subjects Continuing to be Monitored in the Trial
The Discontinuation Visit should occur at the time study treatment is discontinued for any 
reason. If the Discontinuation Visit occurs 30 days from the last dose of study treatment, at 
the time of the mandatory Safety Follow up Visit, procedures do not need to be repeated. 
Visit requirements are outlined in Section 6.0 – Trial Flow Chart.  Specific procedure-related 
details are provided above in Section 7.1 – Trial Procedures. Additional details regarding 
subject withdrawal and discontinuation are presented in Section 5.8.
 
 
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Post-Treatment
7.1.5.4.1 Safety Follow-up 
The mandatory Safety Follow-up Visit should be conducted approximately 30 days after the 
last dose of trial treatment or before the initiation of a new anti-cancer treatment, whichever 
comes first. 
Participants who are eligible for retreatment with pembrolizumab (as described in Section 
7.1.5.5) may have up to 2 safety follow-up visits, 1 after the Treatment Period and 1 after the 
Second Course Phase.
7.1.5.4.2 Follow-up Visits
Subjects who discontinue trial treatment for a reason other than disease progression will 
move into the Follow-up Phase and should be assessed every 6 weeks (42 ± 7 days) by 
radiologic imaging to monitor disease status. The Sponsor may request survival status to be 
assessed at additional time points during the course of the study (not to exceed approximately 
12 weeks). Every effort should be made to collect information regarding disease status until 
the start of new anti-cancer therapy, disease progression determined by the blinded central 
radiologists’ vendor, death, or at end of study. Information regarding post-study anti-cancer 
treatment will be collected if new treatment is initiated.
Subjects who are eligible to receive retreatment with pembrolizumab according to the criteria 
in Section 7.1.5.5 will move from the Follow-up Phase to the Second Course Phase when 
they experience disease progression.  Details are provided in Section 6.2 – Trial Flow Chart 
for retreatment with pembrolizumab.
7.1.5.4.3 Survival Follow-up
Once a subject experiences confirmed disease progression confirmed by central review or 
starts a new anti-cancer therapy, the subject moves into the Survival Follow-up Phase and 
should be contacted by telephone approximately every 12 weeks to assess for survival status 
until death, withdrawal of consent, or the end of the study, whichever occurs first.
7.1.5.4.4 Survival Status
To ensure current and complete survival data are available at the time of database locks, 
updated survival status may be requested during the course of the study by the Sponsor. For 
example, updated survival status may be requested prior to but not limited to an eDMC safety 
review, efficacy interim analysis, and/or final analysis.
Upon Sponsor notification, all 
subjects who do not/will not have a scheduled study visit or study contact during the 
Sponsor-defined time period will be contacted for their survival status (excluding subjects 
that have previously recorded a death he collection tool).
 
 
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Second Course Phase (Retreatment Period) 
Subjects on the pembrolizumab arm who stop treatment with SD or better may be eligible for 
up to one year of additional pembrolizumab therapy if they progress after stopping study 
treatment.  This retreatment is termed the Second Course Phase of this study and is only 
available if the trial remains open and the subject meets the following conditions:

Either 
o
Stopped initial treatment with pembrolizumab after attaining an investigator-
determined confirmed CR according to RECIST 1.1

Was treated for at least 24 weeks with pembrolizumab before 
discontinuing therapy

Received at least two treatments with pembrolizumab beyond the date 
when the initial CR was declared
OR
o
Had SD, PR or CR and stopped pembrolizumab treatment after 35 
administrations (approximately 2 years) of study therapy for reasons other 
than disease progression or intolerability

AND
o
Experienced an investigator-determined radiographic disease progression after 
stopping their initial treatment with pembrolizumab
o
Did not receive any anti-cancer treatment since the last dose of 
pembrolizumab
o
Has a performance status of 0 or 1 on the ECOG Performance Scale
o
Demonstrates adequate organ function as detailed in Section 5.1.2
o
Female subject of childbearing potential should have a negative serum or 
urine pregnancy test within 72 hours prior to receiving retreatment with study 
medication.  
o
Female subject of childbearing potential should be willing to use 2 methods of 
birth control or be surgically sterile, or abstain from heterosexual activity for 
the course of the study through 120 days (Section 5.7.2).  Subjects of child 
bearing potential are those who have not been surgically sterilized or have 
been free from menses for > 1 year. 
o
Male subject should agree to use an adequate method of contraception starting 
with the first dose of study therapy through 120 days. 
 
 
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o
Does not have a history or current evidence of any condition, therapy, or 
laboratory abnormality that might interfere with the subject’s participation for 
the full duration of the trial or is not in the best interest of the subject to 
participate, in the opinion of the treating investigator.
Subjects who restart treatment will be retreated at the same dose frequency as when they last 
received pembrolizumab.  Treatment will be administered for up to one additional year.
Visit requirements for the second course phase are outlined in Section 6.3 – Trial Flow Chart 
– Second Course Phase – Retreatment with pembrolizumab.
Subjects on the paclitaxel arm are not eligible for this course of therapy.
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 treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure. From the time of treatment allocation/randomization through 30 days following 
cessation of treatment, all adverse events must be reported by the investigator. Such events 
will be recorded at each examination on the Adverse Event case report forms/worksheets.  
The reporting timeframe for adverse events meeting any serious criteria is described in 
 
 
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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 Electronic Data Capture (EDC) data 
entry guidelines. Paper reporting procedures can be found in the Investigator Trial File 
Binder (or equivalent).
Adverse events will not be collected for subjects during the pre-screening period (for 
determination of archival tissue status) as long as that subject has not undergone any 
protocol-specified procedure or intervention.  If the subject requires a blood draw, fresh 
tumor biopsy etc., the subject is first required to provide consent to the main study and AEs 
will be captured according to guidelines for standard AE reporting.
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 paclitaxel by 20% and as ≥ 1000 mg (5 times the dose) of pembrolizumab. No 
specific information is available on the treatment of overdose of pembrolizumab or 
paclitaxel. 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 treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure.
 
 
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Pregnancies and lactations that occur from the time of treatment allocation/randomization 
through 120 days following cessation of Sponsor’s product, or 30 days following cessation of 
treatment if the subject initiates new anticancer therapy, whichever is earlier, must be 
reported by the investigator.  All reported pregnancies must be followed to the 
completion/termination of the pregnancy. Pregnancy outcomes of spontaneous abortion, 
missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, 
miscarriage and stillbirth must be reported as serious events (Important Medical Events). If 
the pregnancy continues to term, the outcome (health of infant) must also be reported.
Such events must be reported within 24 hours to the Sponsor either by electronic media or 
paper. Electronic reporting procedures can be found in the EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
Immediate Reporting of Adverse Events to the Sponsor
Serious Adverse Events
A serious adverse event is any adverse event occurring at any dose or during any use of 
Sponsor's product that:
●
Results in death;
●
Is life threatening;
●
Results in persistent or significant disability/incapacity;
●
Results in or prolongs an existing inpatient hospitalization;
●
Is a congenital anomaly/birth defect;
●
Is an other important medical event.
Note: In addition to the above criteria, adverse events meeting either of the below criteria, 
although not serious per ICH definition, are reportable to the Sponsor in the same timeframe 
as SAEs to meet certain local requirements. Therefore, these events are considered serious by 
the Sponsor for collection purposes.
●
Is a new cancer (that is not a condition of the study);
●
Is associated with an overdose.
Refer to Table 9 for additional details regarding each of the above criteria.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any serious adverse event, or follow up to a serious adverse event, 
including death due to any cause other than progression of the cancer under study (reference 
Section 7.2.3.3 for additional details), that occurs to any subject must be reported within 24 
hours to the Sponsor if it causes the subject to be excluded from the trial, or is the result of a 
protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 90 days 
following cessation of treatment, or 30 days following cessation of treatment if the subject 
initiates new anticancer therapy, whichever is earlier, any serious adverse event, or follow up 
 
 
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to a serious adverse event, including death due to any cause other than progression of the 
cancer under study (reference Section 7.2.3.3 for additional details), whether or not related to 
the Sponsor's product, must be reported within 24 hours to the Sponsor either by electronic 
media or paper. Electronic reporting procedures can be found in the EDC data entry 
guidelines. Paper reporting procedures can be found in the Investigator Trial File Binder (or 
equivalent)
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to the Sponsor's product that is brought to the attention of the 
investigator at any time following consent through the end of the specified safety follow-up 
period specified in the paragraph above, or at any time outside of the time period specified in 
the previous paragraph also must be reported immediately to the Sponsor.
All subjects with serious adverse events must be followed up for outcome.
Events of Clinical Interest
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported to the Sponsor.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any subject must be 
reported within 24 hours to the Sponsor if it causes the subject to be excluded from the trial, 
or is the result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 30 days 
following cessation of treatment, any ECI, or follow up to an ECI, whether or not related to 
the Sponsor’s product, must be reported within 24 hours to the Sponsor, either by electronic 
media or paper.  Electronic reporting procedures can be found in the EDC data entry 
guidelines.  Paper reporting procedures can be found in the Investigator Trial File Binder (or 
equivalent).
Events of clinical interest for this trial include:
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 
 
 
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and follow up of these criteria can be found in the Investigator Trial File Binder (or 
equivalent).
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.  Any such event 
will be submitted to the Sponsor within 24 hours either by electronic or paper media.
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study. 
The eDMC 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.
 
 
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Table 9
Evaluating Adverse Events
An investigator who is a qualified physician, will evaluate all adverse events as to:
V4.0 CTCAE 
Grading
Grade 1
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated.
Grade 2
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL.
Grade 3
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or hospitalization indicated; disabling; 
limiting self-care ADL.
Grade 4
Life threatening consequences; urgent intervention indicated.
Grade 5
Death related to AE
Seriousness
A serious adverse event is any adverse event occurring at any dose or during any use of Sponsor’s product that:
†Results in death; or
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include an adverse event 
that, had it occurred in a more severe form, might have caused death.); or
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the hospitalization is a 
precautionary measure for continued observation. (Note: Hospitalization for an elective procedure to treat a pre-existing condition that has not worsened is not a serious adverse 
event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of a Merck product and is documented in the patient’s medical history.); or
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or
Is a new cancer (that is not a condition of the study) (although not serious per ICH definition, is reportable to the Sponsor within 24 hours to meet certain local requirements); 
or
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event for collection purposes. An overdose 
that is not associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 hours.
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, based upon 
appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed previously 
(designated above by a †).
Duration
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units
Action taken 
Did the adverse event cause the Sponsor’s product to be discontinued?
Relationship to 
Sponsor’s 
Product
Did the Sponsor’s product cause the adverse event? The determination of the likelihood that the Sponsor’s product caused the adverse event will be provided by an investigator 
who is a qualified physician. The investigator’s signed/dated initials on the source document or worksheet that supports the causality noted on the AE form, ensures that a 
medically qualified assessment of causality was done. This initialed document must be retained for the required regulatory time frame. The criteria below are intended as 
reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the adverse event based upon the available information.
The following components are to be used to assess the relationship between the Sponsor’s product and the AE; the greater the correlation with the components and their 
respective elements (in number and/or intensity), the more likely the Sponsor’s product caused the adverse event (AE):
Exposure
Is there evidence that the subject was actually exposed to the Sponsor’s product such as: reliable history, acceptable compliance assessment (pill count, 
diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen?
Time Course
Did 
the 
AE 
follow 
in 
a 
reasonable 
temporal 
sequence 
from 
administration 
of 
the 
Sponsor’s 
product? 
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)?
Likely Cause
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental factors
 
 
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Relationship
The following components are to be used to assess the relationship between the test drug and the AE: (continued)
to Sponsor's 
Product
(continued) 
Dechallenge
Was the Sponsor’s product discontinued or dose/exposure/frequency reduced?
If yes, did the AE resolve or improve?
If yes, this is a positive dechallenge. If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite continuation of the 
Sponsor’s product; or (3) the trial is a single-dose drug trial); or (4) Sponsor’s product(s) is/are only used one time.)
Rechallenge
Was the subject re-exposed to the Sponsor’s product in this study?
If yes, did the AE recur or worsen?
If yes, this is a positive rechallenge. If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose drug trial); or (3) 
Sponsor’s product(s) is/are used only one time).
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN CAUSED BY 
THE SPONSOR'S PRODUCT, OR IF REEXPOSURE TO THE SPONSOR'S PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT RISK TO 
THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR CLINICAL DIRECTOR AS PER DOSE 
MODIFICATION GUIDELINES IN THE PROTOCOL.
Consistency 
with Trial 
Treatment 
Profile
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the Sponsor’s product or drug class pharmacology or 
toxicology?
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements.
Record one of the following
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a Sponsor’s product relationship).
Yes, there is a reasonable possibility 
of Sponsor's product relationship.
There is evidence of exposure to the Sponsor's product.  The temporal sequence of the AE onset relative to the administration of the Sponsor's product is 
reasonable.  The AE is more likely explained by the Sponsor's product than by another cause.
No, there is not a reasonable 
possibility of Sponsor's product 
relationship
Subject did not receive the Sponsor's product OR temporal sequence of the AE onset relative to administration of the Sponsor's product is not reasonable OR
the AE is more likely explained by another cause than the Sponsor’s product.  (Also entered for a subject with overdose without an associated AE.)
 
 
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Sponsor Responsibility for Reporting Adverse Events
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations, i.e., per ICH Topic E6 (R1) 
Guidelines for Good Clinical Practice.
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 
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 EOC; 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.
An eDMC recommendation will be communicated to the Sponsor as agreed to in the DMC 
charter.
Treatment-level results of the study interim analysis will be provided by the external 
unblinded statistician to the eDMC. The eDMC will review interim trial results, consider 
overall risk and benefit to trial participants (refer to Section 8.7). The eDMC will make 
 
 
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recommendations to the EOC regarding steps to ensure both subject safety and continued 
ethical integrity of the trial. Limited additional Sponsor personnel may be unblinded to the 
treatment level results of the study interim analysis, if required, in order to act on the 
recommendations of the eDMC or facilitate regulatory filing after the study interim analysis. 
The extent to which individuals are unblinded with respect to results of study interim analysis 
will be documented by the unblinded statistician. Additional logistical details, data 
monitoring guidance and multiplicity adjustment will be provided in the DMC Charter.
8.0 STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study.  If, after 
the study has begun, but prior to any unblinding, changes made to primary and/or key 
secondary hypotheses, or the statistical methods related to those hypotheses, then the 
protocol will be amended (consistent with ICH Guideline E-9).  Changes to exploratory or 
other non-confirmatory analyses made after the protocol has been finalized, but prior to the 
conduct of any analysis, will be documented in a supplemental SAP (sSAP) and referenced 
in the Clinical Study Report (CSR) for the study. A separate PK analysis plan as well as 
biomarker analysis plan will be provided. Post hoc exploratory analyses will be clearly 
identified in the CSR. The PRO analysis plan will also be included in the sSAP.
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized in below; the comprehensive 
plan is provided in Sections 8.2 through 8.12.
Statistical Analysis Plan
Study Design Overview
A Phase III, Randomized, Open-label Clinical Trial of Pembrolizumab (MK-
3475) versus Paclitaxel in Asian Subjects with Advanced Gastric or 
Gastroesophageal Junction Adenocarcinoma who Progressed after First-Line 
Therapy with Platinum and Fluoropyrimidine
Treatment Assignment
Approximately 360 subjects will be randomized in a 1:1 ratio to receive 
pembrolizumab or paclitaxel. Stratification factors are time to progression 
(TTP) on first-line therapy (< 6 months vs. ≥ 6 months) and ECOG PS (0 vs. 
1). This is an open-label study. 
Analysis Populations
Efficacy: Intention to Treat (ITT)
Safety: All Subjects as Treated (ASaT)
Primary Endpoints
1. Overall Survival (OS)  
2. Progression-free Survival (PFS) per RECIST 1.1 by blinded central 
radiologists’ review
Statistical Methods for Key 
Efficacy Analyses
The primary hypotheses will be evaluated by comparing pembrolizumab to 
paclitaxel on PFS per RECIST 1.1 by blinded central radiologists’ review and 
OS 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.
 
 
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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. There are no Tier 1 events 
in this trial. 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 analyzed using the Miettinen and 
Nurminen method [45].
Interim Analysis
No interim analysis for PFS. One interim efficacy analysis planned in this 
study for OS. Results will be reviewed by an external data monitoring 
committee. The interim analysis is summarized below. Details are provided in 
Section 8.7.
The interim analysis of OS will be performed at the time of final PFS analysis
o
Timing: To be performed after: (1) enrollment is completed (2) 
approximately 235 PFS events and 190 OS events have been 
observed. 
o
Purpose: final PFS analysis and interim analysis of OS 
Final analysis (event driven trial)
o
Timing: at least 290 OS events have been observed, estimated to 
be 36 months after study start
o
Purpose: Final analysis of OS
Multiplicity
The overall type I error over the multiple endpoints will be controlled by the 
Bonferroni procedure, which is strongly controlled at 2.5% (one-sided) with 
initially 0.35% allocated to PFS and 2.15% allocated to OS hypotheses, and 
0% to the ORR hypothesis. 
If the PFS hypothesis is rejected, the corresponding alpha level can be shifted 
to the hypotheses for the OS endpoint using the graphical approach of Maurer 
and Bretz [46].
The secondary hypothesis of ORR will be tested only if pembrolizumab arm 
is superior to the control in OS.
Sample Size and Power 
The planned sample size is approximately 360 subjects. 
The final analysis of this study is event driven (i.e., follow-up time is subject 
to change but number of events is not) and will complete after at least 290 OS 
events have been observed. 
For the primary endpoint PFS, the trial has >99% (>90%) power to 
demonstrate that pembrolizumab is superior to paclitaxel at a one-sided 
0.35% alpha-level, if the underlying hazard ratio of PFS is 0.5 (0.6).
For primary endpoint OS, the trial has 91% power to demonstrate that 
pembrolizumab is superior to paclitaxel at a one-sided 2.15% alpha-level, if 
the underlying hazard ratio of OS is 0.67.
Responsibility for Analyses/In-House Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the SPONSOR.
The SPONSOR will generate the randomized allocation schedule(s) for study treatment 
assignment.  The algorithm for the randomized allocation of subjects will be implemented in 
an interactive voice response system (IVRS).
 
 
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Although the trial is open label, analyses or summaries generated by randomized treatment 
assignment, actual treatment received will be limited and documented. In addition, the 
independent radiologist(s) will perform the blinded central radiologists’ review without 
knowledge of treatment group assignment.
The eDMC will serve as the primary reviewer of the unblinded results of the interim analysis 
and will make recommendations for discontinuation of the study or protocol modifications to 
the EOC of this Sponsor. Depending on the recommendation of the eDMC, the Sponsor may 
prepare a regulatory submission.  If the eDMC recommends modifications to the design of 
the protocol or discontinuation of the study, the EOC may be unblinded to results at the 
treatment level in order to act on these recommendations.  
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.0.
Analysis Endpoints
Efficacy Endpoints
Primary
Overall Survival
Overall Survival (OS) is defined as the time from randomization to death due to any cause. 
Subjects without documented death at the time of the final analysis will be censored at the 
date of the last follow-up.
Progression-free survival (PFS) – RECIST 1.1 by blinded central radiologists’ review
Progression-free-survival (PFS) is defined as the time from randomization to the first 
documented disease progression or death due to any cause, whichever occurs first. See 
Section 8.6.1 for definition of censoring.
Secondary
Objective Response Rate (ORR) – RECIST 1.1 by blinded central radiologists’ review 
Objective response rate is defined as the proportion of the subjects in the analysis population 
who have a CR or PR.
Safety Endpoints
Safety measurements are described in Section 7.
 
 
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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.
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 analyzed according to the correct treatment group and a narrative will be 
provided for any events that occur during the cycle for which the subject is incorrectly dosed. 
At least one laboratory or vital sign measurement obtained subsequent to at least one dose of 
study treatment is required for inclusion in the analysis of each specific parameter.  To assess 
change from baseline, a baseline measurement is also required.
Details on the approach to handling missing data for safety analyses are provided in Section 
8.6, Statistical Methods.
Statistical Methods
Statistical Methods for Efficacy Analyses
This section describes the statistical methods that address the primary and secondary 
objectives.  Methods related to exploratory objectives will be described in the supplemental 
SAP.
Efficacy results that will be deemed to be statistically significant after consideration of the 
Type I error control strategy are described in Section 8.8, Multiplicity. Nominal p-values will 
be computed for other efficacy analyses, but should be interpreted with caution due to 
potential issues of multiplicity.
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. A stratified 
 
 
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Cox proportional hazard model with Efron's method of tie handling will be used to assess the 
magnitude of the treatment difference (i.e., the hazard ratio). The hazard ratio and its 95% 
confidence interval from the stratified Cox model with a single treatment covariate will be 
reported. The stratification factors used for randomization will be applied to both the 
stratified log-rank test and the stratified Cox model.
Subjects in the paclitaxel arm are expected to discontinue treatment earlier compared to 
subjects in the pembrolizumab arm, and may switch to another anti PD-1 treatment following 
the verification of progressive disease by blinded central radiologists’ vendor. As an 
exploratory analysis, the Rank Preserving Structural Failure Time (RPSFT) model proposed 
by Robins and Tsiatis (1989) [47] may be used to adjust for the effect of crossover to other 
PD-1 therapies on OS. 
Other sensitivity analyses described for the PFS endpoint will be applied to OS endpoint as 
appropriate. Further details of sensitivity analyses will be described in supplemental SAP.
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 hazard model with Efron's method of tie handling will be 
used to assess the magnitude of the treatment difference (i.e., 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. The stratification factors used for randomization will be applied to both the 
stratified log-rank test and the stratified Cox model. 
Since disease progression is assessed periodically, progressive disease (PD) can occur any       
time in the time interval between the last assessment where PD was not documented and the 
assessment when PD is documented. For the primary analysis, for the subjects who have PD, 
the true date of disease progression will be approximated by the date of the first assessment 
at which PD is objectively documented per RECIST 1.1 by blinded central radiologists’ 
review, regardless of discontinuation of study drug. Death is always considered as a 
confirmed PD event. 
In order to evaluate the robustness of the PFS endpoint 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. If a subject 
meets multiple criteria for censoring, the censoring criterion that occurs earliest will be 
applied. The censoring rules for primary and sensitivity analyses are summarized in Table 
10. 
 
 
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Table 10
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
No PD and no death; ≥ 
2 consecutive missed 
disease assessments
Censored at last disease 
assessment
Censored at last disease 
assessment prior to ≥2 
consecutive missed visits
Censored at last disease 
assessment
PD or death 
documented after ≤ 1 
missed disease 
assessment
Progressed at date of 
documented PD or death
Progressed at date of 
documented PD or death
Progressed at date of 
documented PD or death
PD or death 
documented at any 
time after ≥ 2 
consecutive missed 
disease assessments
Progressed at date of 
documented PD or death
Censored at last disease 
assessment prior to the  ≥ 
2 consecutive  missed 
disease assessment
Progressed at date of 
documented PD or death
The proportional hazards assumption on PFS will be examined using both graphical and 
analytical methods if warranted. The log[-log] of the survival function vs. time for PFS will 
be plotted for the comparison between pembrolizumab and the paclitaxel arm. If the curves 
are not parallel, indicating that hazards are not proportional, supportive analyses may be 
conducted to account for the possible non-proportional hazards effect associated with 
immunotherapies: for example, using Restricted Mean Survival Time (RMST) method [48], 
parametric method [49], etc.
One assumption for stratified Cox proportional hazard model is that, the treatment hazard 
ratio (HR) is constant across the strata. If strong departures from the assumption of the HR 
being the same for all the strata observed (which can result in a notably biased and/or less 
powerful analysis), a sensitivity analysis may be performed based on a two-step weighted 
Cox model approach by Mehrotra 2012 [50], in which the treatment effect is first estimated 
for each stratum and then the stratum specific estimates are combined for overall inference 
using sample size weights.
Further details of sensitivity analyses will be described in supplemental SAP.
Objective Response Rate (ORR)
Stratified Miettinen and Nurminen’s method [45] will be used for comparison of the 
objective response rates between the treatment arms. The difference in ORR and its 95% 
confidence interval from the stratified Miettinen and Nurminen’s method with strata 
 
 
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weighting by sample size will be reported. The stratification factors used for randomization 
will be applied to the analysis.
Table 11 summarizes the primary analysis approach for primary and secondary efficacy 
endpoints. Sensitivity analysis methods are described above for each endpoint.
The strategy to address multiplicity issues with regard to multiple efficacy endpoints and 
interim analysis is described in Section 8.7, Interim Analyses and in Section 8.8, Multiplicity.
Table 11
Analysis Strategy for Key Efficacy Endpoints
Endpoint/Variable
(Description, Time 
Point)
Statistical Method†
Analysis 
Population
Missing Data Approach
Primary Hypothesis #1
OS
Test: Stratified Log-rank test 
Estimation: Stratified Cox model 
with Efron’s tie handling method 
ITT
Censored at last known alive 
date 
Primary Hypothesis #2
PFS per RECIST 1.1 by 
blinded central 
radiologists’ review
Test: 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 are in Table 
10.)
ORR per RECIST 1.1 
by blinded central 
radiologists’ review
Stratified M & N method‡
ITT
Subjects with missing data 
are considered non-
responders.
† Statistical models are described in further detail in the text. For stratified analyses, the stratification factors 
used for randomization (time to progression on first-line therapy (< 6 months vs.  ≥ 6 months) and ECOG 
PS (0 vs. 1)), will be applied to the analysis. 
‡ Miettinen and Nurminen method.
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.
Tiered Approach
The analysis of safety results will follow a tiered approach (Table 12).  The tiers differ with 
respect to the analyses that will be performed. “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.
 
 
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Adverse experiences (specific terms as well as system organ class terms) and predefined 
limits of change in laboratory, vital signs, that are not pre-specified as Tier-1 endpoints will 
be classified as belonging to "Tier 2" or "Tier 3", based on the number of events observed.  
Membership in Tier 2 requires that at least 4 subjects in any treatment group exhibit the 
event; all other adverse experiences and predefined limits of change will belong to Tier 3.
The threshold of at least 4 events was chosen because the 95% confidence interval for the 
between-group difference in percent incidence will always include zero when treatment 
groups of equal size each have less than 4 events and thus would add little to the 
interpretation of potentially meaningful differences.  Because many 95% confidence intervals 
may be provided without adjustment for multiplicity, the confidence intervals should be 
regarded as a helpful descriptive measure to be used in review, not a formal method for 
assessing the statistical significance of the between-group differences in adverse experiences 
and predefined limits of change.
Continuous measures such as changes from baseline in laboratory, vital signs, that are not 
pre-specified as Tier-1 endpoints will be considered Tier 3 safety parameters.  Summary 
statistics for baseline, on-treatment, and change from baseline values will be provided by 
treatment group in table format.    
For this protocol, there are no Tier 1 events. The broad clinical and laboratory AE categories 
consisting of the percentage of subjects with any AE, any drug related AE, any Grade 3-5 
AE, any serious AE, any AE which is both drug-related and Grade 3-5, any AE which is both 
serious and drug-related, dose modification due to AE, and who discontinued due to an AE, 
and death will be considered Tier 2 endpoints.  95% confidence intervals (Tier 2) will be 
provided for between-treatment differences in the percentage of subjects with events; these 
analyses will be performed using the Miettinen and Nurminen method (1985), an 
unconditional, asymptotic method.
To properly account for the potential difference in follow-up time between the study arms, 
which is expected to be longer in the pembrolizumab arm, AE incidence density adjusted for 
treatment exposure analyses may be performed as appropriate.  Based on emerging external 
data, the supportive analysis strategy for safety parameters may be modified to improve the 
integrity and efficiency of the design. Should this happen, the change will be documented in 
supplemental SAP, if not in a protocol amendment, at the earliest time before any unblinding 
of the data.
Detailed kinetics and characteristics of immune mediated AEs will be summarized in this 
study.
 
 
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Table 12
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 Serious AE 
X
X
Any Grade 3-5 AE
X
X
Any Drug-Related AE
X
X
Any Serious and Drug-Related AE
X
X
Any Grade 3-5 and Drug-Related AE
X
X
Dose Modification due to AE
X
X
Discontinuation due to AE
X
X
Death
Specific AEs, SOCs, or PDLCs(incidence ≥4 of 
subjects in one of the treatment groups)
X
X
Tier 3
Specific AEs, SOCs or PDLCs (incidence <4 of 
subjects in all of the treatment groups)
X
Change from Baseline Results (Labs, ECGs, 
Vital Signs)
X
†
Adverse Experience references refer to both Clinical and Laboratory AEs.
Note: SOC=System Organ Class; PDLC=Pre-Defined Limit of Change; X = results will be provided.
Summaries of Demographic and Baseline Characteristics
The comparability of the treatment groups for each relevant characteristic will be assessed by 
the use of tables and/or graphs. No statistical hypothesis tests will be performed on these 
characteristics.  The number and percentage of subjects screened, randomized, the primary 
reasons for screening failure, and the primary reason for discontinuation will be displayed.  
Demographic variables (e.g., age), baseline characteristics, primary and secondary diagnoses, 
and prior and concomitant therapies will be summarized by treatment either by descriptive 
statistics or categorical tables.
Interim Analyses
There is no interim efficacy analysis planned in this study for PFS.
There is one interim efficacy analysis planned in this study for OS. For OS, a Hwang-Shih-
DeCani alpha-spending function with the gamma parameter (-4) is constructed to implement 
group sequential boundaries that control the Type-I error rate. The actual boundaries will be 
determined from the number of OS events observed at the time of the interim analysis, using 
the alpha-spending function.
The interim OS will be performed at the time of final PFS analysis: (1) enrollment is 
completed; (2) approximately 235 PFS events and 190 OS events have been observed. The 
 
 
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final analysis (FA) for OS will be performed when at least 290 OS events have been 
observed (~36 months after trial starts).
The secondary hypothesis of ORR will be tested only if pembrolizumab arm is superior to 
the control in OS. The information fraction for the group sequential boundaries and alpha 
spending function of ORR will be defined by the proportion of subjects whose randomization 
dates are at least 6 months before the data cutoff date of the analysis. Only these eligible 
subjects can be included into the ORR analysis. It is projected that there will be at least 270 
eligible subjects at the interim analysis time point. The nominal Type I error rates for the 
interim analysis and final analysis that will allow tight control of the overall Type I error for 
testing the ORR hypothesis will be derived using the alpha-spending function approach. The 
group sequential testing of the ORR hypothesis will be conducted with an efficacy boundary 
only. The efficacy boundary for the ORR will be set using an Exponential spending function
[51] with parameter ν=0.25, which yields a Pocock-like boundary. 
Table 13 summarizes the timing, number of events and decision guidance for the PFS, OS 
and ORR analysis. The actual boundaries and the alpha level for the OS and ORR analyses 
will be determined from the actual number of events observed at the time of the analysis 
using the corresponding alpha-spending function.
Table 13
Summary of Timing, Sample Size and Decision Guidance of Interim Analysis and 
Final analysis
Analysis
Criteria for Conduct of Analysis
Endpoint
p value 
(1-sided) at 
boundary
Approx. Observed 
HR or ORR-
Difference at 
Boundary
Final PFS 
Analysis/ 
Interim OS 
Analysis 
~ 24  months after trial starts
(1) enrollment is complete 
(2) approximately 235 PFS events and 
190 OS events have been observed 
PFS Events: ~235
OS Events: ~190
PFS
0.0035
0.70
OS 
0.0051
0.69
ORR†
0.0161
10.2%
Final OS 
Analysis
~ 36 mos after trial starts
At least 290 OS events have been 
observed
OS Events: ~290
OS 
0.0198
0.78
ORR†
0.0123
9.3%
†: The secondary hypothesis of ORR will be tested only if pembrolizumab arm is superior to the control in OS. The 
assumed expected ORR in pembrolizumab and control groups are 30% and 10%, respectively. Depending on the results 
of the OS and PFS hypothesis testing, the ORR hypothesis can be tested at Type I error levels of α=2.15% or 2.5%; this 
table assumes an ORR Type I error of 2.15%.
The eDMC will conduct interim safety analyses approximately every 6 months during the 
trial.  For the situation in which the eDMC requests efficacy information to evaluate risk and 
benefit during interim safety analyses, additional details regarding the control of Type I error 
rates for the interim efficacy analysis will be provided in the DMC Charter.
 
 
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Multiplicity
The multiplicity strategy specified in this section will be applied to the two primary 
hypotheses (superiority of pembrolizumab on OS or PFS) and one secondary hypothesis 
(superiority of pembrolizumab on ORR). 
The overall Type-I error is strongly controlled at 2.5% (one-sided), with 0.35% allocated to 
PFS and 2.15% allocated to OS hypothesis and 0% to the ORR hypothesis. 
For the OS and ORR endpoints, the Type-I error rate for the interim analysis and final 
analysis is controlled through alpha-spending functions as described in Section 8.7, Interim 
Analyses. 
By using the graphical approach of Maurer and Bretz [46], if the PFS hypothesis is rejected, 
the corresponding alpha level can be shifted to the OS hypotheses. If the OS hypothesis is 
rejected, the corresponding alpha level can be shifted to the ORR. 
See Figure 3 for the multiplicity strategy diagram of the study.
Figure 3
Multiplicity Strategy
Sample Size and Power Calculations
The study will randomize subjects in a 1:1 ratio into pembrolizumab arm and paclitaxel arm. 
The overall sample size will be approximately 360. However, subjects already in screening 
phase may be enrolled even after we have reached the maximum sample size.
The final analysis of the study is event driven (i.e., follow-up time are subject to change but 
number of events is not) and will complete after at least 290 OS events have been observed. 
PFS analysis: the final PFS analysis will be performed after approximately 235 PFS events 
observed. With ~235 PFS events, this trial has overall 99% (88%) power to demonstrate that 
pembrolizumab is superior to paclitaxel at a one-sided 0.35% alpha-level, if the underlying 
hazard ratio of PFS is 0.5 (0.6). Success for PFS at the main analysis approximately 
corresponds to an observed hazard ratio of < 0.70. 
 
 
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The power calculation is based on the following assumptions for subjects: 1) Progression-
free survival follows an exponential distribution with a median of 4.5 months in the 
paclitaxel arm; 2) An enrollment period of 24 months (IA is conducted after enrollment is 
complete); 3) A yearly drop-out rate of 5%.
OS analysis: The final OS analysis will be carried out when at least 290 OS events have 
occurred. For primary endpoint OS, the trial has 91% (85%) power to demonstrate that 
pembrolizumab is superior to paclitaxel at an one-sided 2.15% alpha-level, if the underlying 
hazard ratio of OS is 0.67 (0.7). Success for OS at the final analysis approximately 
corresponds to an observed hazard ratio of < 0.78 (approximately a 2-month improvement or 
greater in median OS).
The sample size and power calculation is based on the following assumptions for subjects: 1) 
Overall survival follows an exponential distribution with a median of 7.5 months in the 
control arm; 2) An enrollment period of 24 months and a minimum of 12 months follow-up 
after enrollment completion; 3) A yearly dropout rate of 2%.
The assumptions for the median PFS of 4.5 months and the median OS of 7.5 months in the 
paclitaxel arm are based on estimates of median PFS and median OS from China subgroup 
analysis of TyTAN trial [40].
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 dual primary 
endpoints will be estimated and plotted within each category of the following classification 
variables: 

Age category (≤65 vs. >65 years)

Sex (Female vs. Male)

ECOG Performance Scale (0 vs. 1)

Primary location (Stomach vs. GEJ)

Histological subtype (Diffuse vs. intestinal vs. mixed)

Disease Status (Locally advanced vs. Metastatic)

Time to progression on first-line therapy (< 6 months vs. ≥ 6 months)

Geographic region of enrolling site (China vs. ex-China)
Country specific population (e.g. Chinese, etc.) may also be analyzed per local regulatory 
requirements.
Compliance (Medication Adherence)
Drug accountability data for trial treatment will be collected during the study. Any deviation 
from protocol-directed administration will be reported.
 
 
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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 14.
Clinical supplies will be packaged to support enrollment and replacement subjects as 
required.  When a replacement subject is required, the Sponsor or designee needs to be 
contacted prior to dosing the replacement supplies.
Table 14
Product Descriptions
Product Name & Potency
Dosage 
Form
Source/Additional Information
Pembrolizumab (MK-3475), 
25 mg/mL
IV Infusion
Provided centrally by the Sponsor
Paclitaxel, 6 mg/mL
IV Infusion
Provided centrally by the Sponsor or 
locally by the trial site, subsidiary, or 
designee
All supplies indicated in Table 14 will be provided per the “Source/Additional Information” 
column depending on local country operational requirements.
Any commercially available product not included in Table 14 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 for recording the lot number, 
manufacturer, and expiry date for any locally purchased product as per local guidelines 
unless otherwise instructed by the Sponsor.
Packaging and Labeling Information
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
Subjects will receive open label pembrolizumab (MK-3475) vials or paclitaxel kits as 
described in this protocol. Each paclitaxel kit box will contain one commercial vial.
 
 
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Clinical Supplies Disclosure
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded. Study drug identification (name, strength or potency) is included in 
the label text; random code/disclosure envelopes or lists are not provided.
Storage and Handling Requirements
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.  
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site.
Clinical supplies may not be used for any purpose other than that stated in the protocol.
Discard/Destruction/Returns and Reconciliation
The investigator is responsible for keeping accurate records of the clinical supplies received 
from the Sponsor or designee, the amount dispensed to and returned by the subjects and the 
amount remaining at the conclusion of the trial. For all trial sites, the local country Sponsor 
personnel or designee will provide appropriate documentation that must be completed for 
drug accountability and return, or local discard and destruction if appropriate.  Where local 
discard and destruction is appropriate, the investigator is responsible for ensuring that a local 
discard/destruction procedure is documented.
Standard Policies
Trial 
site 
personnel 
will 
have 
access 
to 
a 
central 
electronic 
treatment 
allocation/randomization system (IVRS/IWRS system) to allocate subjects, to assign 
treatment to subjects and to manage the distribution of clinical supplies. Each person 
accessing the IVRS system must be assigned an individual unique PIN.  They must use only 
their assigned PIN to access the system, and they must not share their assigned PIN with 
anyone.
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, 
 
 
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except to the extent that it is included in a publication as provided in the Publications section 
of this protocol.
Confidentiality of Subject Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/ERC, or regulatory authority representatives may consult and/or copy trial documents in 
order to verify worksheet/case report form data.  By signing the consent form, the subject 
agrees to this process.  If trial documents will be photocopied during the process of verifying 
worksheet/case report form information, the subject will be identified by unique code only; 
full names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all subject data used and disclosed in 
connection with this trial in accordance with all applicable privacy laws, rules and 
regulations.
Confidentiality of Investigator Information
By signing this protocol, the investigator recognizes that certain personal identifying 
information with respect to the investigator, and all subinvestigators and trial site personnel, 
may be used and disclosed for trial management purposes, as part of a regulatory 
submissions, and as required by law.  This information may include:
1. name, address, telephone number and e-mail address;
2. hospital or clinic address and telephone number;
3. curriculum vitae or other summary of qualifications and credentials; and
4. other professional documentation.
Consistent with the purposes described above, this information may be transmitted to the 
Sponsor, and subsidiaries, affiliates and agents of the Sponsor, in your country and other 
countries, including countries that do not have laws protecting such information. 
Additionally, the investigator’s name and business contact information may be included 
when reporting certain serious adverse events to regulatory authorities or to other 
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 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.
 
 
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Compliance with Financial Disclosure Requirements
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54).  It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required.  It is the investigator's/subinvestigator's 
responsibility to comply with any such request.  
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements.  
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes.  This may involve the 
transmission of information to countries that do not have laws protecting personal data.
Compliance with Law, Audit and Debarment
By signing this protocol, the investigator agrees to conduct the trial in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of Good 
Clinical Practice (e.g., International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice: 
Consolidated Guideline and other generally accepted standards of good clinical practice); and 
all applicable federal, state and local laws, rules and regulations relating to the conduct of the 
clinical trial.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by 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.
 
 
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Trial documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the trial site upon request for inspection, 
copying, review and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities.  The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor as a result of an audit to cure deficiencies in the trial documentation 
and worksheets/case report forms.
The investigator must maintain copies of all documentation and records relating to the 
conduct of the trial in compliance with all applicable legal and regulatory requirements.  This 
documentation includes, but is not limited to, the protocol, worksheets/case report forms, 
advertising for subject participation, adverse event reports, subject source data, 
correspondence with regulatory authorities and IRBs/ERCs, consent forms, investigator’s 
curricula vitae, monitor visit logs, laboratory reference ranges, laboratory certification or 
quality control procedures and laboratory director curriculum vitae.  By signing this protocol, 
the investigator agrees that documentation shall be retained until at least 2 years after the last 
approval of a marketing application in an ICH region or until there are no pending or 
contemplated marketing applications in an ICH region or until at least 2 years have elapsed 
since the formal discontinuation of clinical development of the investigational product.  
Because the clinical development and marketing application process is variable, it is 
anticipated that the retention period can be up to 15 years or longer after protocol database 
lock. The Sponsor will determine the minimum retention period and notify the investigator 
when documents may be destroyed.  The Sponsor will determine the minimum retention 
period and upon request, will provide guidance to the investigator when documents no longer 
need to be retained.  The sponsor also recognizes that documents may need to be retained for 
a longer period if required by local regulatory requirements. All trial documents shall be 
made available if required by relevant regulatory authorities. The investigator must consult 
with and obtain written approval by the Sponsor prior to destroying trial and/or subject files.  
ICH Good Clinical Practice guidelines recommend that the investigator inform the subject’s 
primary physician about the subject’s participation in the trial if the subject has a primary 
physician and if the subject agrees to the primary physician being informed.
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 
 
 
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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 Protocol/CSR 
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.  
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.
 
 
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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 
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 
 
 
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the order of authors’ names will be made based on participation and actual contributions to 
the trial and writing, as discussed above. The first author is responsible for defending the 
integrity of the data, method(s) of data analysis and the scientific content of the manuscript.
The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or 
presentations regarding this trial 45 days prior to submission for publication/presentation. 
Any information identified by the Sponsor as confidential must be deleted prior to 
submission; this confidentiality does not include efficacy and safety results. Sponsor review 
can be expedited to meet publication timelines.
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Ajani J. Evolving chemotherapy for advanced gastric cancer. Oncologist, 2005, 10(suppl 
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Van Cutsem E, Dicato M, Geva R, Arber Y, Bang A, Benson A, et al. The diagnosis and 
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National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. 
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Kodera Y, Ito S, Mochizuki Y, et al. A phase II study of weekly paclitaxel as second-
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Ueda S, Hironaka S, Yasui H, et al. Randomized phase III study of irinotecan (CPT-11) 
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11. Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, et al. Tumor-
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12. Sharpe AH, Freeman GJ. The B7-CD28 superfamily. Nature 2002;2:116-26.
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programmed death-1 ligands on dendritic cells enhances T cell activation and cytokine 
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14. Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity. 
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16. Talmadge JE, Donkor M, Scholar E. Inflammatory cell infiltration of tumors: Jekyll or 
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Tumor infiltrating lymphocytes: an intriguing player in the survival of colorectal cancer 
patients. BMC Immunol 2010;11:19.
20. Diez M, Pollán M, Enriquez JM, Dominguez P, Santana A, Tobaruela E, et al. 
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21. 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.  
22. Hiraoka N. Tumor-infiltrating lymphocytes and hepatocellular carcinoma: molecular 
biology. Int J Clin Oncol 2010;15:544-51. 
23. 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 
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Tumori 2008;94:426-30.  
 
 
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24. Hodi FS, Dranoff G. The biologic importance of tumor-infiltrating lymphocytes. J Cutan 
Pathol 2010;37(Suppl 1):48-53.  
25. Kloor M. Lymphocyte infiltration and prognosis in colorectal cancer. Lancet 
2009;10:840-841.  
26. 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.  
27. 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.  
28. 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.  
29. Nishimura H, Honjo T, Minato N. Facilitation of ? selection and modification of positive 
selection in the thymus of PD-1-deficient mice. J Exp Med 2000;191(5):891-7.  
30. 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.  
31. Bass, AJ et.al, Comprehensive molecular characterization of gastric adenocarcinoma. 
Nature 513:202-209, 2014.  
32. 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.  
33. 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.  
34. 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.  
35. 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.  
 
 
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36. 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.
37. Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisted. Annu Rev Immunol 
2005;23:515-48
38. Muro K, et al. A Phase Ib Study of MK-3475 in Patients with Gastric Cancer. Ann 
Oncol. 2014;25 (Suppl 4)
39. Wilke H., et al. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients 
with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma 
(RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol 2014; 15: 1224–
35.
40. Satoh et al. Lapatinib Plus Paclitaxel Versus Paclitaxel Alone in the Second-Line 
Treatment of HER2-Amplified Advanced Gastric Cancer in Asian  Populations: TyTAN 
- A Randomized, Phase III Study. J Clin Oncol, 2014, 32:2039-2049.
41. Fuchs, CS, et al. Ramucirumab monotherapy for previously treated advanced gastric or 
gastroesophageal junction adenocarcinoma (REGARD): an international, randomized, 
multicenter, placebo-controlled, phase 3 trial.  Lancet 383: 31-39, 2014).
42. 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.
43. EuroQol--a new facility for the measurement of health-related quality of life. The 
EuroQol Group. Health Policy 1990;16 (3):199-208.
44. Rizzo JD, Somerfield MR, Hagerty KL, Seidenfeld J, Bohlius J, Bennett CL, et al.  Use 
of epoetin and darbepoetin in patients with cancer: 2007 American Society of Clinical 
Oncology / American Society of Hematology Clinical Practice Guideline Update. J Clin 
Oncol. 2008; 26 (1):132-149.
45. Miettinen O, Nurminen M. Comparative analysis of two rates. Statistics in Medicine 
1985; 4:213-226.
46. Maurer W, Bretz F. Multiple Testing in Group Sequential Trials using Graphical 
Approaches. Statistics in Biopharmaceutical Research 2013; 5(4): 311-320.
47. 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.
48. Uno, H.,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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49. Odell P.M., Anderson K.M., Kannel B.W. New models for predicting cardiovascular 
events. Journal of Clinical Epidemiology 1994; 47(6): 583-592.
50. Mehrotra D., Su S.C., Li X.  An efficient alternative to the stratified Cox model analysis. 
Statist. Med. 2012, 31 1849–1856.
51. Anderson KM, Clark JB. Fitting spending functions. Stat Med 2010;29(3):321-7.
 
 
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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 consented and/or collected in this trial as outlined in Section 7.1.3.3 –
Future Biomedical Research Samples will be used in various experiments to understand:
o
The biology of how drugs/vaccines work
o
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
o
Other pathways drugs/vaccines may interact with
o
The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need.  All specimens will be used by the Sponsor or those working for 
or with the Sponsor.
3. Summary of Procedures for Future Biomedical Research
a.
Subjects for Enrollment
All subjects enrolled in the clinical trial will be considered for enrollment in Future 
Biomedical Research.
b. Informed Consent
Informed consent for specimens (i.e., DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all subjects or legal guardians, at a trial 
visit by the investigator or his or her designate.  Informed consent for Future 
Biomedical Research should be presented to the subjects on the visit designated in the 
trial flow chart.  If delayed, present consent at next possible Subject Visit.  Consent 
forms signed by the subject will be kept at the clinical trial site under secure storage 
for regulatory reasons.  
 
 
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A template of each trial site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of subject consent for Future Biomedical Research will be captured in 
the electronic Case Report Forms (eCRFs). Any specimens for which such an 
informed consent cannot be verified will be destroyed.
d. Future Biomedical Research Specimen(s)
Collection of specimens for Future Biomedical Research will be performed as 
outlined in the trial flow chart. In general, if additional blood specimens are being 
collected for Future Biomedical Research, these will usually be obtained at a time 
when the subject is having blood drawn for other trial purposes.
4. Confidential Subject Information for Future Biomedical Research 
In order to optimize the research that can be conducted with Future Biomedical Research 
specimens, it is critical to link subject' clinical information with future test results. In fact 
little or no research can be conducted without connecting the clinical trial data to the 
specimen. The clinical data allow specific analyses to be conducted. Knowing subject 
characteristics like gender, age, medical history and treatment outcomes are critical to 
understanding clinical context of analytical results. 
To maintain privacy of information collected from specimens obtained for Future 
Biomedical Research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below. 
At the clinical trial site, unique codes will be placed on the Future Biomedical Research 
specimens. This 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 unique code will be held at the trial site. No personal identifiers will appear on 
the specimen tube.
5. Biorepository Specimen Usage
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices.  Analyses utilizing the Future Biomedical Research specimens may be 
performed by the Sponsor, or an additional third party (e.g., a university investigator) 
designated by the Sponsor. The investigator conducting the analysis will follow the 
Sponsor’s privacy and confidentiality requirements. Any contracted third party analyses 
will conform to the specific scope of analysis outlined in future biomedical research 
protocol and consent. Future Biomedical Research specimens remaining with the third 
party after specific analysis is performed will be reported to the Sponsor.
6. Withdrawal From Future Biomedical Research 
Subjects may withdraw their consent for Future Biomedical Research and ask that their 
biospecimens not be used for Future Biomedical Research.  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). 
 
 
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Subsequently, the subject's specimens will be flagged in the biorepository and restricted 
to main study use only. If specimens were collected from study participants specifically 
for Future Biomedical Research, these specimens will be removed from the biorepository 
and destroyed. Documentation will be sent to the investigator confirming withdrawal 
and/or destruction, if applicable. It is the responsibility of the investigator to inform the 
subject of completion of the withdrawal and/or destruction, if applicable.  Any analyses 
in progress at the time of request for withdrawal/destruction or already performed prior to 
the request being received by the Sponsor will continue to be used as part of the overall 
research trial data and results. No new analyses would be generated after the request is 
received.
In the event that the medical records for the main trial are no longer available (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 withdrawal of consent and/or destruction cannot be processed.
7. Retention of Specimens 
Future Biomedical Research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being 
answered. In this special circumstance, specimens will be stored until these questions 
have been adequately addressed.
Specimens from the trial site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
trial, the trial site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility which 
operates to assure the integrity of the specimens.  Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated trial administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Subjects
No information obtained from exploratory laboratory studies will be reported to the 
subject, family, or physicians. Principle reasons not to inform or return results to the 
subject include: Lack of relevance to subject health, limitations of predictive capability, 
and concerns regarding misinterpretation.
If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and subjects.  Subjects will not be identified by 
 
 
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name in any published reports about this study or in any other scientific publication or 
presentation.
10. Future Biomedical Research Study Population
Every effort will be made to recruit all subjects diagnosed and treated on Sponsor clinical 
trials for Future Biomedical Research.
11. Risks Versus Benefits of Future Biomedical Research 
For future biomedical research, risks to the subject have been minimized. No additional 
risks to the subject have been identified as no additional specimens are being collected 
for Future Biomedical Research (i.e., only remainder of 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 
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.
The Sponsor has developed strict security, policies and procedures to address subject data 
privacy concerns.  Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality.  In this highly unlikely situation there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be e-mailed directly to 
clinical.specimen.management@merck.com.
13. References
1. National Cancer Institute: http://www.cancer.gov/dictionary/?searchTxt=biomarker
2. International Conference on Harmonization: DEFINITIONS FOR GENOMIC 
BIOMARKERS, PHARMACOGENOMICS, PHARMACOGENETICS, GENOMIC 
DATA 
AND 
SAMPLE 
CODING 
CATEGORIES 
-
E15; 
http://www.ich.org/LOB/media/MEDIA3383.pdf
3. Industry Pharmacogenomics Working Group. Understanding the Intent, Scope and 
Public Health Benefits of Exploratory Biomarker Research: A Guide for IRBs/IECs 
and Investigational Site Staff. Available at http://i-pwg.org/
4. Industry Pharmacogenomics Working Group. Pharmacogenomics Informational 
Brochure for IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/
 
 
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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, e.g., light house work, office work
2
Ambulatory and capable of all selfcare but unable to carry out any work 
activities; up and about more than 50% of waking hours
3
Capable of only limited selfcare; confined to bed or chair more than 50% of 
waking hours
4
Completely disabled; cannot carry on any selfcare; 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 adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.html).
 
 
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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
APaT
All Patients 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
β-HCG
Beta Human Chorionic Gonadotropin
BSA
Body Surface Area
CBC
Complete Blood Count
CD
Cluster of Differentiation
CI
Confidence Interval
CNS
Central Nervous System
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
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 Organisation for Research and Treatment of Cancer
 
 
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Abbreviation/Term
Definition
ERC
Ethics Review Committee
FBR
Future Biomedical Research
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FDAMA
Food and Drug Administration Modernization Act
FNA
Fine Needle Aspirate
GCP
Good Clinical Practice
GEJ
Gastroesophageal Junction
FP
Cisplatin + 5- FU
5-FU
5-fluoruracil 
GFR
Glomerular Filtration Rate
HBsAg
Hepatitis B surface Antigen
HCV
Hepatitis C Virus
HIV
Human Immunodeficiency Virus
HNSCC
Head and Neck Squamous Cell Carcinoma
HPV
Human Papillomavirus
HRQoL
Health Related Quality of Life
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonization
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
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.
 
 
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Confidential
Abbreviation/Term
Definition
NA or N/A
Not Applicable
NCI
National Cancer Institute
NSAID
Non-Steroidal Anti-inflammatory Drug
NSCLC
Non-Small Cell Lung Cancer
ORR
Objective Response Rate
OS
Overall Survival
OTC
Over-the-counter
PD
Progressive Disease
PD-1
Programmed cell death 1
PD-L1
Programmed death-ligand 1
PD-L2
Programmed death-ligand 2
PFS
Progression-Free Survival
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
SAE
Serious Adverse Events
SAP
Statistical Analysis Plan
SFU
Survival Follow-Up
SGOT
Serum Glutamic Oxaloacetic Transaminase
SGPT
Serum Glutamic Pyruvic Transaminase
siDMC
Standing Internal Data Monitoring Committee
SOP
Standard Operating Procedures
TIL
Tumor Infiltrating Lymphocytes
TSH
Thyroid Stimulating Hormone
ULN
Upper Limit of Normal
WBC
White Blood Cell
 
 
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Confidential
13.0 SIGNATURES
Sponsor's Representative
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
Investigator
I agree to conduct this clinical trial in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol (including other manuals and documents 
referenced from this protocol).  I agree to conduct the trial in accordance with generally 
accepted standards of Good Clinical Practice.  I also agree to report all information or data in 
accordance with the protocol and, in particular, I agree to report any serious adverse events 
as defined in Section 7.0 – TRIAL PROCEDURES (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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SAP_001.pdf: 
Official Protocol Title: 
NCT number: 
Document Date: 
A Phase III, Randomized, Open-label Clinical Trial of 
Pembrolizumab (MK-3475) versus Paclitaxel in Asian Subjects 
with Advanced Gastric or Gastroesophageal Junction
Adenocarcinoma who Progressed after First-Line Therapy with 
Platinum and Fluoropyrimidine
1 NOV 2019
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PROTOCOL NO. 063-02
Supplemental SAP
  1 NOV 2019–AMENDMENT #1
Supplemental Statistical Analysis Plan (sSAP) 
TABLE OF CONTENTS
TABLE OF CONTENTS...........................................................................................................1
LIST OF TABLES.....................................................................................................................2
1
INTRODUCTION .............................................................................................................3
2
SUMMARY OF CHANGES.............................................................................................3
3
ANALYTICAL AND METHODOLOGICAL DETAILS................................................3
3.1
Statistical Analysis Plan Summary .............................................................................3
3.2
Responsibility for Analyses/In-House Blinding .........................................................4
3.3
Hypotheses/Estimation................................................................................................5
3.3.1
Primary Objective(s) & Hypothesis(es)...............................................................5
3.3.2
Secondary Objective(s) & Hypothesis(es)...........................................................6
3.3.3
Exploratory Objectives ........................................................................................6
3.4
Analysis Endpoints......................................................................................................6
3.4.1
Efficacy Endpoints...............................................................................................6
3.4.2
Safety Endpoints..................................................................................................7
3.5
Analysis Populations...................................................................................................7
3.5.1
Efficacy Analysis Populations.............................................................................7
3.5.2
Safety Analysis Populations ................................................................................8
3.6
Statistical Methods......................................................................................................8
3.6.1
Statistical Methods for Efficacy Analyses...........................................................8
3.6.2
Statistical Methods for Safety Analyses ............................................................12
3.6.3
Statistical Methods for Exploratory Analyses ...................................................14
3.6.4
Summaries of Demographic and Baseline Characteristics................................16
3.7
Interim Analyses .......................................................................................................16
3.8
Multiplicity................................................................................................................17
3.9
Sample Size and Power Calculations........................................................................18
3.10
Subgroup Analyses and Effect of Baseline Factors...............................................19
3.11
Compliance (Medication Adherence)....................................................................19
3.12
Extent of Exposure ................................................................................................19
4
REFERENCES ................................................................................................................20
 
 
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LIST OF TABLES
Table 1
Statistical Analysis Plan ......................................................................................... 3
Table 2
Censoring rules for Primary and Sensitivity Analyses of PFS............................. 10
Table 3
Analysis Strategy for Key Efficacy Endpoints..................................................... 12
Table 4
Analysis Strategy for Safety Parameters .............................................................. 14
Table 5
Censoring rules for Analyses of TTP ................................................................... 14
Table 6
Censoring Rule of DOR ....................................................................................... 15
Table 7
Summary of Timing, Sample Size and Decision Guidance of Interim Analysis 
and Final analysis.................................................................................................................... 17
 
 
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Supplemental SAP
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1
INTRODUCTION
This supplemental SAP (sSAP) is a companion document to the protocol. In addition to the 
information presented in the protocol SAP which provides the principal features of 
confirmatory analyses for this trial, this supplemental SAP 1) provides additional statistical 
analysis details/data derivations and 2) documents modifications or additions to the analysis 
plan that are not “principal” in nature and result from information that was not available at 
the time of protocol finalization.
2
SUMMARY OF CHANGES
Section Number (s)
Section Title(s)
Description of Change(s)
Rationale
3.10
Subgroup Analyses and 
Effect of Baseline 
Factors
Added a paragraph to specify 
the unstratified Cox model 
and the unstratified log-rank 
test will be used for subgroup 
analyses.
To ensure the subgroup
(s) with small group size
could be analyzed 
properly.
3
ANALYTICAL AND METHODOLOGICAL DETAILS
3.1
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized in below; the comprehensive 
plan is provided in Sections 3.2 through 3.12.
Table 1
Statistical Analysis Plan
Study Design Overview
A Phase III, Randomized, Open-label Clinical Trial of Pembrolizumab (MK-
3475) versus Paclitaxel in Asian
Subjects with Advanced Gastric or 
Gastroesophageal Junction Adenocarcinoma who Progressed after First-Line 
Therapy with Platinum and Fluoropyrimidine
Treatment Assignment
Approximately 360 subjects will be randomized in a 1:1 ratio to receive 
pembrolizumab or paclitaxel. Stratification factors are time to progression (TTP) 
on first-line therapy (< 6 months vs. ≥ 6 months) and ECOG PS (0 vs. 1). This is 
an open-label study. 
Analysis Populations
Efficacy: Intention to Treat (ITT)
Safety: All Subjects as Treated (ASaT)
Primary Endpoints
1. Overall Survival (OS)  
2. Progression-free Survival (PFS) per RECIST 1.1 by blinded central 
radiologists’ review
Statistical Methods for 
Key Efficacy Analyses
The primary hypotheses will be evaluated by comparing pembrolizumab to 
paclitaxel on PFS per RECIST 1.1 by blinded central radiologist review and OS 
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.
 
 
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Supplemental SAP
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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. There are no Tier 1 events in this trial.
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 analyzed using the Miettinen and Nurminen method [1].
Interim Analysis
There is no interim analysis for PFS. One interim efficacy analysis is planned for 
OS. Results will be reviewed by an external data monitoring committee. The 
interim analysis is summarized below. Details are provided in Section 3.7.
The interim analysis of OS will be performed at the time of final (only) PFS 
analysis
o
Timing: To be performed after: (1) enrollment is completed (2) 
approximately both 235 PFS events and 190 OS events have been 
observed.
o
Purpose: final PFS analysis and interim analysis of OS 
Final analysis (event driven trial)
o
Timing: at least 290 OS events have been observed, estimated to be 
36 months after study start
o
Purpose: Final analysis of OS
Multiplicity
The overall type I error for the multiple endpoints will be strongly controlled by 
the Bonferroni procedure at 2.5% (one-sided) with initially 0.35% allocated to 
PFS and 2.15% allocated to OS hypotheses, and 0% to the ORR hypothesis.  
If the PFS null hypothesis is rejected, the corresponding alpha level can be shifted 
to the hypotheses for the OS endpoint using the graphical approach of Maurer and 
Bretz [2].
The secondary hypothesis of ORR will be tested only if pembrolizumab arm is 
superior to the control for OS.
Sample Size and Power 
The planned sample size is approximately 360 subjects. 
The final analysis of this study is event driven (i.e., follow-up time is subject to 
change but the approximate number of events is not) and will complete after at 
least 290 OS events have been observed. 
For the PFS primary endpoint , the trial has >99% (>90%) power to demonstrate 
that pembrolizumab is superior to paclitaxel at a one-sided 0.35% alpha-level, if 
the underlying hazard ratio of PFS is 0.5 (0.6).
For the OS primary endpoint, the trial has 91% power to demonstrate that 
pembrolizumab is superior to paclitaxel at a one-sided 2.15% alpha-level, if the 
underlying hazard ratio of OS is 0.67.
3.2
Responsibility for Analyses/In-House Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the SPONSOR.
The SPONSOR will generate the randomized allocation schedule(s) for study treatment 
assignment.  The algorithm for the randomized allocation of subjects will be implemented in 
an interactive voice response system (IVRS).
 
 
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Although the trial is open label, analyses or summaries generated by randomized treatment 
assignment or actual treatment received will be limited and documented prior to the final 
unblinding for reporting purposes. In addition, the independent radiologist(s) will perform 
the blinded central radiologist review without knowledge of treatment group assignment.
Planned interim analyses are described in Section 3.7. Interim Analysis will be performed 
when enrollment is completed. Access to the allocation schedule for this study will be 
restricted to an external unblinded statistician and, as needed, a scientific programmer 
performing the analysis, who will have no other responsibilities associated with the study.  
Treatment-level results of the interim analyses will be provided by the external unblinded 
statistician to the external Data Monitoring Committee (eDMC). Limited additional Sponsor 
personnel may be unblinded to the treatment level results of the interim analyses, if required, 
in order to act on the recommendations of the eDMC or facilitate regulatory filing after an 
interim analysis. The extent to which individuals are unblinded with respect to results of 
interim analyses will be documented.  
The eDMC will serve as the primary reviewer of the unblinded results of the interim analysis 
and will make recommendations for discontinuation of the study or protocol modifications to 
the Executive Oversight Committee (EOC) of this SPONSOR. Depending on the 
recommendation of the eDMC, the Sponsor may prepare a regulatory submission.  If the 
eDMC recommends modifications to the design of the protocol or discontinuation of the 
study, the EOC may be unblinded to results at the treatment level in order to act on these 
recommendations. Additional logistical details will be provided in the DMC Charter. In 
addition, there will be an unblinding plan to maintain information about unblinding of 
Sponsor Personnel prior to full unblinding at Sponsor. Key aspects of the interim analyses 
are described in Section 3.7.
The personnel who have access to allocation schedule at what time will be documented in 
Appendix 4 Interim Analysis Data Sources Memo in DMC charter.
3.3
Hypotheses/Estimation
In PD-L1 positive subjects with advanced gastric or GEJ adenocarcinoma who have 
progressed on one previous line of therapy. 
3.3.1
Primary Objective(s) & Hypothesis(es)
(1) Objective: To compare OS. 
Hypothesis: Pembrolizumab prolongs OS compared to paclitaxel.
(2) Objective: To compare PFS per RECIST 1.1 by blinded central radiologists’ review.
Hypotheses: Pembrolizumab prolongs PFS per RECIST 1.1 by blinded central 
radiologists’ review compared to paclitaxel.
 
 
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The study is considered to have met its primary objective if pembrolizumab is superior to 
paclitaxel either in OS (interim or final analysis) or in the final PFS analysis.
3.3.2
Secondary Objective(s) & Hypothesis(es)
(1) To evaluate the Objective Response Rate (ORR) per RECIST 1.1 assessed by blinded 
central radiologists’ review.
Hypotheses: Pembrolizumab improves ORR per RECIST 1.1 assessed by blinded central 
radiologists’ review compared to paclitaxel.
(2) Objective: Evaluate the safety and tolerability profile of pembrolizumab compared to 
paclitaxel.
3.3.3
Exploratory Objectives
(1) Objective: To evaluate PFS per irRECIST by blinded central radiologists’ review among 
subjects when treated with pembrolizumab compared to paclitaxel.
(2) Objective: To evaluate the Time to Progression (TTP) and Duration of Response (DOR) 
per RECIST 1.1 by blinded central radiologists’ review among subjects when treated 
with pembrolizumab compared to paclitaxel.
(3) Objective: To evaluate score change of health related quality of Life using the EORTC 
QLQ-C30 and the EORTC QLQ-STO22 from baseline among subjects when treated with 
pembrolizumab compared to paclitaxel.  
(4) Objective: To characterize utilities using EuroQol EQ-5D among subjects when treated 
with pembrolizumab compared to paclitaxel. 
(5) Objective: To explore the relationship between genetic variation and response to the 
treatment(s) administered. Genomic variability will be analyzed for association with 
clinical data collected in this study.
3.4
Analysis Endpoints
3.4.1
Efficacy Endpoints
Primary
Overall Survival
Overall Survival (OS) is defined as the time from randomization to death due to any cause. 
Subjects without documented death at the time of the final analysis will be censored at the 
date of the last follow-up.
 
 
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Progression-free survival (PFS) – RECIST 1.1 by blinded central radiologists’ review
Progression-free-survival (PFS) is defined as the time from randomization to the first 
documented disease progression or death due to any cause, whichever occurs first. See 
Section 3.6.1 for the definition of censoring.
Secondary
Objective Response Rate (ORR) – RECIST 1.1 by blinded central radiologists’ review 
Objective response rate is defined as the proportion of the subjects in the analysis population 
who have a complete response (CR) or partial response (PR).
Exploratory
Progression-free survival (PFS) – irRECIST by blinded central radiologists’ review
Progression-free-survival (PFS) is defined as the time from randomization to the first 
confirmed disease progression or death due to any cause, whichever occurs first.
Time to Progression (TTP) – RECIST 1.1 by blinded central radiologists’ review
Time to Progression (TTP) is defined as the time from randomization to the first documented 
disease progression. If there is no documented disease progression, TTP is censored at last 
tumor assessment date. 
Duration of Overall Response (DOR) – RECIST 1.1 by blinded central radiologists’ 
review
For subjects who demonstrated CR or PR, response duration is defined as the time from first 
documented evidence of CR or PR until disease progression or death due to any cause, 
whichever occurs first. Censoring rules are provided in Section 3.6.3.2. 
3.4.2
Safety Endpoints
Safety measurements are described in Protocol Section 7.
3.5
Analysis Populations
3.5.1
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 3.6 Statistical 
Methods.
 
 
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3.5.2
Safety Analysis Populations
The All Subjects as Treated (ASaT) population will be used for the analysis of safety data in 
this study.  The ASaT population consists of all 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 analyzed according to the correct (randomized) 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.
Details on the approach to handling missing data for safety analyses are provided in Section 
3.6 Statistical Methods.
3.6
Statistical Methods
3.6.1
Statistical Methods for Efficacy Analyses
Efficacy results that will be deemed to be statistically significant after consideration of the 
Type I error control strategy are described in Section 3.8, Multiplicity. Nominal p-values will 
be computed for other efficacy analyses, but should be interpreted with caution due to 
potential issues of multiplicity.
3.6.1.1
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. A stratified 
Cox proportional hazard model with Efron's method of tie handling will be used to assess the 
magnitude of the treatment difference (i.e., the hazard ratio). The hazard ratio and its 95% 
confidence interval from the stratified Cox model with a single treatment covariate will be 
reported. The stratification factors used for randomization will be applied to both the 
stratified log-rank test and the stratified Cox model.
Subjects in the paclitaxel arm are expected to discontinue treatment earlier compared to 
subjects in the pembrolizumab arm, and may switch to another anti PD-1 treatment following 
the verification of progressive disease by blinded central radiologists’ vendor. Exploratory 
analyses to adjust for the effect of crossover [to other PD-1 therapies] on OS may be 
performed based on recognized methods, e.g. the Rank Preserving Structural Failure Time 
(RPSFT) model proposed by Robins and Tsiatis (1989) [3], two stage model [4], etc., based 
 
 
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on an examination of the appropriateness of the data to the assumptions required by the 
methods.  
The RPSFT model provides a randomization-based estimate of the treatment effect corrected 
for bias introduced by crossover from the control arm to active treatment. The model is 
refereed as rank preserving as it is assumed that given two subjects i and j, if i failed before j 
when both were on one treatment, then i would also fail before j if both subjects took the 
same alternative treatment. This assumption may not be plausible with certain subjects likely 
to see more or less benefit than others on different types of treatments due to biological 
factors. However testing for any violations of this assumption in real data may not be 
possible. The method also assumes an equal treatment effect for subjects switching to a 
treatment as for those initially allocated to receive it. For the RPSFT method, time post 
crossover is adjusted using an accelerated failure time model, and then the resulting adjusted 
times to events are analyzed using the same methods as the primary analyses. The 95% 
confidence intervals of the hazard ratio for OS after adjustment of the cross-over effect will 
be provided at the final analysis. More detailed steps to implement the RPSFT method will 
be provided in the Programming Requirement Specification (PRS) for the macro 
implementing the RPSFT method.
If there is no unmeasured confounder at the secondary baseline time-point (disease 
progression), treatment switching only happens after progression, and happens soon after 
progression, the “two-stage” approach may be appropriate. At Stage 1, the date of disease 
progression is used as a secondary baseline for subjects who have a documented progression 
in the standard treatment arm and data from these subjects beyond this time-point are 
considered as an observational dataset.  An accelerated failure time (AFT) model including 
covariates for crossover and other prognostic covariates measured at the secondary baseline 
will be applied to this observational dataset to estimate an acceleration factor.  At Stage 2, a 
counterfactual survival dataset will be constructed such that survival time of subjects with 
treatment switching will be shrunk by the inverse of the acceleration factor, while no 
shrinkage is performed for the survival time of subjects in the control group without 
treatment switching or subjects in the experimental arm.  A Cox model will then be applied 
to the counterfactual survival dataset to estimate the HR from this two-stage method. More 
detailed steps to implement the two-stage method will be provided in the Programming 
Requirement Specification (PRS) for the macro of two-stage method.
It is very important to assess trial data, crossover mechanism, and treatment effect to 
determine which method is likely to be most appropriate to evaluate the cross-over effect as 
well as to evaluate the consistency of alternate approaches.  
3.6.1.2
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 hazard model with Efron's method of tie handling will be 
used to assess the magnitude of the treatment difference (i.e., 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 
 
 
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reported. The stratification factors used for randomization will be applied to both the 
stratified log-rank test and the stratified Cox model. 
Since disease progression is assessed periodically, progressive disease (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, the true date of disease 
progression will be approximated by the date of the first assessment at which PD is 
objectively documented per RECIST 1.1 by central imaging vendor, regardless of 
discontinuation of study drug or missed study visits.  Death is always considered as a 
confirmed PD event. Subjects who do not experience a PFS event will be censored at the last 
disease assessment. Sensitivity analyses will be performed for comparison of PFS based on 
investigator's assessment.
In order to evaluate the robustness of the PFS endpoint per RECIST 1.1 by central imaging 
vendor, two sensitivity analyses with different sets of censoring rules will be performed. The 
first sensitivity analysis is the same as the primary analysis except that the data for any 
subject who misses more than one consecutive disease assessment (with or without a 
subsequent death or progression) are censored at the last disease assessment prior to missing 
visits. 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.  If a subject meets multiple criteria for censoring, 
the censoring criterion that occurs earliest will be applied. The censoring rules for primary 
and sensitivity analyses are summarized in Table 2. 
Additional PFS sensitivity analyses may be performed, including a PFS analysis using time 
to scheduled tumor assessment visit from randomization as opposed to actual tumor 
assessment time.
Table 2
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
No PD and no death; ≥ 
2 consecutive missed 
disease assessments
Censored at last disease 
assessment
Censored at last 
disease assessment 
prior to ≥2 consecutive 
missed visits
Censored at last disease 
assessment
PD or death 
documented after ≤ 1 
Progressed at date of 
documented PD or death
Progressed at date of 
documented PD or 
Progressed at date of 
documented PD or death
 
 
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Situation
Primary Analysis
Sensitivity
Analysis 1
Sensitivity
Analysis 2
missed disease 
assessment
death
PD or death 
documented at any 
time after ≥ 2 
consecutive missed 
disease assessments
Progressed at date of 
documented PD or death
Censored at last 
disease assessment 
prior to the  ≥ 2
consecutive  missed 
disease assessment
Progressed at date of 
documented PD or death
The proportional hazards assumption on PFS will be examined using both graphical and 
analytical methods if warranted. The log[-log] of the survival function vs. time for PFS  will 
be plotted for the comparison between pembrolizumab and the paclitaxel arm. If the curves 
are not parallel, indicating that hazards are not proportional, supportive analyses may be 
conducted to account for the possible non-proportional hazards effect associated with 
immunotherapies: for example, using Restricted Mean Survival Time (RMST) method [5], 
parametric method [6], etc.
The RMST is simply the population average of the amount of event-free survival time 
experienced during the study follow up time. This quantity can be estimated by the area 
under the KM curve up to the follow up time.  The clinical relevance and feasibility of 
conducting the study should be taken into account in the choice of follow-up time to define 
RMST (e.g. near the last observed event time assuming that the period of clinical interest in 
the survival experience is the whole observed follow-up time for the trial). The cut-off will 
be pre-specified prior to unblinding of the study by the Sponsor study team that is blinded to 
treatment results. The difference of two RMSTs for two treatment groups will be estimated 
and 95% confidence interval will be provided.  
One assumption for stratified Cox proportional hazard model is that, the treatment hazard 
ratio (HR) is constant across the strata. If strong departures from the assumption of the HR 
being the same for all the strata observed (which can result in a notably biased and/or less 
powerful analysis), a sensitivity analysis may be performed based on a two-step weighted 
Cox model approach by Mehrotra 2012 [7], in which the treatment effect is first estimated for 
each stratum and then the stratum specific estimates are combined for overall inference using 
sample size weights.
3.6.1.3
Objective Response Rate (ORR)
The stratified Miettinen and Nurminen method [1] with strata weighting by sample size will 
be used for comparison of the objective response rates between the treatment arms. A 95% 
confidence interval for the difference in response rates between the pembrolizumab arm and 
paclitaxel arm will be provided. The stratification factors used for randomization will be 
applied to the analysis.
Table 3 summarizes the primary analysis approaches for primary and secondary efficacy 
endpoints. Sensitivity analysis methods are described above for each endpoint.
 
 
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The strategy to address multiplicity issues with regard to multiple efficacy endpoints and 
interim analysis is described in Section 3.7 Interim Analyses and in Section 3.8 Multiplicity.
Table 3
Analysis Strategy for Key Efficacy Endpoints
Endpoint/Variable
(Description, Time Point)
Statistical Method†
Analysis Population
Missing Data Approach
Primary Hypothesis #1
OS
Test: Stratified Log-rank test 
Estimation: Stratified Cox 
model with Efron’s tie 
handling method 
ITT
Censored at last known alive 
date 
Primary Hypothesis #2
PFS per RECIST 1.1 by 
blinded central radiologists’
review
Test: 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 are in Table 2)
Secondary Hypothesis
ORR per RECIST 1.1 by 
blinded central radiologists’ 
review
Stratified M & N method‡
ITT
Subjects with missing data 
are considered non-
responders
† Statistical models are described in further detail in the text. For stratified analyses, the stratification factors 
used for randomization (time to progression on first-line therapy (< 6 months vs.  ≥ 6 months) and ECOG 
PS (0 vs. 1)), will be applied to the analysis. 
‡ Miettinen and Nurminen method.
3.6.2
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
adverse experiences (AEs), laboratory tests, vital signs, etc.
Tiered Approach
The analysis of safety results will follow a tiered approach (Table 4).  The tiers differ with 
respect to the analyses that will be performed. “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 
 
 
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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, that are not pre-specified as Tier-1 endpoints will 
be classified as belonging to "Tier 2" or "Tier 3", based on the number of events observed.  
Membership in Tier 2 requires that at least 4 subjects in any treatment group exhibit the 
event; all other adverse experiences and predefined limits of change will belong to Tier 3.
The threshold of at least 4 events was chosen because the 95% confidence interval for the 
between-group difference in percent incidence will always include zero when treatment 
groups of equal size each have less than 4 events and thus would add little to the 
interpretation of potentially meaningful differences. Because many 95% confidence intervals 
may be provided without adjustment for multiplicity, the confidence intervals should be 
regarded as a helpful descriptive measure to be used in review, not a formal method for 
assessing the statistical significance of the between-group differences in adverse experiences 
and predefined limits of change.
Continuous measures such as changes from baseline in laboratory, vital signs, that are not 
pre-specified as Tier-1 endpoints will be considered Tier 3 safety parameters.  Summary 
statistics for baseline, on-treatment, and change from baseline values will be provided by 
treatment group in table format.    
There are no events of interest that warrant elevation to Tier 1 in this study. The broad 
clinical and laboratory AE categories consisting of the percentage of subjects with any AE, 
any drug related AE, any Grade 3-5 AE, any serious AE, any AE which is both drug-related 
and Grade 3-5, any AE which is both serious and drug-related, dose modification due to AE, 
and who discontinued due to an AE, and death will be considered Tier 2 endpoints. 95% 
confidence intervals (Tier 2) will be provided for between-treatment differences in the 
percentage of subjects with events; these analyses will be performed using the Miettinen and 
Nurminen method (1985), an unconditional, asymptotic method.
To properly account for the potential difference in follow-up time between the study arms, 
which is expected to be longer in the pembrolizumab arm, AE incidence density adjusted for 
treatment exposure analyses may be performed as appropriate. Based on emerging external 
data, the supportive analysis strategy for safety parameters may be modified to improve the 
integrity and efficiency of the design. Should this happen, the change will be documented in 
supplemental SAP, if not in a protocol amendment, at the earliest time before any unblinding 
of the data.
 
 
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Table 4
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 Serious AE 
X
X
Any Grade 3-5 AE
X
X
Any Drug-Related AE
X
X
Any Serious and Drug-Related AE
X
X
Any Grade 3-5 and Drug-Related AE
X
X 
Dose Modification due to AE
X
X
Discontinuation due to AE
X
X
Death
Specific AEs, SOCs, or PDLCs(incidence ≥4 of 
subjects in one of the treatment groups)
X
X
Tier 3
Specific AEs, SOCs or PDLCs (incidence <4 of 
subjects in all of the treatment groups)
X
Change from Baseline Results (Labs, ECGs, Vital 
Signs)
X
†
Adverse Experience references refer to both Clinical and Laboratory AEs.
Note: SOC=System Organ Class; PDLC=Pre-Defined Limit of Change; X = results will be provided.
3.6.3
Statistical Methods for Exploratory Analyses
3.6.3.1
Time to Progression (TTP)
The non-parametric Kaplan-Meier method will be used to estimate the TTP curve in each
treatment group. The treatment difference in TTP will be assessed by the stratified log-rank 
test. A stratified Cox proportional hazard model with Efron's method of tie handling will be 
used to assess the magnitude of the treatment difference (i.e., 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. The stratification factors used for randomization will be applied to both the 
stratified log-rank test and the stratified Cox model. The censoring rules for analysis of TTP
are summarized in Table 5.
Table 5
Censoring rules for Analyses of TTP
Situation
Analysis
No PD;new anticancer treatment is not initiated
Censored at last disease Assessment
No PD;new anticancer treatment is initiated
Censored at last disease,assessment before new 
anticancer treatment
PD 
Progressed at date of documented PD 
 
 
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3.6.3.2
Duration of Response (DOR)
If sample size permits, response duration will be summarized descriptively using Kaplan-
Meier method.  Only the subset of subjects who show a complete response or partial response 
will be included in this analysis.  
Censoring rules for DOR are summarized in Table 6. For each DOR analysis, a 
corresponding summary of the reasons responding subjects are censored will also be 
provided. Responding subjects who are alive, have not progressed, have not initiated new 
anti-cancer treatment, have not been determined to be lost to follow-up, and have had a 
disease assessment within ~5 months of the data cutoff date are considered ongoing 
responders at the time of analysis. If a subject meets multiple criteria for censoring, the 
censoring criterion that occurs earliest will be applied.
Table 6
Censoring Rule of DOR
Situation
Date of Progression or Censoring
Outcome
No progression nor death, no new 
anti-cancer therapy initiated
Last adequate disease assessment
Censor
(non-event)
No progression nor death, new 
anti-cancer therapy initiated
Last adequate disease assessment 
before new anti-cancer therapy 
initiated
Censor
(non-event)
Death or progression after ≥ 2 
consecutive 
missed 
disease 
assessments 
Last adequate disease assessment 
prior to ≥ 2 missed adequate 
disease assessments
Censor
(non-event)
Death or progression after ≤ 1 
missed disease assessments
PD or death
End of response
(Event)
A missed disease assessment includes any assessment that is not obtained or is considered inadequate for 
evaluation of response.
3.6.3.3
Progression-Free Survival 2 (PFS2)
An exploratory analysis of PFS2, defined as the time from randomization to disease 
progression on the next line of therapy post study drug, or death from any cause, whichever 
first, may be carried out. 
The analysis of PFS2 will be conducted using the same statistical methods as the primary 
analysis of PFS and OS, for example, the stratified log-rank test and Cox model. 
 
 
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3.6.4
Summaries of Demographic and Baseline Characteristics
The comparability of the treatment groups for each relevant characteristic will be assessed by 
the use of tables and/or graphs. No statistical hypothesis tests will be performed on these 
characteristics.  The number and percentage of subjects screened, randomized, the primary 
reasons for screening failure, and the primary reason for discontinuation will be displayed.  
Demographic variables (e.g., age), baseline characteristics, primary and secondary diagnoses, 
and prior and concomitant therapies will be summarized by treatment either by descriptive 
statistics or categorical tables.
Statistical testing and inference for safety analyses are described in Section 3.6.2. Efficacy 
results that will be considered to be statistically significant after consideration of the strategy 
for controlling the type I error are described in Section 3.8– Multiplicity. Nominal p-values 
may be computed for other efficacy analyses as a measure of strength of association between 
the endpoint and the treatment effect rather than formal tests of hypotheses.
3.7
Interim Analyses
There is no interim efficacy analysis planned in this study for PFS. 
There is one interim efficacy analysis planned in this study for OS. For OS, a Hwang-Shih-
DeCani alpha-spending function with the gamma parameter (-4) is constructed to implement 
group sequential boundaries that control the Type-I error rate. The actual boundaries will be 
determined from the number of OS events observed at the time of the interim analysis, using 
the alpha-spending function.
The interim OS will be performed at the time of final PFS analysis: (1) enrollment is 
completed; (2) approximately 235 PFS events and 190 OS events have been observed. The 
final analysis (FA) for OS will be performed when at least 290 OS events have been 
observed (~36 months after trial starts).
The secondary hypothesis of ORR will be tested only if pembrolizumab arm is superior to 
the control in OS. The information fraction for the group sequential boundaries and alpha 
spending function of ORR will be defined by the proportion of subjects whose randomization 
dates are at least 6 months before the data cutoff date of the analysis. Only these eligible 
subjects can be included into the ORR analysis. It is projected that there will be at least 270 
eligible subjects at the interim analysis time point. The nominal Type I error rates for the 
interim analysis and final analysis that will allow tight control of the overall Type I error for 
testing the ORR hypothesis will be derived using the alpha-spending function approach. The 
group sequential testing of the ORR hypothesis will be conducted with an efficacy boundary 
only. The efficacy boundary for the ORR will be set using an Exponential spending function 
fሺtሻൌα୲షಕ[8] with parameter ν=0.25, which yields a Pocock-like boundary. 
Table 7 summarizes the timing, number of events and decision guidance for the PFS, OS and 
ORR analysis. The actual boundaries and the alpha level for the OS and ORR analyses will 
be determined from the actual number of events observed at the time of the analysis using the 
corresponding alpha-spending function.


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&*=%
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Table 7
Summary of Timing, Sample Size and Decision Guidance of Interim Analysis 
and Final analysis
Analysis
Criteria for Conduct of Analysis
Endpoint
p value (1-sided) 
at boundary
Approx. Observed HR 
or ORR-Difference at 
Boundary
Final PFS 
Analysis/ 
Interim OS 
Analysis 
~ 24  months after trial starts
(1) 
enrollment 
is 
complete 
(2) 
approximately 235 PFS events and 190 
OS events have been observed 
PFS Events: ~235
OS Events: ~190
PFS
0.0035
0.70
OS 
0.0051
0.69
ORR†
0.0161
10.2%
Final 
OS 
Analysis
~ 36 mos after trial starts
At least 290 OS events have been observed
OS Events: ~290
OS 
0.0198
0.78
ORR†
0.0123
9.3%
†: The secondary hypothesis of ORR will be tested only if pembrolizumab arm is superior to the control in OS. The assumed expected ORR 
in pembrolizumab and control groups are 30% and 10%, respectively. Depending on the results of the OS and PFS hypothesis testing, the 
ORR hypothesis can be tested at Type I error levels of α=2.15% or 2.5%; this table assumes an ORR Type I error of 2.15%.
3.8
Multiplicity
The multiplicity strategy specified in this section will be applied to the two primary 
hypotheses (superiority of pembrolizumab for OS or PFS) and one secondary hypothesis 
(superiority of pembrolizumab for ORR). 
The overall Type-I error is strongly controlled at 2.5% (one-sided), with 0.35% allocated to 
PFS and 2.15% allocated to OS hypothesis and 0% to the ORR hypothesis. 
For the OS and ORR endpoints, the Type-I error rate for the interim analysis and final 
analysis is controlled through alpha-spending functions as described in Section 3.7 Interim 
Analyses. 
By using the graphical approach of Maurer and Bretz [2], if the PFS hypothesis is rejected, 
the corresponding alpha level can be shifted to the OS hypotheses. If the OS hypothesis is 
rejected, the corresponding alpha level can be shifted to the ORR hypothesis. 
See Figure 1 for the multiplicity strategy diagram of the study.
 
 
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Figure 1
Multiplicity Strategy
3.9
Sample Size and Power Calculations
The study will randomize subjects in a 1:1 ratio into pembrolizumab arm and paclitaxel arm. 
The overall sample size will be approximately 360. However, subjects already in screening 
phase may be enrolled even after we have reached the maximum sample size.
The final analysis of the study is event driven (i.e., follow-up time are subject to change but 
number of events is not) and will complete after at least 290 OS events have been observed. 
PFS analysis: the final PFS analysis will be performed after approximately 235 PFS events 
observed. With ~235 PFS events, this trial has overall 99% (88%) power to demonstrate that 
pembrolizumab is superior to paclitaxel at a one-sided 0.35% alpha-level, if the underlying 
hazard ratio of PFS is 0.5 (0.6). Success for PFS at the main analysis approximately 
corresponds to an observed hazard ratio of < 0.70. 
The power calculation is based on the following assumptions for subjects: 1) Progression-
free survival follows an exponential distribution with a median of 4.5 months in the 
paclitaxel arm; 2) An enrollment period of 24 months (IA is conducted after enrollment is 
complete); 3) A yearly drop-out rate of 5%.
OS analysis: The final OS analysis will be carried out when at least 290 OS events have 
occurred. For primary endpoint OS, the trial has 91% (85%) power to demonstrate that 
pembrolizumab is superior to paclitaxel at an one-sided 2.15% alpha-level, if the underlying 
hazard ratio of OS is 0.67 (0.7). Success for OS at the final analysis approximately 
corresponds to an observed hazard ratio of < 0.78 (approximately a 2-month improvement or 
greater in median OS).
The sample size and power calculation is based on the following assumptions for subjects: 1) 
Overall survival follows an exponential distribution with a median of 7.5 months in the 
PFS
ORR
OS
If significant, pass full α
 
 
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control arm; 2) An enrollment period of 24 months and a minimum of 12 months follow-up 
after enrollment completion; 3) A yearly dropout rate of 2%.
The assumptions for the median PFS of 4.5 months and the median OS of 7.5 months in the 
paclitaxel arm are based on estimates of median PFS and median OS from China subgroup 
analysis of TyTAN trial [9].
3.10 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 dual primary 
endpoints will be estimated and plotted within each category of the following classification 
variables: 

Age category (≤65 vs. >65 years)

Sex (Female vs. Male)

ECOG Performance Scale (0 vs. 1)

Primary location (Stomach vs. GEJ)

Histological subtype (Diffuse vs. intestinal vs. mixed)

Disease Status (Locally advanced vs. Metastatic)

Time to progression on first-line therapy (< 6 months vs. ≥ 6 months)

Geographic region of enrolling site (China vs. ex-China)
Country specific population (e.g. Chinese, etc.) may also be analyzed per local regulatory 
requirements.
For analysis in subgroup of the ITT population, the unstratified Cox model will be used to 
estimate the OS and PFS hazard ratio between the treatment arms and the unstratified log-
rank test will be used to assess the treatment difference. If any level of a subgroup variable 
has fewer than 20% of the ITT population, above analysis will not be performed for this level 
of the subgroup variable.
3.11 Compliance (Medication Adherence)
Drug accountability data for trial treatment will be collected during the study. Compliance 
with trial treatment administration will be measured by subjects: 1) receiving unscheduled 
study agent infusions/injections; 2) missing an infusion/injection. Numbers and percentages 
of subjects and infusion/injection visits with any deviation in these measures will be reported 
for the ITT population.
3.12 Extent of Exposure
The extent of exposure will be summarized as duration of treatment in cycles. Dose intensity 
will also be summarized as appropriate.
 
 
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4
REFERENCES
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1985; 4:213-226.
2. Maurer W, Bretz F. Multiple Testing in Group Sequential Trials using Graphical 
Approaches. Statistics in Biopharmaceutical Research 2013; 5(4): 311-320.
3. 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.
4. Latimer, N.R., Abrams, K.R., Lambert, P.C., Crowther, M.J., Wailoo, A.J., 
Morden,J.P. et al. Adjusting Survival Time Estimates to Account for Treatment 
Switching in Randomized controlled Trials - an Economic Evaluation Context: 
Methods, Limitations, and Recommendations.  Medical Decision Making  2014 
Apr;34(3):387-402.
5. 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. 
6. Odell P.M., Anderson K.M., Kannel B.W. New models for predicting cardiovascular 
events. Journal of Clinical Epidemiology 1994; 47(6): 583-592.
7. Mehrotra D., Su S.C., Li X.  An efficient alternative to the stratified Cox model 
analysis. Statist. Med. 2012, 31 1849–1856.
8. Anderson KM, Clark JB. Fitting spending functions. Stat Med 2010;29(3):321-7.
9. Satoh et al. Lapatinib Plus Paclitaxel Versus Paclitaxel Alone in the Second-Line 
Treatment of HER2-Amplified Advanced Gastric Cancer in Asian  Populations: 
TyTAN - A Randomized, Phase III Study. J Clin Oncol, 2014, 32:2039-2049.
 
 
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Revision History
Date
Summary of Change
16FEB2017
Original Document
 
 
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