Conditions: Gastric Adenocarcinoma Gastroesophageal Junction Adenocarcinoma
Keywords: Gastric cancer Gastroesophageal junction cancer PD1 PD-1 PDL1 PD-L1
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 592
Healthy volunteers: no

Brief summary:
This is a study for participants with advanced gastric or gastroesophageal junction adenocarcinoma who have had tumor progression after first-line treatment with platinum and fluoropyrimidine doublet therapy. The primary study hypotheses are that pembrolizumab (MK-3475) prolongs progression free survival (PFS) and overall survival (OS) for participants with tumors that show positive programmed cell death ligand 1 (PD-L1) expression.

As of 20-March-2016, enrollment will be limited to PD-L1 positive participants.

Detailed description:

Arms:
arm 1: Participants receive 200 mg intravenous (IV) pembrolizumab on Day 1 of each 21-day cycle, for up to 35 administrations (approximately 2 years). arm 2: Participants receive 80 mg/m\^2 IV paclitaxel on Days 1, 8, and 15 of each 28-day cycle, until disease progression or unacceptable toxicity.

Interventions: intervention 1: pembrolizumab intervention 2: paclitaxel
Intervention descriptions: intervention 1: 200 mg administered as IV infusion on Day 1 of each 21-day cycle. intervention 2: 80 mg/m\^2 administered as IV infusion on Days 1, 8, and 15 of each 28-day cycle.

Protocol document:
Prot_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 Subjects with 
Advanced Gastric or Gastroesophageal Junction 
Adenocarcinoma who Progressed after First-Line Therapy 
with Platinum and Fluoropyrimidine
09-Mar-2020
NCT02370498


Product:  MK-3475 
1
Protocol/Amendment No.: 061-13 
MK-3475-061-13 Final Protocol
09-Mar-2020
Confidential
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., 
WHITEHOUSE STATION, NJ, U.S.A.
SPONSOR:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. 
(hereafter referred to as the Sponsor or Merck)
One Merck Drive
P.O. Box 100
Whitehouse Station, NJ 08889-0100, U.S.A.
Protocol-specific Sponsor Contact information can be found in the Investigator Trial File
Binder (or equivalent).
TITLE:
A Phase III, Randomized, Open-label Clinical Trial of Pembrolizumab (MK-3475) versus 
Paclitaxel in Subjects with Advanced Gastric or Gastroesophageal Junction Adenocarcinoma 
who Progressed after First-Line Therapy with Platinum and Fluoropyrimidine
IND NUMBER:  123,482
EudraCT NUMBER:  2014-005241-45
 
 
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TABLE OF CONTENTS
DOCUMENT HISTORY ..................................................................................................... 11
SUMMARY OF CHANGES................................................................................................ 14
1.0
TRIAL SUMMARY.................................................................................................. 19
2.0
TRIAL DESIGN........................................................................................................ 21
Trial Design ........................................................................................................... 21
Trial Diagram........................................................................................................ 23
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 24
Primary Objective(s) & Hypothesis(es).............................................................. 24
Secondary Objective(s) & Hypothesis(es)........................................................... 24
Exploratory Objectives......................................................................................... 25
4.0
BACKGROUND & RATIONALE.......................................................................... 25
Background ........................................................................................................... 25
Pharmaceutical and Therapeutic Background .................................................... 25
Anti-PD-1 Blockage for Malignancy........................................................... 25
Anti-PD-1 Antibody, Pembrolizumab ......................................................... 26
Pre-clinical Studies of Pembrolizumab............................................................... 26
Ongoing Clinical Trials....................................................................................... 27
Ongoing Clinical Trials in Gastric Cancer................................................... 27
Rationale................................................................................................................ 28
Rationale for the Trial and Selected Subject Population .................................... 28
Rationale for Dose Selection/Regimen/Modification......................................... 28
Rationale for Paclitaxel as the Comparator ................................................. 29
Rationale for Endpoints ...................................................................................... 30
Efficacy Endpoints....................................................................................... 30
Safety Endpoints.......................................................................................... 30
Exploratory Endpoints ................................................................................. 31
4.2.3.3.1
Patient Reported Outcomes .................................................................. 31
4.2.3.3.2
Exploratory Biomarkers........................................................................ 32
Future Biomedical Research........................................................................ 33
 
 
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Benefit/Risk ........................................................................................................... 33
5.0
METHODOLOGY ................................................................................................... 34
Entry Criteria........................................................................................................ 34
Diagnosis/Condition for Entry into the Trial ...................................................... 34
Subject Inclusion Criteria.................................................................................... 34
Subject Exclusion Criteria .................................................................................. 37
Trial Treatment(s) ................................................................................................ 38
Dose Selection/Modification .............................................................................. 39
Dose Selection (Preparation) ....................................................................... 39
Dose Modification (Escalation/Titration/Other).......................................... 39
5.2.1.2.1
Dose Modification for Pembrolizumab ................................................ 39
5.2.1.2.2
Dose Modification for Paclitaxel.......................................................... 43
Timing of Dose Administration.......................................................................... 44
Pembrolizumab ............................................................................................ 44
Paclitaxel...................................................................................................... 45
Trial Blinding/Masking....................................................................................... 45
Randomization or Treatment Allocation............................................................ 45
Stratification.......................................................................................................... 45
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 46
Prohibited Concomitant Medication................................................................... 46
Rescue Medications & Supportive Care............................................................. 47
Supportive Care Guidelines ................................................................................ 47
Supportive Care Guidelines for Paclitaxel.......................................................... 51
Diet/Activity/Other Considerations..................................................................... 52
Diet...................................................................................................................... 52
Contraception...................................................................................................... 52
Use in Pregnancy ................................................................................................ 52
Use in Nursing Women....................................................................................... 53
Subject Withdrawal/Discontinuation Criteria................................................... 53
Discontinuation of Treatment ............................................................................. 53
Discontinuation of Study Therapy after Complete Response............................. 54
Withdrawal from the Trial .................................................................................. 54
 
 
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Subject Replacement Strategy............................................................................. 55
Beginning and End of the Trial ........................................................................... 55
Clinical Criteria for Early Trial Termination ................................................... 55
6.0
TRIAL FLOW CHART ........................................................................................... 56
Trial Flow Chart – Initial Treatment Phase for Pembrolizumab Arm........... 56
Trial Flow Chart – Initial Treatment Phase for Paclitaxel Arm...................... 60
Second Course Phase (Retreatment with Pembrolizumab).............................. 63
7.0
TRIAL PROCEDURES ........................................................................................... 65
Trial Procedures ................................................................................................... 65
Administrative Procedures.................................................................................. 65
Informed Consent......................................................................................... 65
7.1.1.1.1
General Informed Consent.................................................................... 65
7.1.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research................................................................................................ 65
Inclusion/Exclusion Criteria ........................................................................ 66
Subject Identification Card .......................................................................... 66
Medical History ........................................................................................... 66
7.1.1.4.1
Disease Details...................................................................................... 66
Prior and Concomitant Medications Review............................................... 66
7.1.1.5.1
Prior Medications.................................................................................. 66
7.1.1.5.2
Concomitant Medications..................................................................... 66
Assignment of Screening Number............................................................... 67
Assignment of Randomization Number....................................................... 67
Trial Compliance (Medication/Diet/Activity/Other) ................................... 67
Clinical Procedures/Assessments........................................................................ 67
Adverse Event Monitoring........................................................................... 67
Physical Exam.............................................................................................. 68
7.1.2.2.1
Full Physical Exam ............................................................................... 68
7.1.2.2.2
Directed Physical Exam........................................................................ 68
Vital Signs.................................................................................................... 68
12-Lead Electrocardiogram ......................................................................... 68
Eastern Cooperative Oncology Group Performance Status......................... 68
 
 
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Tumor Imaging and Assessment of Disease................................................ 68
7.1.2.6.1
Initial Tumor Imaging........................................................................... 68
7.1.2.6.2
Tumor Imaging During Trial ................................................................ 69
7.1.2.6.3
Second Course (Retreatment) Tumor Imaging..................................... 69
7.1.2.6.4
Assessment of Disease.......................................................................... 70
irRECIST........................................................................................ 70
Tumor Tissue Collection and Correlative Blood Sampling......................... 72
Blood Collections – Samples for Correlative and Genetic Analyses .......... 72
Patient Reported Outcomes (PRO).............................................................. 72
Laboratory Procedures/Assessments .................................................................. 73
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) .. 73
Serum/Urine β-hCG..................................................................................... 74
Pharmacokinetic/Pharmacodynamic Evaluations........................................ 74
Planned Genetic Analysis Sample Collection.............................................. 74
Future Biomedical Research........................................................................ 74
Other Procedures................................................................................................. 74
Withdrawal/Discontinuation........................................................................ 74
7.1.4.1.1
Withdrawal From Future Biomedical Research ................................... 75
Blinding/Unblinding .................................................................................... 75
Calibration of Critical Equipment................................................................ 75
Visit Requirements.............................................................................................. 75
Screening...................................................................................................... 76
Treatment Period.......................................................................................... 76
Discontinuation Visit ................................................................................... 76
Post-Treatment............................................................................................. 76
7.1.5.4.1
Safety Follow-up................................................................................... 76
7.1.5.4.2
Follow-up Visits ................................................................................... 77
7.1.5.4.3
Survival Follow-up ............................................................................... 77
7.1.5.4.4
Survival Status...................................................................................... 77
Second Course Phase (Retreatment Period) ................................................ 77
Assessing and Recording Adverse Events .......................................................... 79
Definition of an Overdose for This Protocol and Reporting of Overdose to 
the Sponsor.......................................................................................................... 80
 
 
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Reporting of Pregnancy and Lactation to the Sponsor ....................................... 80
Immediate Reporting of Adverse Events to the Sponsor.................................... 81
Serious Adverse Events ............................................................................... 81
Events of Clinical Interest............................................................................ 82
Protocol-Specific Exceptions to Serious Adverse Event Reporting............ 83
Evaluating Adverse Events................................................................................. 83
Sponsor Responsibility for Reporting Adverse Events ...................................... 86
TRIAL GOVERNANCE AND OVERSIGHT................................................... 86
Scientific Advisory Committee........................................................................... 86
Executive Oversight Committee......................................................................... 86
Data Monitoring Committee............................................................................... 86
8.0
STATISTICAL ANALYSIS PLAN ........................................................................ 87
Statistical Analysis Plan Summary ..................................................................... 87
Responsibility for Analyses/In-House Blinding ................................................. 89
Hypotheses/Estimation ......................................................................................... 89
Analysis Endpoints ............................................................................................... 89
Efficacy Endpoints.............................................................................................. 89
Safety Endpoints ................................................................................................. 90
Analysis Populations............................................................................................. 90
Efficacy Analysis Populations ............................................................................ 90
Safety Analysis Populations ............................................................................... 91
Statistical Methods................................................................................................ 91
Statistical Methods for Efficacy Analyses .......................................................... 91
PFS............................................................................................................... 91
OS ................................................................................................................ 93
TTP .............................................................................................................. 93
ORR ............................................................................................................. 94
DOR............................................................................................................. 94
Statistical Methods for Safety Analyses ............................................................. 95
Summaries of Demographic and Baseline Characteristics ................................. 97
Interim Analyses ................................................................................................... 97
Multiplicity ............................................................................................................ 99
 
 
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Sample Size and Power Calculations ................................................................ 100
Subgroup Analyses and Effect of Baseline Factors ......................................... 101
Compliance (Medication Adherence)................................................................ 102
Extent of Exposure.............................................................................................. 102
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ............................................................................................................... 102
Investigational Product ...................................................................................... 102
Packaging and Labeling Information ............................................................... 102
Clinical Supplies Disclosure............................................................................... 103
Storage and Handling Requirements................................................................ 103
Discard/Destruction/Returns and Reconciliation ............................................ 103
Standard Policies................................................................................................. 103
10.0
ADMINISTRATIVE AND REGULATORY DETAILS..................................... 103
Confidentiality..................................................................................................... 103
Confidentiality of Data ..................................................................................... 103
Confidentiality of Subject Records................................................................... 104
Confidentiality of Investigator Information...................................................... 104
Confidentiality of IRB/IEC Information........................................................... 104
Compliance with Financial Disclosure Requirements..................................... 105
Compliance with Law, Audit and Debarment ................................................. 105
Compliance with Trial Registration and Results Posting Requirements ...... 107
Quality Management System............................................................................. 107
Data Management............................................................................................... 107
Publications ......................................................................................................... 107
11.0
LIST OF REFERENCES....................................................................................... 109
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 .................................................................................... 121
 
 
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ECOG Performance Status................................................................................ 132
Common Terminology Criteria for Adverse Events V4.0 (CTCAE)............. 133
List of Abbreviations .......................................................................................... 134
13.0
SIGNATURES......................................................................................................... 137
Sponsor's Representative ................................................................................... 137
Investigator.......................................................................................................... 137
 
 
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09-Mar-2020
Confidential
LIST OF TABLES
Table 1
Adequate Organ Function Laboratory Values........................................................ 36
Table 2
Trial Treatment....................................................................................................... 38
Table 3
Dose Modification and Toxicity Management Guidelines for Immune-related 
AEs with Pembrolizumab....................................................................................... 40
Table 4
Criteria for Paclitaxel Treatment on Each Cycle.................................................... 43
Table 5
Guidelines for Hypersensitivity Reactions in Paclitaxel Arm................................ 44
Table 6
Infusion Reaction Treatment Guidelines................................................................ 50
Table 7
Imaging and Treatment after 1st Radiologic Evidence of Progressive Disease..... 71
Table 8
Laboratory Tests..................................................................................................... 73
Table 9
Evaluating Adverse Events .................................................................................... 84
Table 10 Statistical Analysis Plan ......................................................................................... 87
Table 11 Censoring rules for Primary and Sensitivity Analyses of PFS............................... 92
Table 12 Analysis Strategy for Key Efficacy Endpoints....................................................... 94
Table 13 Analysis Strategy for Safety Parameters................................................................ 97
Table 14 Summary of Timing, Sample Size and Decision Guidance of Interim Analysis 
and Final Analysis.................................................................................................. 99
Table 15 Product Descriptions ............................................................................................ 102
 
 
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LIST OF FIGURES
Figure 1 Trial Design Schematic .......................................................................................... 23
Figure 2 Multiplicity Strategy............................................................................................. 100
 
 
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
3475-061-13 (Global Amendment)
09-MAR-2020
To include an extension study.
3475-061-12 (UK-Specific Amendment)
28-NOV-2017
To clarify language in alignment with the 
labels – USPI and SmPC and the core data 
sheet and to add guidelines for the 
management of myocarditis to the table 
based upon health authority feedback.
To allow flexibility in the entire follow-up 
period beyond just the current survival 
follow-up portion to enable more frequent 
follow-ups as necessary.
3475-061-11 (Global Amendment)
03-NOV-2017
To clarify language in alignment with the 
labels – USPI and SmPC and the core data 
sheet and to add guidelines for the 
management of myocarditis to the table 
based upon health authority feedback.
To allow flexibility in the entire follow-up 
period beyond just the current survival 
follow-up portion to enable more frequent 
follow-ups as necessary.
3475-061-10 (UK-Specific Amendment)
13-SEP-2017
The timing was updated to allow for 
adequate follow-up time before the final 
analysis in order to account for a potential 
delayed 
treatment 
effect 
on 
overall 
survival.
 
 
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Document
Date of Issue
Overall Rationale
3475-061-09 (Global Amendment)
25-AUG-2017
The timing was updated to allow for 
adequate follow-up time before the final 
analysis in order to account for a potential 
delayed 
treatment 
effect 
on 
overall 
survival.
3475-061-08 (UK-Specific Amendment)
29-AUG-2016
The 
revisions 
were 
based 
on 
the 
recommendations from the external Data 
Monitoring Committee to no longer enroll 
PD-L1 negative participants as of 20-
MAR-2016.
3475-061-07 (Global Amendment)
18-AUG-2016
The 
revisions 
were 
based 
on 
the 
recommendations from the external Data 
Monitoring Committee to no longer enroll 
PD-L1 negative participants as of 20-
MAR-2016.
3475-061-06 (UK-Specific Amendment)
21-DEC-2015
Due to the higher than anticipated 
prevalence rate for PD-L1+ patients, the 
interim futility analysis for PD-L1patientsis 
no longer necessary.
3475-061-05 (Global Amendment)
23-NOV-2015
Due to the higher
than anticipated 
prevalence rate for PD-L1+ patients, the 
interim futility analysis for PD-L1patientsis 
no longer necessary.
 
 
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Document
Date of Issue
Overall Rationale
3475-061-04 (UK-Specific Amendment)
10-JUN-2015
Enable to better monitor disease response 
and progression based on evolving gastric 
cancer studies. Additionally, increasing the 
imaging interval after median progression 
may artificially lengthen the progression 
time in a substantial number of patients.
Disease stratification factors (time to 
progression on first-line therapy and PD-L1 
expression 
status) 
may 
help 
predict 
response in second-line gastric cancer 
treatment and consequently overall survival 
in gastric cancer patients.
3475-061-03 (UK-Specific Amendment)
01-MAY-2015 
To 
align 
with 
country-specific 
local 
regulations regarding pregnancy testing in 
UK.
3475-061-02 (Global Amendment)
05-MAY-2015
Enable to better monitor disease response 
and progression based on evolving gastric 
cancer studies. Additionally, increasing the 
imaging interval after median progression 
may artificially lengthen the progression 
time in a substantial number of patients.
Disease stratification factors (time to 
progression on first-line therapy and PD-L1 
expression 
status) 
may 
help 
predict 
response in second-line gastric cancer 
treatment and consequently overall survival 
in gastric cancer patients.
3475-061-00
15-JAN-2015
Original
 
 
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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: Pembrolizumab 
Extension Study.
5.10
Beginning and End of the Trial
Added: Upon study 
completion, participants will be
discontinued and may be
enrolled in a pembrolizumab 
extension study.
 
 
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ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title(s)
Description of Change (s)
Rationale
7.1.1.8
Trial 
Compliance 
(Medication/Diet/Activity/Other)
Changed the word “witnessed” 
to “monitored”
To describe appropriately the 
work 
being 
done 
by 
the 
investigator and/or trial staff.
7.1.2.6.3 (Added)
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 iCRO 
for quality control, storage, and 
possible retrospective review.
To 
clarify 
tumor 
imaging 
procedures
during 
Second 
Course Phase.
 
 
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Section Number (s)
Section Title(s)
Description of Change (s)
Rationale
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.
 
 
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Section Number (s)
Section Title(s)
Description of Change (s)
Rationale
7.1.2.6.4
Assessment of Disease
Originally Section 7.1.2.6.3 but 
moved to 7.1.2.6.4. Therefore, 
all references to Assessment of 
Disease 
was 
updated 
to 
7.1.2.6.4.
Due to the addition of Second 
Course (Retreatment) Tumor 
Imaging (Section 7.1.2.6.3), 
Assessment of Disease was 
moved to Section 7.1.2.6.4.
6.3
Second 
Course 
Phase 
(Retreatment 
with 
Pembrolizumab)
Footnote
m: 
Added 
“See 
Section 7.1.2.6.3.”
4.2.3.4
Future Biomedical Research
Statement updated to: The 
details 
of 
this
Future 
Biomedical Research sub-trial
are presented in Section 12.2.
Due to EU CTR changes that 
will require FBR results to be 
reported if FBR is indicated as 
a sub-study to the clinical 
protocol.
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.
 
 
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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.
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 
returned to the sponsor or 
destroyed and documentation 
of destruction will be reported 
to Merck.
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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1.0 TRIAL SUMMARY
Abbreviated Title
Pembrolizumab (MK-3475) vs Paclitaxel in 2L Participants 
with Advanced Gastric Adenocarcinoma
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 up to 720 subjects will be enrolled.
Estimated duration of trial The sponsor 
estimates that the trial will 
require 
approximately 36 months from the time the first subject 
signs the informed consent until the last subject’s last visit.
Duration of Participation
Each participant will participate in the trial from the time the 
participant signs the informed consent form (ICF) through 
the final contact. After a screening phase of up to 28 days, 
eligible participants 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) (AEs), intercurrent illness that prevents further 
administration of treatment, investigator’s decision to 
withdraw the participant, participant withdraws consent, 
pregnancy of the participant, noncompliance with trial 
treatment or procedure requirements, participant receives 
35 administrations 
(approximately 
2 
years) 
of 
pembrolizumab, 
or 
administrative 
reasons 
requiring 
cessation of treatment. After the end of treatment, each 
participant will be followed for 30 days for AE monitoring 
(serious adverse events and events of clinical interest will be 
collected for 90 days after the end of treatment or 30 days 
after the end of treatment if the participant initiates new 
anticancer therapy, whichever is earlier).
 
 
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Participants 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 complete response may be 
eligible for up to one year of retreatment after they have 
experienced radiographic disease progression.
Participants 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 participants will be followed by telephone for overall 
survival until death, withdrawal of consent, or the end of the 
study.
Once the participant has achieved the study objective or the 
study has ended, the participant is discontinued from the 
study and may be enrolled in an extension study to continue 
protocol-defined assessments and treatment.
Randomization Ratio
1:1
A list of abbreviations used in this document can be found in Section 12.6.
 
 
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2.0 TRIAL DESIGN
Trial Design
This is a randomized, multicenter, open-label trial of pembrolizumab (MK-3475) versus 
paclitaxel in participants with advanced gastric or GEJ adenocarcinoma who have progressed 
after failure of any combination chemotherapy containing a platinum and a fluoropyrimidine
agent.  
In this trial, up to approximately 720 participants will be randomized to compare the efficacy 
and safety of pembrolizumab versus paclitaxel. Participants will be randomized in a 1:1 ratio 
to receive pembrolizumab or paclitaxel and stratified by geographic region, time to 
progression on first-line therapy, and programmed cell death ligand 1 (PD-L1) expression 
status.  
Based on recommendations from an external Data Monitoring Committee, PD-L1 negative 
participants are no longer eligible for enrollment into the study as of 20-MAR-2016; 
however, all participants enrolled prior to 20-MAR-2016 may continue on the study 
regardless of PD-L1 status.  Therefore, as of 20-MAR-2016, enrollment will only include
those participants with PD-L1 positive expressions on their tumor. This enrollment change 
does not impact the Statistical Analysis Plan. Enrollment was completed on 27-JUL-2016.
Participants will be required to provide tissue of a tumor lesion to be evaluated at a central 
laboratory for expression status of PD-L1. An evaluable specimen for PD-L1 status must be 
available and confirmed prior to enrollment. As of 20-MAR-2016, a PD-L1 positive result 
must be confirmed prior to enrollment.
The overall study enrollment will be driven by the number of participants with PD-L1 
positive expression on their tumor (n = 360). That is, enrollment will stop when
approximately 360 participants with PD-L1 positive expression on their tumor have been 
randomized. Additionally, there will be a cap on enrollment (approximately 30% of total) for 
randomized participants residing in the Asia Pacific region for this study.  
All study participants 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 progression free survival (PFS) and overall survival (OS). 
The primary PFS analysis will be based on Response Evaluation Criteria In Solid Tumors 
Version 1.1 (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 has been modified as described in 
Section 7.1.2.6.4.1 to allow for continued treatment and a repeat confirmatory scan in 
participants with initial evidence of progressive disease (PD) by standard RECIST 1.1 
(hereafter referred to as immune-related RECIST [irRECIST]). If a participant has 
progression of disease by RECIST 1.1, it is recommended that the participant be 
discontinued from the study treatment unless, in the investigator’s opinion, the participant is 
deriving benefit from treatment. Clinically stable participants, as defined in Section 
7.1.2.6.4.1, may continue to receive trial therapy at the discretion of the investigator. If a 
 
 
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repeat scan confirms progression of disease and the participant remains clinically stable, the 
participant may continue treatment after consultation with the Sponsor.
AEs will be monitored throughout the trial and graded in severity according to the guidelines 
outlined in the National Cancer Institute’s (NCI) Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.0.  
Except as noted above, treatment with pembrolizumab or paclitaxel will continue until 
documented disease progression, unacceptable AEs, intercurrent illness that prevents further 
administration of treatment, investigator’s decision to withdraw the participant, participant
withdraws consent, pregnancy of the participant, noncompliance with trial treatment or 
procedure requirements, completion of 35 administrations (approximately 2 years) of 
pembrolizumab, or administrative reasons requiring the cessation of treatment. 
Participants 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. Participants 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 re-treat will be at the discretion of the investigator only if no cancer treatment was 
administered since the last dose of pembrolizumab, the participant 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). Participants within the paclitaxel arm will continue on 
treatment until disease progression or unacceptable toxicity. A crossover of treatment groups 
after documented disease progression on the study treatment will not be allowed. 
After the end of treatment, each participant will be followed for 30 days for AE monitoring 
(serious adverse events [SAEs] and events of clinical interest [ECIs] will be collected for 
90 days after the end of treatment or 30 days after the end of treatment if the participant
initiates new anticancer therapy, whichever is earlier). Participants 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 participants will be followed by telephone contact for OS
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 adaptive design based on pre-specified criteria, using 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 is one planned interim analysis
(IA). 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
 
 
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3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
Primary Objective(s) & Hypothesis(es)
(1) Objective:  To evaluate PFS per RECIST 1.1 by blinded central radiologists’ review of
participants with PD-L1 positive expression with advanced
gastric or GEJ
adenocarcinoma who have progressed on one previous line of therapy, when treated with 
pembrolizumab compared to paclitaxel. 
Hypothesis: Pembrolizumab prolongs PFS per RECIST 1.1 by blinded central 
radiologists’ review of participants with PD-L1 positive expression (with advanced
gastric or GEJ adenocarcinoma who have progressed on 1 previous line of therapy), 
compared to paclitaxel. 
(2) Objective:  To evaluate OS of participants with PD-L1 positive expression with 
advanced gastric or GEJ adenocarcinoma who have progressed on one previous line of 
therapy, when treated with pembrolizumab compared to paclitaxel. 
Hypothesis:  Pembrolizumab prolongs OS of participants with PD-L1 positive 
expression (with advanced gastric or GEJ adenocarcinoma who have progressed on 1 
previous line of therapy), compared to paclitaxel.  
The study is considered to have met its primary objective in the primary population of 
participants with positive PD-L1 expression if pembrolizumab is superior to paclitaxel either 
in PFS or in OS at IA or the final analysis (FA).
Secondary Objective(s) & Hypothesis(es)
If either endpoint (PFS or OS) is successful in the participants with positive PD-L1 
expression, the trial is successful for that endpoint in the all participants if pembrolizumab is 
superior to paclitaxel in the all participants. 
(1) Objective: To evaluate PFS per RECIST 1.1 by blinded central radiologists’ review of 
all participants with advanced gastric or GEJ adenocarcinoma who have progressed on 1 
previous line of therapy, when treated with pembrolizumab compared to paclitaxel. 
Hypothesis: 
Pembrolizumab prolongs PFS per RECIST 1.1 by blinded central 
radiologists’ review of all participants (with advanced gastric or GEJ adenocarcinoma 
who have progressed on one previous line of therapy), compared to paclitaxel. 
(2) Objective:  To evaluate OS of all participants with advanced gastric or GEJ
adenocarcinoma who have progressed on one previous line of therapy, when treated with 
pembrolizumab compared to paclitaxel.
Hypothesis: Pembrolizumab prolongs OS of all participants (with advanced gastric or 
GEJ adenocarcinoma) who have progressed on one previous line of therapy), compared 
to paclitaxel.  
(3) Objective: To evaluate PFS per RECIST 1.1 by investigator assessment and PFS per 
irRECIST by blinded central radiologists’ review, among participants with PD-L1 
positive expression and all participants, when treated with pembrolizumab compared to
paclitaxel.
 
 
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(4) Objective: To evaluate the Time to Progression (TTP), Overall Response Rate (ORR), 
and Duration of Response (DOR), per RECIST 1.1 by blinded central radiologists’ 
review and per RECIST 1.1 by investigator assessment among participants with PD-L1 
positive expression and all participants, when treated with pembrolizumab compared to
paclitaxel. 
(5) Objective: Evaluate the safety and tolerability profile of pembrolizumab in participants 
with PD-L1 positive expression and all participants compared to paclitaxel.
Exploratory Objectives 
(1) Objective:  To evaluate score change of health-related quality-of-life (HRQoL) using the 
European Organisation for Research and Treatment of Cancer (EORTC) Quality-of-Life 
Questionnaire (QLQ)-Core Questionnaire (C30) and the EORTC QLQ-Gastic Cancer 
Module (STO22) from baseline among participants when treated with pembrolizumab 
compared to paclitaxel.  
(2) Objective: To characterize utilities using European Quality-of-Life Scale 5 Dimension 
(EuroQol EQ-5D) among participants when treated with pembrolizumab compared to 
paclitaxel.
(3) Objective: To explore the relationship between genetic variation and response to the 
treatment(s) administered. Genomic variability may 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.
Pharmaceutical and Therapeutic Background
Anti-PD-1 Blockage for Malignancy
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades [1]. Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies [2] [3] [4] [5] [6]. In particular, the presence of 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), which has been shown to negatively regulate antigen receptor signaling 
upon engagement of its ligands (PD-L1 and/or programmed cell death ligand 2 [PD-L2]) [7] 
[8]. The structure of murine PD-1 has been resolved [9]. PD-1 and family members are type I 
 
 
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transmembrane glycoproteins containing an immunoglobulin Variable-type (IgV) 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 [7] [10] [11] [12]. The mechanism by which 
PD-1 down modulates T-cell responses is similar to, but distinct from that of CTLA-4, as 
both molecules regulate an overlapping set of signaling proteins [13] [14]. 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 [15] [16]. Expression has also been shown during 
thymic development on CD4-CD8- (double negative) T-cells, as well as subsets of 
macrophages and dendritic cells [17]. 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 [18] [19] [20] [13]. Both ligands are type-
I transmembrane receptors containing both IgV- and immunoglobulin constant (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 [13]. 
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 [21].  
In gastric cancer PD-L1 and PD-L2 overexpression have recently been associated with 
Epstein-Barr virus-positive tumors [22]. 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 (US) for the treatment of patients with unresectable or metastatic 
melanoma and disease progression following ipilimumab 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 monotherapy or in combination with other treatment 
modalities. Anti-mouse PD-1 or anti-mouse PD-L1 antibodies have demonstrated antitumor
 
 
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responses as a monotherapy in models of squamous cell carcinoma, pancreatic carcinoma, 
melanoma and colorectal carcinoma. Blockade of the PD-1 pathway effectively promoted 
CD8+ T-cell infiltration into the tumor and the presence of interferon-, granzyme B, and 
perforin, indicating that the mechanism of action involved local infiltration and activation of 
effector T-cell function in vivo [23] [24] [25] [26] [27] [28]. Experiments have confirmed the 
in vivo efficacy of PD-1 blockade as a monotherapy as well as in combination with 
chemotherapy in syngeneic mouse tumor models (see the IB).
Clinical trials have demonstrated efficacy in participants 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, non-small cell lung 
cancer, 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 are available from a cohort of gastric adenocarcinoma participants
studied in trial KEYNOTE 012 (KN012) [29]. Thirty-nine participants (19 from clinical trial 
sites in Asia and 20 from trial sites outside Asia) who had metastatic gastric or GEJ
adenocarcinoma, Eastern Cooperative Oncology Group (ECOG) performance status (PS) 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 (Q2W). The number of prior systemic 
treatments for metastatic disease ranged from zero to greater than 4. The primary efficacy 
endpoint was ORR. Overall, the interim ORR is 30.8% (95% confidence interval [CI] 17.0%, 
47.6%; all partial responses [PRs]), while the interim disease control rate (DCR) is 43.6% 
(95% CI 27.8%, 60.4%). ORR was similar in participants 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, participants had less prior therapy 
relative to the Asian participants, and that ORR in later line participants (≥3L) was higher in 
the Asian group (1 PR/7 participants in the non-Asia group, 4 PR/13 participants 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 participants 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 participants in KN012, single-agent pembrolizumab at 10 mg/kg Q2W
was generally well tolerated, with the type, severity, and frequency of AEs similar to that 
observed in other indications (see the IB for information about AEs in other indications). 
There was 1 death reported in the gastric cancer cohort. This was a participant who had AEs
of tracheomalacia (Grade 3) and hypoxia (Grade 5). The investigator considered the Grade 5 
hypoxia related to the study treatment.
 
 
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Rationale
Rationale for the Trial and Selected Subject Population
Trials evaluating pembrolizumab in gastric cancer have demonstrated clinical activity in 
participants with metastatic disease. Refer to Section 4.1.3, Ongoing Clinical Trials, for
results from the Phase Ib study of pembrolizumab in participants with gastric cancer
(KN012). This study is designed to investigate if pembrolizumab monotherapy in second-line 
gastric cancer participants improves PFS and OS.   
The gastric cancer proof-of-concept from KN012 data was obtained in participants with a 
PD-L1 positive expression only; no data are currently available regarding the performance of 
pembrolizumab in participants without a detectable PD-L1 expression. Due to the limited 
treatment opinions currently available, second-line participants without a detectable PD-L1 
expression may benefit from pembrolizumab.  
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 Q2W
•
Clinical data showing meaningful improvement in benefit-risk including OS at 200 
mg Q3W across multiple indications
•
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 participants 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 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 
 
 
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saturation of PD-1 in systemic circulation at doses much lower than 200 mg Q3W. Secondly, 
a physiologically based PK 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 participant covariates on exposure, has shown that the fixed dosing 
provides similar control of PK variability as weight-based dosing, with considerable overlap 
in the distribution of exposures from the 200 mg Q3W fixed dose and 2 mg/kg Q3W dose. 
Supported by these PK characteristics and given that the fixed dose has advantages of 
reduced dosing complexity and reduced potential of dosing errors, the 200 mg Q3W fixed
dose was selected for evaluation across all pembrolizumab protocols.
Rationale for Paclitaxel as the Comparator
The use of paclitaxel at a dose of 80 mg/m2 intravenously (IV) 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 [30].
Ramucirumab, an anti-vascular endothelial growth factor receptor 2 antibody, was approved 
by the US Food and Drug Administration (FDA) as monotherapy for second-line gastric 
cancer in April 2014, based on the results from the REGARD study [31]. The REGARD 
study was a Phase 3 study comparing ramucirumab monotherapy (8 mg/kg IV infusion on 
Days 1 and 15 every 4 weeks), versus best supportive care (BSC) in participants refractory to 
previous fluoropyrimidine treatment (with or without platinum). Ramucirumab significantly 
improved OS (5.2 month [mo] vs 3.8 mo with BSC, hazard ratio [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 [30].
RAINBOW was a Phase III study testing paclitaxel (80 mg/kg on Days 1, 8, and 15, of a 
28-day cycle) with or without ramucirumab (8 mg/kg IV infusion on Days 1 and 15 of a 
28-day cycle) in participants with metastatic gastric cancer refractory or progressive after 
first-line therapy with a platinum and a fluoropyrimidine. Median OS 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 PFS was 4.4 months and 2.9 months, respectively, 
with a HR of 0.635 (P < 0.0001). AEs of Grade ≥3 were somewhat greater with combination 
treatment vs paclitaxel alone and respectively, included incidences of 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.
 
 
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Rationale for Endpoints
Efficacy Endpoints
This trial will use PFS and OS 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 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 CR assessment 
of immunotherapeutic agents such as pembrolizumab. Therefore, RECIST 1.1 will be used 
with the following adaptation, outlined in Section 7.1.2.6.4.1, termed irRECIST.
When feasible, participants 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 participants can have a transient 
tumor flare in the first few months after the start of immunotherapy, but with subsequent 
disease response.
Safety Endpoints
The primary safety objective of this trial is to characterize the safety and tolerability of 
pembrolizumab in participants with metastatic gastric cancer. The primary safety analysis 
will be based on participants who experienced toxicities as defined by CTCAE criteria. 
Safety will be assessed by quantifying the toxicities and grades experienced by participants 
who have received pembrolizumab compared to paclitaxel including SAEs and ECIs.
Safety will be assessed by reported AEs using CTCAE, Version 4.0. The attribution to drug, 
time-of-onset, duration of the event, its resolution, and any concomitant medications 
administered will be recorded. Adverse events will be analyzed including but not limited to 
all AEs, SAEs, fatal AEs, and laboratory changes. Furthermore, specific immune-related AEs
(irAEs) will be collected and designated as immune-related ECIs as described in Section 
7.2.3.2.
 
 
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Exploratory Endpoints
4.2.3.3.1 Patient Reported Outcomes
As part of the exploratory analyses, participants will provide information regarding their 
HRQoL via the following assessment tools:  EORTC QLQ-C30 and QLQ-STO22, electronic
(eEQ-5D) questionnaires. Additionally, the Health Economic Assessment (HEA) form will 
also be collected. These measures are not pure efficacy or safety endpoints because they are 
affected by both disease progression and treatment tolerability.
eEORTC QLQ-C30 and eEORTC QLQ-STO22
The EORTC-QLQC30 is the most widely used cancer-specific HRQoL instrument, which 
contains 30 items and measures, 5 functioning dimensions (physical, role, cognitive, 
emotional, and social), 3 symptom items (fatigue, nausea/vomiting, pain), 6 single items 
(dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, and financial impact), and a 
global health and quality-of-life scale [32]. This instrument has been translated and validated 
into 81 languages and used in more than 3000 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 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 (4 items), pain or 
discomfort (3 items), upper gastrointestinal (GI) symptoms (3 items), eating restrictions 
(5 items), emotional (3 items), dry mouth, hair loss, and body image.
The EORTC QLQ-C30 and EORTC QLQ-STO22 are to be completed at various time points 
as specified in the Trial Flow Chart, beginning with Cycle 1 until 30 days post-treatment 
discontinuation.
eEQ-5D 
The eEQ-5D is a standardized instrument for use as a measure of health outcome. The eEQ-
5D will provide data for use in economic models and analyses including developing health 
utilities or quality adjusted life years. The 5 health state dimensions in this instrument include 
the following: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression 
[33]. Each dimension is rated on a three-point scale from 1 (extreme problem) to 3 (no 
problem). The eEQ-5D also includes a graded (0 to 100) vertical visual analog scale on 
which the participant rates his or her general state of health at the time of the assessment. The 
eEQ-5D will always be completed by participants 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. 
Health Economic Assessment
The HEA form will be completed via an interview with the participant by trained study site 
personnel. The objective of the HEA form is for the site personnel to collect information 
from participants on all the non-study related health care contacts made throughout the study. 
The form captures non-study related healthcare visits, including healthcare provider visits, 
emergency room visits, and hospitalizations (including admission and discharge dates and 
 
 
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primary discharge diagnosis). The HEA is to be completed at various time points as specified 
in the Trial Flow Chart, beginning with Cycle 2 until 30 days post-treatment discontinuation.
4.2.3.3.2 Exploratory Biomarkers
Understanding genetic determinants of drug response is an important endeavor during 
medical research. This research will evaluate whether genetic variation within a clinical trial 
population correlates with response to the treatment(s) under evaluation. If genetic variation 
is found to predict efficacy or AEs, the data might inform future optimal use of therapies in 
the patient population. This research contributes to understanding genetic determinants of 
efficacy and safety associated with the treatments in this study.
Assays may include but are not be limited to:
Transcriptional Analyses
Messenger ribonucleic acid (RNA) expression profiling in archival material will be 
completed to assess expression of approximately 700 genes and attempt to define a gene set 
critical for clinical response to pembrolizumab (MK-3475). The hypothesis to be tested is 
that pembrolizumab (MK-3475) induces responses in tumors that reflect an inflamed/ 
immune phenotype based on gene expression signatures capturing PD-L1 and interferon-
gamma transcriptional programs. Global profiling will also be pursued. Expression of 
individual genes related to the immune system may also be evaluated such as immune 
signatures and critical cytokines (e.g., interleukin-10). MicroRNA profiling may also be 
pursued in serum samples.
Proteomic Analysis
In addition to expression on the tumor tissue, PD-L1 can be shed from tumor and released 
into the blood. Enzyme-linked immunoassay can measure PD-L1 in serum and correlate this 
expression with response to pembrolizumab (MK-3475) therapy, as well as levels of PD-L1
immunohistochemistry or protein in the tumor. Blood would be a less invasive compartment 
compared to tumor from which to measure PD-L1 protein biomarker. In addition to this 
specific protein biomarker, both tissue and blood derivatives can be subjected to proteomic 
profiling studies using a variety of platforms that could include but are not limited to 
immunoassay, liquid chromatography/mass spectrometry. This approach could identify novel 
protein biomarkers that could aid in participant selection for pembrolizumab (MK-3475) 
therapy.
Gene Analyses
Additional biomarker research to identify factors important for pembrolizumab (MK-3475) 
therapy may also be pursued. For example, tumor and blood samples (including serum and 
plasma) from this study may undergo proteomic, genomic, metabolomic, and transcriptional 
analyses. Additional research may evaluate factors important for predicting responsiveness or 
resistance to pembrolizumab therapy and other immunologic targets.
Microsatellite Instability 
Next generation sequencing of tumor deoxyribonucleic acid (DNA) has revealed certain 
tumors to be ‘hypermutated’. There is a potential that the hypermutated state may correlate 
with response to immunotherapy such as pembrolizumab (MK-3475) as ‘hypermutated’ cells 
 
 
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are assumed to be more immunogenic. Hypermutation in some cancers is driven by a 
defective DNA mismatch repair (MMR) process as a consequence of germline genetic 
defects in one of the MMR genes. MMR defects lead to microsatellite instability (MSI); the 
frequent deletion and insertion in arrays loci containing very short direct repeat sequences 
(microsatellites). Internal data from KN016 colorectal cancer trial has demonstrated 
exquisitely a selective response to pembrolizumab in those tumors that are MSI-high as 
detected by polymerase chain reaction and subsequent capillary electrophoresis. The 
hypothesis to be tested is that pembrolizumab induces responses in gastric tumors that have a 
high degree of MSI. DNA from tumors will be compared with that isolated from 
corresponding patient whole blood (representing normal DNA) or from adjacent normal 
tissue if blood sample is not available.
Other exploratory biomarkers (e.g., PD-1 expression, markers of T-cell phenotype) may also 
be evaluated.
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 collected for future 
biomedical research during this clinical trial.  This research may include genetic analyses 
(DNA), gene expression profiling (RNA), proteomics, metabolomics (serum, plasma) and/or 
the measurement of other analytes.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main trial) and will only be conducted on specimens from 
appropriately consented subjects. The objective of collecting specimens for Future 
Biomedical Research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. For instance, exploratory 
pharmacogenetic 
(PGt) 
studies 
may 
be 
performed 
if 
significant 
Pharmacokinetic/Pharmacodynamic (PK/PD) relationships are observed or adverse events 
are identified.  Genomic markers of disease may also be investigated.  Such retrospective 
pharmacogenetic studies will be conducted with appropriate biostatistical design and analysis 
and compared to PK/PD results or clinical outcomes. Any significant PGt relationships to 
outcome would require validation in future clinical trials. The overarching goal is to use such 
information to develop safer, more effective drugs/vaccines, and/or to ensure that subjects 
receive the correct dose of the correct drug/vaccine at the correct time.  The details of Future 
Biomedical Research are presented in Section 12.2 - Collection and Management of 
Specimens for Future Biomedical Research.  Additional informational material for 
institutional review boards/ethics committees (IRBs/ERCs) and investigational site staff is 
provided in Section 12.3.
Benefit/Risk
Participants 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 participants participating in this 
clinical trial may be found in the accompanying IB and informed consent documents.
5.0 METHODOLOGY
Entry Criteria
Diagnosis/Condition for Entry into the Trial
Male/Female 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 
participant may also provide consent for Future Biomedical Research. However, the 
participant 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 the 
investigator. Tumor lesions situated in a previously irradiated area are considered 
measurable if progression has been demonstrated in such lesions. 
a.
Note:  The exact same image acquisition and processing parameters should be 
used throughout the study.
6. Have a PS of 0 or 1 on the ECOG Performance Scale.
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 participant needs to have the 
documentation of disease progression on first-line treatment. The disease 
progression can be confirmed by computed tomography (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 participant 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 participant 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, participants 
with discontinuation due to AEs 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, received permission for 
enrollment 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. Participants for whom newly-
obtained endoscopic samples cannot be provided (e.g., inaccessible or 
participant safety concern) may submit an archived specimen.
b. 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 participant will not be 
precluded from participating in the study if an archived tissue sample is not 
available for collection or is otherwise insufficient for analysis.
c.
As of 20-MAR-2016, participants must be PD-L1 positive to be enrolled. 
9. Participants with human epidermal growth factor receptor 2 (HER-2/neu) negative
tumors are eligible.  For participants with HER2/neu positive tumors or have an 
unknown tumor status, need to match the following:
a.
If HER2/neu positive, participant must have documentation of disease 
progression on treatment containing trastuzumab.
b. Participants with unknown status must have their HER2/neu status determined 
locally. If HER2/neu-negative, the participant
will be eligible. If 
HER2/neu-positive, the participant must have documentation of disease 
progression on treatment containing trastuzumab.
10. Female participants 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 (Reference Section 5.7.2). Participants of childbearing potential are 
those who have not been surgically sterilized or have not been free from menses for 
>1 year.  
 
 
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Male participants 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.
11. Demonstrate adequate organ function as defined in Table 1. All screening labs 
should be performed within 10 days of treatment initiation.
Table 1
Adequate Organ Function 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 participant 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 participants with total 
bilirubin levels >1.5 ULN
AST (SGOT) and ALT (SGPT)
≤ 2.5 X ULN OR
≤ 5 X ULN for participants 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 
participant
is 
receiving 
anticoagulant therapy as long as PT or PTT is within 
therapeutic range of intended use of anticoagulants
≤1.5 X 
ULN 
unless 
participant
is 
receiving 
anticoagulant therapy
as long as PT or PTT is within therapeutic range of 
intended use of anticoagulants
12. Female participants of childbearing potential should have a negative urine or serum 
pregnancy test within 72 hours prior to receiving the first dose of study medication. If 
the urine test is positive or cannot be confirmed as negative, a serum pregnancy test 
will be required.
 
 
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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 therapy for adrenal or pituitary insufficiency) 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 anticancer mAb within 4 weeks prior to study Day 1 or who has not 
recovered (i.e., ≤Grade 1 or at baseline) from AEs due to agents administered more 
than 4 weeks earlier.
6. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy 
within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤Grade 1 or at 
baseline) from AEs due to a previously administered agent.
Note:  Participants with ≤Grade 2 neuropathy or ≤Grade 2 alopecia are an exception 
to this criterion and may qualify for the study.
a. If participant 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 requires active treatment. 
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.
8. Has known active central
nervous system metastases and/or carcinomatous 
meningitis. Participants with previously treated brain metastases may participate 
provided they are stable (without evidence of progression by imaging for at least 
4 weeks prior to the first dose of trial treatment and any neurologic symptoms have 
returned to baseline), have no evidence of new or enlarging brain metastases, and are 
not using steroids for at least 7 days prior to trial treatment. This exception does not 
include carcinomatous meningitis which is excluded regardless of clinical stability.
9. Has a history of (noninfectious) pneumonitis that required steroids or current 
pneumonitis.
10. Has an active infection requiring systemic therapy.
 
 
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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 participant’s 
participation for the full duration of the trial, or is not in the best interest of the 
participant to participate, in the opinion of the treating investigator.
12. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial.
13. Is pregnant, or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the screening visit through 120 days after 
the last dose of 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 immunotherapy including anti-PD-1, anti-PD-L1, or anti-PD-L2 
agent, or if the participant has previously participated in Merck pembrolizumab 
(MK-3475) clinical trials.
15. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
16. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C.
17. Has received a live vaccine within 30 days of planned start of study therapy.
Note:  Seasonal influenza vaccines for injection are generally inactivated flu vaccines 
and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live 
attenuated vaccines, and are not allowed.
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
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 for Cycle 1 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.
 
 
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For any commercially available product that is provided by the trial site, subsidiary or 
designee every attempt will be made to source these supplies from a single lot/batch number. 
The trial site will be responsible for recording the lot number, manufacturer and expiry date 
of any locally purchased product.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of trial 
treatments in accordance with the protocol and any applicable laws and regulations.
Dose Selection/Modification
Dose Selection (Preparation)
The rationale for selection of doses to be used in this trial is provided in Section 4.0 –
Background & Rationale. Details on preparation and administration of pembrolizumab 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 for Pembrolizumab
Dose modification and toxicity management for immune-related AEs associated with 
pembrolizumab
AEs associated with pembrolizumab exposure may represent an immunologic etiology. 
These 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 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 1-2mg/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 1-2mg/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- 1mg/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 1-2mg/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 
liothyroinine) 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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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, participant
vacation, and/or holidays). Participants 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 participant’s study record.  
In case toxicity does not resolve to Grade 0-1 within 12 weeks after the last infusion, trial
treatment should be discontinued after consultation with the Sponsor. With investigator and
Sponsor agreement, participants with a laboratory AE still at Grade 2 after 12 weeks may 
continue in the trial only if asymptomatic and controlled.
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 4), 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 
medication guidelines may be approved after being discussed with a medically qualified 
Sponsor representative.  
Table 4
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 5), the 
investigator should institute treatment measures according to the best available medical 
practice.
 
 
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Table 5
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 IV
and 
dexamethasone 
8-20 
mg 
IV
(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 IV
diphenhydramine and dexamethasone (per 
institutional
guidelines). 
Add 
epinephrine 
or 
bronchodilators if indicated. The participant should be 
removed from paclitaxel treatment.
At 
first 
occurrence
In addition, investigators may withdraw a participant from paclitaxel therapy for any of the 
following reasons:

An unacceptable AE/toxicity (e.g., a persistent moderate toxicity that is intolerable to the 
participant) and is, in the opinion of the investigator, clearly attributed to paclitaxel 

Any event which would warrant paclitaxel therapy to be modified by more than 2 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, participant
vacation, and/or holidays). Participants 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 participant’s study record.
Timing of Dose Administration
All trial treatments may be administered on an outpatient basis.
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 participant 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 recalculated to 
account for the weekly dosing visits.
Pembrolizumab
Pembrolizumab should be administered on Day 1 of each three-week cycle 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.
 
 
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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 4-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 participant’s baseline BSA. Subsequent doses of paclitaxel must be 
recalculated if there is a ≥10% change (increase or decrease) in BSA from baseline; 
subsequent doses may be recalculated if there is a <10% change (increase or decrease) in 
BSA 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 orally (PO) 12 and 6 hours or 
(IV)
30-60 minutes before paclitaxel), an antihistamine (H1 antagonist) such as 
diphenhydramine hydrochloride 50 mg IV (or equivalent), cimetidine (H2 antagonist) 
300 mg IV or equivalent, and an antiemetic (such as ondansetron 8 mg dose PO or 
0.15 mg/kg IV 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 (CRF).  
Trial Blinding/Masking
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.
See Section 7.1.4.2, Blinding/Unblinding, for a description of the method of unblinding a 
participant during the trial, should such action be warranted.
Randomization or Treatment Allocation
Randomization will occur centrally using an interactive voice response system / integrated 
web response system (IVRS/IWRS). There are 2 treatment arms.  Subjects will be assigned 
randomly in a 1:1 ratio to pembrolizumab or paclitaxel.
Stratification
Randomization will be stratified according to the following factors:
1. Geographic region (Europe/Israel/North America/Australia vs. Asia (including Japan, 
Korea, Hong Kong, Taiwan, Malaysia, Philippines, Singapore) vs. Rest of World 
(including South America)
 
 
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2. TTP on first-line therapy (<6 months vs. ≥6 months)
3.
PD-L1 expression status (positive vs. negative)
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 participant’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care. All concomitant medication will be recorded on the CRF including all 
prescription, over-the-counter (OTC), 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.
All concomitant medications received within 28 days before the first dose of trial treatment 
and 30 days after the last dose of trial treatment should be recorded. Concomitant 
medications administered after 90 days after the last dose of trial treatment should be 
recorded for SAEs and ECIs as defined in Section 7.2.
Prohibited Concomitant Medication
Participants are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-CR 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, bacille
Calmette-Guerin, 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., Flu - Mist®) are not allowed.
 
 
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
Pembrolizumab arm only: Systemic glucocorticoids for any purpose other than to 
modulate symptoms from an ECI of suspected 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).
Participants 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. 
Participants 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, premedication with 
steroids is acceptable.
Rescue Medications & Supportive Care
Supportive Care Guidelines 
Participants 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 below. 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 the event is determined not to be related, 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.

Pneumonitis: 
o
For Grade 2 events, treat with systemic corticosteroids. When symptoms 
improve to Grade 1 or less, steroid taper should be started and continued over 
no less than 4 weeks.
o
For Grade 3-4 events, immediately treat with IV steroids. Administer 
additional anti-inflammatory measures, as needed.
o
Add prophylactic antibiotics for opportunistic infections in the case of 
prolonged steroid administration.
 
 
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
Diarrhea/Colitis:
Participants should be carefully monitored for signs and symptoms of enterocolitis 
(such as diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and 
of bowel perforation (such as peritoneal signs and ileus).  
o
All participants who experience 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. For Grade 2 or 
higher diarrhea, consider GI consultation and endoscopy to confirm or rule out 
colitis.
o
For Grade 2 diarrhea/colitis that persists greater than 3 days, administer oral 
corticosteroids. 
o
For Grade 3 or 4 diarrhea/colitis that persists >1 week, treat with IV steroids 
followed by high dose oral steroids.  
o
When symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks.

Type 1 diabetes mellitus (TIDM, if new onset, including diabetic ketoacidosis 
[DKA]) or ≥Grade 3 hyperglycemia, if associated with ketosis (ketonuria) or 
metabolic acidosis (DKA):
o
For T1DM or Grade 3-4 Hyperglycemia

Insulin replacement therapy is recommended for TIDM and for Grade 
3-4 hyperglycemia associated with metabolic acidosis or ketonuria. 

Evaluate patients with serum glucose and a metabolic panel, urine 
ketones, glycosylated hemoglobin, and C-peptide. 

Hypophysitis:
o
For Grade 2 events, treat with corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 
4 weeks. Replacement of appropriate hormones may be required as the steroid 
dose is tapered.
o
For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed 
by oral corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. Replacement 
of appropriate hormones may be required as the steroid dose is tapered.

Hyperthyroidism or Hypothyroidism: 
Thyroid disorders can occur at any time during treatment. Monitor participants for 
changes in thyroid function (at the start of treatment, periodically during treatment, 
and as indicated based on clinical evaluation) and for clinical signs and symptoms of 
thyroid disorders.
 
 
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o
Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism):

In hyperthyroidism, non-selective beta-blockers (e.g., propranolol) are 
suggested as initial therapy.

In hypothyroidism, thyroid hormone replacement therapy, with 
levothyroxine or liothyroinine, is indicated per standard of care.
o
Grade 3-4 hyperthyroidism 

Treat with an initial dose of IV corticosteroid followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid 
dose is tapered.

Hepatic:
o
For Grade 2 events, monitor liver function tests more frequently until 
returned to baseline values (consider weekly).

Treat with IV or oral corticosteroids
o
For Grade 3-4 events, treat with IV corticosteroids for 24 to 48 hours. 
o
When symptoms improve to Grade 1 or less, a steroid taper should be started 
and continued over no less than 4 weeks.

Renal Failure or Nephritis:
o
For Grade 2 events, treat with corticosteroids.
o
For Grade 3-4 events, treat with systemic corticosteroids.
o
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.

Management of Infusion Reactions: Signs and symptoms usually develop during or 
shortly after drug infusion and generally resolve completely within 24 hours of 
completion of infusion. 
Table 6 below shows treatment guidelines for participants who experience an infusion 
reaction associated with administration of pembrolizumab (MK-3475).
 
 
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Table 6
Infusion Reaction Treatment Guidelines
NCI-CTCAE Grade
Treatment
Premedication at 
subsequent dosing
Grade 1
Mild 
reaction; 
infusion 
interruption 
not indicated;
intervention not indicated
Increase monitoring of vital signs as 
medically indicated until the participant is 
deemed medically stable in the opinion of 
the investigator.
None
Grade 2
Requires therapy or infusion 
interruption 
but 
responds 
promptly 
to 
symptomatic 
treatment 
(e.g., 
antihistamines, 
NSAIDS, 
narcotics, 
IV 
fluids); 
prophylactic 
medications 
indicated for ≤24 hrs
Stop Infusion and monitor symptoms.
Additional appropriate medical therapy may 
include but is not limited to:
IV fluids
Antihistamines
NSAIDS
Acetaminophen
Narcotics
Increase monitoring of vital signs as 
medically indicated until the participant is 
deemed medically stable in the opinion of 
the investigator.
If symptoms resolve within one hour of 
stopping drug infusion, the infusion may be 
restarted at 50% of the original infusion rate 
(e.g., from 100 mL/hr to 50 mL/hr).  
Otherwise dosing will be held until 
symptoms resolve and the participant
should be premedicated for the next 
scheduled dose.
Participants 
who 
develop 
Grade 
2 
toxicity despite adequate premedication 
should be permanently discontinued 
from 
further 
trial 
treatment 
administration.
Participant may be 
premedicated 1.5h (± 30 
minutes) prior to 
infusion of 
pembrolizumab 
(MK-3475) with:
Diphenhydramine 50 mg 
PO (or equivalent dose 
of antihistamine).
Acetaminophen 
500-
1000 
mg 
PO
(or 
equivalent 
dose 
of 
antipyretic).
Grades 3 or 4
Grade 3:
Prolonged (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:
IV fluids
Antihistamines
NSAIDS
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Epinephrine
Increase monitoring of vital signs as 
medically indicated until the participant is 
deemed medically stable in the opinion of 
the investigator.
Hospitalization may be indicated.
Participant is permanently discontinued 
from 
further 
trial 
treatment 
administration.
No subsequent dosing
Appropriate resuscitation equipment should be available in the room and a physician readily available during the 
period of drug administration.
 
 
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Supportive Care Guidelines for Paclitaxel
Palliative and supportive care for other disease-related symptoms and for toxicity associated 
with treatment will be offered to participants within the paclitaxel arm of this trial. 
Supportive care measures may include, but are not limited to, antidiarrheal agents, antiemetic 
agents, opiate and non-opiate 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 electronic case report form (eCRF). 
Appropriate management of hypersensitivity reactions is described in Section 5.2.1.2.2 and 
Table 5. The use of other specific supportive care agents is presented below.
Diarrhea: In the event of Grade 3 or 4 diarrhea, supportive measures may include hydration, 
loperamide, octreotide, and antidiarrheals. If diarrhea is severe (i.e., requires IV hydration) 
and associated with fever or severe (Grade 3 or 4) neutropenia, broad-spectrum antibiotics 
may be prescribed. Participants with severe diarrhea or any diarrhea associated with severe 
nausea or vomiting must be hospitalized for IV hydration and correction of electrolyte 
imbalance.
Nausea/Vomiting:  The use of antiemetic agents is permitted at the discretion of the 
investigator.
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 participant. 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 (absolute neutrophil count 
[ANC] <1.0 x 109/L with temperature ≥38.5°C).
Erythroid Growth Factors: The use of erythroid-stimulating factors (e.g., erythropoietin) is 
permitted at the discretion of the investigator based on American Society of Clinical 
Oncology and FDA guidelines, or according to local guidelines [34] [35].
Please refer to the product label or local standards of care for additional paclitaxel supportive 
measures.
 
 
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Diet/Activity/Other Considerations
Diet
Participants 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 2 birth control methods can either be 2 barrier methods or a barrier method plus a 
hormonal method to prevent pregnancy. Participants 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. Participants 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.
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 
participant.
Participants 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 participant will not 
reliably comply with the requirements for contraception, that participant should not be 
entered into the study.
Use in Pregnancy
If a participant inadvertently becomes pregnant while on treatment with pembrolizumab or 
paclitaxel, the participant will immediately be removed from the study. The site will contact 
the participant at least monthly and document the participant’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 an SAE (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 
 
 
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participant 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, participants 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 
Section 6.0 - Trial Flow Chart.
Subjects may discontinue treatment at any time for any reason or be dropped from treatment
at the discretion of the investigator should any untoward effect occur.  In addition, a subject 
may be discontinued from treatment by the investigator or the Sponsor if treatment is 
inappropriate, the trial plan is violated, or for administrative and/or other safety reasons.  
Specific details regarding procedures to be performed at treatment discontinuation are 
provided in Section 7.1.4 – Other Procedures.
A subject must be discontinued from treatment but continue to be monitored in the trial for 
any of the following reasons:
○
The subject or subject’s legally acceptable representative requests to discontinue 
treatment.
o
Confirmed radiographic disease progression per the terms outlined in Section 7.1.2.6.4.  
o
Unacceptable adverse experiences as described in Section 5.2.1.2.
o
Intercurrent illness that prevents further administration of treatment.
o
Investigator’s decision to withdraw the participant.
o
The participant has a confirmed positive serum pregnancy test.
o
The participant has a positive urine drug screen at any time during the course of the 
trial. 
o
Noncompliance with trial treatment or procedure requirements.
o
The participant has a medical condition or personal circumstance which, in the opinion 
of the investigator and/or Sponsor, placed the participant at unnecessary risk from 
continued administration of study drug.
 
 
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o
Completed 35 administrations (approximately 2 years) of uninterrupted treatment with 
pembrolizumab.
o
Administrative reasons.
Note: Participants who stop pembrolizumab after 35 administrations (approximately 
2 years) may be eligible for up to one year of additional study treatment if they 
progress after stopping study treatment, provided they meet the requirements detailed 
in Section 7.1.5.5.   
The End of Treatment and Follow-up visit procedures are listed in Section 6 (Trial Flow 
Chart) and Section 7.1.5 (Visit Requirements). After the end of treatment, each participant
will be followed for 30 days for AE monitoring (SAEs will be collected for 90 days after the 
end of treatment or 30 days after the end of treatment if the participant initiates new 
anticancer therapy, whichever is earlier, as described in Section 7.2.3.1). Participants who 
discontinue for reasons other than PD will have post-treatment follow-up for disease status 
until disease progression, initiating a non-study cancer treatment, withdrawing consent or 
becoming lost to follow-up. After documented disease progression each participant will be 
followed by telephone for OS until death, withdrawal of consent, or the end of the study, 
whichever occurs first.
Discontinuation of Study Therapy after Complete Response
Discontinuation of treatment may be considered for participants who have attained a 
confirmed CR that have been treated for at least 24 weeks with pembrolizumab and had at 
least 2 treatments with pembrolizumab beyond the date when the initial CR was declared. 
Participants 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 participant meets the safety parameters listed in the Inclusion/Exclusion 
criteria, and the trial is open. Participants 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, 
all visits and procedures, as outlined in the trial flowchart, should be completed.
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.  The overall 
trial ends when the last subject completes the last trial visit, discontinues from the trial or is 
lost to follow-up (ie, the subject is unable to be contacted by the investigator). Upon study 
completion, subjects will be discontinued and may be enrolled in a pembrolizumab extension 
study. Enrollment in the extension study is conditional on subject consent.
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 participants
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 participant treatment can be made.
 
 
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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
ePROs (HRQoL Measures)i
X
X
X
X
Xi
X
X
Health Economic Assessment (HEA)i
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
X
X
X
X
X
X
X
X
Post-study Anticancer Therapy Status
X
X
Survival Statusc
X
Trial Treatment Administration
Pembrolizumabk
X
X
X
X
X
X
Laboratory Procedures/Assessments:  
Analysis performed by LOCAL laboratory
Pregnancy Test – Urine or Serum -HCGl
X
PT/INR and aPTTm
X
CBC with Differentialn
X
X
X
X
X
Xn
X
Xn
Chemistry Paneln
X
X
X
X
X
Xn
X
Xn
 
 
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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
Urinalysisn
X
T3, FT4 and TSH
X n
X
X
X
X
Serum carcinoembryonic antigen (CEA) n
X
X
Xn
Serum CA 19-9n
X
X
Xn
Laboratory Procedures/Assessments:
Analysis performed by CENTRAL 
laboratory
Blood for Geneticso
X
Correlative Blood Samples (DNA)p
X
X
X
X
Correlative Blood Samples (RNA)p
X
X
X
X
Correlative Blood Samples (plasma)p
X
Correlative Blood Samples (serum)p
X
Efficacy Measurements
Tumor Imagingq
X
X
X
Xr
X
Tumor Tissue Collection
Archival and/or Newly-Obtained Tissue 
Collection 
Xs
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 participants 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 anticancer treatment, (2) disease progression as assessed by the central imaging vendor, (3) death, or (4) the end of 
the study, whichever occurs first.
c.
After the start of new anticancer treatment or documented disease progression by the central imaging vendor, the participant 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 participant 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).
Informed consent may be signed prior to the Screening Period specified above in the Trial Flow Chart (-28 to -1 days) 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.
 
 
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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
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 occurring within 30 days after the last dose of trial treatment.  Report all SAEs (related and unrelated to trial treatment) and ECIs occurring up until 90 days 
after the last dose of trial treatment or 30 days following last dose of trial treatment if the participant 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 electronic Patient Reported Outcomes (ePROs) 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 and HEA; an exception to this recommendation may occur at the 
treatment Discontinuation Visit where participants may have already been notified of their disease status or an AE evaluation is known prior to them arriving to the clinic.   All
ePROs (except the HEA) are to be performed at Cycle 1, Cycle 2, Cycle 3, Cycle 4, Cycle 5, Cycle 7, and Cycle 9. After Week 24, ePROs 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. The HEA is to
be completed by trained study site personnel and will begin at Cycle 2 then follow the above listed time points. If the participant does not complete the ePROs, 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.
Pembrolizumab should be administered on Day 1 of each three-week cycle after all procedures/assessments have been completed. 
l.
For women of reproductive potential, a serum pregnancy test should be performed within 72 hours prior to first dose of trial treatment. A urine test can be considered if serum 
is not appropriate.  Pregnancy tests (serum and/or urine tests) should be repeated if required by local guidelines.
m.
Coagulation factors (PT/INR and aPTT) should be tested as part of the screening procedures for all participants.
n.
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.  Complete Blood Count (CBC) with Differential and Chemistry panel is 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. 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. 
o.
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 participant 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.
p.
Whole blood sample for correlative studies should be collected at Cycle 1, Day 1- Predose, Cycle 2 Day 1- Predose, Cycle 3 Day 1 Predose and again at treatment 
discontinuation.   Blood for serum and blood for plasma to be collected only prior to Cycle 1 Day 1. See Procedures Manual.
q.
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 central imaging vendor.  
 
 
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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
r.
In participants 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.
s.
Endoscopic biopsies are permitted. Any leftover tumor will be stored for future biomedical research if the participant signs the FBR consent.
 
 
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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
ePROs (HRQoL Measures) i
X
X
X
X
X
Health Economic Assessment (HEA)i
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
X
X
X
X
X
X
X
X
Post-study Anticancer Therapy Status
X
X
Survival Status c
X
Trial Treatment Administration
Paclitaxelk
X
X
X
X
X
X
Laboratory Procedures/Assessments:  
Analysis performed by LOCAL laboratory
Pregnancy Test – Urine or Serum -HCGl
X
PT/INR and aPTT m
X
CBC with Differentialn
X
X
X
X
X
X
X
X
Chemistry Paneln
X
X
X
X
X
X
X
X
Urinalysis n
X
T3, FT4 and TSH
X n
X
X
X
 
 
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Protocol/Amendment No.: 061-13 
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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 antigenn
X
Xn
Serum CA19-9n
X
Xn
Laboratory Procedures/Assessments:
Analysis performed by CENTRAL 
laboratory
Blood for Geneticso
X
Correlative Blood Samples (DNA)p
X
X
X
Correlative Blood Samples (RNA)p
X
X
X
Correlative Blood Samples (plasma)p
X
Correlative Blood Samples (serum)p
X
Efficacy Measurements
Tumor Imagingq
X
Xq
Xr
X
Tumor Tissue Collection
Archival and/or Newly-Obtained Tissue 
Collection 
Xs
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 participants 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 anticancer treatment, (2) disease progression as assessed by the central imaging vendor, (3) death, or (4) the end of 
the study, whichever occurs first.
c.
After the start of new anticancer treatment or documented disease progression by the central imaging vendor, the participant should be contacted by telephone 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 participant 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). Informed 
consent may be signed prior to the Screening Period specified above in the Trial Flow Chart (-28 to -1 days) 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.
h. Record all AEs occurring within 30 days after the last dose of trial treatment.  Report all SAEs (related and unrelated to trial treatment) and ECIs occurring up until 90 days after 
 
 
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Protocol/Amendment No.: 061-13 
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09-Mar-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
the last dose of trial treatment or 30 days following last dose of trial treatment if the participant 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 electronic Patient Reported Outcomes (ePROs) 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 and HEA; an exception to this recommendation may occur at the 
treatment Discontinuation Visit where participants may have already been notified of their disease status or an AE evaluation is known prior to them arriving to the clinic.  All 
ePROs (except the HEA) 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.  The HEA is to be completed 
by trained study site personnel and will begin at Cycle 2 then follow the above listed time points. If the participant does not complete the ePROs, 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. Paclitaxel should be administered on Day 1, 8, and 15 of each 28-day (4-week) cycle after all procedures/assessments have been completed.   
l.
For women of reproductive potential, a serum pregnancy test should be performed within 72 hours prior to first dose of trial treatment. A urine test can be considered if serum is 
not appropriate.  Pregnancy tests (serum and/or urine tests) should be repeated if required by local guidelines.
m. Coagulation factors (PT/INR and aPTT) should be tested as part of the screening procedures for all participants.
n. 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. Serum CEA and CA19-9 should be collected at screening (baseline) and every 6 weeks (conducted at 
corresponding study visits) until study treatment discontinuation.
o. 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 participant 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.
p. Whole blood sample for correlative studies should be collected at Cycle 1, Day 1- Predose, Cycle 2 Day 1- Predose, Cycle 3 Day 1 Predose and again at treatment 
discontinuation.   Blood for serum and blood for plasma to be collected only prior to Cycle 1 Day 1. See Procedures Manual.
q. 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 central 
imaging vendor.  
r.
In participants 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.
s.
Endoscopic biopsies are permitted. Any leftover tumor will be stored for future biomedical research if the participant signs the FBR consent.
 
 
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Protocol/Amendment No.: 061-13 
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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
± 3
± 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
X
X
X
X
X
X
X
Pembrolizumab Administrationi
X
X
X
X
X
X
Post-study Anticancer Therapy Status
X
X
Survival Statusc
X
Laboratory Procedures/Assessments:  Analysis 
performed by LOCAL laboratory
Pregnancy Test – Urine or Serum -HCGj
X
PT/INR and aPTTk
X
CBC with Differentiall
X
X
X
X
X
Xk
X
X
Chemistry Panell
X
X
X
X
X
Xk
X
X
Urinalysisl
X
T3, FT4 and TSHl
X
X
X
X
Efficacy Measurements
Tumor Imagingm
X
X
X
Xn
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 participants 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 anticancer treatment, (2) disease progression as assessed by the central imaging vendor, (3) death, or (4) the 
end of the study, whichever occurs first.
c.
After the start of new anticancer treatment or documented disease progression by the central imaging vendor, the participant should be contacted by telephone 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 
 
 
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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
± 3
± 7
± 7
participants that have a death event previously recorded).
d. In general, the window for each visit is ± 3 days unless otherwise noted.
e.
Participants 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 occurring within 30 days after the last dose of trial treatment.  Report all SAEs (related and unrelated to trial treatment) and ECIs occurring up until 90 days 
after the last dose of trial treatment or 30 days following last dose of trial treatment if the participant initiates new anticancer 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.
Participants who restart treatment should resume at the same dose and schedule which they were receiving prior to discontinuation.
j.
For women of reproductive potential, a serum pregnancy test should be performed within 72 hours prior to first dose of trial retreatment. A urine test can be considered if 
serum is not appropriate.  Pregnancy tests (serum and/or urine tests) should be repeated if required by local guidelines.
k. Coagulation factors (PT/INR and aPTT) should be tested as part of the screening procedures for all participants.
l.
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.
m. 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.
n. In participants 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.
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.
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 
 
 
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performing any procedure related to Future Biomedical Research.  A copy of the informed 
consent will be given to the subject.
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.
Subject Identification Card
All subjects will be given a Subject Identification Card identifying them as participants in a 
research trial.  The card will contain trial site contact information (including direct telephone 
numbers) to be utilized in the event of an emergency.  The investigator or qualified designee 
will provide the subject with a Subject Identification Card immediately after the subject 
provides written informed consent.
The subject identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about trial 
medication/vaccination in emergency situations where the investigator is not available.
Medical History
A medical history will be obtained by the investigator or qualified designee. Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
are considered to be clinically significant by the investigator. Details regarding the 
participant’s gastric or GEJ adenocarcinoma will be recorded separately and not listed as 
medical history.
Please note that if the participant has lost at least 15 lbs. (6.8 kg.) over the 3 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 
participant’s gastric or GEJ adenocarcinoma.
Prior and Concomitant Medications Review
7.1.1.5.1 Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant
within 30 days before starting the trial. Details regarding the participant’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 participant
during the trial from the time of signing the ICF until the Safety Follow-up Visit. All 
medications related to reportable SAEs and ECIs should be recorded as defined in Section 
7.2.
 
 
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Assignment of Screening Number
All consented subjects will be given a unique screening number that will be used to identify 
the subject for all procedures that occur prior to randomization or allocation.  Each subject 
will be assigned only one screening number.  Screening numbers must not be re-used for 
different subjects.
Any subject who is screened multiple times will retain the original screening number 
assigned at the initial screening visit.
Specific details on the screening visit requirements (screening/rescreening) are provided in
Section 7.1.5.1.  
Assignment of Randomization Number
All eligible subjects will be randomly allocated and will receive a randomization number.  
The randomization number identifies the subject for all procedures occurring after 
randomization.  Once a randomization number is assigned to a subject, it can never be re-
assigned to another subject.
A single subject cannot be assigned more than 1 randomization number.
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 doses require consultation between the investigator and the Sponsor and 
written documentation of the collaborative decision on subject management.
Administration of trial medication will be monitored by the investigator and/or trial staff.
Clinical Procedures/Assessments
Adverse Event Monitoring
The investigator or qualified designee will assess each participant to evaluate for potential 
new or worsening AEs as specified in the Trial Flow Chart and more frequently if clinically 
indicated. AEs will be graded and recorded throughout the study and during the follow-up 
period according to NCI-CTCAE Version 4.0 (see Appendix 12.5). Toxicities will be 
characterized in terms regarding seriousness, causality, toxicity grading, and action taken 
with regard to trial treatment.  
For participants receiving treatment with pembrolizumab all AEs of unknown etiology 
associated with pembrolizumab exposure should be evaluated to determine if it is possibly an 
ECI of a potentially immunologic etiology (termed irAEs); see Section 7.2.3.2.
Please refer to Section 7.2 for detailed information regarding the assessment and recording of 
AEs.
 
 
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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 electrocardiography (ECG) will be performed using local standard 
procedures once at screening. Clinically significant abnormal findings should be recorded as 
medical history. Additional time points may be performed as clinically necessary.
Eastern Cooperative Oncology Group Performance Status
The investigator or qualified designee will assess ECOG PS (see Appendix 12.6) 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 participant has at least one target 
lesion per standard RECIST 1.1.
 
 
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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). Imaging may be more frequent if clinically indicated. Imaging should not 
be delayed for delays in cycle starts or extension of cycle intervals.  
Note: The exact same image acquisition and processing parameters should be used 
throughout the study.
Per RECIST 1.1, response should be confirmed by a repeat radiographic assessment not less 
than 4 weeks from the date the response was first documented. The scan for confirmation of 
response may be performed at the earliest 4 weeks after the first indication of response, or at 
the next scheduled scan (i.e., 6 weeks later), whichever is clinically indicated.  
At the time of the initial PD by RECIST 1.1 imaging scans should be sent to central vendor 
to verify progressive disease. If PD is verified, the investigator may choose to continue 
treatment if the participant is clinically stable and repeat imaging in 4 weeks to confirm PD 
(by the site) and then follow irRECIST. Imaging should continue to be performed until 
documented disease progression, the start of new anticancer treatment, withdrawal of 
consent, death, or the end of the trial, whichever occurs first. For participants receiving 
pembrolizumab, per irRECIST, disease progression should be confirmed at least 4 weeks 
after the first scan indicating PD in clinically stable participants. Participants who have 
unconfirmed disease progression may continue on treatment until progression is confirmed,
provided they have met the conditions detailed in Section 7.1.2.6.4.1.
In clinically stable participants, disease progression may be confirmed by the site at least 
4 weeks after the first scan indicating PD.  
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
 
 
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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 Assessment of Disease
Standard RECIST 1.1 will be applied by the central imaging vendor as the primary measure 
for assessment of tumor response, date of disease progression, and as a basis for all protocol 
guidelines related to disease status (e.g., discontinuation of study therapy). Scans showing 
site-assessed PD should be submitted to the central imaging vendor immediately. The site 
will be notified when the imaging vendor verifies disease progression using RECIST 1.1.
irRECIST
Following PD by RECIST, sites will assess tumor response and progression per irRECIST 
for participants receiving pembrolizumab as this data will be collected in the clinical 
database. 
irRECIST is RECIST 1.1 adapted for use with immunotherapies as described in the 
Procedure Manual and irRECIST Tip Sheet.  
If initial imaging shows PD, tumor assessment may be repeated by the site at least 4 weeks 
later in order to confirm PD with the option of continuing treatment until this scan is obtained 
for clinically stable participants (see Table 7). Clinically stable is defined by the following 
criteria:

Absence of signs and symptoms indicating disease progression

No decline in ECOG PS

Absence of rapid progression of disease

Absence of progressive tumor at critical anatomical sites (e.g., cord compression) 
requiring urgent alternative medical intervention
 
 
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Table 7
Imaging and Treatment after 1st Radiologic Evidence of Progressive Disease 
Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
1st
radiologic 
evidence of 
PD
Repeat imaging at 
4 
weeks 
to 
confirm PD
May 
continue 
study treatment at 
the 
investigator’s 
discretion 
while 
awaiting 
confirmatory scan.
Repeat imaging 
at 4 weeks to 
confirm PD if 
possible
Discontinue 
treatment
Repeat scan 
confirms PD
No 
additional 
imaging required
Discontinue 
treatment 
(exception 
is 
possible 
upon 
consultation 
with 
Sponsor).
No 
additional 
imaging required
N/A
Repeat scan
shows 
SD, 
PR or CR
Continue 
regularly 
scheduled 
imaging 
assessments every 
6 weeks
Continue 
study 
treatment at the 
investigator’s 
discretion.
Continue 
regularly 
scheduled 
imaging 
assessments 
every 6 weeks
May restart study 
treatment 
if 
condition 
has 
improved and/or 
clinically stable 
per investigator’s 
discretion
In determining whether or not the tumor burden has increased or decreased, investigators 
should consider all target lesions as well as non-target lesions (please refer to the irRECIST 
Tip Sheet). Participants that are deemed clinically unstable are not required to have repeat 
imaging for confirmation. If radiologic progression is confirmed, it is recommended that the 
participant be discontinued from trial treatment unless, in the investigator’s opinion, the 
participant is deriving benefit from treatment. Clinically stable participants as defined above 
may continue to receive trial therapy after discussion with the Sponsor. 
If a participant has unconfirmed progression of disease and is clinically stable, it is at the
discretion of the investigator to continue treating the participant with the assigned treatment 
per protocol until progression of disease is confirmed at least 28 days from the date of the 
scan suggesting progression of disease. If progression is not confirmed on the subsequent 
scan, the participant should continue to receive study therapy and radiographic scans 
obtained to monitor for disease status every 6 weeks (42 ± 7 days). The same imaging 
technique, acquisition, and processing parameters should be used in a participant throughout 
the trial. Details are provided in the Site Imaging Manual. 
NOTE: 
In participants who discontinue study therapy without documented disease 
progression, every effort should be made to continue monitoring their disease status by 
radiologic imaging every 6 weeks (± 7 days) until (1) the start of new anticancer treatment, 
(2) disease progression (3) death, or (4) the end of the study, whichever occurs first. If 
radiologic progression is not confirmed, then the participant should resume or continue trial 
treatment and have their next scan according to the protocol schedule. During the follow-up 
period, imaging will be repeated every 12 weeks (± 7 days). See the Trial Flow Charts in 
Section 6 for information about the Follow-up Visits.
 
 
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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 FFPE block 
specimens are preferred to slides. The specimen will be evaluated at a central laboratory 
facility for expression status of PD-L1.  
Note: A fine needle aspirate 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.
If the participant 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.
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 participant
has provided the relevant informed consent.
Details regarding time points for blood collection are outlined in the Trial Flow Chart –
Section 6. Further details can also be found in Section 4.2.3.3 and further detailed 
instructions for tissue collection, processing and shipment are provided in the Procedures 
Manual.
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 electronically by participants. It 
is strongly recommended that the electronic EORTC QLQ-C30, EORTC QLQ-STO22 and 
EuroQol EQ-5D is completed by the participant prior to drug administration, AE evaluation 
and disease status notification; an exception to this recommendation may occur at the 
treatment Discontinuation Visit. ePROs will be administrated in the following order: 
EuroQol EQ-5D first, then EORTC QLQ-C30, and lastly the EORTC QLQ-STO22 at the 
time points specified in the Trial Flow Chart. The HEA form will be completed via an 
 
 
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interview with the participant by trained study site personnel after the participant completes 
all other questionnaires. The form captures non-study related healthcare visits, including 
healthcare provider visits, ER visits, and hospitalizations (including admission and discharge 
dates and primary discharge diagnosis). 
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 participant 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
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.
 
 
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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, predose laboratory procedures can 
be conducted up to 72 hours prior to dosing for the pembrolizumab arm.  For participants 
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 be 
acceptable prior to each dose of trial treatment.
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 medication, 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. The results of the pregnancy testing will not be recorded.
Pharmacokinetic/Pharmacodynamic Evaluations
The accumulation of robust PK and anti-drug antibodies (ADA) data has allowed for the 
adequate characterization of the clinical pharmacology of pembrolizumab across indications. 
Therefore, upon approval of Amendment 11, each site should stop the collection of PK and 
ADA samples for all participants. Blood samples for PK and ADA collected prior to 
Amendment 11 will be stored and analysis will be performed if required.
Planned Genetic Analysis Sample Collection
Sample collection, storage and shipment instructions for planned genetic analysis samples 
will be provided in the Procedures Manual.
Future Biomedical Research
The following specimens are to be obtained as part of Future Biomedical Research:

Leftover DNA

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.  Participants 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 
 
 
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35 administrations (~ 2 years) of treatment, these participants should return to the site for a 
Safety Follow-up Visit (described in Section 7.1.5.4.1) and then proceed to the follow-up 
period of the study (described in Section 7.1.5.4.2).
7.1.4.1.1 Withdrawal From Future Biomedical Research
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   Subjects may withdraw consent at any time by 
contacting the principal investigator for the main trial.  If medical records for the main trial 
are still available, the investigator will contact the Sponsor using the designated mailbox 
(clinical.specimen.management@merck.com), and a form will be provided by the Sponsor to 
obtain appropriate information to complete specimen withdrawal.  Subsequently, the
subject's specimens will be removed from the biorepository and be destroyed.  A letter will 
be sent from the Sponsor to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for destruction or already performed prior to the 
request being received by the Sponsor will continue to be used as part of the overall research 
trial data and results.   No new analyses would be generated after the request is received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial records) or 
the specimens have been completely anonymized, there will no longer be a link between the 
subject’s personal information and their specimens.  In this situation, the request for 
specimen destruction cannot be processed.
Blinding/Unblinding
This is an open label trial; there is no blinding for this trial.
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 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.
 
 
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Screening
Approximately 28 days prior to randomization, potential participants 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 – Trial Flow Chart.
Results of a test performed prior to the participant 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 and ECOG PS are to be performed within 10 days prior to the first 
dose of trial treatment.

For women of reproductive potential, a serum pregnancy test will be performed 
within 72 hours prior to the first dose of trial treatment.  A urine test may be 
considered if serum test is not appropriate.

Baseline tumor imaging will be performed within 14 days prior to randomization for 
all participants.  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.
Participants 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. Participants who are rescreened will retain their original 
screening number.
Treatment Period
Visit requirements are outlined in Section 6 – Trial Flow Chart.  Specific procedure-related 
details are provided above in Section 7.1 – Trial Procedures.
Discontinuation Visit
The Discontinuation Visit should occur at the time study treatment is discontinued for any 
reason.  If the Discontinuation Visit occurs 30 days from the last dose of study treatment, at 
the time of the mandatory Safety Follow-up Visit, procedures do not need to be repeated.  
Visit requirements are outlined in Section 6 – Trial Flow Chart.  Specific procedure-related 
details are provided above in Section 7.1 – Trial Procedures.  Additional details regarding 
participant withdrawal and discontinuation are presented in Section 5.8.
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 anticancer treatment, whichever 
comes first.  All AEs that occur prior to the Safety Follow-up Visit should be recorded.  
 
 
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Participants 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 anticancer therapy, whichever occurs first.  SAEs 
and ECIs will be collected for 90 days after the end of treatment or 30 days following last 
dose of trial treatment if the participant initiates new anticancer therapy, whichever occurs 
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, one after the Treatment Period and 
one after the Second Course Phase.
7.1.5.4.2 Follow-up Visits
Participants 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 anticancer therapy, disease progression determined by the central imaging 
vendor, death, or at end of study. Information regarding post-study anticancer treatment will 
be collected if new treatment is initiated.
Participants 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 participant experiences confirmed disease progression confirmed by central review or 
starts a new anticancer therapy, the participant 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 IA, and/or FA. Upon Sponsor notification, all participants who do not/will 
not have a scheduled study visit or study contact during the Sponsor-defined time period will 
be contacted for their survival status (excluding participants that have a previously recorded 
death event in the collection tool).
Second Course Phase (Retreatment Period) 
Participants on the pembrolizumab arm who stop treatment with stable disease (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 
 
 
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and is only available if the trial remains open and the participant 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 2 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 (approx. 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 anticancer
treatment since the last dose of 
pembrolizumab.
o
Has a performance status of 0 or 1 on the ECOG PS.
o
Demonstrates adequate organ function as detailed in Section 5.1.2.
o
Female participant of childbearing potential should have a negative serum or 
urine pregnancy test within 72 hours prior to receiving retreatment with study 
medication.  
o
Female participant 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).  
Participants of child bearing potential are those who have not been surgically 
sterilized or have been free from menses for >1 year. 
o
Male participant should agree to use an adequate method of contraception 
starting with the first dose of study therapy through 120 days.
o
Does not have a history or current evidence of any condition, therapy, or 
laboratory abnormality that might interfere with the participant’s participation 
for the full duration of the trial or is not in the best interest of the participant to 
participate, in the opinion of the treating investigator.
Participants who restart treatment will be re-treated at the same dose frequency as when they 
last received pembrolizumab.  Treatment will be administered for up to one additional year.
 
 
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Visit requirements for the Second Course Phase are outlined in Section 6.3 – Trial Flow 
Chart – Second Course Phase – Retreatment with pembrolizumab.
Participants 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 
randomization/treatment allocation must be reported by the investigator if they cause the 
subject to be excluded from the trial, or are the result of a protocol-specified intervention, 
including but not limited to washout or discontinuation of usual therapy, diet, placebo 
treatment or a procedure.
From the time of randomization/treatment allocation through 30 days following cessation of 
treatment, all adverse events must be reported by the investigator. Such events will be 
recorded at each examination on the Adverse Event case report forms/worksheets.  The 
reporting timeframe for adverse events meeting any serious criteria is described in Section 
7.2.3.1. The investigator will make every attempt to follow all subjects with non-serious 
adverse events for outcome.
Electronic reporting procedures can be found in the EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
 
 
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Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor
For purposes of this trial, an overdose will be defined as any dose exceeding the prescribed 
dose for 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 within 24 hours 
to the Sponsor either by electronic media or paper.  Sponsor Contact information can be 
found in the Investigator Trial File Binder (or equivalent).
Reporting of Pregnancy and Lactation to the Sponsor
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them) that occurs during the trial.
Pregnancies and lactations that occur after the consent form is signed but before 
randomization/treatment allocation must be reported by the investigator if they cause the 
subject to be excluded from the trial, or are the result of a protocol-specified intervention, 
including but not limited to washout or discontinuation of usual therapy, diet, placebo 
treatment or a procedure.
Pregnancies and lactations that occur from the time of randomization/treatment allocation 
through 120 days following cessation of Sponsor’s product, or 30 days following cessation of 
treatment if the subject initiates new anticancer therapy, whichever is earlier, must be 
reported by the investigator.  All reported pregnancies must be followed to the
completion/termination of the pregnancy.  Pregnancy outcomes of spontaneous abortion, 
missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, 
miscarriage and stillbirth must be reported as serious events (Important Medical Events).  If 
the pregnancy continues to term, the outcome (health of infant) must also be reported.
Such event must be reported within 24 hours to the Sponsor either by electronic media or 
paper.  Electronic reporting procedures can be found in the EDC data entry guidelines.  Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
 
 
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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 
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.
 
 
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Events of Clinical Interest
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported to the Sponsor.
For the time period beginning when the consent form is signed until randomization/treatment 
allocation, any ECI, or follow up to an ECI, that occurs to any subject must be reported 
within 24 hours to the Sponsor if it causes the subject to be excluded from the trial, or is the 
result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at randomization/treatment allocation through 90 days 
following cessation of treatment, or 30 days following cessation of treatment if the subject 
initiates new anticancer therapy, whichever is earlier, any ECI, or follow up to an ECI, 
whether or not related to the Sponsor’s product, must be reported within 24 hours to the 
Sponsor, either by electronic media or paper.  Electronic reporting procedures can be found 
in the EDC data entry guidelines. Paper reporting procedures can be found in the Investigator 
Trial File Binder (or equivalent).
Events of clinical interest for this trial include:
1. an overdose of Sponsor's product, as defined in Section 7.2.1 - Definition of an Overdose 
for This Protocol and Reporting of Overdose to the Sponsor, that is not associated with 
clinical symptoms or abnormal laboratory results. 
2. an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less 
than 2X the upper limit of normal, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.*
*Note:  These criteria are based upon available regulatory guidance documents. The purpose 
of the criteria is to specify a threshold of abnormal hepatic tests that may require an 
additional evaluation for an underlying etiology.  The trial site guidance for assessment and 
follow up of these criteria can be found in the Investigator Trial File Binder (or equivalent).
3. Additional Adverse Events:
Participants should be assessed for possible ECIs prior to each dose. Lab results should be 
evaluated, and participants should be asked for signs and symptoms suggestive of an 
immune-related event.  Participants who develop an ECI thought to be immune-related 
should have additional testing to rule out other etiologic causes.  If lab results or symptoms 
indicate a possible immune-related ECI, then additional testing should be performed to rule 
out other etiologic causes.  If no other cause is found, then it is assumed to be immune-
related.
 
 
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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 participants 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
external Data Monitoring Committee (eDMC) regarding the trial.
Data Monitoring Committee
To supplement the routine trial monitoring outlined in this protocol, an external Data 
Monitoring Committee (DMC) will monitor the interim data from this trial.  The voting 
members of the committee are external to the Sponsor.  The members of the DMC must not 
be involved with the trial in any other way (e.g., they cannot be trial investigators) and must 
have no competing interests that could affect their roles with respect to the trial. 
The DMC will make recommendations to the EOC regarding steps to ensure both subject 
safety and the continued ethical integrity of the trial.  Also, the DMC will review interim trial 
results, consider the overall risk and benefit to trial participants (see Section 8.7 - Interim 
Analyses) and recommend to the EOC if the trial should continue in accordance with the 
protocol.
Specific details regarding composition, responsibilities, and governance, including the roles 
and responsibilities of the various members and the Sponsor protocol team; meeting 
facilitation; the trial governance structure; and requirements for and proper documentation of 
DMC reports, minutes, and recommendations will be described in a separate charter that is 
reviewed and approved by the DMC.  The DMC will monitor the trial at an appropriate 
frequency, as described in the detailed DMC charter.  The DMC will also make 
recommendations to the Sponsor protocol team regarding steps to ensure both subject safety 
and the continued ethical integrity of the trial.
An eDMC recommendation will be communicated to the Sponsor as agreed to in the 
Document Review Committee charter.
Treatment-level results of the IA 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 recommendations to the EOC 
regarding steps to ensure both participant safety and continued ethical integrity of the trial.  
 
 
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Limited additional Sponsor personnel may be unblinded to the treatment-level results of the 
IA, if required, in order to act on the recommendations of the eDMC or facilitate regulatory 
filing after the IA. The extent to which individuals are unblinded with respect to results of IA
will be documented by the unblinded statistician. Additional logistical details and data 
monitoring guidance 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 
unblinding, will be documented in a supplemental SAP (sSAP) and referenced in the Clinical 
Study Report (CSR) for the study. Post hoc exploratory analyses will be clearly identified in 
the CSR.
In this section, “PD-L1 positive participants” means “participants with tumor PD-L1 
expression”, and “PD-L1 negative participants” means “participants with no detectable PD-
L1 expression”.
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized in Table 10 below; the 
comprehensive plan is provided in Sections 8.2 through 8.12.
Table 10
Statistical Analysis Plan
Study Design Overview
A Phase III, Randomized, Open-label Clinical Trial of Pembrolizumab 
(MK-3475) versus Paclitaxel in Subjects with Advanced Gastric or 
Gastroesophageal Junction Adenocarcinoma who Progressed after First-
Line Therapy with Platinum and Fluoropyrimidine
Treatment Assignment
Approximately up to 720 participants will be randomized in a 1:1 ratio 
to receive pembrolizumab or paclitaxel. Stratification factors are 
geographic region (Europe/Israel/North America/Australia vs. Asia vs. 
Rest of World), TTP on first-line therapy (<6 months vs. ≥6 months) 
and PD-L1 status (positive vs. negative). This is an open-label study.
Analysis Populations
Efficacy: Intention-to-Treat (ITT)
Safety: All Subjects as Treated (ASaT)
Primary Endpoints
1. PFS per RECIST 1.1 by blinded central radiologists’ review in PD-
L1 positive participants
2. OS in PD-L1 positive participants
Key Secondary Endpoints
1. PFS per RECIST 1.1 by blinded central radiologists’ review in all 
participants 
2. OS in all participants
Statistical Methods for Key 
Efficacy Analyses
The primary and key secondary 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 HR 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.  Safety 
parameters or adverse experiences of special interest that are identified a 
priori constitute “Tier 1” safety endpoints that will be subject to 
inferential testing for statistical significance with p-values and 95% CIs
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% CIs provided for between-group comparisons; 
only point estimates by treatment group are provided for Tier 3 safety 
parameters. There are no Tier 1 events in this trial. The between-treatment 
difference will be analyzed using the Miettinen and Nurminen method
[36].
Interim Analysis
One interim analysis (IA) will be performed in this study.  Results will 
be reviewed by an eDMC. The IA is summarized below.  Details are 
provided in Section 8.7.

IA
o
Timing:  To be performed after: (1) enrollment is completed
(2) approximately 240 OS events have been observed among
PD-L1 positive participants and 3) a minimum of 260 PFS 
events have been observed among PD-L1 positive 
participants
o
Purpose: IA for OS and main efficacy analysis for PFS       

FA
o
Timing: at least 290 OS events have been observed among 
PD-L1 positive participants, or approximately 15 months 
after last patient randomized, whichever is later.
o
Purpose: Main efficacy analysis for 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 0.35% allocated to PFS and 2.15% allocated to OS 
hypotheses.  
Within each endpoint, the Type-I error rate for hypotheses on different 
populations will then be controlled by step-down testing procedure
(PD-L1 positive participants first and then all participants). If PFS 
hypotheses are rejected for both populations (PD-L1 positive and all 
participants), the corresponding alpha level can be shifted to the 
hypotheses for the OS endpoint using the graphical approach of Maurer 
and Bretz [37].
Sample Size and Power 
The planned sample size is approximately up to 720 participants. 
The FA of this study will complete after at least 290 OS events have 
been observed in the PD-L1 positive participants, or approximately 15 
months after last patient randomized, whichever is later.
For the primary endpoint PFS in the PD-L1 positive participants, the 
trial has 99% (97%) power to demonstrate that pembrolizumab is 
superior to paclitaxel at a one-sided 0.35% alpha-level, if the underlying 
HR of PFS is 0.5 (0.6).
For primary endpoint OS in the PD-L1 positive participants, the trial has 
91% power to demonstrate that pembrolizumab is superior to paclitaxel 
at a one-sided 2.15% alpha-level, if the underlying HR of OS is 0.67 and 
290 OS events are observed.
 
 
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Responsibility for Analyses/In-House Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
Although the trial is open-label, analyses or summaries generated by randomized treatment 
assignment, actual treatment received, and/or PD-L1 biomarker status will be limited and 
documented. In addition, the independent radiologist(s) will perform the central imaging 
review without knowledge of treatment group assignment.
The IVRS Vendor will generate the randomized allocation schedule(s) for study treatment 
assignment.  The algorithm for the randomized allocation of participants will be implemented 
in an IVRS.
Planned interim analyses are described in Section 8.7.  IA 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 unblinded statistician 
to the 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 IA. The extent to which individuals are 
unblinded with respect to results of IA will be documented.  
The eDMC will serve as the primary reviewer of the unblinded results of the IA 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.  Additional logistical details will 
be provided in the DMC Charter.  Key aspects of the IA are described in Section 8.7.
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.0.
Analysis Endpoints
Efficacy Endpoints
Primary
PFS – RECIST 1.1 by blinded central radiologists’ review
PFS is defined as the time from randomization to the first documented disease progression 
per RECIST 1.1 based on blinded central radiologists’ review or death due to any cause, 
whichever occurs first. See Section 8.6.1 for definition of censoring.
 
 
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OS
OS is defined as the time from randomization to death due to any cause. Participants without 
documented death at the time of the FA will be censored at the date of the last follow-up.
Secondary
PFS – RECIST 1.1 by investigator assessment 
PFS is defined as the time from randomization to the first documented disease progression or 
death due to any cause, whichever occurs first.
PFS – irRECIST by blinded central radiologists’ review
PFS is defined as the time from randomization to the first confirmed disease progression or 
death due to any cause, whichever occurs first.
TTP – RECIST 1.1 by blinded central radiologists’ review, and RECIST 1.1 by 
investigator assessment
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. 
ORR – RECIST 1.1 by blinded central radiologists’ review, and RECIST 1.1 by 
investigator assessment
ORR is defined as the proportion of the participants in the analysis population who have a
CR or PR.
DOR – RECIST 1.1 by blinded central radiologists’ review, and RECIST 1.1 by 
investigator assessment
For participants 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. Response duration for participants who have not progressed or died at 
the time of analysis will be censored at the date of their last tumor assessment.  
Safety Endpoints
Safety measurements are described in Section 7.
Analysis Populations
Efficacy Analysis Populations
The Intention-to-Treat (ITT) population will serve as the population for primary efficacy 
analysis. All randomized participants will be included in this population. Participants will be 
included in the treatment group to which they are randomized.
Details on the approach to handling missing data are provided in Section 8.6 - Statistical 
Methods.
 
 
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Safety Analysis Populations
The All Subjects as Treated (ASaT) population will be used for the analysis of safety data in 
this study.  The ASaT population consists of all randomized participants who received at 
least one dose of study treatment. Participants 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 participants this will be the treatment group to which 
they are randomized.  Participants 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 participant 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 participant 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.
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., HR) between the treatment 
arms. The HR and its 95% CI 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, 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 participants 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 
 
 
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of discontinuation of study drug. Death is always considered as a confirmed PD event. 
Sensitivity analyses will be performed for comparison of PFS based on investigator’s 
assessment.
In order to evaluate the robustness of the PFS endpoint per RECIST 1.1 by blinded central 
radiologists’ review, 2 sensitivity analyses will be performed 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 participants without documented PD or death. The censoring rules 
for primary and sensitivity analyses are summarized in Table 11.  In case there is an 
imbalance between the treatment groups on disease assessment schedules or censoring 
patterns, the following 2 additional PFS sensitivity analyses may also be performed: 1) a PFS 
analysis using time to scheduled tumor assessment visit from randomization as opposed to 
actual tumor assessment time; 2) Finkelstein (1986)’s likelihood-based score test [38] for 
interval-censored data, which modifies the Cox proportional hazard model for interval-
censored data, will be used as a supportive analysis for the PFS endpoint. The interval will be 
constructed so that the left endpoint is the date of the last disease assessment without 
documented PD and the right endpoint is the date of documented PD or death, whichever 
occurs earlier.
Table 11
Censoring rules for Primary and Sensitivity Analyses of PFS
Situation
Primary Analysis
Sensitivity
Analysis 1
Sensitivity
Analysis 2
No PD and no death; 
new 
anticancer 
treatment 
is 
not 
initiated
Censored at last disease 
assessment 
Censored 
at 
last 
disease assessment 
Censored at last disease 
assessment if still on 
study therapy; progressed 
at 
treatment 
discontinuation otherwise
No PD and no death; 
new 
anticancer 
treatment is initiated
Censored at last disease 
assessment before new 
anticancer treatment
Censored 
at 
last 
disease 
assessment 
before new anticancer 
treatment
Progressed at date of new 
anticancer treatment
PD 
or 
death 
documented after ≤1 
missed 
disease 
assessment
Progressed at date of 
documented PD or death
Progressed at date of 
documented 
PD 
or 
death
Progressed at date of 
documented PD or death
PD 
or 
death 
documented after ≥2 
missed 
disease 
assessments
Progressed at date of 
documented PD or death
Censored 
at 
last 
disease 
assessment 
prior to the ≥ 2 missed 
disease assessment
Progressed at date of 
documented PD or death
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 
 
 
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immunotherapies:
for example, using Restricted Mean Survival Time method [39], 
parametric method [40], etc.
One assumption for stratified Cox proportional hazard model is that the treatment effect (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 [41], 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.
The enrollment of the study is driven by the number of PD-L1 positive participants. The 
enrollment will stop when approximately 360 PD-L1 positive participants are enrolled. To 
estimate the treatment effect in overall population with natural prevalence of PD-L1 positive 
and negative participants, a sensitivity analysis using the two-step weighted Cox model 
approach may be performed by weighting the subgroups (PD-L1 positive and PD-L1
negative) according to the natural prevalence (estimated from participants screening data) in 
the overall population.
Further details of sensitivity analyses will be described in supplemental SAP.
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 HR). The HR and its 95% CI from the 
stratified Cox model with a single treatment covariate will be reported. The stratification 
factors used for will be applied to both the stratified log-rank test and the stratified Cox 
model.
Participants in the paclitaxel arm are expected to discontinue treatment earlier compared to 
participants in the pembrolizumab arm and may switch to another anti-PD-1 treatment 
following the verification of progressive disease by blinded central radiologists’ review. 
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 model proposed by Robins and Tsiatis (1989) [42], two-stage model, etc., based on an 
examination of the appropriateness of the data to the assumptions required by the methods.
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.
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., HR) between the treatment 
arms. The HR and its 95% CI 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 
 
 
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for randomization will be applied to both the stratified log-rank test and the stratified Cox 
model.
ORR
Stratified Miettinen and Nurminen’s method will be used for comparison of the ORRs
between the treatment arms. A 95% CI 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.  
DOR
If sample size permits, response duration will be summarized descriptively using the 
Kaplan-Meier medians and quartiles.  Only the subset of participants who show a CR or PRs
will be included in this analysis.  
Table 12 summarizes the primary analysis approach for primary and secondary efficacy 
endpoints. Sensitivity analysis methods are described above for each endpoint.
The strategy to address multiplicity issues with regard to multiple efficacy endpoints, 
multiple populations, and IA is described in Section 8.7 - Interim Analyses and in Section 8.8 
- Multiplicity.
Table 12
Analysis Strategy for Key Efficacy Endpoints
Endpoint/Variable
(Description, Time Point)
Statistical Method†
Analysis 
Population
Missing Data 
Approach
Primary Hypothesis #1
PFS per RECIST 1.1 by 
blinded central radiologists’ 
review in PD-L1 positive 
participants
Test: Stratified Log-rank 
test 
Estimation: Stratified 
Cox model with Efron’s 
tie handling method
ITT in PD-L1 
positive participants
Primary censoring rule 
Sensitivity analysis 1
Sensitivity analysis 2
(More details are in 
Table 11.)
Primary Hypothesis #2
OS in PD-L1 positive 
participants          
Test: Stratified Log-rank 
test 
Estimation: Stratified 
Cox model with Efron’s 
tie handling method 
ITT in PD-L1 
positive participants 
Censored at last known 
alive date 
Secondary Endpoints/Hypotheses
Secondary Hypothesis#1
PFS per RECIST 1.1 by 
blinded central radiologists’ 
review in all participants
Test: Stratified Log-rank 
test 
Estimation: Stratified 
Cox model with Efron’s 
tie handling method
ITT in all 
participants
Primary censoring rule 
Sensitivity analysis 1
Sensitivity analysis 2
(More details are in
Table 11.)
Secondary Hypothesis#2
OS in all participants
Test: Stratified Log-rank 
test 
Estimation: Stratified 
Cox model with Efron’s 
tie handling method
ITT in all 
participants
Censored at last known 
alive date
 
 
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Endpoint/Variable
(Description, Time Point)
Statistical Method†
Analysis 
Population
Missing Data 
Approach
Other Secondary Endpoints
PFS 
per RECIST 1.1 by 
investigator 
assessment 
Test: Stratified Log-rank 
test 
Estimation: Stratified 
Cox model with Efron’s 
tie handling method
ITT in all below 
populations:

PD-L1 positive

All participants
Primary censoring rule 
in Table 11
per irRECIST  by 
blinded central 
radiologists’ review
TTP
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 in all below 
populations:

PD-L1 positive

All participants
Censored 
at 
last 
assessment date if no 
documented PD
per RECIST 1.1 by 
investigator 
assessment
ORR 
per RECIST 1.1 by 
blinded central 
radiologists’ review   
Stratified M & N method‡
ITT in all below 
populations:

PD-L1 positive

All participants
Participants with missing 
data 
are 
considered 
nonresponders
per RECIST 1.1 by 
investigator 
assessment
DOR
per RECIST 1.1 by 
blinded central 
radiologists’ review 
Summary statistics using 
Kaplan-Meier method
All responders in 
ITT 
among 
all 
below populations:
PD-L1 positive
All participants
Censored 
at 
last 
assessment 
date 
if 
responding at the time of 
analysis
per RECIST 1.1 by 
investigator 
assessment
  † Statistical models are described in further detail in the text. For stratified analyses, the stratification factors 
used for randomization (geographic region (Europe/Israel/North America/Australia vs. Asia vs. Rest of 
World), TTP on first-line therapy (< 6 months vs.  ≥ 6 months) and PD-L1 status (positive vs. negative), 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 
AEs, laboratory tests, vital signs, etc.
Tiered Approach
The analysis of safety results will follow a tiered approach (Table 13).  The tiers differ with 
respect to the analyses that will be performed.  Safety parameters or adverse experiences of 
special interest that are identified a priori constitute “Tier 1” safety endpoints that will be 
participant to inferential testing for statistical significance with p-values and 95% CIs 
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% CIs 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 
 
 
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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 participants 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% CI 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% CIs 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 participants 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% CIs (Tier 2) will be provided for 
between-treatment differences in the percentage of participants 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 13
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
X
X
Specific AEs, SOCs, or PDLCs (incidence ≥4 
of participants in one of the treatment groups)
X
X
Tier 3
Specific AEs, SOCs or PDLCs (incidence <4 
of participants 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=Predefined Limit of Change; X = results will be provided.
Time to Grade 3-5 AE
In addition to tiered approach, exploratory analysis will be performed on time to first 
Grade 3-5 AE. Time to first Grade 3-5 AE is defined as the time from the first day of study 
drug to the first event of Grade 3-5 AE. The Kaplan-Meier method will be used to estimate 
the curve of time to first Grade 3-5 AE.  The treatment difference in time to first Grade 3-5 
AE will be assessed by the log-rank test.  A Cox proportional hazard model with Efron’s 
method of tie handling will be used to assess the magnitude of the treatment difference (i.e., 
the HR).  The HR and its 95% CI from the Cox model with a single treatment covariate will 
be reported. See details in sSAP.
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 participants 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 one planned IA in this trial. Results will be reviewed by an eDMC.
 
 
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The primary purpose of the IA is to evaluate superiority of pembrolizumab in OS and PFS. It 
will be performed after: (1) enrollment is completed; (2) approximately 240 OS events have 
been observed among PD-L1 positive participants; and 3) a minimum of 260 PFS events 
have been observed among PD-L1 positive participants.
For the PFS hypothesis, the boundary to demonstrate PFS superiority is shown in
Table 14 which corresponds to an approximate observed HR of 0.74 or less at IA at α = 
0.35% (one-sided), if 320 PFS events are analyzed at this time.
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 information fraction of the number of OS events 
observed at the time of the IA over 290 events, using the alpha-spending function.
If the time from the IA to the FA is estimated to increase (e.g., 16 months after IA), adding 
an additional IA approximately 1 year after the first IA may be considered. In this case, the 
boundaries for the additional IA and FA will be adjusted, but the alpha-spending function 
with gamma parameter (-4) remains unchanged during the course of trial. The overall type-I 
error control is not affected.  
In order to account for potential delayed treatment effect, which was observed with 
immunotherapy study data external to this study, the FA will be at least 290 OS events 
among the PD-L1 positive participants or approximately 15 months after last patient 
randomized, whichever is later [43] [44] [45]. The additional follow-up time is incorporated 
into the trial to ensure that the FA is conducted at an appropriate time to characterize the 
potential benefit of immunotherapy, where the treatment effect is most pronounced toward 
the tail of the survival curve. The boundary for the FA will be adjusted according to the 
actual alpha spent at IA and the actual number of events at IA and FA.
Table 14 summarizes the timing, sample size and decision guidance of the IA and FA.
Bounds are based on estimated number of events and will be updated at times of analyses 
using spending functions as noted above.
 
 
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Table 14
Summary of Timing, Sample Size and Decision Guidance of Interim Analysis 
and Final Analysis
Analysis
Criteria for Conduct of 
Analysis
Endpoint
Value
Efficacy
Futility
Interim Analysis: 
Interim OS 
Analysis /Main 
PFS Analysis
(1) enrollment is complete (2)
approximately 240 OS events 
have been observed among PD-
L1 positive participants 3) a 
minimum of 260 PFS events 
have been observed among PD-
L1 positive participants
PFS 
Events
among 
PD-L1 
positive participants: ~320
OS 
Events
among 
PD-L1 
positive participants: ~240
PFS in PD-L1 
positive 
participants
p value (1-
sided) at 
boundary
<=0.0035
NA
~ HR at 
boundary
0.74
NA
OS in PD-L1 
positive 
participants
p value (1-
sided) at 
boundary
<=0.0107 
    NA
~ HR at 
boundary
  0.74
    NA
Final Analysis: 
Main OS 
Analysis
At least 290 OS events have been 
observed among PD-L1 positive 
participants, or approximately 15 
months 
after 
last 
patient 
randomized, whichever is later.
OS 
Events
among 
PD-L1 
positive participants: ~290
OS in PD-L1 
positive 
participants
p value (1-
sided) at 
boundary
~ HR at 
boundary
<=0.0187
0.78
NA
NA
Multiplicity
The multiplicity strategy specified in this section will be applied to the 2 primary hypotheses 
(superiority of pembrolizumab on PFS or OS in PD-L1 positive participants) and the 2
secondary hypotheses (superiority of pembrolizumab on PFS or OS in all participants). 
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. 
For OS, the Type-I error rate for the IA and FA is controlled through alpha-spending 
functions for the PD-L1 positive population as described in Section 8.7 - Interim Analyses.
For the overall population at IA, the same alpha level allocated to the PD-L1 positive 
population at IA will be used. For the overall population at FA, the alpha level will be 
calculated based on the total alpha for the OS endpoint, alpha used at IA, and actual number 
of events at IA and FA.
Within each endpoint at IA and FA, the Type-I error rate for hypotheses on different 
populations will then be controlled by step-down method (PD-L1 positive participants first 
and then the all participants).  
If pembrolizumab arm demonstrates superior PFS in both PD-L1 positive participants and all 
participants, then the corresponding alpha level can be shifted to the hypotheses for the OS 
endpoint using the graphical approach of Maurer and Bretz (2013) [37].
 
 
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See Figure 2 for the multiplicity strategy diagram of the study.
Figure 2
Multiplicity Strategy
Sample Size and Power Calculations
The study will randomize participants in a 1:1 ratio into pembrolizumab arm and paclitaxel
arm. The overall sample size will be up to approximately 720 (~360 PD-L1 positive 
participants and up to approximately 360 PD-L1 negative participants). That is, enrollment of 
the PD-L1 negative participants will be stopped, either when 360 PD-L1 positive participants 
have been enrolled or when 360 PD-L1 negative participants have been enrolled, whichever 
comes first. However, participants already in screening phase may be enrolled even after the 
maximum sample size has been reached.
Based on recommendations from an eDMC, PD-L1 negative participants are no longer 
eligible for enrollment into the study as of 20-MAR-2016; however, all participants enrolled 
prior to 20-MAR-2016 may continue on the study regardless of PD-L1 status.  Therefore, as 
of 20-MAR-2016, enrollment will only include those participants with PD-L1 positive 
expressions on their tumor. This enrollment change does not impact the statistical analysis 
plan. Enrollment was completed on 27-JUL-2016.
The FA of the study will complete after at least 290 OS events have been observed in the 
PD-L1 positive participants, or approximately 15 months after last patient randomized, 
whichever is later.
PFS analysis: As described in Section 8.7 - Interim Analyses, the main PFS analysis will be 
carried out at the IA. Approximately 320 PFS events will be accumulated in the positive 
PD-L1 participants at that time. An alpha of 0.35% will be allocated to PFS in the positive 
participants at this analysis. With ~320 PFS events in the PD-L1 positive participants, this IA
has 99% (97%) power to demonstrate that pembrolizumab is superior to paclitaxel at a one-
 
 
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sided 0.35% alpha-level, if the underlying HR of PFS is 0.5 (0.6). Success for PFS at the 
main analysis approximately corresponds to an observed HR of <0.74.
The power calculation is based on the following assumptions for participants in the positive 
PD-L1 population: 1) PFS follows an exponential distribution with a median of 3 months in
the paclitaxel arm; 2) An enrollment period of 14 months (IA is conducted when enrollment
is complete); 3) A yearly dropout rate of 5%.
OS analysis: The final OS analysis will be carried out when at least 290 OS events have 
occurred in the PD-L1 positive participants, or approximately 15 months after last patient 
randomized, whichever is later. For primary endpoint OS in the PD-L1 positive participants, 
the trial has 91% (85%) power to demonstrate that pembrolizumab is superior to paclitaxel at 
a one-sided 2.15% alpha-level, if the underlying HR of OS is 0.67 (0.7) and 290 OS events 
are observed. Success for OS at the FA approximately corresponds to an observed HR of 
<0.78 (approximately a 2-month improvement or greater in median OS).
The sample size and power calculation are based on the following assumptions for 
participants in the positive PD-L1 population: 1) OS follows an exponential distribution with 
a median of 7.5 months in the control arm; 2) An enrollment period of 14 months; 3) A 
yearly dropout rate of 2%.
The assumptions for the median PFS of 3 months and the median OS of 7.5 months in the
paclitaxel arm are based on estimates of median PFS and median OS from RAINBOW trial
[30].
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)

Geographic region (Europe/Israel/North America/Australia vs. Asia vs. Rest of 
World) 

Ethnic origin (Hispanic vs. Non-Hispanic)

PD-L1 (Positive vs. Negative)

ECOG PS (0 vs. 1)

Primary location (Stomach vs. GEJ)

Histological subtype (Diffuse vs. intestinal vs. mixed)

Disease Status (Locally advanced vs. Metastatic)

TTP on first-line therapy (< 6 months vs.  ≥ 6 months)
 
 
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Compliance (Medication Adherence)
Drug accountability data for trial treatment will be collected during the study. Any deviation 
from protocol-directed administration will be reported. 
Extent of Exposure
The extent of exposure will be summarized as duration of treatment in cycles.
9.0 LABELING, PACKAGING, STORAGE 
AND 
RETURN 
OF 
CLINICAL 
SUPPLIES
Investigational Product
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations.
Clinical Supplies will be provided by the Sponsor as summarized in Table 15.
Clinical supplies will be packaged to support enrollment and replacement subjects as 
required.  When a replacement subject is required, the Sponsor or designee needs to be 
contacted prior to dosing the replacement supplies.
Table 15
Product Descriptions
Product Name & Potency
Dosage 
Form
Source/Additional Information
Pembrolizumab (MK-3475), 25 mg/mL
Injection
Provided centrally by the Sponsor
Paclitaxel, 6 mg/mL
Injection
Provided centrally by the Sponsor 
or 
locally 
by 
the 
trial 
site, 
subsidiary, or designee
All supplies indicated in Table 15 will be provided per the “Source/Additional Information” 
column depending on local country operational requirements.
Any commercially available product not included in Table 15 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.
 
 
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Participants 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.
Clinical Supplies Disclosure
The 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 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 member that 
reviews and approves this trial.  The Sponsor is also required to document that each IRB/IEC 
meets regulatory and ICH GCP requirements by requesting and maintaining records of the 
names and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
 
 
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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 or through a secure password-protected electronic portal provided by the 
Sponsor.  The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes.  This may involve the 
transmission of information to countries that do not have laws protecting personal data.
Compliance with Law, Audit and Debarment
By signing this protocol, the investigator agrees to conduct the trial in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of Good 
Clinical Practice (e.g., International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice: 
Consolidated Guideline and other generally accepted standards of good clinical practice); and 
all applicable federal, state and local laws, rules and regulations relating to the conduct of the 
clinical trial.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by Merck, is provided in Section 12.1 -
Merck Code of Conduct for Clinical Trials.
The investigator also agrees to allow monitoring, audits, IRB/ERC review and regulatory 
authority inspection of trial-related documents and procedures and provide for direct access 
to all trial-related source data and documents.
The investigator agrees not to seek reimbursement from subjects, their insurance providers or 
from government programs for procedures included as part of the trial reimbursed to the 
investigator by the Sponsor.
The investigator shall prepare and maintain complete and accurate trial documentation in 
compliance with Good Clinical Practice standards and applicable federal, state and local 
laws, rules and regulations; and, for each subject participating in the trial, provide all data, 
and, upon completion or termination of the clinical trial, submit any other reports to the 
Sponsor as required by this protocol or as otherwise required pursuant to any agreement with 
the Sponsor.
Trial documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the trial site upon request for inspection, 
copying, review and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities.  The investigator agrees to promptly take any reasonable steps that are 
 
 
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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 
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 
 
 
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individual to serve as the Protocol CI and or CSR CI (e.g., availability of the CI during the 
anticipated review process, thorough understanding of clinical trial methods, appropriate 
enrollment of subject cohort, timely achievement of trial milestones).  The Protocol CI must 
be a participating trial investigator.
Compliance with Trial Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Amendments Act (FDAAA) of 2007, 
and the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, the Sponsor 
of the trial is solely responsible for determining whether the trial and its results are subject to 
the requirements for submission to http://www.clinicaltrials.gov, www.clinicaltrialregister.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 trials directive mandated trials. Information posted will allow 
subjects to identify potentially appropriate trials for their disease conditions and pursue 
participation by calling a central contact number for further information on appropriate trial 
locations and trial site contact information.   
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this trial or its results to those 
registries.
Quality Management System
By signing this protocol, the Sponsor agrees to be responsible for implementing and 
maintaining a quality management system with written development procedures and 
functional area standard operating procedures (SOPs) to ensure that trials are conducted and 
data are generated, documented, and reported in compliance with the protocol, accepted 
standards of Good Clinical Practice, and all applicable federal, state, and local laws, rules and 
regulations relating to the conduct of the clinical trial.
Data Management
The investigator or qualified designee is responsible for recording and verifying the accuracy 
of subject data.  By signing this protocol, the investigator acknowledges that his/her 
electronic signature is the legally binding equivalent of a written signature.  By entering 
his/her electronic signature, the investigator confirms that all recorded data have been 
verified as accurate.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
Publications
This trial is intended for publication, even if terminated prematurely. Publication may include 
any or all of the following: posting of a synopsis online, abstract and/or presentation at a 
scientific conference, or publication of a full manuscript.  The Sponsor will work with the 
authors to submit a manuscript describing trial results within 12 months after the last data 
become available, which may take up to several months after the last subject visit in some 
 
 
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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 
the order of authors’ names will be made based on participation and actual contributions to 
the trial and writing, as discussed above. The first author is responsible for defending the 
integrity of the data, method(s) of data analysis and the scientific content of the manuscript.
The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or 
presentations regarding this trial 45 days prior to submission for publication/presentation. 
Any information identified by the Sponsor as confidential must be deleted prior to 
submission; this confidentiality does not include efficacy and safety results. Sponsor review 
can be expedited to meet publication timelines.
 
 
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11.0 LIST OF REFERENCES
[1]
Disis ML. Immune regulation of cancer. J Clin Oncol 2010;28(29):4531-8.
[2]
Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, et al. Tumor-
associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune 
evasion. Nat Med 2002;8(8):793-800.
[3]
Sharpe AH, Freeman GJ. The B7-CD28 superfamily. Nat Rev Immunol 
2002;2(2):116-26.
[4]
Brown JA, Dorfman DM, Ma F-R, Sullivan EL, Munoz O, Wood CR, et al. 
Blockade of programmed death-1 ligands on dendritic cells enhances T cell 
activation and cytokine production. J Immunol 2003;170(3):1257-66.
[5]
Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and 
autoimmunity. Immunol Rev 2010;236:219-42.
[6]
Thompson RH, Dong H, Lohse CM, Leibovich BC, Blute ML, Cheville JC, et al. 
PD-1 is expressed by tumor-infiltrating immune cells and is associated with poor 
outcome for patients with renal cell carcinoma. Clin Cancer Res 2007;13(6):1757-
61.
[7]
Talmadge JE, Donkor M, Scholar E. Inflammatory cell infiltration of tumors: 
Jekyll or Hyde. Cancer Metastasis Rev 2007;26(3-4):373-400.
[8]
Usubütün A, Ayhan A, Uygur MC, Özen H, Toklu C, Ruacan S. Prognostic 
factors in renal cell carcinoma. J Exp Clin Cancer Res 1998;17(1):77-81.
[9]
Al-Shibli KI, Donnem T, Al-Saad S, Persson M, Bremnes RM, Busund L-T. 
Prognostic effect of epithelial and stromal lymphocyte infiltration in non-small 
cell lung cancer. Clin Cancer Res 2008;14(16):5220-7.
[10]
Deschoolmeester V, Baay M, Van Marck E, Weyler J, Vermeulen P, Lardon F, et 
al. Tumor infiltrating lymphocytes: an intriguing player in the survival of 
colorectal cancer patients. BMC Immunol. 2010 Apr 12;11:19.
[11]
Diez M, Pollán M, Enriquez JM, Dominguez P, Santana A, Tobaruela E, et al. 
Histopathologic prognostic score in colorectal adenocarcinomas. Anticancer Res 
1998;18(1B):689-94.
[12]
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(5795):1960-4.
[13]
Hiraoka N. Tumor-infiltrating lymphocytes and hepatocellular carcinoma: 
molecular biology. Int J Clin Oncol 2010;15(6):544-51.
[14]
Nobili C, Degrate L, Caprotti R, Franciosi C, Leone BE, Trezzi R, et al. Prolonged 
survival of a patient affected by pancreatic adenocarcinoma with massive 
lymphocyte and dendritic cell infiltration after interleukin-2 immunotherapy. 
Report of a case. Tumori 2008;94(3):426-30.
 
 
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[15]
Hodi FS, Dranoff G. The biologic importance of tumor-infiltrating lymphocytes. J 
Cutan Pathol 2010;37(Suppl 1):48-53.
[16]
Kloor M. Lymphocyte infiltration and prognosis in colorectal cancer. Lancet 
Oncol. 2009 Sep;10(9):840-1.
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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(1):97-106.
[18]
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.
[19]
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(3):449-59.
[20]
Nishimura H, Honjo T, Minato N. Facilitation of beta selection and modification 
of positive selection in the thymus of PD-1-deficient mice. J Exp Med. 2000 Mar 
6;191(5):891-8.
[21]
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 Int 2011;107(9):1500-
6.
[22]
Cancer 
Genome 
Atlas 
Research 
Network. 
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molecular 
characterization of gastric adenocarcinoma. Nature. 2014 Sep 11;513(7517):202-9.
[23]
Ropponen KM, Eskelinen MJ, Lipponen PK, Alhava E, Kosma V-M. Prognostic 
value of tumour-infiltrating lymphocytes (TILs) in colorectal cancer. J Pathol 
1997;182(3):318-24.
[24]
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.
[25]
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 Jun 19;358(25):2698-703.
[26]
Pölcher M, Braun M, Friedrichs N, Rudlowski C, Bercht E, Fimmers R, et al. 
Foxp3(+) cell infiltration and granzyme B(+)/Foxp3(+) cell ratio are associated 
with outcome in neoadjuvant chemotherapy-treated ovarian carcinoma. Cancer 
Immunol Immunother 2010;59(6):909-19.
 
 
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[27]
Okazaki T, Maeda A, Nishimura H, Kurosaki T, Honjo T. PD-1 immunoreceptor 
inhibits B cell receptor-mediated signaling by recruiting src homology 2-domain-
containing tyrosine phosphatase 2 to phosphotyrosine. Proc Natl Acad Sci U S A 
2001;98(24):13866-71.
[28]
Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Annu Rev
Immunol 2005;23:515-48.
[29]
Muro K, Bang Y, Shankaran V, Geva R, Catenacci DV, Gupta S, et al. LBA15 - A 
phase 1b study of pembrolizumab (Pembro; MK-3475) in patients (Pts) with 
advanced gastric cancer. European Society for Medical Oncology (ESMO); 2014
Sep 26-30; Madrid, ES.
[30]
Wilke H, Muro K, Van Cutsem E, Oh SC, Bodoky G, Shimada Y, et al. 
Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with 
previously 
treated 
advanced 
gastric 
or 
gastro-oesophageal 
junction 
adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet 
Oncol. 2014 Oct;15(11):1224-35.
[31]
Fuchs CS, Tomasek J, Yong CJ, Dumitru F, Passalacqua R, Goswami C, et al. 
Ramucirumab monotherapy for previously treated advanced gastric or gastro-
oesophageal junction adenocarcinoma (REGARD): an international, randomised, 
multicentre, placebo-controlled, phase 3 trial. Lancet. 2014 Jan 4;383(9911):31-9.
[32]
Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, et al. The 
European Organization for Research and Treatment of Cancer QLQ-C30: a 
quality-of-life instrument for use in international clinical trials in oncology. J Natl 
Cancer Inst 1993;85(5):365-76.
[33]
EuroQol Group. EuroQol - a new facility for the measurement of health-related 
quality of life. Health Policy. 1990 Dec;16(3):199-208.
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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):132-49.
[35]
National Comprehensive Cancer Network. Cancer- and chemotherapy- induced 
anemia, 2014.
[36]
Miettinen O, Nurminen M. Comparative analysis of two rates. Stat Med 
1985;4:213-26.
[37]
Maurer W, Bretz F. Multiple testing in group sequential trials using graphical 
approaches. Stat Biopharm Res 2013;5(4):311-20.
[38]
Finkelstein DM. A proportional hazards model for interval-censored failure time 
data. Biometrics 1986;42:845-54.
[39]
Uno H, Claggett B, Tian L, Inoue E, Gallo P, Miyata T, et al. Moving beyond the 
hazard ratio in quantifying the between-group difference in survival analysis. J 
Clin Oncol. 2014 Aug 1;32(22):2380-5.
 
 
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[40]
Odell PM, Anderson KM, Kannel WB. New models for predicting cardiovascular 
events. J Clin Epidemiol. 1994 Jun;47(6):583-92.
[41]
Mehrotra DV, Su SC, Li X. An efficient alternative to the stratified Cox model 
analysis. Stat Med. 2012 Jul 30;31(17):1849-56.
[42]
Robins JM, Tsiatis AA. Correcting for non-compliance in randomized trials using 
rank preserving structural failure time models. Commun Stat-Theor M 
1991;20(8):2609-31.
[43]
Ferris RL, Blumenschein G Jr, Fayette J, Guigay J, Colevas AD, Licitra L, et al. 
Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck. N 
Engl J Med. 2016 Nov 10;375(19):1856-1867.
[44]
Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, et al. 
Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung 
Cancer. N Engl J Med. 2015 Oct 22;373(17):1627-39.
[45]
Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, et al. Pembrolizumab 
as Second-Line Therapy for Advanced Urothelial Carcinoma. N Engl J Med. 2017 
Mar 16;376(11):1015-1026.
 
 
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12.0 APPENDICES
Merck Code of Conduct for Clinical Trials
Merck*
Code of Conduct for Clinical Trials
I.
Introduction
A. Purpose
Merck, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing and reporting these trials in 
compliance with the highest ethical and scientific standards. Protection of subject safety is the overriding concern in 
the design of clinical trials. In all cases, Merck clinical trials will be conducted in compliance with local and/or 
national regulations and in accordance with the ethical principles that have their origin in the Declaration of Helsinki. 
B. Scope
Such standards shall be endorsed for all clinical interventional investigations sponsored by Merck irrespective of the 
party (parties) employed for their execution (e.g., contract research organizations, collaborative research efforts). This 
Code is not intended to apply to trials which are observational in nature, or which are retrospective. Further, this Code 
does not apply to investigator-initiated trials which are not under the control of Merck.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of Merck or comparator products.  Alternatively, Merck may 
conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to determine 
subject preferences, etc.  
The design (i.e., subject population, duration, statistical power) must be adequate to address the specific purpose 
of the trial.  Research subjects must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
Merck selects investigative sites based on medical expertise, access to appropriate subjects, adequacy of facilities 
and staff, previous performance in Merck trials, as well as budgetary considerations.  Prior to trial initiation, sites 
are evaluated by Merck personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Trial sites are monitored to assess compliance with the trial protocol and general principles of Good Clinical 
Practice.  Merck reviews clinical data for accuracy, completeness and consistency. Data are verified versus source 
documentation according to standard operating procedures.  Per Merck policies and procedures, if fraud, 
misconduct or serious GCP-non-Compliance are suspected, the issues are promptly investigated. When necessary, 
the clinical site will be closed, the responsible regulatory authorities and ethics review committees notified and 
data disclosed accordingly. 
B. Publication and Authorship
To the extent scientifically appropriate, Merck seeks to publish the results of trials it conducts.  Some early phase or 
pilot trials are intended to be hypothesis-generating rather than hypothesis testing.  In such cases, publication of 
results may not be appropriate since the trial may be underpowered and the analyses complicated by statistical issues 
of multiplicity.
Merck’s policy on authorship is consistent with the requirements outlined in the ICH-Good Clinical Practice 
guidelines. In summary, authorship should reflect significant contribution to the design and conduct of the trial, 
performance or interpretation of the analysis, and/or writing of the manuscript.  All named authors must be able to 
defend the trial results and conclusions.  Merck funding of a trial will be acknowledged in publications. 
 
 
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III. Subject Protection
A. IRB/ERC review
All clinical trials will be reviewed and approved by an independent IRB/ERC before being initiated at each site.  
Significant changes or revisions to the protocol will be approved by the IRB/ERC prior to implementation, except that 
changes required urgently to protect subject safety and well-being may be enacted in anticipation of IRB/ERC 
approval. For each site, the IRB/ERC and Merck will approve the subject informed consent form. 
B. Safety
The guiding principle in decision-making in clinical trials is that subject welfare is of primary importance.  Potential 
subjects will be informed of the risks and benefits of, as well as alternatives to, trial participation. At a minimum, trial
designs will take into account the local standard of care.  Subjects are never denied access to appropriate medical care 
based on participation in a Merck clinical trial. 
All participation in Merck clinical trials is voluntary.  Subjects are enrolled only after providing informed consent for 
participation.  Subjects may withdraw from a Merck trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
Merck is committed to safeguarding subject confidentiality, to the greatest extent possible. Unless required by law, 
only the investigator, sponsor (or representative) and/or regulatory authorities will have access to confidential medical 
records that might identify the research subject by name.  
D. Genomic Research
Genomic Research will only be conducted in accordance with informed consent and/or as specifically authorized by 
an Ethics Committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive.  It is Merck’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of Merck trials.   Merck does not pay incentives to 
enroll subjects in its trials.  However, when enrollment is particularly challenging, additional payments may be made 
to compensate for the time spent in extra recruiting efforts.
Merck does not pay for subject referrals.  However, Merck may compensate referring physicians for time spent on 
chart review to identify potentially eligible subjects.
B. Clinical Research Funding 
Informed consent forms will disclose that the trial is sponsored by Merck, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial.  However, the local IRB/ERC may wish to alter 
the wording of the disclosure statement to be consistent with financial practices at that institution.  As noted above, 
publications resulting from Merck trials will indicate Merck as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices including, in the U.S., those established by the American Medical 
Association (AMA). 
V. Investigator Commitment
Investigators will be expected to review Merck’s Code of Conduct as an appendix to the trial protocol, and in signing 
the protocol, agree to support these ethical and scientific standards.
* In this document, "Merck" refers to Merck Sharp & Dohme Corp. and Schering Corporation, each of which is a 
subsidiary of Merck & Co., Inc.  Merck is known as MSD outside of the United States and Canada.  As warranted by 
context, Merck also includes affiliates and subsidiaries of Merck & Co., Inc."
 
 
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Collection and Management of Specimens for Future Biomedical Research
1. Definitions
a.
Biomarker:  A biological molecule found in blood, other body fluids, or tissues that is 
a sign of a normal or abnormal process or of a condition or disease.  A biomarker may 
be used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics:  The investigation of variations of DNA and RNA characteristics 
as related to drug/vaccine response.2
c.
Pharmacogenetics:  A subset of pharmacogenomics, pharmacogenetics is the 
influence of variations in DNA sequence on drug/vaccine response.2
d. DNA:  Deoxyribonucleic acid.
e.
RNA:  Ribonucleic acid.
2. Scope of Future Biomedical Research
The specimens collected in this trial as outlined in Section 7.1.3.5 – Future Biomedical 
Research will be used to study various causes for how subjects may respond to a 
drug/vaccine.  Future biomedical research specimen(s) will be stored to provide a 
resource for future trials conducted by Merck focused on the study of biomarkers 
responsible for how a drug/vaccine enters and is removed by the body, how a 
drug/vaccine works, other pathways a drug/vaccine may interact with, or other aspects of 
disease.  The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need.  All specimens will be used by Merck or designees and research 
will be monitored and reviewed by a committee of our scientists and clinicians.
3. Summary of Procedures for Future Biomedical Research
a.
Subjects for Enrollment
All subjects enrolled in the clinical trial will be considered for enrollment in Future 
Biomedical Research.
b. Informed Consent
Informed consent for specimens (i.e., DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all subjects or legal guardians, at a trial 
visit by the investigator or his or her designate.  Informed consent for Future 
Biomedical Research should be presented to the subjects on Visit 1.  If delayed, 
present consent at next possible Subject Visit. Informed consent must be obtained 
prior to collection of all Future Biomedical Research specimens.  Consent forms 
signed by the subject will be kept at the clinical trial site under secure storage for 
regulatory reasons.  Information contained on the consent form alone cannot be traced 
 
 
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to any specimens, test results, or medical information once the specimens have been 
rendered de-identified
A template of each trial site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.  Each consent will be assessed for 
appropriate specimen permissions.  
Each informed consent approved by an ethics committee is assigned a unique tracking 
number.  The tracking number on this document will be used to assign specimen 
permissions for each specimen into the Entrusted Keyholder’s Specimen Database.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of both consent and acquisition of Future Biomedical Research 
specimens will be captured in the electronic Case Report Forms (eCRFs).  
Reconciliation of both forms will be performed to assure that only appropriately-
consented specimens are used for this sub-trial's research purposes. Any specimens 
for which such an informed consent cannot be verified will be destroyed.
d. Future Biomedical Research Specimen Collections
Blood specimens for DNA or RNA isolation will usually be obtained at a time when 
the participant is having blood drawn for other trial purposes. Specimens like tissue 
and bone marrow will usually be obtained at a time when the subject is having such a 
procedure for clinical purposes.
Specimens will be collected and sent to the laboratory designated for the trial where 
they will be processed (e.g., DNA or RNA extraction, etc) following the Merck 
approved policies and procedures for specimen handling and preparation.
If specimens are collected for a specific genotype or expression analysis as an 
objective to the main trial, this analysis is detailed in the main body of this protocol 
(Section 8.0 – Statistical Analysis Plan).  These specimens will be processed, 
analyzed, and the remainder of the specimen will be destroyed.  The results of these 
analyses will be reported along with the other trial results.  A separate specimen will 
be obtained from properly-consented subjects in this protocol for storage in the 
biorepository for Future Biomedical Research.
4. Confidential Subject Information for Future Biomedical Research 
In order to optimize the research that can be conducted with Future Biomedical Research 
specimens, it is critical to link subject' clinical information with future test results. In fact 
little or no research can be conducted without connecting the clinical trial data to the 
specimen. The clinical data allow specific analyses to be conducted. Knowing subject 
characteristics like gender, age, medical history and treatment outcomes are critical to 
understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for Future 
Biomedical Research, Merck has developed secure policies and procedures.  All 
specimens will be de-identified as described below. 
At the clinical trial site, unique codes will be placed on the Future Biomedical Research 
specimens for transfer to the storage facility.  This first code is a random number which 
 
 
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does not contain any personally identifying information embedded within it. The link (or 
key) between subject identifiers and this first unique code will be held at the trial site.  No 
personal identifiers will appear on the specimen tube.  
This first code will be replaced with a second code at a Merck designated storage/lab 
facility.  The second code is linked to the first code via a second key. The specimen is 
now double coded.  Specimens with the second code are sometimes referred to as de-
identified specimens. The use of the second code provides additional confidentiality and 
privacy protection for subjects over the use of a single code.  Access to both keys would 
be needed to link any data or specimens back to the subject's identification.
The second code is stored separately from the first code and all associated personal 
specimen identifiers.  A secure link, the second key, will be utilized to match the second 
code to the first code to allow clinical information collected during the course of the trial 
to be associated with the specimen.  This second key will be transferred under secure 
procedures by the Merck designated facility to an Entrusted Keyholder at Merck.  The 
second code will be logged into the primary biorepository database at Merck and, in this 
database, this identifier will not have identifying demographic data or identifying clinical 
information (i.e., race, sex, age, diagnosis, lab values) associated with it. The specimen 
will be stored in a designated biorepository site with secure policies and procedures for 
specimen storage and usage.
The second key can be utilized to reconstruct the link between the results of future 
biomedical research and the clinical information, at the time of analysis.  This linkage 
would not be possible for the scientist conducting the analysis, but can only be done by 
the Merck Entrusted Keyholder under strict security policies and procedures.  The Merck 
Entrusted Keyholder will link the information and then issue a de-identified data set for 
analysis.  The only other circumstance by which future biomedical research data would 
be directly linked to the full clinical data set would be those situations mandated by 
regulatory authorities (e.g., EMEA, FDA), whereby this information would be directly 
transferred to the regulatory authority.
5. Biorepository Specimen Usage
Specimens obtained for the Merck Biorepository will be used for analyses using good 
scientific practices.  However, exploratory analyses will not be conducted under the 
highly validated conditions usually associated with regulatory approval of diagnostics.  
The scope of research performed on these specimens is limited to the investigation of the 
variability in biomarkers that may correlate with a clinical phenotype in subjects.
Analyses utilizing the Future Biomedical Research specimens may be performed by 
Merck, or an additional third party (e.g., a university investigator) designated by Merck.  
The investigator conducting the analysis will be provided with double coded specimens.  
Re-association of analysis results with corresponding clinical data will only be conducted 
by the Merck Entrusted Keyholder.  Any contracted third party analyses will conform to 
the specific scope of analysis outlined in future biomedical research protocol and consent.  
Future Biomedical Research specimens remaining with the third party after the specific 
analysis is performed will be returned to the sponsor or destroyed and documentation of 
destruction will be reported to Merck.
 
 
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6. Withdrawal From Future Biomedical Research 
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   Subjects may withdraw consent at any time by 
contacting the principal investigator for the main trial.  If medical records for the main 
trial are still available, the investigator will contact Merck using the designated mailbox 
(clinical.specimen.management@merck.com) and a form will be provided by Merck to 
obtain appropriate information to complete specimen withdrawal.  Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed. A letter 
will be sent from Merck to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for destruction or already performed prior to 
the request being received by the Sponsor will continue to be used as part of the overall 
research trial data and results. No new analyses would be generated after the request is 
received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the subject’s personal information and their specimens. In this situation, the 
request for specimen destruction can not be processed. 
7. Retention of Specimens 
Future Biomedical Research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from acquisition.  Specimens may be stored for longer if a 
regulatory or governmental authority has active questions that are being answered.  In 
this special circumstance, specimens will be stored until these questions have been 
adequately addressed.
Specimens from the trial site will be shipped to a central laboratory and then shipped to 
the Merck designated biorepository.  The specimens will be stored under strict 
supervision in a limited access facility which operates to assure the integrity of the 
specimens.  Specimens will be destroyed according to Merck policies and procedures and 
this destruction will be documented in the biorepository database.
8. Data Security
Separate databases for specimen information and for results from the Future Biomedical 
Research sub-trial will be maintained by Merck.  This is done to separate the future 
exploratory test results (which include genetic data) from the clinical trial database 
thereby maintaining a separation of subject number and these results.  The separate 
databases are accessible only to the authorized Sponsor and the designated trial 
administrator research personnel and/or collaborators.  Database user authentication is 
highly secure, and is accomplished using network security policies and practices based in 
international standards (e.g., ISO17799) to protect against unauthorized access.  The 
Merck Entrusted Keyholder maintains control over access to all specimen data.  These 
data are collected for future biomedical research purposes only as specified in this sub-
trial will not be used for any other purpose.
 
 
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9. Reporting of Future Biomedical Research Data to Subjects
There is no definitive requirement in either authoritative ethical guidelines or in relevant 
laws/regulations globally that research results have to be, in all circumstances, returned to 
the trial participant.  Some guidelines advocate a proactive return of data in certain 
instances.  No information obtained from exploratory laboratory studies will be reported 
to the subject or family, and this information will not be entered into the clinical database 
maintained by Merck on subjects.  Principle reasons not to inform or return results to the 
subject include: lack of relevance to subject health, limitations of predictive capability, 
concerns of misinterpretation and absence of good clinical practice standards in 
exploratory research typically used for diagnostic testing.
If any exploratory results are definitively associated with clinical significance for subjects 
while the clinical trial is still ongoing, investigators will be contacted with information as 
to how to offer clinical diagnostic  testing (paid for by Merck) to subjects enrolled and 
will be advised that counseling should be made available for all who choose to participate 
in this diagnostic testing. 
If any exploratory results are definitively associated with clinical significance after 
completion of a clinical trial, Merck will publish the results without revealing specific 
subject information, inform all trial sites who participated in the Merck clinical trial and 
post anonymized results on our website or other accredited website(s) that allow for 
public access (e.g., disease societies who have primary interest in the results) in order that 
physicians and patients may pursue clinical diagnostic testing if they wish to do so.
10. Gender, Ethnicity and Minorities
Although many diagnoses differ in terms of frequency by ethnic population and gender, 
every effort will be made to recruit all subjects diagnosed and treated on Merck clinical 
trials for future biomedical research.  When trials with specimens are conducted and 
subjects identified to serve as controls, every effort will be made to group specimens 
from subjects and controls to represent the ethnic and gender population representative of 
the disease under current investigation.
11. Risks Versus Benefits of Future Biomedical Research 
For future biomedical research, risks to the participant have been minimized. 
No 
additional risks to the participant 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 
 
 
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be released to outside persons or agencies, in any way that could be tied to an individual 
subject.
12. Self-Reported Ethnicity
Subjects who participate in future biomedical research will be asked to provide self-
reported ethnicity.  Subjects who do not wish to provide this data may still participate in 
future biomedical research.
13. Questions
Any questions related to the future biomedical research should be e-mailed directly to 
clinical.specimen.management@merck.com.
14. References
1. National Cancer Institute: http://www.cancer.gov/dictionary/?searchTxt=biomarker
2. International Conference on Harmonization: DEFINITIONS FOR GENOMIC 
BIOMARKERS, PHARMACOGENOMICS, PHARMACOGENETICS, GENOMIC 
DATA 
AND 
SAMPLE 
CODING 
CATEGORIES 
-
E15; 
http://www.ich.org/LOB/media/MEDIA3383.pdf
 
 
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Understanding the Intent, Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff
 
 
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ECOG Performance Status
GRADE ECOG PERFORMANCE STATUS
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature, e.g., light house work, office work
2
Ambulatory and capable of all self-care but unable to carry out any work activities; up 
and about more than 50% of waking hours
3
Capable of only limited self-care; confined to bed or chair more than 50% of waking 
hours
4
Completely disabled; cannot carry on any self-care; totally confined to bed or chair
5
Dead
*Oken M, Creech R, Tormey D, et al. Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol. 1982;5:649-655
http://ecog-acrin.org/resources/ecog-performance-status
 
 
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Common Terminology Criteria for Adverse Events V4.0 (CTCAE)
The descriptions and grading scales found in the revised NCI-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
2L
Second-line
ADA
Anti-drug antibodies
AE
Adverse event
ALT
Alanine aminotransferase
ANC
Absolute neutrophil count
aPTT
Activated partial thromboplastin time
ASaT
All Subjects as Treated
AST
Aspartate aminotransferase
ß-hCG
Beta-human chorionic gonadotropin
BP
Blood pressure
BRAF
Proto-oncogene that encodes a protein called B-Raf
BSA
Body surface area
BSC
Best supportive care
C30
Core Questionnaire
CA 19-9
Carbohydrate antigen 19-9
CBC
Complete blood count
CD
Cluster of differentiation
CEA
Carcinoembryonic antigen
CI
Confidence interval
CO2
Carbon dioxide
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
DKA
Diabetic ketoacidosis
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic acid
DOR
Duration of response
ECG
Electrocardiogram
ECI
Events of Clinical Interest
ECOG
Eastern Cooperative Oncology Group
EDC
Electronic Data Capture
eDMC
External Data Monitoring Committee
EMA/EMEA
European Medicines Agency
EOC
Executive Oversight Committee
EORTC
European Organisation for Research and Treatment of Cancer
EPO
Erythropoietin
ePRO
Electronic Patient Reported Outcomes
ERC
Ethics Review Committee
EuroQoL EQ-5D
European Quality-of-Life 5 Dimension
FA
Final analysis
FBR
Future Biomedical Research
FDA
Food and Drug Administration
FFPE
Formalin-fixed paraffin-embedded
FT4
Free thyroxine
GBS
Guillain-Barre Syndrome
 
 
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Abbreviation/Term
Definition
GCP
Good Clinical Practice
G-CSF
Granulocyte-colony stimulating factor
GEJ
Gastroesophageal Junction
GFR
Glomerular filtration rate
GI
Gastrointestinal
HBsAg
Hepatitis B surface antigen
HEA
Health Economic Assessment
HER2/neu
Human epidermal growth factor receptor 2
HIV
Human Immunodeficiency Virus
HPV
Human Papillomavirus
HR
Hazard ratio
HRQoL
Health-related quality-of-life
IA
Interim analysis
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IgC
Immunoglobulin constant
IgV
Immunoglobulin variable type
INR
International Normalized Ratio
irAEs
Immune-related adverse events
IRB
Institutional Review Board
irRECIST
Immune-related RECIST
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
KN
KEYNOTE
mAb
Monoclonal antibody
MMR
Mismatch repair
MSD
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
MSI
Microsatellite instability
NA or N/A
Not applicable
NCI
National Cancer Institute
NSAID
Non-steroidal anti-inflammatory drug
NSCLC
Non-small cell lung cancer
ORR
Overall response rate
OS
Overall survival
OTC
Over-the-counter
P
Pulse
PD
Progressive disease
PD-1
Programmed cell death 1
PD-L1
Programmed cell death ligand 1
PD-L2
Programmed cell death ligand 2
PDLC
Predefined limit of change
PFS
Progression-free survival
PGt
Pharmacogenetic
PIN
Personal Identification Number
PK
Pharmacokinetic
 
 
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Abbreviation/Term
Definition
PK/PD
Pharmacokinetic/pharmacodynamic
PO
Oral administration
PR
Partial response
PRO
Patient Reported Outcomes
PS
Performance Status
PT
Prothrombin Time
PTT
Partial thromboplastin time
Q2W
Every 2 weeks
Q3W
Every 3 weeks
QLQ
Quality-of-Life Questionnaire
RECIST 1.1
Response Evaluation Criteria in Solid Tumors Version 1.1
RNA
Ribonucleic acid
RR
Respiratory rate
SAE
Serious adverse events
SAP
Statistical Analysis Plan
SD
Stable disease
SGOT
Serum glutamic oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transaminase
SOC
System Organ Class
SOP
Standard Operating Procedures
SOTR
Solid organ transplant rejection
sSAP
Supplemental Statistical Analysis Plan
STO22
Gastric Cancer Module
T
Temperature
T1DM
Type 1 diabetes mellitus
T3
Triiodothyronine
TIL
Tumor-infiltrating lymphocytes
TSH
Thyroid-stimulating hormone
TTP
Time to progression
ULN
Upper limit of normal
US
United States
WBC
White blood cell
 
 
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13.0 SIGNATURES
Sponsor's Representative
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
Investigator
I agree to conduct this clinical trial in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol (including other manuals and documents 
referenced from this protocol).  I agree to conduct the trial in accordance with generally 
accepted standards of Good Clinical Practice.  I also agree to report all information or data in 
accordance with the protocol and, in particular, I agree to report any serious adverse events 
as defined in Section 7.0 – Assessing and Recording Adverse Events.  I also agree to handle 
all clinical supplies provided by the Sponsor and collect and handle all clinical specimens in 
accordance with the protocol.  I understand that information that identifies me will be used 
and disclosed as described in the protocol, and that such information may be transferred to 
countries that do not have laws protecting such information.  Since the information in this
protocol and the referenced Investigator’s Brochure is confidential, I understand that its 
disclosure to any third parties, other than those involved in approval, supervision, or conduct 
of the trial is prohibited.  I will ensure that the necessary precautions are taken to protect such 
information from loss, inadvertent disclosure or access by third parties.
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
 
 
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