Clinical trial NCT04003636
Conditions: Biliary Tract Carcinoma
Keywords: Programmed cell death 1 (PD-1) Pembrolizumab Cholangiocarcinoma Gallbladder cancer Checkpoint inhibitor Immunotherapy Biliary Keytruda Bile Duct Cancer
Sponsor: Merck Sharp & Dohme LLC
Start date: 2019-09-24; Completion date: 2025-04-01
Enrollment: 1069 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a study of pembrolizumab plus gemcitabine/cisplatin versus placebo plus gemcitabine/cisplatin as first-line therapy in participants with advanced and/or unresectable biliary tract carcinoma. The primary hypothesis is pembrolizumab plus gemcitabine/cisplatin is superior to placebo plus gemcitabine/cisplatin with respect to overall survival (OS).

Detailed description:

Arms: arm 1: Pembrolizumab, 200 mg, every 3 weeks (Q3W), Day 1 of each 3-week cycle for up to 35 cycles PLUS Gemcitabine, 1000 mg/m\^2, Q3W, Day 1 and Day 8 of each cycle until progressive disease or unacceptable toxicity PLUS Cisplatin, 25 mg/m\^2, Q3W, Day 1 and Day 8 of each cycle for up to 8 cycles. arm 2: Placebo to Pembrolizumab, 200 mg, every 3 weeks (Q3W), Day 1 of each 3-week cycle for up to 35 cycles PLUS Gemcitabine, 1000 mg/m\^2, Q3W, Day 1 and Day 8 of each cycle until progressive disease or unacceptable toxicity PLUS Cisplatin, 25 mg/m\^2, Q3W, Day 1 and Day 8 of each cycle for up to 8 cycles.
Interventions: intervention 1: Pembrolizumab intervention 2: Gemcitabine intervention 3: Cisplatin intervention 4: Placebo
Intervention descriptions: intervention 1: Pembrolizumab by intravenous (IV) infusion intervention 2: Gemcitabine by IV infusion intervention 3: Cisplatin by IV infusion intervention 4: Placebo to pembrolizumab

Protocol documents:
Prot_SAP_000.pdf: 
Official Protocol Title:
NCT number:
Document Date:
A Phase 3 Randomized, Double Blind Study of 
Pembrolizumab Plus Gemcitabine/Cisplatin versus 
Placebo Plus Gemcitabine/Cisplatin as First-Line 
Therapy in Participants with Advanced and/or 
Unresectable Biliary Tract Carcinoma
NCT04003636
16-June-2022


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Title Page
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME LLC, RAHWAY, NJ, USA (MSD).
Protocol Title: A Phase 3 Randomized, Double Blind Study of Pembrolizumab Plus 
Gemcitabine/Cisplatin versus Placebo Plus Gemcitabine/Cisplatin as First-Line Therapy in 
Participants with Advanced and/or Unresectable Biliary Tract Carcinoma
Protocol Number: 966-06
Compound Number: MK-3475
Sponsor Name:
Merck Sharp & Dohme LLC
(hereafter referred to as the Sponsor or MSD)
Legal Registered Address:
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Regulatory Agency Identifying Number(s):
IND
EudraCT
123482
2019-000944-82
Approval Date: 16 June 2022
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 6
16-JUN-2022
Merck Sharp & Dohme Corp. underwent an entity name and address change 
to Merck Sharp & Dohme LLC, Rahway, NJ, USA. This conversion 
resulted only in an entity name change and update to the address.
Amendment 5
18-NOV-2021
To add a new, earlier interim analysis for OS due to recently emerging 
external data showing positive results for immunotherapy plus
chemotherapy as first-line therapy for patients with advanced biliary tract 
carcinoma, and 
Amendment 4
26-AUG-2021
To update Statistical Analysis plan accounting for faster event accumulation 
than initially projected by increasing the number of events at final analysis 
and specifying time and event triggers for analyses to ensure sufficient 
minimum follow-up time for a longer potential delayed effect.
Amendment 3
11-MAR-2021
The Dose Modification and Toxicity Management Guidelines for irAEs and 
table were updated to align with the USPI 
In addition,
updates were made to address 
Cisplatin unit dose strengths were added.
Amendment 2
08-DEC-2020
To revise the primary endpoint to OS only with a more conservative hazard 
ratio assumption accounting for possible delayed treatment effect; to change 
PFS to a secondary endpoint; and to remove the futility analysis. Also, to 
update interim and final analysis timing from calendar-based to event based.
CCI
CCI
CCI
CCI
CCI
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Document
Date of Issue
Overall Rationale
Amendment 1
23-JAN-2020
To limit the second course only to those participants who received 
pembrolizumab in the first course after unblinding participants individually,
to address
and minimize unnecessary participant 
visits and procedures.
Original Protocol
21-JUN-2019
Not applicable.
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 06
Overall Rationale for the Amendments:
Merck Sharp & Dohme Corp. underwent an entity name and address change to Merck Sharp & Dohme LLC, Rahway, NJ, USA. This 
conversion resulted only in an entity name change and update to the address.
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
Title Page
Section 10.1.1 Code of 
Conduct for Clinical Trials
Throughout
Sponsor entity name and address change.
Merck Sharp & Dohme Corp. underwent an entity name 
and address change to Merck Sharp & Dohme LLC, 
Rahway, NJ, USA. This conversion resulted only in an 
entity name change and update to the address.
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................5
1
PROTOCOL SUMMARY ............................................................................................15
1.1
Synopsis.................................................................................................................15
1.2
Schema ..................................................................................................................19
1.3
Schedule of Activities (SoA)................................................................................20
1.3.1
Schedule of Activities Initial Intervention Phase.........................................20
1.3.2
Schedule of Activities Second Course Phase...............................................37
2
INTRODUCTION..........................................................................................................47
2.1
Study Rationale....................................................................................................47
2.2
Background ..........................................................................................................47
2.2.1
Pharmaceutical and Therapeutic Background .............................................47
2.2.2
Biliary Tract Cancer: Epidemiology and Current Therapeutic Options......48
2.2.3
Rationale for Immunotherapy in Biliary Cancer: Preclinical and Clinical 
Studies..........................................................................................................51
2.2.4
Ongoing Clinical Studies in Biliary Cancer.................................................52
2.2.5
Rationale and Safety of Combining Pembrolizumab with Gemcitabine 
and Cisplatin ................................................................................................53
2.2.6
Delayed Treatment Effect With Immunotherapy ........................................55
2.3
Benefit/Risk Assessment......................................................................................55
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................56
4
STUDY DESIGN............................................................................................................58
4.1
Overall Design......................................................................................................58
4.2
Scientific Rationale for Study Design.................................................................60
4.2.1
Rationale for Stratification Factors..............................................................61
4.2.2
Rationale for Endpoints ...............................................................................61
4.2.2.1
Efficacy Endpoints.............................................................................61
4.2.2.2
RECIST 1.1........................................................................................62
4.2.2.3
iRECIST.............................................................................................62
4.2.2.4
Safety Endpoints................................................................................63
4.2.2.5
Patient-reported Outcomes.................................................................63
4.2.2.5.1
EORTC QLQ-C30 ...................................................................63
4.2.2.5.2
EuroQoL EQ-5D-5L ................................................................63
4.2.2.5.3
EORTC QLQ-BIL21 ...............................................................63
4.2.2.6
Pharmacokinetic Endpoints ...............................................................64
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4.2.2.7
Planned Exploratory Biomarker Research.........................................64
4.2.2.8
Future Biomedical Research..............................................................66
4.2.3
Rationale for the Use of Comparator/Placebo .............................................66
4.3
Justification for Dose...........................................................................................67
4.4
Beginning and End of Study Definition .............................................................68
4.4.1
Clinical Criteria for Early Study Termination .............................................68
5
STUDY POPULATION ................................................................................................68
5.1
Inclusion Criteria.................................................................................................68
5.2
Exclusion Criteria................................................................................................72
5.3
Lifestyle Considerations......................................................................................75
5.4
Screen Failures.....................................................................................................75
5.5
Participant Replacement Strategy......................................................................75
6
STUDY INTERVENTION............................................................................................76
6.1
Study Intervention(s) Administered...................................................................76
6.1.1
Treatment .....................................................................................................79
6.1.2
Second Course .............................................................................................79
6.2
Preparation/Handling/Storage/Accountability .................................................80
6.2.1
Dose Preparation..........................................................................................80
6.2.2
Handling, Storage, and Accountability........................................................80
6.3
Measures to Minimize Bias: Randomization and Blinding..............................81
6.3.1
Intervention Assignment..............................................................................81
6.3.2
Stratification.................................................................................................81
6.3.3
Blinding........................................................................................................81
6.4
Study Intervention Compliance..........................................................................81
6.5
Concomitant Therapy..........................................................................................82
6.5.1
Rescue Medications and Supportive Care ...................................................84
6.6
Dose Modification (Escalation/Titration/Other)...............................................85
6.6.1
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue).................................................................................................85
6.6.1.1
Dose Modification of Pembrolizumab...............................................86
6.6.1.2
Dose Modification of Gemcitabine or Cisplatin................................93
6.6.1.3
Guidance for Management of Hepatic Events of Clinical Interest....96
6.7
Intervention After the End of the Study............................................................99
6.8
Clinical Supplies Disclosure................................................................................99
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL..........................................................................................................100
7.1
Discontinuation of Study Intervention.............................................................100
7.2
Participant Withdrawal From the Study.........................................................101
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7.3
Lost to Follow-up ...............................................................................................102
8
STUDY ASSESSMENTS AND PROCEDURES......................................................102
8.1
Administrative and General Procedures .........................................................103
8.1.1
Informed Consent.......................................................................................103
8.1.1.1
General Informed Consent...............................................................103
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research...........................................................................................104
8.1.2
Inclusion/Exclusion Criteria ......................................................................104
8.1.3
Participant Identification Card...................................................................104
8.1.4
Medical History .........................................................................................104
8.1.5
Prior and Concomitant Medications Review.............................................105
8.1.5.1
Prior Medications.............................................................................105
8.1.5.2
Concomitant Medications................................................................105
8.1.6
Assignment of Screening Number.............................................................105
8.1.7
Assignment of Treatment/Randomization Number...................................105
8.1.8
Study Intervention Administration ............................................................106
8.1.8.1
Timing of Dose Administration.......................................................106
8.1.8.1.1
Pembrolizumab ......................................................................106
8.1.8.1.2
Gemcitabine/Cisplatin............................................................106
8.1.9
Discontinuation and Withdrawal ...............................................................107
8.1.9.1
Withdrawal From Future Biomedical Research ..............................107
8.1.10
Participant Blinding/Unblinding................................................................107
8.1.11
Calibration of Equipment...........................................................................108
8.1.12
Tumor Tissue for Biomarker Status...........................................................109
8.2
Efficacy/Immunogenicity Assessments ............................................................109
8.2.1
Tumor Imaging and Assessment of Disease..............................................109
8.2.1.1
Initial Tumor Imaging......................................................................110
8.2.1.2
Tumor Imaging During the Study....................................................110
8.2.1.3
End-of-Treatment and Follow-up Tumor Imaging..........................111
8.2.1.4
Second Course (Retreatment) Tumor Imaging................................112
8.2.1.5
RECIST 1.1 Assessment of Disease................................................112
8.2.1.6
iRECIST Assessment of Disease.....................................................114
8.2.2
Patient-reported Outcomes.........................................................................115
8.3
Safety Assessments.............................................................................................115
8.3.1
Physical Examinations...............................................................................115
8.3.1.1
Full Physical Examination...............................................................115
8.3.1.2
Directed Physical Examination........................................................115
8.3.2
Audiometry ................................................................................................116
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8.3.3
Vital Signs..................................................................................................116
8.3.4
Electrocardiograms ....................................................................................116
8.3.5
Clinical Safety Laboratory Assessments ...................................................116
8.3.5.1
Laboratory Safety Evaluations (Hematology, Chemistry and 
Urinalysis)........................................................................................117
8.3.5.2
Pregnancy Testing............................................................................117
8.3.6
Performance Assessments..........................................................................118
8.3.6.1
Eastern Cooperative Oncology Group (ECOG) Performance 
Scale.................................................................................................118
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Reportable Safety Events ..................................................................................118
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ........................................................119
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events....120
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information.121
8.4.4
Regulatory Reporting Requirements for SAE ...........................................121
8.4.5
Pregnancy and Exposure During Breastfeeding ........................................121
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs..........................................................................................122
8.4.7
Events of Clinical Interest (ECIs)..............................................................122
8.5
Treatment of Overdose......................................................................................122
8.6
Pharmacokinetics...............................................................................................123
8.6.1
Blood Collection for PK for MK-3475......................................................123
8.6.2
Blood Collection for Anti-pembrolizumab Antibodies .............................123
8.6.3
Blood Collection for RNA Analyses and Plasma and Serum Biomarker 
Analyses.....................................................................................................123
8.7
Pharmacodynamics............................................................................................123
8.8
Biomarkers .........................................................................................................124
8.8.1
Planned Genetic Analysis Sample Collection............................................124
8.8.2
Tissue Sample............................................................................................124
8.9
Future Biomedical Research Sample Collection.............................................125
8.10
Health Economics Medical Resource Utilization and Health Economics.....125
8.11
Visit Requirements.............................................................................................125
8.11.1
Screening....................................................................................................125
8.11.1.1
Rescreening......................................................................................126
8.11.2
Study Intervention Period ..........................................................................126
8.11.3
Post-intervention Visit ...............................................................................126
8.11.3.1
Safety Follow-up Visit.....................................................................126
8.11.3.2
Efficacy Follow-up Visits................................................................126
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8.11.3.3
Survival Follow-up Assessments.....................................................127
8.11.4
Vital Status.................................................................................................127
9
STATISTICAL ANALYSIS PLAN ...........................................................................127
9.1
Statistical Analysis Plan Summary...................................................................128
9.2
Responsibility for Analyses/In-house Blinding ...............................................129
9.3
Hypotheses/Estimation ......................................................................................130
9.4
Analysis Endpoints.............................................................................................130
9.4.1
Efficacy Endpoints.....................................................................................130
9.4.2
Safety Endpoints........................................................................................131
9.4.3
Patient-Reported Outcome Endpoints........................................................131
9.5
Analysis Populations..........................................................................................131
9.5.1
Efficacy Analysis Populations...................................................................131
9.5.2
Safety Analysis Populations ......................................................................132
9.5.3
PRO Analysis Populations.........................................................................132
9.6
Statistical Methods.............................................................................................132
9.6.1
Statistical Methods for Efficacy Analyses.................................................132
9.6.1.1
Overall Survival...............................................................................133
9.6.1.2
Progression-free Survival.................................................................133
9.6.1.3
Objective Response Rate .................................................................134
9.6.1.4
Duration of Response.......................................................................135
9.6.1.5
Analysis Strategy for Key Efficacy Endpoints................................135
9.6.2
Statistical Methods for Safety Analyses ....................................................136
9.6.3
Statistical Methods for Patient-reported Outcome Analyses.....................138
9.6.4
Statistical Methods for Pharmacokinetics (PK) Analyses .........................138
9.6.5
Summaries of Baseline Characteristics and Demographics.......................138
9.7
Interim Analyses ................................................................................................138
9.7.1
Efficacy Interim Analyses..........................................................................138
9.7.2
Safety Interim Analyses.............................................................................139
9.8
Multiplicity .........................................................................................................139
9.8.1
Overall Survival.........................................................................................140
9.8.2
Progression-free Survival...........................................................................142
9.8.3
Objective Response....................................................................................143
9.8.4
Safety Analyses..........................................................................................144
9.9
Sample Size and Power Calculations ...............................................................144
9.10
Subgroup Analyses.............................................................................................147
9.11
Compliance (Medication Adherence)...............................................................148
9.12
Extent of Exposure.............................................................................................148
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SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...................................................................................................149
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations......149
10.1.1
Code of Conduct for Clinical Trials...........................................................149
10.1.2
Financial Disclosure...................................................................................151
10.1.3
Data Protection...........................................................................................151
10.1.3.1
Confidentiality of Data ....................................................................152
10.1.3.2
Confidentiality of Participant Records.............................................152
10.1.3.3
Confidentiality of IRB/IEC Information..........................................152
10.1.4
Committees Structure.................................................................................152
10.1.4.1
Scientific Advisory Committee (SAC)............................................152
10.1.4.2
Executive Oversight Committee......................................................153
10.1.4.3
External Data Monitoring Committee .............................................153
10.1.5
Publication Policy......................................................................................153
10.1.6
Compliance with Study Registration and Results Posting Requirements .153
10.1.7
Compliance with Law, Audit, and Debarment ..........................................154
10.1.8
Data Quality Assurance .............................................................................155
10.1.9
Source Documents .....................................................................................156
10.1.10
Study and Site Closure...............................................................................156
10.2
Appendix 2: Clinical Laboratory Tests............................................................157
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................159
10.3.1
Definition of AE ........................................................................................159
10.3.2
Definition of SAE ......................................................................................160
10.3.3
Additional Events Reported in the Same Manner as SAE.........................161
10.3.4
Recording AE and SAE .............................................................................161
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................165
10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation..................................167
10.5
Appendix 5: Contraceptive Guidance..............................................................168
10.5.1
Definitions..................................................................................................168
10.5.2
Contraception Requirements......................................................................169
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................170
10.7
Appendix 7: Country-specific Requirements..................................................175
10.7.1
China..........................................................................................................175
10.7.2
France.........................................................................................................176
10.7.3
Germany.....................................................................................................176
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10.7.4
Norway.......................................................................................................176
10.7.5
United Kingdom.........................................................................................176
10.7.6
Argentina....................................................................................................177
10.7.7
Japan ..........................................................................................................177
10.8
Appendix 8: Description of the iRECIST Process for Assessment of 
Disease Progression............................................................................................178
10.9
Appendix 9: ECOG Performance Status.........................................................182
10.10 Appendix 10: Calculated Creatinine Clearance..............................................183
10.11 Appendix 11: Abbreviations .............................................................................184
11
REFERENCES.............................................................................................................188
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LIST OF TABLES
Table 1
Study Schedule of Activities – Initial Intervention....................................20
Table 2
Schedule of Activities – Second Course Phase (Retreatment) ..................37
Table 3
Adequate Organ Function Laboratory Values ...........................................72
Table 4
Study Interventions....................................................................................77
Table 5
Dose Modification and Toxicity Management Guidelines for Non-
hepatic Immune-related Adverse Events Associated with 
Pembrolizumab Monotherapy, Coformulations, or IO Combinations.......87
Table 6
Pembrolizumab Monotherapy, Coformulations, or IO Combinations 
Infusion Reaction Dose Modification and Treatment Guidelines .............91
Table 7
Dose Modification Guidelines for Gemcitabine/Cisplatin-related 
Adverse Events ..........................................................................................94
Table 8
Management of HECI for Pembrolizumab Monotherapy, 
Coformulations, or IO Combinations ........................................................98
Table 9
Reporting Time Periods and Time Frames for Adverse Events and 
Other Reportable Safety Events...............................................................120
Table 10
Censoring Rules for Primary and Sensitivity Analyses of PFS...............134
Table 11
Censoring Rules for DOR........................................................................135
Table 12
Analysis Strategy for Key Efficacy Endpoints........................................136
Table 13
Analysis Strategy for Safety Parameters..................................................137
Table 14
Summary of Interim and Final Analyses Strategy...................................139
Table 15
Efficacy Boundaries and Properties for Overall Survival Analyses........141
Table 16
Efficacy Boundaries and Properties for Progression-free Survival 
Analyses...................................................................................................143
Table 17
Efficacy Boundaries and Properties for Objective Response Analyses...144
Table 18
Protocol-required Safety Laboratory Assessments..................................157
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LIST OF FIGURES
Figure 1
Study Schema.............................................................................................19
Figure 2
Study Intervention Decision Making Process When Progression per 
RECIST 1.1 is Observed by the Investigator (PFS Endpoint).................114
Figure 3
Multiplicity Diagram for Type I Error Control........................................140
Figure 4
OS Survival Curves Under the Working Model With Delayed 
Treatment Effect ......................................................................................145
Figure 5
PFS Curves Under the Working Model With Delayed Treatment 
Effect........................................................................................................146
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 3 Randomized, Double Blind Study of Pembrolizumab Plus 
Gemcitabine/Cisplatin versus Placebo Plus Gemcitabine/Cisplatin as First-Line Therapy in 
Participants with Advanced and/or Unresectable Biliary Tract Carcinoma
Short Title: Pembrolizumab or Placebo Plus Gemcitabine/Cisplatin for First-Line Advanced
and/or Unresectable BTC
Acronym: KEYNOTE-966
Hypotheses, Objectives, and Endpoints:
In first-line therapy for participants with advanced and/or unresectable biliary tract 
carcinoma:
Although the original RECIST 1.1 publication recommends a maximum of 5 target lesions in 
total and 2 per organ, throughout this protocol, the term RECIST 1.1 refers to an adjustment
of RECIST 1.1 to allow a maximum of 10 target lesions in total and 5 per organ. Refer to 
Section 4.2.2.2 for further details.
Primary Objectives
Primary Endpoints
- Objective: To compare overall survival 
(OS) between pembrolizumab plus 
gemcitabine/cisplatin and placebo plus 
gemcitabine/cisplatin
- Hypothesis (H1): Pembrolizumab plus 
gemcitabine/cisplatin is superior to placebo 
plus gemcitabine/cisplatin with respect to OS
- OS: the time from randomization to death 
due to any cause
Secondary Objectives
Secondary Endpoints
- Objective: To compare progression-free 
survival (PFS) per RECIST 1.1 as assessed 
by blinded independent central review 
(BICR) between pembrolizumab plus 
gemcitabine/cisplatin and placebo plus 
gemcitabine/cisplatin
- Hypothesis (H2): Pembrolizumab plus 
gemcitabine/cisplatin is superior to placebo 
plus gemcitabine/cisplatin with respect to 
PFS per RECIST 1.1 by BICR
- PFS: the time from randomization to the 
first documented PD per RECIST 1.1 by 
BICR, or death due to any cause, 
whichever occurs first
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16-JUN-2022
- Objective: To compare objective response 
rate (ORR) per RECIST 1.1 as assessed by 
BICR between pembrolizumab plus 
gemcitabine/cisplatin and placebo plus 
gemcitabine/cisplatin
- Hypothesis (H3): Pembrolizumab plus 
gemcitabine/cisplatin is superior to placebo 
plus gemcitabine/cisplatin with respect to 
ORR per RECIST 1.1 as assessed by BICR
- Objective Response (OR): complete 
response (CR) or partial response (PR)
- Objective: To evaluate duration of response 
(DOR) per RECIST 1.1 as assessed by BICR
- DOR: for participants who demonstrate 
confirmed CR or PR, the time from the 
first documented evidence of CR or PR 
until disease progression or death due to 
any cause, whichever occurs first
- Objective: To evaluate the safety and 
tolerability profile of pembrolizumab plus 
gemcitabine/cisplatin
- Adverse events (AEs)
- Study intervention discontinuations due 
to AEs
Overall Design:
Study Phase
Phase 3
Primary Purpose
Treatment
Indication
Biliary Tract Carcinoma
Population
Participants with Advanced and/or Unresectable Biliary Tract 
Carcinoma (Intrahepatic, Extrahepatic, or Gallbladder)
Study Type
Interventional
Intervention Model
Parallel
This is a multi-site study.
Type of Control
Placebo
Study Blinding
Double-blind with in-house blinding
Masking
Sponsor
Investigator
Participant
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Estimated Duration 
of Study
The Sponsor estimates that the study will require approximately 38
months from the time the first participant (or their legally acceptable 
representative) provides documented informed consent until the last 
participant’s last study-related contact.
Extension Portion of the Study in China: The study may remain 
open longer than 38 months to complete a potential extension 
portion of the study in China.
Number of Participants:
Approximately 1048 participants will be randomized 1:1 with approximately 524 participants 
in each arm to the global portion of this study. After enrollment of the global portion of the 
study is complete, the study may remain open to enrollment in China alone until 
approximately 158 participants from China have been enrolled to meet local regulatory 
requirements.
Intervention Groups and Duration:
Intervention 
Groups
Inter-
vention 
Group 
Name
Drug
Dose 
Strength
Dose 
Frequency
Route of 
Adminis-
tration
Regimen/ 
Treatment 
Period/ 
Vaccination 
Regimen
Use
Arm A
Pembrolizumab
200 mg
Q3W
IV Infusion
Day 1 of each 
cycle for up to 
35 
administrations
Experimental
Gemcitabine
1000 mg/m2
Q3W
IV Infusion
Day 1 and Day 
8 of each cycle 
until PD or 
unacceptable 
toxicity
Background 
Treatment
Cisplatin
25 mg/m2
Q3W
IV Infusion
Day 1 and Day 
8 of each cycle 
for up to 8 
cycles
Background 
Treatment
Arm B
Placebo
N/A
Q3W
IV Infusion
Day 1 of each 
cycle for up to 
35 
administrations
Experimental
Gemcitabine
1000 mg/m2
Q3W
IV Infusion
Day 1 and Day 
8 of each cycle 
until PD or 
unacceptable 
toxicity
Background 
Treatment
Cisplatin
25 mg/m2
Q3W
IV Infusion
Day 1 and Day 
8 of each cycle 
for up to 8 
cycles
Background 
Treatment
Abbreviations: IV=intravenous, PD=disease progression, Q3W=every 3 weeks
Other current or former name(s) or alias(es) for study intervention(s) are as 
follows: Pembrolizumab, MK-3475
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Total Number
of Intervention 
Groups/ Arms
2 arms
Duration of 
Participation
Each participant will participate in the study from the time the participant 
provides documented informed consent through the final protocol-
specified contact.
After a screening phase of up to 28 days, each participant will be assigned 
to receive study intervention until one of the conditions for discontinuation 
of study intervention is met. Participants who complete study intervention 
after receiving 35 administrations of pembrolizumab and without disease 
progression or intolerability, or participants who attain a complete response 
and stop study intervention with pembrolizumab may be eligible for up to 
17 additional administrations of pembrolizumab (approximately 1 year) 
upon experiencing disease progression.
After the end of treatment, each participant will be followed for the 
occurrence of adverse events and spontaneously reported pregnancy.
Participants who discontinue study intervention for reasons other than 
radiographic disease progression will have post-intervention follow-up 
imaging for disease status until any of the conditions for discontinuation of 
imaging are met.
All participants will be followed for overall survival until death, 
withdrawal of consent, or the end of the study.
Once the study has ended, the participant is discontinued from this study 
and may be enrolled in an extension study to continue protocol-defined 
assessments and treatment.
Study Governance Committees:
Steering Committee
No
Executive Oversight Committee
Yes
Data Monitoring Committee
Yes
Clinical Adjudication Committee
No
Study governance considerations are outlined in Appendix 1.
Study Accepts Healthy Volunteers: No
A list of abbreviations used in this document can be found in Appendix 11.
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1.2
Schema
The study design is depicted in Figure 1.
Figure 1
Study Schema
Abbreviations: ECOG=Eastern Cooperative Oncology Group; IV=intravenous; max = maximum; 
PD=progressive disease; Q3W=every 3 weeks
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1.3
Schedule of Activities (SoA)
1.3.1
Schedule of Activities Initial Intervention Phase
Table 1
Study Schedule of Activities – Initial Intervention
Study Period
Screen
ing
Phasea
Study Intervention Phase
21-Day Cycles
EOI
Post-Intervention
Notes
Intervention Cycle(s)
Cycle
1
Cycle
2
Cycles 3 to last
Cycle
Safety 
FUb
(Efficacy)
FU
Survival 
FU
Day
D1
D8
D1
D8
D1
D8
Scheduling Window 
(Days):
–28 to 
–1
±3
±3
±3
±3
±3
At 
Time 
of D/C
30 Days 
After 
Last Dose 
(+ 7 days)
Q6W or 
Q12W
(± 7 days)
Q12W 
(± 7 days)
Administrative and General Procedures
Informed Consent
X
Documented informed consent can be 
obtained at any time before any 
protocol-specific screening procedures 
being performed.
If the investigator recommends 
continuation of study intervention
beyond disease progression, the 
participant or their legally acceptable 
representative will be asked to provide 
documented informed consent.
Informed Consent for 
Future Biomedical 
Research
X
Participation in FBR is optional, but 
documented informed consent is 
mandatory if participating and should 
be performed before obtaining samples
for FBR (refer to Section 8.9).
Inclusion/ Exclusion 
Criteria
X
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Study Period
Screen
ing
Phasea
Study Intervention Phase
21-Day Cycles
EOI
Post-Intervention
Notes
Intervention Cycle(s)
Cycle
1
Cycle
2
Cycles 3 to last
Cycle
Safety 
FUb
(Efficacy)
FU
Survival 
FU
Day
D1
D8
D1
D8
D1
D8
Scheduling Window 
(Days):
–28 to 
–1
±3
±3
±3
±3
±3
At 
Time 
of D/C
30 Days 
After 
Last Dose 
(+ 7 days)
Q6W or 
Q12W
(± 7 days)
Q12W 
(± 7 days)
Participant ID Card
X
X
Update ID card at randomization visit 
with randomization number.
Demographics
X
Medical/Surgical 
Histories (including 
investigator-assessed 
risk factor for biliary 
cancer, smoking and 
alcohol use)
X
Smoking and alcohol use will be 
collected on eCRF. Investigators will be 
asked to enter biliary cancer risk factors 
(gallstones, infections, autoimmune 
diseases, cirrhosis, primary sclerosing
cholangitis, and others/unknown).
Prior and Concomitant 
Medication Review
X
X
X
X
X
X
X
X
X
Record all prior medications taken 
within 28 days before C1D1. Enter new 
medications started during the study 
through the Safety Follow-up. Record 
concomitant medications beyond 
30 days after treatment discontinuation 
if related to SAE or ECI.
Note: All corticosteroid use must be 
reported.
CM review on Day 8 is not required 
after both chemotherapy agents 
(gemcitabine/ cisplatin) are 
permanently discontinued.
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Study Period
Screen
ing
Phasea
Study Intervention Phase
21-Day Cycles
EOI
Post-Intervention
Notes
Intervention Cycle(s)
Cycle
1
Cycle
2
Cycles 3 to last
Cycle
Safety 
FUb
(Efficacy)
FU
Survival 
FU
Day
D1
D8
D1
D8
D1
D8
Scheduling Window 
(Days):
–28 to 
–1
±3
±3
±3
±3
±3
At 
Time 
of D/C
30 Days 
After 
Last Dose 
(+ 7 days)
Q6W or 
Q12W
(± 7 days)
Q12W 
(± 7 days)
Randomization and 
Study Treatment 
Assignment via IRT
X
Randomization must be completed 
within 3 days before C1D1 and after 
confirmation of eligibility.
All procedures and assessments on 
C1D1 should be performed after 
randomization.
Subsequent 
Antineoplastic
Treatment Status
X
X
X
All anticancer therapy will be recorded 
until time of death or termination of 
survival follow-up.
If a clinic visit is not feasible, follow-up 
information may be obtained via other 
means of contact (eg, telephone, video 
call, mail or email).
Survival (Vital) Status
Upon Sponsor request, participants may 
be contacted for survival (vital) status at 
any time during the course of the study.
Administration of Study Intervention
Pembrolizumab or
Placebo 
X
X
X
Pembrolizumab 200 mg IV Q3W or 
placebo (normal saline) IV Q3W for up 
to 35 administrations. Refer to 
Section 8.1.8.1. for timing and order of 
dose administration.
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Study Period
Screen
ing
Phasea
Study Intervention Phase
21-Day Cycles
EOI
Post-Intervention
Notes
Intervention Cycle(s)
Cycle
1
Cycle
2
Cycles 3 to last
Cycle
Safety 
FUb
(Efficacy)
FU
Survival 
FU
Day
D1
D8
D1
D8
D1
D8
Scheduling Window 
(Days):
–28 to 
–1
±3
±3
±3
±3
±3
At 
Time 
of D/C
30 Days 
After 
Last Dose 
(+ 7 days)
Q6W or 
Q12W
(± 7 days)
Q12W 
(± 7 days)
Gemcitabine
X
X
X
X
X
X
1000 mg/m2 IV on Day 1 and Day 8 
Q3W until PD or unacceptable toxicity. 
Refer to Section 8.1.8.1. for timing and 
order of dose administration.
Cisplatin 
X
X
X
X
X
(Up to 
Cycle 
8)
X
(Up to 
Cycle 
8)
25 mg/m2 IV on Day 1 and Day 8 Q3W 
for up to 8 cycles. Refer to 
Section 8.1.8.1. for timing and order of 
dose administration.
Efficacy Procedures
Tumor Imaging – (CT 
of the chest, CT or MRI 
of the abdomen and 
pelvis)
X
X
X
On study imaging assessment must be 
performed 6 weeks (42 days +7 days) 
from the date of randomization. 
Subsequent tumor imaging should be 
performed every 6 weeks (42 days 
±7 days) through Week 54. Participants 
who remain on treatment beyond 
Week 54 will have imaging performed 
every 12 weeks (84 days ±7 days). All 
imaging assessments should follow 
calendar days and not be adjusted for 
cycle delays.
Imaging at EOI is not required if the 
previous tumor imaging assessment was 
within 4 weeks before the EOI visit.
Refer to Section 8.2.1 for additional 
details for tumor imaging assessment.
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Study Period
Screen
ing
Phasea
Study Intervention Phase
21-Day Cycles
EOI
Post-Intervention
Notes
Intervention Cycle(s)
Cycle
1
Cycle
2
Cycles 3 to last
Cycle
Safety 
FUb
(Efficacy)
FU
Survival 
FU
Day
D1
D8
D1
D8
D1
D8
Scheduling Window 
(Days):
–28 to 
–1
±3
±3
±3
±3
±3
At 
Time 
of D/C
30 Days 
After 
Last Dose 
(+ 7 days)
Q6W or 
Q12W
(± 7 days)
Q12W 
(± 7 days)
Clinical Procedures or Assessments
Adverse Event 
Monitoring
X
X
X
X
X
X
X
X
X
X
AEs: monitored up to 30 days after last 
dose.
SAEs: monitored up to 90 days after 
last dose, or 30 days after last dose if 
participant starts a new anticancer 
therapy, whichever occurs first.
AE review on Day 8 is not required 
after both chemotherapy agents 
(gemcitabine/cisplatin) are permanently 
discontinued.
Full Physical 
Examination
X
X
Perform within 14 days before the start 
of study intervention.
Directed Physical 
Examination
X
X
X
X
X
X
X
Conduct on Day 1 and Day 8 of each 
cycle before administration of study 
intervention.
Conducting within 1 day before 
administration of study intervention is 
acceptable.
Note: Day 8 directed physical 
examination is not required after both 
chemotherapy agents (gemcitabine/
cisplatin) are permanently discontinued.
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Study Period
Screen
ing
Phasea
Study Intervention Phase
21-Day Cycles
EOI
Post-Intervention
Notes
Intervention Cycle(s)
Cycle
1
Cycle
2
Cycles 3 to last
Cycle
Safety 
FUb
(Efficacy)
FU
Survival 
FU
Day
D1
D8
D1
D8
D1
D8
Scheduling Window 
(Days):
–28 to 
–1
±3
±3
±3
±3
±3
At 
Time 
of D/C
30 Days 
After 
Last Dose 
(+ 7 days)
Q6W or 
Q12W
(± 7 days)
Q12W 
(± 7 days)
Audiometry
X
Perform at Screening, or as required per 
local standard, repeat if clinically 
indicated.
Vital Signs and Weight
X
X
X
X
X
X
X
X
X
Refer to Section 8.3.3, vital signs 
include blood pressure, pulse rate, 
respiratory rate, and temperature.
Conducting within 1 day before 
administration of study intervention is 
acceptable.
Note: Day 8 vital signs and weight are 
not required after both chemotherapy 
agents (gemcitabine/cisplatin) are 
permanently discontinued.
Height
X
12-lead ECG
X
Perform single 12-lead ECG. 
Participants must be in the recumbent 
position for a period of 5 minutes 
before the ECG.
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Study Period
Screen
ing
Phasea
Study Intervention Phase
21-Day Cycles
EOI
Post-Intervention
Notes
Intervention Cycle(s)
Cycle
1
Cycle
2
Cycles 3 to last
Cycle
Safety 
FUb
(Efficacy)
FU
Survival 
FU
Day
D1
D8
D1
D8
D1
D8
Scheduling Window 
(Days):
–28 to 
–1
±3
±3
±3
±3
±3
At 
Time 
of D/C
30 Days 
After 
Last Dose 
(+ 7 days)
Q6W or 
Q12W
(± 7 days)
Q12W 
(± 7 days)
ECOG Performance 
Status
X
X
X
X
X
X
X
X
X
If ECOG is performed before dosing on 
C1D1, then Screening ECOG is not 
mandatory.
Should be assessed before dosing at 
treatment visits. Conducting within 1 
day before administration of study 
intervention is acceptable.
Note: Day 8 ECOG PS will not be 
performed after both chemotherapy 
agents (gemcitabine/cisplatin) are 
permanently discontinued.
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Study Period
Screen
ing
Phasea
Study Intervention Phase
21-Day Cycles
EOI
Post-Intervention
Notes
Intervention Cycle(s)
Cycle
1
Cycle
2
Cycles 3 to last
Cycle
Safety 
FUb
(Efficacy)
FU
Survival 
FU
Day
D1
D8
D1
D8
D1
D8
Scheduling Window 
(Days):
–28 to 
–1
±3
±3
±3
±3
±3
At 
Time 
of D/C
30 Days 
After 
Last Dose 
(+ 7 days)
Q6W or 
Q12W
(± 7 days)
Q12W 
(± 7 days)
Local Laboratory Procedures and Assessmentsc
Pregnancy Test 
(WOCBP only)d
X
X
X
X
X
X
Assess within 24 hours (urine) or 
72 hours (serum) before study 
intervention administration on Day 1 of 
each cycle. If pregnancy testing during 
the Screening Phase occurs within
24 hours (urine) or 72 hours (serum) 
before the first dose, it does not have to 
be repeated at C1D1. In regions where 
required via documented regulatory 
request (and subsequently approved by 
the Sponsor), pregnancy tests within 
24 hours prior to treatment allocation
will be required.
During the Post-Intervention Phase, 
perform a serum or urine pregnancy test 
approximately 240 days after the last 
dose of chemotherapy or 150 days after 
the last dose of pembrolizumab or 
placebo, whichever is greater, or 
30 days after cessation of study 
intervention if the participant initiates 
new anticancer therapy.
Pregnancy testing should be conducted 
as per local regulations, where 
applicable.
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Study Period
Screen
ing
Phasea
Study Intervention Phase
21-Day Cycles
EOI
Post-Intervention
Notes
Intervention Cycle(s)
Cycle
1
Cycle
2
Cycles 3 to last
Cycle
Safety 
FUb
(Efficacy)
FU
Survival 
FU
Day
D1
D8
D1
D8
D1
D8
Scheduling Window 
(Days):
–28 to 
–1
±3
±3
±3
±3
±3
At 
Time 
of D/C
30 Days 
After 
Last Dose 
(+ 7 days)
Q6W or 
Q12W
(± 7 days)
Q12W 
(± 7 days)
PT/INR and aPTT
X
Screening: collect within 14 days 
before the first dose of study 
intervention.
Additional testing to be conducted as 
clinically indicated for participants 
taking anticoagulant therapy. Refer to 
Section 6.5 for additional requirements 
during gemcitabine administration.
Hematology
X
X
X
X
X
X
X
X
X
Screening: perform within 14 days 
before the first dose of study 
intervention.
Perform on Day 1 and Day 8 before
administration of study intervention
(within 1 day before administration of 
study intervention is acceptable).
For laboratory details refer to
Section 10.2, Appendix 2, Table 18.
Note: Day 8 hematology blood samples 
will not be collected after both 
chemotherapy agents (gemcitabine/
cisplatin) are permanently discontinued.
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Study Period
Screen
ing
Phasea
Study Intervention Phase
21-Day Cycles
EOI
Post-Intervention
Notes
Intervention Cycle(s)
Cycle
1
Cycle
2
Cycles 3 to last
Cycle
Safety 
FUb
(Efficacy)
FU
Survival 
FU
Day
D1
D8
D1
D8
D1
D8
Scheduling Window 
(Days):
–28 to 
–1
±3
±3
±3
±3
±3
At 
Time 
of D/C
30 Days 
After 
Last Dose 
(+ 7 days)
Q6W or 
Q12W
(± 7 days)
Q12W 
(± 7 days)
Chemistry Panel and 
Liver Panel
X
X
X
X
X
X
X
X
X
Screening: perform within 14 days 
before the first dose of study 
intervention.
Collect liver panel on Day 1 and Day 8
before administration of study 
intervention (within 1 day before
administration of study intervention is 
acceptable).
For laboratory details refer to
Section 10.2, Appendix 2, Table 18.
Note: Day 8 chemistry and liver panel 
blood samples will not be collected 
after both chemotherapy agents 
(gemcitabine/ cisplatin) are 
permanently discontinued.
Urinalysis 
X
X
Screening: perform within 14 days 
before the first dose of study 
intervention. Repeat as clinically 
indicated.
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Study Period
Screen
ing
Phasea
Study Intervention Phase
21-Day Cycles
EOI
Post-Intervention
Notes
Intervention Cycle(s)
Cycle
1
Cycle
2
Cycles 3 to last
Cycle
Safety 
FUb
(Efficacy)
FU
Survival 
FU
Day
D1
D8
D1
D8
D1
D8
Scheduling Window 
(Days):
–28 to 
–1
±3
±3
±3
±3
±3
At 
Time 
of D/C
30 Days 
After 
Last Dose 
(+ 7 days)
Q6W or 
Q12W
(± 7 days)
Q12W 
(± 7 days)
T3, FT4, and TSH
X
X
X
(Even 
Cycles)
X
Screening: perform within 14 days 
before the first dose of study 
intervention. If testing is performed
centrally, must perform within 28 days.
Perform on Day 1 of every other cycle 
starting from Cycle 2 (eg, Cycle 2, 4, 6, 
8, etc) and at EOI.
After Cycle 1, participant may be dosed 
even if thyroid evaluations are not 
available prior to dosing; however, the 
results must be available and reviewed 
before the next scheduled visit.
Free T3 is acceptable where T3 cannot 
be determined.
Tuberculosis screeningd
X
Per local regulations.
HIVd
X
Per local regulations.
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Study Period
Screen
ing
Phasea
Study Intervention Phase
21-Day Cycles
EOI
Post-Intervention
Notes
Intervention Cycle(s)
Cycle
1
Cycle
2
Cycles 3 to last
Cycle
Safety 
FUb
(Efficacy)
FU
Survival 
FU
Day
D1
D8
D1
D8
D1
D8
Scheduling Window 
(Days):
–28 to 
–1
±3
±3
±3
±3
±3
At 
Time 
of D/C
30 Days 
After 
Last Dose 
(+ 7 days)
Q6W or 
Q12W
(± 7 days)
Q12W 
(± 7 days)
Central Laboratory Assessmentsc
Anti-HCV (IgG)
X
If Anti-HCV (IgG) 
positive:
If these conditions are met, the 
following test will be performed within 
28 days before study intervention.
For repeat hepatitis testing during 
rescreening, the site may proceed with 
randomization in certain cases after 
collecting hepatitis blood samples but 
before results are available only with 
approval by the Sponsor.
HCV viral load
X
Participants with no HBV infection 
may be randomized if HCV viral load
samples were drawn before
randomization and results are pending
at the time of randomization.
For repeat hepatitis testing during 
rescreening, the site may proceed with 
randomization in certain cases after 
collecting hepatitis blood samples but 
before results are available only with 
approval by the Sponsor.
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Study Period
Screen
ing
Phasea
Study Intervention Phase
21-Day Cycles
EOI
Post-Intervention
Notes
Intervention Cycle(s)
Cycle
1
Cycle
2
Cycles 3 to last
Cycle
Safety 
FUb
(Efficacy)
FU
Survival 
FU
Day
D1
D8
D1
D8
D1
D8
Scheduling Window 
(Days):
–28 to 
–1
±3
±3
±3
±3
±3
At 
Time 
of D/C
30 Days 
After 
Last Dose 
(+ 7 days)
Q6W or 
Q12W
(± 7 days)
Q12W 
(± 7 days)
Anti-HBc (total and 
IgM), HBV viral load, 
HBsAg 
X
For participants not taking HBV 
antiviral therapy, repeat HBV viral load 
and HBsAg tests approximately every 
6 weeks if HBsAg negative, anti-HBc 
positive, and HBV viral load is 
undetectable at screening. Repeat HBV 
viral load and HBsAg tests
approximately every 12 weeks for all 
participants on HBV antiviral therapy
until the end of study intervention and 
then per local standard of care. This
testing should be aligned with study 
intervention visits.
For HBV viral load over 100 IU/mL
start HBV treatment. For repeat 
hepatitis testing during rescreening, the 
site may proceed with randomization in 
certain cases after collecting hepatitis 
blood samples but before results are 
available only with approval by the 
Sponsor.
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Study Period
Screen
ing
Phasea
Study Intervention Phase
21-Day Cycles
EOI
Post-Intervention
Notes
Intervention Cycle(s)
Cycle
1
Cycle
2
Cycles 3 to last
Cycle
Safety 
FUb
(Efficacy)
FU
Survival 
FU
Day
D1
D8
D1
D8
D1
D8
Scheduling Window 
(Days):
–28 to 
–1
±3
±3
±3
±3
±3
At 
Time 
of D/C
30 Days 
After 
Last Dose 
(+ 7 days)
Q6W or 
Q12W
(± 7 days)
Q12W 
(± 7 days)
PK/Pharmacodynamic/Biomarker Assessment
Pembrolizumab 
Pharmacokinetics
X
X
X
(C4, 
and 
every 4 
cycles 
starting 
there-
after)
Predose PK and ADA samples will be 
collected at Day 1 of Cycles 1, 2, 4 and
every 4 cycles thereafter (eg, C8, C12, 
C16, etc).
All predose samples should be drawn 
within 24 hours before infusion of
pembrolizumab or placebo. Additional 
postdose peak PK samples will be drawn 
within 30 mins (+15 minutes time 
window) after the end of pembrolizumab 
or placebo infusion at Cycle 1 and 
Cycle 8.
Pembrolizumab 
Antidrug Antibodies
X
X
X
(C4, 
and 
every 4 
cycles 
there-
after)
Predose PK and ADA samples will be 
collected at Day 1 of Cycles 1, 2, 4 and 
every 4 cycles thereafter (eg, C8, C12, 
C16, etc).
All predose samples should be drawn 
within 24 hours before infusion of 
pembrolizumab or placebo.
X
If sample is not available at C1D1, it 
may be collected at a subsequent visit.
CCI
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Study Period
Screen
ing
Phasea
Study Intervention Phase
21-Day Cycles
EOI
Post-Intervention
Notes
Intervention Cycle(s)
Cycle
1
Cycle
2
Cycles 3 to last
Cycle
Safety 
FUb
(Efficacy)
FU
Survival 
FU
Day
D1
D8
D1
D8
D1
D8
Scheduling Window 
(Days):
–28 to 
–1
±3
±3
±3
±3
±3
At 
Time 
of D/C
30 Days 
After 
Last Dose 
(+ 7 days)
Q6W or 
Q12W
(± 7 days)
Q12W 
(± 7 days)
Analysisd,e
X
Collect predose C1D1. This sample 
should be drawn for planned analysis of 
Refer to 
Section 8.8.1 for additional details.
Analysisd
X
X
X
(C5)
X
Collect predose.
Analysisd
X
X
X
(C5)
X
Collect predose.
Analysisd
X
X
X
(C5)
X
Collect predose.
Analysisd
X
X
X
(C5)
X
Collect predose.
analysis (optional)d
X
X
X
(C5)
X
Collection at home within 1 week 
before the specified visit and brought 
into site on C1D1, C2D1, C5D1, and at 
EOI.
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
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Study Period
Screen
ing
Phasea
Study Intervention Phase
21-Day Cycles
EOI
Post-Intervention
Notes
Intervention Cycle(s)
Cycle
1
Cycle
2
Cycles 3 to last
Cycle
Safety 
FUb
(Efficacy)
FU
Survival 
FU
Day
D1
D8
D1
D8
D1
D8
Scheduling Window 
(Days):
–28 to 
–1
±3
±3
±3
±3
±3
At 
Time 
of D/C
30 Days 
After 
Last Dose 
(+ 7 days)
Q6W or 
Q12W
(± 7 days)
Q12W 
(± 7 days)
Archival or Newly 
Obtained Tissue 
Collectiond
X
Tissue is required for enrollment. The 
tumor tissue must be received by the 
central vendor and deemed adequate for 
Refer to Section 8.8.2 for additional 
information.
Patient-reported Outcomes
ePROs in the following 
order: EQ-5D-5L, 
EORTC QLQ-C30, 
EORTC QLQ-BIL21
X
X
X
X
X
Administer questionnaires before the
AE evaluation, disease status 
notification, and dosing on Day 1 of
Cycle 1 through Cycle 10 and every 
2 cycles thereafter (ie, Cycles 12, 14, 
16, 18) up to Cycle 18, at EOI, and at 
the 30-day Safety Follow-up.
CCI
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PRODUCT: MK-3475  
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Study Period
Screen
ing
Phasea
Study Intervention Phase
21-Day Cycles
EOI
Post-Intervention
Notes
Intervention Cycle(s)
Cycle
1
Cycle
2
Cycles 3 to last
Cycle
Safety 
FUb
(Efficacy)
FU
Survival 
FU
Day
D1
D8
D1
D8
D1
D8
Scheduling Window 
(Days):
–28 to 
–1
±3
±3
±3
±3
±3
At 
Time 
of D/C
30 Days 
After 
Last Dose 
(+ 7 days)
Q6W or 
Q12W
(± 7 days)
Q12W 
(± 7 days)
Abbreviations: ADA=antidrug antibodies; AE=adverse event; Anti-HBc=hepatitis B core antibody; Anti-HCV=hepatitis C virus antibody; aPTT=activated partial 
thromboplastin time; C1D1=Cycle 1 Day 1; CM=concomitant medication; CT=computed tomography; ctDNA=circulating tumor DNA; CX=Cycle X; D/C=discontinuation; 
DNA=deoxyribonucleic acid; DX=Day X; ECG=electrocardiogram; ECI=event of clinical interest; ECOG=Eastern Cooperative Oncology Group; eCRF=electronic case report 
form; EOI=end of intervention; EORTC=European Organisation for Research and Treatment of Cancer; ePRO=electronic patient-reported outcome; FBR=future biomedical 
research; FT4=free thyroxine; FU=follow-up; HBsAg=hepatitis B surface antigen; HBV=hepatitis B virus; HCV=hepatitis C virus; HIV=human immunodeficiency virus; 
ID=identification; IgG=immunoglobulin G; IgM=immunoglobulin M; INR=international normalized ratio; IRT=interactive response technology; IV=intravenous; 
MRI=magnetic resonance imaging; MSI=microsatellite instability; PCR=polymerase chain reaction; PD=disease progression; PD-L1= programmed cell death ligand 1; 
PK=pharmacokinetics; PS=performance status; PT=prothrombin time; Q3W=every 3 weeks; Q6W=every 6 weeks; Q12W=every 12 weeks; QLQ=Quality of Life Questionnaire;
RNA=ribonucleic acid; SAE=serious adverse event; T3=triiodothyronine; TSH=thyroid-stimulating hormone; WOCBP=women of childbearing potential.
a.
Screening procedures can be performed within 28 days before randomization, unless otherwise specified.
b.
If EOI visit occurs ≥30 days from last dose of study treatment, a Safety Follow-up Visit is not required. In this situation, all procedures required at both the EOI visit and the 
Safety Follow-up Visit should be performed.
c.
Clinical laboratory assessments may be conducted any time within 72 hours before the scheduled visit, unless otherwise specified. Procedures/assessments should be 
performed before administration of study intervention.
d.
Refer to Section 10.7 (Appendix 7) for country-specific requirements.
CCI
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1.3.2
Schedule of Activities Second Course Phase
Table 2
Schedule of Activities – Second Course Phase (Retreatment)
Study Period
Second Course Phase (Retreatment)
21-Day Cycles
EOI
Post-Intervention
Notes
Intervention 
Cycle
Cycle 1
Cycle 2
Cycles 3 to17
Safety FUa
Efficacy 
FU 
Survival 
FU
Day
D1
D8
D1
D8
D1
D8
Scheduling 
Window (Days):
±3
±3
±3
±3
±3
±3
At Time of 
D/C
30 Days 
After Last 
Dose 
(+ 7 days)
Q6W or 
Q12W
(±7 days)
Q12W
(± 7 days)
Administrative and General Procedures
Eligibility Criteria
X
Concomitant 
Medication Review
X
X
X
X
X
X
X
X
Enter new medications started during 
the study through the post-treatment 
Safety Follow-up. Record concomitant 
medications beyond 30 days after 
treatment discontinuation if related to 
SAE or ECI.
CM review on Day 8 is not required 
after gemcitabine is permanently 
discontinued.
Subsequent 
Antineoplastic
Treatment Status
X
X
X
All anticancer therapy will be recorded 
until time of death or termination of 
survival follow-up.
If a clinic visit is not feasible, follow-up 
information may be obtained via other 
means of contact (eg, telephone, video 
call, mail, or email).
Survival (Vital) 
Status
X
Upon Sponsor request, participants may 
be contacted for survival (vital) status at 
any time during the course of the study.
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Study Period
Second Course Phase (Retreatment)
21-Day Cycles
EOI
Post-Intervention
Notes
Intervention 
Cycle
Cycle 1
Cycle 2
Cycles 3 to17
Safety FUa
Efficacy 
FU 
Survival 
FU
Day
D1
D8
D1
D8
D1
D8
Scheduling 
Window (Days):
±3
±3
±3
±3
±3
±3
At Time of 
D/C
30 Days 
After Last 
Dose 
(+ 7 days)
Q6W or 
Q12W
(±7 days)
Q12W
(± 7 days)
Administration of Study Intervention
Pembrolizumab 
X
X
X
Pembrolizumab 200 mg IV Q3W for up 
to 17 administrations. Refer to Section 
8.1.8.1. for timing and order of dose 
administration.
Gemcitabine
X
X
X
X
X
X
The decision of whether or not to 
continue gemcitabine during second 
course will be at the discretion of the 
investigator. If continued, the dose of 
gemcitabine will be given in clinic on 
Day 1 and Day 8 of each SC cycle. 
Refer to Section 8.1.8.1. for timing and 
order of dose administration.
Treatment with gemcitabine will 
continue until unacceptable toxicity or 
PD.
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PRODUCT: MK-3475  
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Study Period
Second Course Phase (Retreatment)
21-Day Cycles
EOI
Post-Intervention
Notes
Intervention 
Cycle
Cycle 1
Cycle 2
Cycles 3 to17
Safety FUa
Efficacy 
FU 
Survival 
FU
Day
D1
D8
D1
D8
D1
D8
Scheduling 
Window (Days):
±3
±3
±3
±3
±3
±3
At Time of 
D/C
30 Days 
After Last 
Dose 
(+ 7 days)
Q6W or 
Q12W
(±7 days)
Q12W
(± 7 days)
Efficacy Procedures
Tumor Imaging -
(CT of the chest, 
CT or MRI of the 
abdomen and 
pelvis)b
X
X
Tumor imaging should be performed 
within 28 days before restarting study 
intervention. The initial second course
imaging assessment should be 
performed at 6 weeks (42 days +7 days) 
after the restart of study intervention. 
Subsequent tumor imaging should be 
performed every 12 weeks (84 days 
±7 days) or more frequently, if 
clinically indicated. All imaging 
assessments should follow calendar 
days and not be adjusted for cycle 
delays.
Imaging at EOI is not required if the 
previous tumor imaging assessment 
was within 4 weeks prior to the EOI
visit.
Refer to Section 8.2.1 for additional 
details on tumor imaging assessment.
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PRODUCT: MK-3475  
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Study Period
Second Course Phase (Retreatment)
21-Day Cycles
EOI
Post-Intervention
Notes
Intervention 
Cycle
Cycle 1
Cycle 2
Cycles 3 to17
Safety FUa
Efficacy 
FU 
Survival 
FU
Day
D1
D8
D1
D8
D1
D8
Scheduling 
Window (Days):
±3
±3
±3
±3
±3
±3
At Time of 
D/C
30 Days 
After Last 
Dose 
(+ 7 days)
Q6W or 
Q12W
(±7 days)
Q12W
(± 7 days)
Clinical Procedures or Assessmentsb
Adverse Event
Monitoring
X
X
X
X
X
X
X
X
X
AEs: monitored up to 30 days after last 
dose.
SAEs: monitored up to 90 days after 
last dose, or 30 days after last dose if 
participant starts a new anticancer 
therapy, whichever occurs first.
AE review on Day 8 is not required 
after gemcitabine is permanently 
discontinued.
Vital Signs and 
Weight
X
X
X
X
X
X
X
X
Refer to Section 8.3.3, vital signs 
include blood pressure, pulse rate, 
respiratory rate, and temperature.
Conducting within 1 day before 
administration of study intervention is 
acceptable.
Note: Day 8 vital signs and weight will 
not be performed after gemcitabine is 
permanently discontinued.
Full Physical 
Examination
X
X
Perform within 14 days prior to start of 
study intervention for second course.
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PRODUCT: MK-3475  
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Study Period
Second Course Phase (Retreatment)
21-Day Cycles
EOI
Post-Intervention
Notes
Intervention 
Cycle
Cycle 1
Cycle 2
Cycles 3 to17
Safety FUa
Efficacy 
FU 
Survival 
FU
Day
D1
D8
D1
D8
D1
D8
Scheduling 
Window (Days):
±3
±3
±3
±3
±3
±3
At Time of 
D/C
30 Days 
After Last 
Dose 
(+ 7 days)
Q6W or 
Q12W
(±7 days)
Q12W
(± 7 days)
Directed Physical 
Examination
X
X
X
X
X
X
Conduct on Day 1 and Day 8 of each 
cycle prior to the administration of 
study intervention.
Conducting within 1 day before 
administration of study intervention is 
acceptable.
Note: Day 8 directed physical 
examination is not required after 
gemcitabine is permanently 
discontinued.
ECOG 
Performance Status
X
X
X
X
X
X
X
X
Should be assessed prior to dosing at 
treatment visits. Conducting within 
1 day before administration of study 
intervention is acceptable.
Note: Day 8 ECOG PS will not be 
performed after gemcitabine is
permanently discontinued.
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Study Period
Second Course Phase (Retreatment)
21-Day Cycles
EOI
Post-Intervention
Notes
Intervention 
Cycle
Cycle 1
Cycle 2
Cycles 3 to17
Safety FUa
Efficacy 
FU 
Survival 
FU
Day
D1
D8
D1
D8
D1
D8
Scheduling 
Window (Days):
±3
±3
±3
±3
±3
±3
At Time of 
D/C
30 Days 
After Last 
Dose 
(+ 7 days)
Q6W or 
Q12W
(±7 days)
Q12W
(± 7 days)
Local Laboratory Procedures and Assessmentsb
Pregnancy Test 
(WOCBP only)c
X
X
X
X
X
Assess within 24 hours (urine) or 
72 hours (serum) prior to study 
intervention administration on Day 1 of 
each cycle. In regions where required 
via documented regulatory request (and 
subsequently approved by the Sponsor), 
pregnancy tests within 24 hours prior to 
study intervention will be required.
During the Post-Intervention Phase, 
perform a serum or urine pregnancy test 
at least 240 days after the last dose of 
chemotherapy or 150 days after the last 
dose of pembrolizumab, whichever is 
greater, or 30 days after cessation of 
study intervention if the participant 
initiates a new anticancer therapy.
Pregnancy testing should be conducted 
as per local regulations where 
applicable.
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Study Period
Second Course Phase (Retreatment)
21-Day Cycles
EOI
Post-Intervention
Notes
Intervention 
Cycle
Cycle 1
Cycle 2
Cycles 3 to17
Safety FUa
Efficacy 
FU 
Survival 
FU
Day
D1
D8
D1
D8
D1
D8
Scheduling 
Window (Days):
±3
±3
±3
±3
±3
±3
At Time of 
D/C
30 Days 
After Last 
Dose 
(+ 7 days)
Q6W or 
Q12W
(±7 days)
Q12W
(± 7 days)
PT/INR and aPTT
X
Collect samples within 14 days before
starting second course study 
intervention.
Additional testing to be conducted as 
clinically indicated for participants 
taking anticoagulant therapy. Refer to 
Section 6.5 for additional requirements 
during gemcitabine administration.
Hematology
X
X
X
X
X
X
X
X
Perform within 14 days before starting 
second course study intervention.
Perform on Day 1 and Day 8 before
administration of study intervention
(within 1 day before administration of 
study intervention is acceptable).
For laboratory details refer to
Section 10.2, Appendix 2, Table 18.
Note: Day 8 hematology blood samples 
will not be performed after
chemotherapy is permanently 
discontinued.
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PRODUCT: MK-3475  
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16-JUN-2022
Study Period
Second Course Phase (Retreatment)
21-Day Cycles
EOI
Post-Intervention
Notes
Intervention 
Cycle
Cycle 1
Cycle 2
Cycles 3 to17
Safety FUa
Efficacy 
FU 
Survival 
FU
Day
D1
D8
D1
D8
D1
D8
Scheduling 
Window (Days):
±3
±3
±3
±3
±3
±3
At Time of 
D/C
30 Days 
After Last 
Dose 
(+ 7 days)
Q6W or 
Q12W
(±7 days)
Q12W
(± 7 days)
Chemistry Panel 
and Liver Panel
X
X
X
X
X
X
X
X
Perform within 14 days before starting 
second course study intervention.
Collect liver panel on Day 1 and Day 8 
before administration of study 
intervention (within 1 day before
administration of study intervention is 
acceptable).
For laboratory details refer to
Section 10.2, Appendix 2, Table 18.
Note: Day 8 chemistry and liver panel
blood samples will not be performed 
after gemcitabine is permanently 
discontinued.
Urinalysis
X
X
Perform within 14 days prior to starting 
second course study intervention.
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16-JUN-2022
Study Period
Second Course Phase (Retreatment)
21-Day Cycles
EOI
Post-Intervention
Notes
Intervention 
Cycle
Cycle 1
Cycle 2
Cycles 3 to17
Safety FUa
Efficacy 
FU 
Survival 
FU
Day
D1
D8
D1
D8
D1
D8
Scheduling 
Window (Days):
±3
±3
±3
±3
±3
±3
At Time of 
D/C
30 Days 
After Last 
Dose 
(+ 7 days)
Q6W or 
Q12W
(±7 days)
Q12W
(± 7 days)
T3, FT4, and TSH
X
X
X
(Even 
Cycles)
X
Perform within 14 days prior to starting 
second course study intervention.
Perform on Day 1 of every other cycle 
starting from Cycle 2 (eg, Cycle 2, 4, 6, 
8, etc) and at EOI.
After Cycle 1, participant will be dosed 
even if thyroid evaluations are not 
available prior to dosing; however, the 
results must be available and reviewed 
before the next scheduled visit.
Free T3 is acceptable where T3 cannot 
be determined.
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PRODUCT: MK-3475  
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Study Period
Second Course Phase (Retreatment)
21-Day Cycles
EOI
Post-Intervention
Notes
Intervention 
Cycle
Cycle 1
Cycle 2
Cycles 3 to17
Safety FUa
Efficacy 
FU 
Survival 
FU
Day
D1
D8
D1
D8
D1
D8
Scheduling 
Window (Days):
±3
±3
±3
±3
±3
±3
At Time of 
D/C
30 Days 
After Last 
Dose 
(+ 7 days)
Q6W or 
Q12W
(±7 days)
Q12W
(± 7 days)
Central Laboratory Assessmentsb
HBsAg and HBV 
viral load 
X
For participants not taking HBV 
antiviral therapy, repeat HBV viral load 
and HBsAg tests approximately every 
6 weeks if HBsAg negative and anti-
HBc positive, and HBV viral load is 
undetectable at screening. Repeat HBV 
viral load and HBsAg tests 
approximately every 12 weeks for all 
participants on HBV antiviral therapy
until the end of study intervention and 
then per local standard of care. This
testing should be aligned with study 
intervention visits.
For HBV viral load over 100 IU/mL, 
start HBV treatment.
Abbreviations: AE=adverse event; aPTT=activated partial thromboplastin time; CT=computed tomography; D/C=discontinuation; DX=Day X; ECI=event of clinical interest; 
ECOG=Eastern Cooperative Oncology Group; EOI=End of intervention; FT4=free thyroxine; FU=Follow-up; HBsAg=hepatitis B surface antigen; HBV=hepatitis B virus; 
INR=international normalized ratio; IV=intravenous; MRI=magnetic resonance imaging; PD=disease progression; PS=performance status; PT=prothrombin time; Q3W=every 3 
weeks; Q6W=every 6 weeks; Q12W=every 12 weeks; SAE=serious adverse event; SC=second course; T3=triiodothyronine; TSH=thyroid-stimulating hormone; 
WOCBP=women of childbearing potential.
a.
If EOI visit occurs ≥30 days from last dose of study intervention, a Safety Follow-up Visit is not required. In this situation, all procedures required at both the EOI visit and 
the Safety Follow-up Visit should be performed.
b.
Clinical laboratory assessments may be conducted anytime within 72 hours before the scheduled visit, unless otherwise specified. Procedures/assessments should be 
performed before administration of study intervention.
c.
Refer to Section 10.7 (Appendix 7) for country-specific requirements.
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2
INTRODUCTION
2.1
Study Rationale
Biliary tract cancer (BTC) comprises cancers of intra- and extrahepatic bile ducts 
(cholangiocarcinoma [CCA]) and gallbladder. Biliary tract cancer is a rare but aggressive 
malignancy with limited treatment options. The majority of patients present with advanced or 
unresectable disease and undergo systemic chemotherapy. Patients presenting with earlier 
stage disease may undergo curative surgical resection but have a high rate of recurrence and 
metastases [Zhu, A. X., et al 2010] [Margonis, G. A., et al 2016]. Gemcitabine in 
combination with cisplatin is the standard of care (SOC) first-line therapy worldwide, with S-
1 (an oral fluoropyrimidine containing tegafur, gimeracil, and oteracil) also being used in 
Japan. Despite advances in supportive care along with combination chemotherapy, median 
PFS is approximately 6 to 7 months, and the median survival of advanced BTC patients 
remains dismal at approximately 12 months [Valle, J., et al 2010] [Okusaka, T., et al 2010]. 
An additional challenge in this patient population is the high risk of infection due to frequent 
biliary obstruction, particularly when exposed to immunosuppressive combination
chemotherapy regimens. Poor prognosis and limited treatment options in this challenging 
cancer highlight the unmet medical need for more effective therapies for those with advanced 
disease.
2.2
Background
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody 
(mAb) with high specificity of binding to the programmed cell death 1 (PD-1) receptor, thus 
inhibiting its interaction with programmed cell death ligand 1 (PD-L1) and programmed cell 
death ligand 2 (PD-L2). Based on preclinical in vitro data, pembrolizumab has high affinity 
and potent receptor blocking activity for PD-1. Pembrolizumab has an acceptable preclinical 
safety profile and is in clinical development as an intravenous (IV) immunotherapy for 
advanced malignancies. KEYTRUDA® (pembrolizumab) is indicated for the treatment of 
patients across a number of indications. For more details on specific indications refer to the 
Investigator’s Brochure (IB).
2.2.1
Pharmaceutical and Therapeutic Background
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades [Disis, M. L. 2010]. Accumulating evidence 
shows a correlation between tumor-infiltrating lymphocytes in cancer tissue and favorable 
prognosis in various malignancies. In particular, the presence of CD8+ T-cells and the ratio 
of CD8+ effector T-cells/FoxP3+ regulatory T-cells (T-regs) correlates with improved 
prognosis and long-term survival in solid malignancies, such as ovarian, colorectal, and 
pancreatic cancer; hepatocellular carcinoma; malignant melanoma; and renal cell carcinoma. 
Tumor-infiltrating lymphocytes can be expanded ex vivo and reinfused, inducing durable 
objective tumor responses in cancers such as melanoma [Dudley, M. E., et al 2005] [Hunder, 
N. N., et al 2008].
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The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control. The normal function of PD-1, expressed on the cell surface of activated 
T-cells under healthy conditions, is to down-modulate unwanted or excessive immune
responses, including autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an
immunoglobulin (Ig) superfamily member related to cluster of differentiation 28 (CD28) and
cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) that has been shown to negatively
regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2)
[Greenwald, R. J., et al 2005] [Okazaki, T., et al 2001].
The structure of murine PD-1 has been resolved [Zhang, X., et al 2004]. PD-1 and its family 
members are type I transmembrane glycoproteins containing an Ig-variable–type (IgV-type) 
domain responsible for ligand binding and a cytoplasmic tail responsible for the binding of 
signaling molecules. The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, 
an immunoreceptor tyrosine-based inhibition motif, and an immunoreceptor tyrosine-based 
switch motif. Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases, SHP-1 
and SHP-2, to the immunoreceptor tyrosine-based switch motif within its cytoplasmic tail, 
leading to the dephosphorylation of effector molecules such as CD3 zeta (CD3ζ), protein 
kinase C-theta (PKCθ), and zeta-chain-associated protein kinase (ZAP70), which are 
involved in the CD3 T-cell signaling cascade [Okazaki, T., et al 2001] [Chemnitz, J. M., et al 
2004] [Sheppard, K-A, et al 2004] [Riley, J. L. 2009]. The mechanism by which PD-1 down-
modulates T-cell responses is similar to, but distinct from, that of CTLA-4, because both 
molecules regulate an overlapping set of signaling proteins [Parry, R. V., et al 2005] 
[Francisco, L. M., et al 2010].
2.2.2
Biliary Tract Cancer: Epidemiology and Current Therapeutic Options
Biliary tract cancer arises from the epithelial lining of the biliary tree and is comprised of 
cancers of the bile ducts called cholangiocarcinoma (CCA), gallbladder, and ampulla.
Cholangiocarcinoma is classified as intrahepatic or extrahepatic. Ampullary cancers have 
been excluded from the current protocol due to potentially better prognosis [Hatzaras, I., et al
2010] [Park, I., et al 2009]. Additionally, ampullary cancer diagnosis and distinction from 
pancreatic and duodenal cancers could be challenging in a global study. Biliary tract cancer
subtypes differ in their cancer biology, clinical presentation, and are often diagnosed in the 
advanced stage. Nonetheless, for advanced or metastatic BTC (CCA and gallbladder), 
platinum-based chemotherapy is the SOC irrespective of subtype.
BTC also has a variable geographic distribution and incidence. Based on Surveillance, 
Epidemiology, and End Results Program (SEER) data the estimated incidence of BTCs in 
United States in 2018 was about 17,000 cases per year (including biliary, which account for 
approximately10 % of liver and bile duct cancers) [Siegel, R. L., et al 2018]. In the West, the 
incidence of CCA is low, while in Asia (eg, Thailand, China, Korea, Vietnam), rates are 
much higher [Bragazzi, M. C., et al 2012]. Northeast Thailand has the highest CCA rate in 
the world, accounting for >80% of all primary liver cancers [Shin, H. R., et al 2010]. 
Similarly, the incidence of gallbladder cancer (GBC) in the West is generally low; however, 
it is a significant health problem in Chile, India and Central/Eastern Europe. There are 
various risk factors associated with BTC. High rates of liver fluke infection have been 
associated with CCA risk in Asia. Gallstones and Salmonella Typhi infections are considered 
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to be strong risk factors for GBC in India and Chile [Lazcano-Ponce, E. C., et al 2001]. In 
Europe and the United States, inflammatory disorder of the biliary tract, primary sclerosing 
cholangitis, and fibro-polycystic liver disease have been associated with BTC. Other general
risk factors include intrahepatic stone disease, chronic liver disease, biliary papillomatosis, 
and genetic predisposition in Lynch syndrome.
Systemic combination chemotherapy consisting of gemcitabine and cisplatin is the SOC first-
line therapy in most countries for patients with advanced BTC. This is based on the study 
ABC-02 [Valle, J., et al 2010]. ABC-02 was a randomized Phase 3 study with a primary end 
of OS and enrolled 410 participants. Cisplatin 25 mg/m2 followed by gemcitabine
1000 mg/m2, each administered on Days 1 and 8, Q3W for 8 cycles, was shown to be 
associated with improved OS compared to single agent gemcitabine (1000 mg/m2 on Days 1, 
8, and 15, every 4 weeks for 6 cycles) (11.7 months versus 8.1 months respectively; hazard 
ratio [HR] 0.64, 95% CI: 0.52–0.80, p <0.001). In ABC-02, dose modifications and delays 
were allowed for hematologic toxicity, abnormal renal function, nausea, vomiting, peripheral 
neuropathy, edema, or tinnitus. There was one death from renal failure in the gemcitabine 
and cisplatin group, possibly related to cisplatin.
A similar randomized Phase 2 study (BT22) with cisplatin 25 mg/m2 followed by 
gemcitabine 1000 mg/m2 on Days 1 and 8 of a 21-day cycle or single agent gemcitabine 
1000 mg/m2 on Days 1, 8 and 15 of a 28-day cycle was conducted in Japan and showed an 
improvement in one-year survival rate (11.2 months versus 7.7 months; HR 0.69, 95% CI: 
0.42-1.13, p <0.139), median PFS (5.8 months versus 3.7 months; HR 0.66, 95% CI: 0.41-
1.05, p <0.077) and ORR (19.5% versus 11.9%) favoring the combination of gemcitabine 
and cisplatin compared to single agent gemcitabine [Okusaka, T., et al 2010]. In BT22, the 
most common AEs were related to myelosuppression seen in both groups but more common 
with combination therapy, as anticipated. Overall, the gemcitabine and cisplatin combination 
was well tolerated in both ABC-02 and BT22.
In Japan, an alternative first-line option is gemcitabine in combination with S-1. This is based 
on a Phase 3 study (FUGA-BT; JCOG1113) that demonstrated noninferiority of gemcitabine 
plus S-1 when compared to gemcitabine plus cisplatin [Mizusawa, J., et al 2016]. However, 
S-1 is not currently approved in multiple countries, hence, there is limited access to this 
regimen. Other potential options include 5- fluorouracil based options, gemcitabine with 
oxaliplatin (GEMOX), and taxane (docetaxel and paclitaxel) combinations. GEMOX was 
studied both in first-line and refractory settings in a Phase 2 study. An ORR of 36% with 
median OS of 15.4 months was observed in the first-line setting, while in second or third 
line, both ORR and OS were less favorable at 22% and 7.6 months, respectively [Andre, T., 
et al 2004]. The use of taxane combinations in BTC have primarily been reported in small, 
nonrandomized studies [Sahai, V., et al 2018] [Tajima, H., et al 2017].
A particular phenotype called microsatellite instability-high (MSI-H) or mismatch repair 
deficient (dMMR) found in several types of solid tumors is associated with increased 
mutation rate and genomic instability due to failure to repair the DNA mismatches that occur 
during normal DNA synthesis. A Phase 2 multicohort study evaluated the efficacy of 
pembrolizumab in the setting of MSI-H/dMMR tumors. The first cohort included MSI-H or 
dMMR metastatic colorectal cancer. The study was subsequently expanded to include 12 
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different tumor types with MSI-H or dMMR. A total of 86 participants were enrolled with 
objective radiographic responses in 53% of participants (46 of 86 participants; 95% CI, 42–
64%), and 21% (n = 18) achieved a complete radiographic response [Le, D. T., et al 2017]. 
Responses were found to be durable and similar between colorectal cancer and other cancer 
subtypes. This led to approval of pembrolizumab by the FDA in May 2017 for adult and 
pediatric patients with unresectable or metastatic, MSI-H or dMMR solid tumors that have 
progressed following prior treatment and who have no satisfactory alternative treatment 
options or with MSI-H or dMMR colorectal cancer that has progressed following treatment 
with a fluoropyrimidine, oxaliplatin, and irinotecan. A number of other countries have 
approved pembrolizumab in a similar fashion.
There are also multiple studies evaluating the use of FOLFOX for the treatment of BTCs in 
second-line setting. A single-arm Phase 2 study involving 37 participants refractory to 
gemcitabine and cisplatin treated with FOLFOX reported an ORR of 21.6% and median 
time-to-progression (TTP) of 3.1 months (95% CI: 2.3-3.6) with a manageable AE profile 
[He, S., et al 2014]. A randomized Phase 3 study (ABC-06; NCT01926236) evaluating 
FOLFOX in second-line advanced BTC has completed enrollment and results are anticipated.
Targeted therapy options capable of advancing precision medicine for the treatment of BTC 
are currently being explored. Comprehensive genomic analysis of BTC with next generation 
sequencing has led to the identification and characterization of several genomic alterations as 
potential targets in distinct subgroups of BTC [Nakamura, H., et al 2015]. FGFR2 fusion, 
IDH1/2 and BAP1 mutations have been associated with intrahepatic CCA while 
PRKACA/PRKACB fusions, ELF3 and ARID1B are more specific for extrahepatic CCA. 
Gallbladder cancer has been shown to harbor EGFR, ERBB3, ARID2 and TERT promoter 
mutations [Nakamura, H., et al 2015] and HER2/neu mutations [Javle, M., et al 2015]. 
Clinical studies utilizing interventions targeting genomic alterations in BTC are ongoing. 
Overall, these alterations are seen in about 40% of biliary cancers, but individual alterations 
are limited to a small proportion of patients [Nakamura, H., et al 2015].
Locoregional therapies like hepatic arterial infusion radiofrequency ablation, transarterial 
chemoembolization (TACE) or transarterial radioembolization (TARE) have also been used 
in patients with unresectable biliary cancer and liver predominant disease [Han, K., et al 
2015]. There are no randomized controlled studies and most studies included a heterogenous,
small group of participants without standardization of intervention modalities. Though some 
have reported encouraging results, there have been concerns about potential toxicity. Due to 
lack of validated data, these therapies are not considered as part of SOC.
Photodynamic therapy (PDT), a direct ablative technique using a photosensitizing agent, has 
also been of interest though more commonly used for palliation of biliary obstruction [Gao, 
F., et al 2010]. In patients with localized disease, liver transplant is a potential option for 
treatment. Some studies have reported improved outcome compared to surgical resection, 
however a direct comparison in randomized fashion has not been performed. With scarcity of 
donors, lack of Phase 3 studies, and a requirement for expertise, liver transplant has not been 
widely adopted [Banales, J. M., et al 2016] [Sapisochin, G., et al 2015]. External beam 
radiation and intraluminal brachytherapy have been used and reported in management of 
BTC for patients with localized disease. There is conflicting evidence of use of radiation 
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alone, but data with concurrent chemoradiation appear more promising. Small 
nonrandomized studies have reported improved outcomes with adjuvant concurrent 
chemoradiation [Kim, S., et al 2002] [Nakeeb, A. 2005]. In the adjuvant setting, the Phase 3 
study PRODIGE 12-ACCORD 18 (UNICANCER GI group) showed participants with 
localized BTC that received GEMOX did not have statistically improved recurrence-free 
survival (RFS) compared to surveillance [Edeline, J., et al 2019]. In a Phase 3 study utilizing 
capecitabine as an adjuvant therapy in BTC (BILCAP), although an improvement in OS was 
reported, the primary endpoint of improving OS was not met [Primrose, J. N., et al 2019].
Although several studies are evaluating potential cytotoxic and molecularly targeted therapy 
options, the limitation of increased toxicity with cytotoxic chemotherapy and small selected 
populations for molecularly targeted therapy highlights the need for a more effective therapy 
than can be used for the majority of BTC patients. Current data support PD-1/PD-L1 
mediated inhibition of adaptive immune response to carcinogenesis and, hence the role of 
checkpoint inhibition as a therapeutic option.
2.2.3
Rationale for Immunotherapy in Biliary Cancer: Preclinical and Clinical Studies
The PD-1/PD-L1 pathway is an attractive target for therapeutic intervention in BTC. 
Therapeutic studies in mouse models have shown that the administration of antibodies 
blocking the 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 and anti-mouse PD-L1 antibodies have demonstrated 
antitumor responses as monotherapy in models of squamous cell carcinoma, pancreatic 
carcinoma, melanoma, and colorectal carcinoma. Blockade of the PD-1 pathway effectively 
promotes CD8+ T-cell infiltration into the tumor and the presence of interferon-γ, granzyme 
B and perforin, indicating that the mechanism of action involves local infiltration and 
activation of effector T-cell function in vivo [Ropponen, K. M., et al 1997] [Dudley, M. E., et 
al 2005] [Hunder, N. N., et al 2008] [Pölcher, M., et al 2010] [Okazaki, T., et al 2001] 
[Greenwald, R. J., et al 2005]. 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 (refer to the pembrolizumab IB).
As discussed, inflammation plays a key role in the development of BTC worldwide. The role 
of immune modulation and adaptive immune response to tumor antigens is an area of active 
research in variety of cancers including BTC. In a retrospective analysis of BTC, presence of 
tumor-infiltrating lymphocytes (TILs) was associated with improved outcome [Goeppert, B., 
et al 2013]. A total of 375 cases were analyzed, which included intra-/extrahepatic CCA and 
GBC. Of note, the presence of intraepithelial tumor-infiltrating CD4+, CD8+ and FoxP3+ 
TILs were associated with longer survival. This study also reported decline in adaptive 
immune response and increase in innate immune response components during dysplasia to 
primary carcinoma to metastases progression. Additionally, a large meta-analysis of 12 
studies and over 2,000 participants showed similar results indicating association of improved 
clinical outcome with higher expression of TILs [Wang, Y., et al 2017]. These findings 
theorize evasion of immune surveillance and adaptive immune response in BTC and, hence,
support the role of checkpoint inhibitor therapy in this patient population.
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Clinical studies have demonstrated efficacy of pembrolizumab in participants with multiple 
tumor types, including advanced melanoma, nonsmall cell lung cancer (NSCLC), head and 
neck cancer, bladder cancer, Hodgkin’s lymphoma, triple negative breast cancer, and gastric 
adenocarcinoma. In addition, recent data demonstrate emerging evidence of single agent 
activity in additional tumor types such as mesothelioma, urothelial cancer, ovarian cancer, 
neuroendocrine carcinoma, and small cell lung cancer.
Single agent pembrolizumab has shown efficacy in several gastrointestinal tumors. 
Pembrolizumab has been approved by the FDA for PD-L1 + advanced refractory metastatic 
gastric cancer based on KEYNOTE-059 (NCT02335411) and hepatocellular cancer after 
progression on sorafenib based on KEYNOTE-224 (NCT02702414).
Early clinical studies have evaluated the prevalence of PD-L1 expression in BTC. 
KEYNOTE-028, a multicohort Phase 1b study, assessed pembrolizumab in PD-L1 positive 
solid tumors. This was a population with refractory disease and a large proportion (39.1%) 
had undergone ≥3 prior lines of therapy [Ott, P. A., et al 2018]. A total of 89 participants
with advanced BTC were screened and 37 (42%) had PD-L1 positive tumors; of these, 24 
participants were enrolled [Bang, Y. J., et al 2015], and data were reported for 23 participants 
[Ott, P. A., et al 2018]. In the BTC cohort, the median PFS was 1.8 months, and the median
OS was 6.2 months. The 6-month and 12-month OS rates were 53% and 29%, respectively. 
The ORR (confirmed and unconfirmed) per RECIST 1.1 by investigator review was 17% 
(95% CI: 5%-39%) [Bang, Y. J., et al 2015] [Ott, P. A., et al 2018]. One response was a CR 
and 3 responses were PRs by investigator review (n=4). Across all cohorts in KEYNOTE-
028, AEs were reported for 96% of the 475 participants treated with pembrolizumab. The AE 
profile was favorable, and only 4% of participants discontinued treatment due to an AE.
KEYNOTE-158 (NCT02628067) [Ueno, M., et al 2018] a Phase 2, multicohort study 
included participants with advanced BTC with prior progression or intolerance on standard 
chemotherapy. A total of 104 participants were enrolled, and among those, 61 had a tumor 
positive for PD-L1 expression (combined positive score [CPS] ≥1). Approximately half 
(52%) of participants had 2 or more prior lines of therapy. An overall response rate of 5.8% 
was noted with a DOR of >15 months in 2 participants. The median DOR was not reached. 
The median PFS was 2.0 months (95% CI: 1.9–2.1) and median OS was 9.1 months (95% CI:
5.6–10.4). Among participants with PD-L1 CPS ≥1, the ORR was 6.6 %, the median PFS 
was 2.1 months and the median OS was 9.6 months. Participants with CPS <1 had an ORR 
of 2.9%, median PFS was 1.9 months, and OS was 7.2 months. None of the participants were 
found to be microsatellite instability-high (MSI-H). The overall toxicity profile was 
manageable, and activity was seen regardless of PD-L1 status.
These data support modest efficacy of pembrolizumab monotherapy in advanced BTC.
2.2.4
Ongoing Clinical Studies in Biliary Cancer
Several other PD-1 and PD-L1 inhibitors are under investigation for BTC. Nivolumab is 
being evaluated as a single agent in the second-line setting (NCT02829918) in a Phase 2
study. Data from first 34 participants was reported. Out of 29 participants evaluable for 
response, 5 pts (17%) achieved PR and 11 pts (38%) achieved SD. The DCR was 55%. The
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median PFS was 3.5 months [Kim, R., et al 2018]. At median follow-up of 8 months, OS had 
not been reached; the 6-month OS was 76.3%. In a Phase 1 study conducted in Japan,
nivolumab in combination with gemcitabine and cisplatin in first-line was compared to single
agent nivolumab in a refractory setting [Ikeda, M., et al 2019]. A total of 60 participants were 
enrolled, 30 participants in each cohort, and treatment was well tolerated in both cohorts. An 
ORR of 3.3% (90% CI: 0.7–13.6%) and a median OS of 5.2 months (90% CI: 4.5–8.7 
months) was reported with nivolumab monotherapy. In the combination cohort, the ORR was 
36.7% (90% CI: 23.9–51.7%) and the median OS was 15.4 months (90% CI: 11.8–Not 
estimable). Combination therapy seemed tolerable in this patient population with an expected 
adverse effect profile. In the combination arm, though a higher response rate was observed in 
the subgroup with PD-L1 expression ≥1% in tumor cells (n = 8), OS was better in the group 
with PD-L1 expression <1% in tumor cells (n = 21), however, due to the small number of 
participants, a reliable correlation could not be established with PD-L1 status.
A randomized Phase 2 study of nivolumab in combination with gemcitabine and cisplatin 
versus ipilimumab is ongoing with PFS as the primary endpoint (NCT03101566). Other 
agents under active investigation include durvalumab, tremelimumab and atezolizumab. A 
Phase 1 study from Asia evaluating durvalumab and durvalumab/tremelimumab combination 
included advanced BTC in an expansion cohort. Safety and efficacy data were reported after 
107 participants were enrolled [Ioka, T., et al 2019]. A total of 42 participants were recruited 
to the durvalumab cohort followed by 65 participants in the durvalumab and tremelimumab 
combination group. Partial response was seen in 2/42 participants in the monotherapy group 
(4.8%) and 7/65 in the combination group (10.8%). Median OS was 8.1 months (95% CI, 
5.6–10.1) for the monotherapy group and 10.1 months (95% CI, 6.2–11.4) for the 
combination group. The DOR was 9.6 months and 9.7 months for the 2 participants in the 
monotherapy group. The median DOR was 8.5 months for participants receiving 
combination therapy.
Atezolizumab is being studied in combination with pegvorhyaluronidase alfa (PEGPH20), 
cisplatin, and gemcitabine in a Phase 1b study in advanced biliary cancers. After enrollment 
of the first 48 participants, no significant toxicities were reported. One dose-limiting toxicity 
with febrile neutropenia was seen in the initial Run-in Phase.
2.2.5
Rationale and Safety of Combining Pembrolizumab with Gemcitabine and 
Cisplatin
Cisplatin-based combination chemotherapy with gemcitabine is the standard first-line 
treatment in the US (NCCN Guidelines), Japan (Japanese Society of Hepato-Biliary-
Pancreatic Surgery guidelines), Europe (ESMO guidelines) and several other countries 
worldwide for patients with advanced or unresectable BTC. Several lines of evidence support 
the rationale to add pembrolizumab therapy to gemcitabine/cisplatin. First, gemcitabine has 
been shown to lead to immunogenic cell death. However, gemcitabine may have 
additive/synergistic effects with anti-PD-L1. Despite modest single agent activity, and a 
reduction in the levels of activated intratumoral CD8+ T-cells, combination of gemcitabine 
and anti-PD-L1 treatment resulted in enhanced antitumor responses with 40% CRs [Cubas, 
R., et al 2018]. There is no antagonistic effect of gemcitabine/cisplatin in combination with 
concurrent pembrolizumab. Phase 2 combination of ipilimumab with gemcitabine/cisplatin in 
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bladder cancer has shown in pharmacodynamic (PD) data that the addition of ipilimumab 
leads to immunostimulatory effects in circulating cells, suggesting that chemotherapy may 
not necessarily abrogate immune effects of checkpoint blockade [Galsky, M. D., et al 2018].
Additionally, Phase 1 combinations of an immune checkpoint inhibitor therapy with 
platinum-containing doublet chemotherapy have been reported to show tolerability in 
NSCLC [Papadimitrakopoulou, V., et al 2015]. In metastatic NSCLC, a Phase 3 study
KEYNOTE-189 shown that treatment with pembrolizumab, pemetrexed, and platinum
resulted in significantly longer OS and PFS than pemetrexed plus platinum alone in the first-
line setting. Additionally, KEYNOTE-407 shown that pembrolizumab in combination with 
chemotherapy (carboplatin and either paclitaxel or nab-paclitaxel) led to an improvement in 
OS, PFS and ORR when compared to chemotherapy alone in first-line metastatic NSCLC. 
KEYNOTE-048 (NCT02358031) and KEYNOTE-059 (NCT02335411) have been 
investigating the addition of pembrolizumab to chemotherapy in head and neck cancer, and 
gastric cancer, respectively. Early reports from KEYNOTE-059 have shown manageable
toxicities [Bang, Y. J., et al 2019]. KEYNOTE-361 is a randomized, open label, Phase 3 
study of pembrolizumab with or without chemotherapy versus chemotherapy alone in 
participants with advanced urothelial carcinoma.
Nivolumab with gemcitabine and cisplatin has been evaluated in BTC in a Phase 1 study 
involving 2 patient cohorts [Ikeda, M., et al 2019]. Participants refractory or intolerant to 
gemcitabine/cisplatin were treated with nivolumab monotherapy and therapy naïve 
participants were treated with nivolumab in combination with gemcitabine and cisplatin in 
the first-line setting. A total of 60 participants were enrolled, 30 participants in each cohort 
and the AE profile was manageable in both cohorts. An ORR of 3.3% (0.7-13.6) and a 
median OS of 5.2 months (4.5-8.7) was reported with nivolumab monotherapy. In the 
combination cohort the ORRs were 36.7 % (23.9-51.7) and the median OS was 15.4 months 
(11.8-Not estimable) [Ueno, M., et al 2019]. In a study evaluating nivolumab monotherapy in 
participants in China with metastatic BTC treated in a nonclinical trial setting at a hospital, 
the median PFS was reported as 3.1 months (95% CI: 2.13–4.06 months) [Gou, M., et al 
2019]. One participant (3.3%) achieved CR, 5 (16.7%) achieved PR, 12 (40%) were SD, and 
12 (40%) were PD. The ORR and DCR were 20% and 60%, respectively, and the OS was not 
reported.
In summary, there are early phase data supporting safety and modest efficacy of 
pembrolizumab monotherapy in advanced BTC (KEYNOTE-158 and KEYNOTE-028), as 
well as studies showing safety and efficacy of pembrolizumab plus platinum chemotherapy 
combinations in several cancers including biliary, head and neck, lung and bladder cancers. 
The present randomized Phase 3 study has been designed to investigate the use of 
pembrolizumab in first-line setting in combination with SOC cytotoxic chemotherapy for 
potential additive or synergistic therapeutic advantage. The primary study hypothesis is that 
combination therapy (pembrolizumab + chemotherapy) is superior to chemotherapy only 
with respect to OS in nonbiomarker selected participants. A similar Phase 2 study involving 
CCI
CCI
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50 participants with advanced CCA in combination with the same chemotherapy 
(gemcitabine/cisplatin) is planned in collaboration with European Organization for Research 
and Treatment of Cancer (EORTC). Any early data about unexpected toxicity or efficacy 
seen in this study will be used for future considerations in the proposed study.
2.2.6
Delayed Treatment Effect With Immunotherapy
Immune agents like checkpoint inhibitors have an indirect mechanism of action on tumor 
cells unlike standard chemotherapeutic agents and hence may have a delay in treatment 
effect. Although not universal, delayed treatment effect has been observed in several studies 
evaluating immunotherapy. In a first-line study of melanoma comparing ipilimumab plus 
dacarbazine versus placebo plus dacarbazine, overall survival benefit was observed after the 
initial 4 months as seen in delayed separation of the survival curve [Robert, C., et al 2011]. In 
CheckMate 057, a study of nivolumab versus docetaxel for previously treated metastatic 
nonsquamous nonsmall-cell lung cancer, the experimental arm with immunotherapy was 
actually worse initially with subsequent improvement. The study led to FDA approval of 
nivolumab for metastatic nonsquamous non-small cell lung cancer after prior platinum-based 
chemotherapy [Kazandjian, D., et al 2016]. More recently, delayed separation of survival 
curves was seen in KEYNOTE-048, a Phase 3 study of pembrolizumab alone or with 
chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell 
carcinoma of the head and neck [Burtness, B., et al 2019]. Other examples include IMpower 
133 [Horn, L., et al 2018], IMpower 150 [Socinski, M. A., et al 2018], and KEYNOTE-062 
[Shitara, K., et al 2020].
In summary, delayed treatment effect has been noted with immunotherapy and may have a 
significant impact on statistical design and results of clinical studies with these agents. It 
would be prudent to account for delayed effect in the study design to make it more applicable 
to such agents and avoid stopping a study with a potentially effective regimen based on early 
results. 
2.3
Benefit/Risk Assessment
It cannot be guaranteed that participants in clinical studies will directly benefit from 
treatment during participation, as clinical studies are designed to provide information about 
the safety and effectiveness of an investigational medicine.
The benefit-risk profile for pembrolizumab in combination with chemotherapy in advanced
and/or unresectable BTC population is unknown since these participants have not been 
previously studied with this combination. The safety and efficacy data generated to date 
provide a favorable benefit/risk assessment for the continued use of pembrolizumab as a 
treatment for multiple indications including adjuvant and advanced/metastatic melanoma and 
advanced/metastatic NSCLC, head and neck carcinoma, urothelial tract cancer, 
adenocarcinoma of the stomach/gastroesophageal junction, cervical cancer and as an 
investigational medicinal product in participants with triple negative breast cancer, colorectal 
cancer, hematologic malignancies, and other advanced solid tumors.
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Based on pembrolizumab chemotherapy combination data from other indications and from 
data in early phase studies with BTC treated with pembrolizumab, a favorable benefits-risk 
profile is anticipated.
Participants in clinical studies generally cannot expect to receive direct benefit from 
treatment during participation, as clinical studies are designed to provide information about 
the safety and effectiveness of an investigational medicine. However, experience with this 
drug in combination with chemotherapy approved in other indications, suggests that study 
participants may receive a clinical benefit.
Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the accompanying IB and informed consent documents.
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
In first-line therapy for participants with advanced and/or unresectable biliary tract 
carcinoma:
Although the original RECIST 1.1 publication recommends a maximum of 5 target lesions in 
total and 2 per organ, throughout this protocol, the term RECIST 1.1 refers to an adjustment
of RECIST 1.1 to allow a maximum of 10 target lesions in total and 5 per organ. Refer to 
Section 4.2.2.2 for further details.
Objectives
Endpoints
Primary

Objective: To compare overall survival 
(OS) between pembrolizumab plus 
gemcitabine/cisplatin and placebo plus 
gemcitabine/cisplatin

Hypothesis (H1): Pembrolizumab plus 
gemcitabine/cisplatin is superior to 
placebo plus gemcitabine/cisplatin with 
respect to OS

OS: the time from randomization to 
death due to any cause
Secondary

Objective: To compare progression-free 
survival (PFS) per RECIST 1.1 as 
assessed by blinded independent central 
review (BICR) between pembrolizumab 
plus gemcitabine/cisplatin and placebo 
plus gemcitabine/cisplatin

Hypothesis (H2): Pembrolizumab plus 
gemcitabine/cisplatin is superior to 
placebo plus gemcitabine/cisplatin with 
respect to PFS per RECIST 1.1 by BICR

PFS: the time from randomization to 
the first documented PD per RECIST 
1.1 by BICR, or death due to any
cause, whichever occurs first
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Objectives
Endpoints

Objective: To compare objective 
response rate (ORR) per RECIST 1.1 as 
assessed by BICR between 
pembrolizumab plus 
gemcitabine/cisplatin and placebo plus 
gemcitabine/cisplatin

Hypothesis (H3): Pembrolizumab plus 
gemcitabine/cisplatin is superior to 
placebo plus gemcitabine/cisplatin with 
respect to ORR per RECIST 1.1 as 
assessed by BICR

Objective Response (OR): complete 
response (CR) or partial response (PR)

Objective: To evaluate duration of 
response (DOR) per RECIST 1.1 as 
assessed by BICR

DOR: for participants who show
confirmed CR or PR, the time from the 
first documented evidence of CR or PR 
until disease progression or death due 
to any cause, whichever occurs first

Objective: To evaluate the safety and 
tolerability profile of pembrolizumab 
plus gemcitabine/cisplatin

Adverse events (AEs)

Study intervention discontinuations 
due to AEs
Tertiary/Exploratory

Objective: To evaluate disease control 
rate (DCR) per RECIST 1.1 as assessed 
by BICR

Disease Control (DC): a best overall 
response of CR, PR, or stable disease 
(SD). SD must be achieved at ≥6 
weeks after randomization to be 
considered best overall response

Objective: To evaluate efficacy outcomes 
per RECIST 1.1 modified for immune-
based therapeutics (iRECIST) as assessed 
by the investigator

PFS, OR, DOR, DC

Objective: To evaluate efficacy outcomes 
per RECIST 1.1 as assessed by the 
investigator

PFS, OR, DOR, DC

Objective: To compare PFS and ORR per 
RECIST 1.1 as assessed by BICR and OS 
by PD-L1 status (CPS ≥1 versus <1, and 
additional cutoff ≥10) between 
pembrolizumab plus 
gemcitabine/cisplatin and placebo plus 
gemcitabine/cisplatin

PFS, OR, OS
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Objectives
Endpoints

To evaluate PFS per RECIST 1.1 as 
assessed by BICR and OS by MSI status

PFS, OS

Objective: To identify molecular 
plus 
gemcitabine/cisplatin 


Objective: To compare time to 
deterioration (TTD) and score change 
from baseline in global quality of life 
using the EORTC Quality of Life (QOL) 
Questionnaire (EORTC QLQ) -C30 and 
EORTC QLQ-BIL21 between 
pembrolizumab plus 
gemcitabine/cisplatin and placebo plus 
gemcitabine/cisplatin

Scores from the global health 
status/QOL scale on the EORTC QLQ-
C30 and EORTC QLQ- BIL21

TTD: the time to first onset of a 10 
point or more decrease from baseline. 
TTD evaluated for EORTC QLQ-C30 
and EORTC QLQ-BIL21 global health 
status/QOL 

Objective: To characterize health utilities 
using the EuroQoL-5 Dimension 
Questionnaire, 5-Level (EQ-5D-5L) 
healthy utility scores

EQ-5D-5L health utility score

Objective:
of adverse events

4
STUDY DESIGN
4.1
Overall Design
This is a randomized, placebo-controlled, parallel-group, multi-site, double blind study of 
pembrolizumab plus gemcitabine/cisplatin versus placebo plus gemcitabine/cisplatin in 
participants with advanced (metastatic) and/or unresectable (locally advanced) biliary tract 
carcinoma (intra- or extrahepatic cholangiocarcinoma or gallbladder). Participants must have 
measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, as 
determined by investigator/site radiologist. Lesions situated in a previously irradiated area by 
either radiotherapy, photodynamic therapy, or arterial embolization are considered 
measurable if progression has been shown in such lesions. Other key eligibility criteria 
include no prior systemic therapy, and an ECOG performance scale (PS) score of 0 or 1.
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Approximately 1048 participants are expected to be randomized 1:1 into 1 of the 2 treatment 
arms:
Arm A:
Pembrolizumab 200 mg IV on Day 1 Q3W + gemcitabine 1000 mg/m2 IV and cisplatin 
25 mg/m2 IV on Day 1 and Day 8 Q3W.
Arm B:
Placebo (saline) IV on Day 1 Q3W + gemcitabine 1000 mg/m2 IV and cisplatin 25 mg/m2 IV 
on Day 1 and Day 8 Q3W.
Eligible participants will be stratified by 1) Region (Region 1: Asia versus Region 2: Non-
Asia), 2) locally advanced versus metastatic, and 3) site of origin (gallbladder, intrahepatic, 
or extrahepatic).
After enrollment of the global portion of the study is complete, the study may remain open to 
enrollment in China alone until approximately 158 participants in China have been enrolled 
to meet local regulatory requirements. An extension portion of the study will be identical to 
the global portion (eg, inclusion and exclusion criteria, study endpoints, primary and 
secondary objectives, and study procedures) in general, with the exception of an additional 
statistical analysis plan for China participants. Details of the analysis will be provided in a 
separate supplemental statistical analysis plan (sSAP).
This protocol does not allow participants to cross over between arms. During the initial 
intervention phase, cisplatin is given for a maximum of 8 cycles. Pembrolizumab or placebo
will continue until up to 35 administrations, documented disease progression, unacceptable 
adverse event(s), intercurrent illness that prevents further administration of study 
intervention, investigator’s decision to withdraw the participant, participant withdraws 
consent, pregnancy of the participant, noncompliance with study intervention or procedure 
requirements, or administrative reasons. Gemcitabine will continue until documented disease 
progression, unacceptable adverse event(s), intercurrent illness that prevents further 
administration of study intervention, investigator’s decision to withdraw the participant, 
participant withdraws consent, pregnancy of the participant, noncompliance with study 
intervention or procedure requirements, or administrative reasons.
Participants in Arm A who stop study intervention after achieving SD or better may be 
eligible to receive additional pembrolizumab for up to 17 cycles if they experience 
radiographic disease progression while off study intervention, according to the criteria in 
Section 6.1.2. Gemcitabine may be continued until PD or unacceptable toxicity during 
second course at investigator’s discretion. This retreatment is termed the Second Course 
Phase of this study. Participants are unblinded individually upon disease progression while 
off study intervention, and are able to participate in the Second Course Phase only if they 
were receiving pembrolizumab originally, and if the study remains open. An objective 
response or disease progression that occurs during the Second Course Phase for a participant 
will not be counted as an event for the primary analysis in this study. The decision to re-treat 
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will be at the discretion of the investigator only if no cancer treatment was administered since 
the last dose of study intervention and the participant still meets the safety parameters listed 
in the inclusion/exclusion criteria (refer to Sections 5.1 and 5.2 for further details). During 
this phase, the participant may resume the same previously administered systemic cytotoxic 
chemotherapy at the discretion of the local site investigator.
The primary endpoint in this study is OS.
Adverse events will be monitored throughout the study and graded in severity according to 
the guidelines outlined in the National Cancer Institute (NCI) Common Terminology Criteria 
for Adverse Events (CTCAE) Version 5.0.
The first on treatment imaging assessment will be performed at 6 weeks (42 days +7 days) 
from the date of randomization. Subsequent tumor imaging should be performed Q6W (42 
days ±7 days) through Week 54 and Q12W (84 days ± 7 days) thereafter. Progressive disease 
will be verified by BICR per RECIST 1.1 and may be further confirmed at the site by 
subsequent imaging per iRECIST. Refer to Section 8.2.1 for details about tumor imaging and 
assessments.
After verification of progression by BICR per RECIST 1.1 and/or initiation of a subsequent 
anticancer treatment, all participants will be followed for survival until death, withdrawal of 
consent, loss to follow-up, or until the study is concluded or terminated early, whichever 
comes first.
Specific procedures to be performed during the study, as well as their prescribed times and 
associated visit windows, are outlined in the SoA in Section 1.3. Details of each procedure 
are provided in Section 8.
There are interim efficacy/immunogenicity analyses in this study. Details of these interim 
analyses are described in Section 9.
4.2
Scientific Rationale for Study Design
This study is designed as a double blind placebo-controlled study evaluating addition of 
pembrolizumab to the SOC chemotherapy combination of gemcitabine and cisplatin. The 
experimental arm (Arm A) consists of chemotherapy with pembrolizumab, and the 
comparator arm (Arm B) consists of chemotherapy with placebo. The use of a placebo 
control with pembrolizumab will allow unbiased evaluation of this novel combination 
therapy. Additionally, pembrolizumab in combination with gemcitabine and cisplatin is 
currently being evaluated in participants with advanced urothelial carcinoma. The adverse 
event profile of the combination of pembrolizumab with chemotherapy has been generally 
comparable to chemotherapy alone. This allows blinding to be an appropriate strategy for 
evaluation of the combined activity in this population with few options for treatment.
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4.2.1
Rationale for Stratification Factors
Geographic region stratification includes 2 categories: a) Asia b) Non-Asia. Because of 
known ethnic differences in incidence, clinical practice, primary tumor location, and 
prognosis of BTC, stratification of geographic region is required to get equal distribution of 
treatment groups in different populations.
Presentation with locally advanced disease, which is unresectable, versus Stage IV disease 
with distant organ metastatic involvement has been shown to have significant impact on 
clinical outcome and, hence, is used for stratification to ensure balance between treatment 
arms.
Location of tumor is an important consideration as the subtypes of BTC 
(gallbladder/intrahepatic/extrahepatic bile duct cancers) are distinct biological entities based 
on molecular characterization and clinical behavior. Site of origin has been used as a 
stratification factor in a number of studies involving BTC including ABC-02 [Valle, J., et al 
2010]. Additionally, based on next generation sequencing data, there is variability in these 
subtypes with respect to actionable mutations [Nakamura, H., et al 2015] [Shibata, T., et al 
2018] [Chan-On, W., et al 2013] [Javle, M., et al 2015] and potential targeted therapy 
options.
4.2.2
Rationale for Endpoints
4.2.2.1
Efficacy Endpoints
This study will use OS as the primary endpoint.
The endpoint of OS is the gold standard for demonstrating superiority of antineoplastic 
therapy in clinical studies. In biliary tract cancer, life expectancy is short and hence OS as a 
sole primary endpoint is feasible. Additionally, PFS improvement in the absence of OS may 
not be clinically meaningful, supporting OS as a sole primary endpoint and PFS, OR, and 
DOR as secondary endpoints. Progression-free survival as a secondary endpoint is an 
acceptable measure of clinical benefit for a late stage study that shows superiority of a new 
antineoplastic therapy, especially if the magnitude of the effect is large and the therapy has 
an acceptable risk/benefit profile. The use of BICR and RECIST 1.1 to assess PFS is 
typically considered acceptable by regulatory authorities. Images will be submitted to an 
imaging CRO (iCRO) and read by an independent central review blinded to treatment 
assignment to minimize bias in the response assessments. In addition, the final determination 
of radiologic progression will be based on the central assessment of progression, rather than a 
local site investigator/radiology assessment. Expedited verification of radiologic progression, 
as determined by central review, will be communicated to the site.
OR is an acceptable measure of clinical benefit for a late stage study that shows superiority 
of a new antineoplastic therapy, especially if the magnitude of the effect is large and the 
therapy has an acceptable risk/benefit profile. Images will be read per RECIST 1.1 by BICR
to minimize bias in the response assessments.
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DOR per RECIST 1.1, assessed by BICR, will serve as an additional measure of efficacy and 
is a commonly accepted endpoint by both regulatory authorities and the oncology 
community.
4.2.2.2
RECIST 1.1
RECIST 1.1 will be used when assessing images for efficacy measures. Although the original
RECIST 1.1 publication recommends a maximum of 5 target lesions in total and 2 per organ, 
this protocol has implemented an adjustment to RECIST 1.1 to allow a maximum of 10 target 
lesions in total and 5 per organ, if a larger number of target lesions is needed to adequately 
represent the tumor burden. Refer to Section 8.2.1.5 for additional detail.
4.2.2.3
iRECIST
RECIST 1.1 will be adapted to account for the unique tumor response characteristics seen 
following treatment with pembrolizumab (refer to Section 8.2.1.6). Immunotherapeutic 
agents such as pembrolizumab may produce antitumor effects by potentiating endogenous 
cancer-specific immune responses. The response patterns seen with such an approach may 
extend beyond the typical time course of responses seen with cytotoxic agents, and patients 
treated with pembrolizumab may manifest a clinical response after an initial increase in 
tumor burden or even the appearance of new lesions. Thus, standard RECIST 1.1 may not 
provide an accurate response assessment of immunotherapeutic agents such as 
pembrolizumab. Based on an analysis of participants with melanoma enrolled in KEYNOTE-
001 (KN001), 7% of evaluable participants experienced delayed or early tumor pseudo-
progression. Of note, participants who had progressive disease (PD) by RECIST 1.1 but not 
by the immune-related response criteria [Wolchok, J. D., et al 2009] had longer overall 
survival than participants with PD by both criteria [Hodi, F. S., et al 2014]. Additionally, the 
data suggest that RECIST 1.1 may underestimate the benefit of pembrolizumab in 
approximately 15% of participants. These findings support the need to apply a modification 
to RECIST 1.1 that takes into account the unique patterns of atypical responses in 
immunotherapy and enables treatment beyond initial radiographic progression, if the 
participant is clinically stable.
Modified RECIST 1.1 for immune-based therapeutics (iRECIST) assessment has been 
developed and published by the RECIST Working Group, with input from leading experts 
from industry and academia, along with participation from the US Food and Drug 
Administration and the European Medicines Agency [Seymour, L., et al 2017]. The 
unidimensional measurement of target lesions, qualitative assessment of nontarget lesions, 
and response categories are identical to RECIST 1.1, until progression is seen by RECIST 
1.1. However, if a participant is clinically stable, additional imaging may be performed to 
confirm radiographic progression. iRECIST will be used by investigators to assess tumor 
response and progression and make treatment decisions as well as for exploratory efficacy 
analyses when specified.
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4.2.2.4
Safety Endpoints
Safety parameters commonly used for evaluating investigational systemic anticancer 
treatments are included as safety endpoints including, but not limited to, the incidence of, 
causality, and outcome of adverse events (AEs)/serious adverse events (SAEs); and changes 
in vital signs and laboratory values. AEs will be assessed as defined by CTCAE, Version 5.0.
4.2.2.5
Patient-reported Outcomes
The EORTC QLQ-C30, EuroQoL-5D-5L (EQ-5D-5L), and EORTC QLQ-BIL21 patient-
reported outcomes (PROs) are not pure efficacy or safety endpoints because they are affected 
by both disease progression and treatment tolerability.
4.2.2.5.1
EORTC QLQ-C30
EORTC QLQ-C30 is the most widely used cancer-specific, health-related quality of life 
(QOL) instrument, which contains 30 items and measures 5 functional dimensions (physical, 
role, emotional, cognitive, and social), 3 symptom items (fatigue, nausea/vomiting, and pain), 
6 single items (dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, and financial 
impact), and a global health and QOL scale [Aaronson, N. K., et al 1993]. It is scored on a 4-
point scale (1=not at all, 2=a little, 3=quite a bit, 4=very much). The EORTC QLQ-C30 
global health status/QOL scale uses a 7-point scale scoring with anchors (1=very poor and 
7=excellent). The EORTC QLQ-C30 is a psychometrically and clinically validated 
instrument appropriate for assessing QOL in oncology studies [Aaronson, N. K., et al 1993].
4.2.2.5.2
EuroQoL EQ-5D-5L
The EQ-5D-5L is a standardized instrument for use as a measure of health outcome and will 
provide data to develop health utilities for use in health economic analyses [Rabin, R. 2001]. 
The 5 health state dimensions in the EQ-5D-5L include the following: mobility, selfcare, 
usual activities, pain/discomfort, and anxiety/depression. Each dimension is rated on a 5-
point scale from 1 (no problem) to 5 (unable to/extreme problems). The EQ-5D-5L 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. This instrument has been used 
extensively in cancer studies and published results from these studies support its validity and 
reliability [Pickard, A. S., et al 2007].
4.2.2.5.3
EORTC QLQ-BIL21
The EORTC QLQ-BIL21 is a validated questionnaire for the assessment of QOL in patients 
with CCA and GBC. The EORTC QLQ-BIL21 consists of 21 questions. Three single items 
assess treatment side effects, difficulties with drainage bags/tubes and concerns regarding 
weight loss. Eighteen items are grouped into 5 scales: eating symptoms (4 items), jaundice 
symptoms (3 items), tiredness (3 items), pain symptoms (4 items) and anxiety symptoms (4 
items). The response is provided on a 4-point Likert scale.
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4.2.2.6
Pharmacokinetic Endpoints
Based on pharmacokinetic (PK) data obtained in this study and from other studies, observed 
pembrolizumab data coadministered with gemcitabine/cisplatin will be compared to 
historical monotherapy pembrolizumab PK data to support the proposed dosing regimen.
Blood samples will also be obtained to measure antidrug antibodies (ADA) of 
pembrolizumab. Simultaneous PK sampling is required for interpretation of ADA analysis.
4.2.2.7
Planned Exploratory Biomarker Research
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4.2.2.8
Future Biomedical Research
The Sponsor will conduct future biomedical research on specimens for which consent was 
provided during this study. This research may include
depending on which specimens are consented for 
future biomedical research.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main study) and will only be conducted on specimens from 
appropriately consented participants. The objective of collecting/retaining specimens for 
future biomedical research is
The 
4.2.3
Rationale for the Use of Comparator/Placebo
In this study, all participants will receive the current SOC, gemcitabine and cisplatin. 
Participants will be randomized at enrollment to the pembrolizumab or placebo plus 
gemcitabine/cisplatin. Intervention groups are expected to receive 35 administrations of 
pembrolizumab or placebo (approximately 2 years). Placebo will be normal saline solution 
prepared by the local unblinded pharmacist, dosed and administered in the same manner as 
the investigational product. The Phase 3 ABC-02 study has established the 
gemcitabine/cisplatin combination as a SOC for BTC for patients with ECOG PS 0 or 1, 
achieving a median survival close to a year (11.7 months) for gemcitabine/cisplatin, 
compared with 8.1 months for gemcitabine alone (HR 0.64, 95% CI: 0.52-0.80; p <0.001) 
[Valle, J., et al 2010] with a similar benefit in the randomized Phase 2 Japanese study, BT22
[Okusaka, T., et al 2010]. Placebo is being used as a control to allow for a blinded study,
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thereby limiting bias and providing a control arm that is consistent with SOC for patients 
with BTC.
4.3
Justification for Dose
The planned dose of pembrolizumab for this study is 200 mg every 3 weeks (Q3W). Based 
on the totality of data generated in the Keytruda development program, 200 mg Q3W is the 
appropriate dose of pembrolizumab for adults across all indications and regardless of tumor 
type. As outlined below, this dose is justified by:
•
Clinical data from 8 randomized studies demonstrating flat dose- and exposure-efficacy 
relationships from 2 mg/kg Q3W to 10 mg/kg every 2 weeks (Q2W),
•
Clinical data showing meaningful improvement in benefit-risk including overall survival 
at 200 mg Q3W across multiple indications, and
•
Pharmacology data showing full target saturation in both systemic circulation (inferred 
from pharmacokinetic [PK] data) and tumor (inferred from physiologically-based PK 
[PBPK] analysis) at 200 mg Q3W
Among the 8 randomized dose-comparison studies, a total of 2262 participants were enrolled 
with melanoma and non-small cell lung cancer (NSCLC), covering different disease settings 
(treatment naïve, previously treated, PD-L1 enriched, and all-comers) and different treatment 
settings (monotherapy and in combination with chemotherapy). Five studies compared 2 
mg/kg Q3W versus 10 mg/kg Q3W (KN001 Cohort B2, KN001 Cohort D, KN002, KN010, 
and KN021), and 3 studies compared 10 mg/kg Q3W versus 10 mg/kg Q2W (KN001 Cohort 
B3, KN001 Cohort F2 and KN006). All of these studies demonstrated flat dose- and 
exposure-response relationships across the doses studied representing an approximate 5- to 
7.5-fold difference in exposure. The 2 mg/kg (or 200 mg fixed-dose) Q3W provided similar 
responses to the highest doses studied. Subsequently, flat dose-exposure-response
relationships were also observed in other tumor types including head and neck cancer, 
bladder cancer, gastric cancer and classical Hodgkin Lymphoma, confirming 200 mg Q3W 
as the appropriate dose independent of the tumor type. These findings are consistent with the 
mechanism of action of pembrolizumab, which acts by interaction with immune cells, and 
not via direct binding to cancer cells.
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W. First, PK 
data in KN001 evaluating target-mediated drug disposition (TMDD) conclusively 
demonstrated saturation of PD-1 in systemic circulation at doses much lower than 200 mg 
Q3W. Second, a PBPK analysis was conducted to predict tumor PD-1 saturation over a wide 
range of tumor penetration and PD-1 expression. This evaluation concluded that 
pembrolizumab at 200 mg Q3W achieves full PD-1 saturation in both blood and tumor.
Finally, population PK analysis of pembrolizumab, which characterized the influence of 
body weight and other 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. 
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Supported by these PK characteristics, and given that fixed-dose has advantages of reduced 
dosing complexity and reduced potential of dosing errors, the 200 mg Q3W fixed-dose was 
selected for evaluation across all pembrolizumab protocols.
Gemcitabine at 1000 mg/m2 and cisplatin at 25 mg/m2 are administered on Day 1 and Day 8 
of a 21-Day cycle. This dose of gemcitabine/cisplatin was used in the ABC-02 study, which
defined gemcitabine/cisplatin as the SOC for advanced BTC. Based on global clinical 
practice patterns, gemcitabine will be administered until PD or unacceptable toxicity, 
cisplatin will be administered for a maximum of 8 cycles.
4.4
Beginning and End of Study Definition
The overall study begins when the first participant (or their legally acceptable representative) 
provides documented informed consent. The overall study ends when the last participant 
completes the last study-related contact, withdraws consent, or is lost to follow-up (ie, the 
participant is unable to be contacted by the investigator).
Upon study completion, participants are discontinued and may be enrolled in a 
pembrolizumab extension study.
4.4.1
Clinical Criteria for Early Study Termination
The clinical study 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 study population 
as a whole is unacceptable. In addition, further recruitment in the study or at (a) particular 
study site(s) may be stopped due to insufficient compliance with the protocol, Good Clinical 
Practice (GCP), and/or other applicable regulatory requirements, procedure-related problems 
or the number of discontinuations for administrative reasons is too high.
5
STUDY POPULATION
Participants with advanced and/or unresectable hepatobiliary carcinoma will be enrolled in 
this study.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
A participant will be eligible for inclusion in the study if the participant:
Type of Participant and Disease Characteristics
1. Has histologically confirmed diagnosis of advanced (metastatic) and/or unresectable 
(locally advanced) biliary tract cancer (intra-or extrahepatic cholangiocarcinoma or 
gallbladder cancer).
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2. Has measurable disease based on RECIST 1.1, as determined by the site investigator.
Lesions situated in a previously treated area by either radiotherapy, photodynamic 
therapy, or arterial embolization are considered measurable if progression has been 
shown in such lesions and they meet criteria for measurable disease per RECIST 1.1.
3. Participants with past or ongoing HCV infection are eligible for the study.
4. Participants with controlled hepatitis B are eligible for the study, as long as they meet the 
following criteria:
•
•
Demographics
5. Is male or female, from at least 18 years of age inclusive, at the time of signing the 
informed consent.
Male Participants
6. Male participants are eligible to participate if they agree to the following during the 
intervention period and for at least and through 180 days after the last dose of 
chemotherapy:
•
Refrain from donating sperm
PLUS either:
•
Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent 
on a long-term and persistent basis) and agree to remain abstinent
OR
CCI
CCI
CCI
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•
Must agree to use contraception unless confirmed to be azoospermic (vasectomized or 
secondary to medical cause [Appendix 5]), as detailed below:
-
Agree to use a male condom plus partner use of an additional contraceptive method 
when having penile-vaginal intercourse with a WOCBP who is not currently 
pregnant. Note: Men with a pregnant or breastfeeding partner must agree to remain 
abstinent from penile-vaginal intercourse or use a male condom during each episode 
of penile-vaginal penetration.
•
Male participants must also agree to use a male condom when engaging in any activity 
that allows for passage of ejaculate to another person of any sex.
•
Contraceptive use by men should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies. If the contraception 
requirements in the local label for any of the study interventions is more stringent than 
the requirements above, the local label requirements are to be followed.
Female Participants
7. A female participant is eligible to participate if she is not pregnant or breastfeeding, and 
at least one of the following conditions applies:
•
Is not a woman of childbearing potential (WOCBP)
OR
•
Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate 
of <1% per year), with low user dependency, or be abstinent from heterosexual 
intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent 
basis), as described in Appendix 5 during the intervention period and for at least and 
through 210 days after the last dose of chemotherapy or through 120 days after the last 
dose of pembrolizumab or placebo, whichever is greater, and agrees not to donate eggs 
(ova, oocytes) to others or freeze/store for her own use for the purpose of reproduction 
during this period. The investigator should evaluate the potential for contraceptive 
method failure (ie, noncompliance, recently initiated) in relationship to the first dose of 
study intervention.
-
A WOCBP must have a negative highly sensitive pregnancy test (urine or serum, as 
required by local regulations) within 24 hours (urine) or 72 hours (serum) before the 
first dose of study intervention.
Note: If 24 hours (for urine) or 72 hours (for serum) have elapsed between the 
screening pregnancy test and the first dose of study treatment, another pregnancy test 
(urine or serum) must be performed and must be negative in order for participant to 
start receiving study medication.
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Note: In regions where required via documented regulatory request (and subsequently 
approved by the Sponsor), pregnancy tests within 24 hours prior to treatment 
allocation will be required.
-
If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum 
pregnancy test is required. In such cases, the participant must be excluded from 
participation if the serum pregnancy result is positive.
-
Additional requirements for pregnancy testing during and after study intervention are 
located in Appendix 2.
-
The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy.
-
Contraceptive use by women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies. If the 
contraception requirements in the local label for any of the study interventions is 
more stringent than the requirements above, the local label requirements are to be 
followed.
Informed Consent
8. The participant (or legally acceptable representative) has provided documented informed 
consent for the study. The participant may also provide consent for future biomedical 
research. However, the participant may participate in the study without participating in 
future biomedical research.
Additional Categories
9. Have a performance status of 0 or 1 on the ECOG performance scale within 3 days prior 
to the first dose of study intervention.
10. Provide archival tumor tissue sample or newly obtained core or excisional biopsy of a 
tumor lesion not previously irradiated (ie, obtained for histological confirmation) for 
biomarker analysis. The tumor tissue must be received by the central vendor and be
deemed adequate for biomarker analysis evaluation, including but not limited to PD-L1 
and MSI biomarker analysis, prior to participant randomization. Formalin-fixed, paraffin-
embedded (FFPE) tissue blocks are preferred to slides. Newly obtained biopsies are 
preferred to archived tissue.
Note: Details pertaining to tumor tissue submission can be found in the laboratory 
manual.
11. Have a life expectancy of greater than 3 months.
Note: Participants with malignant ascites at baseline will be excluded.
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12. Have adequate organ function, as defined in the following table (Table 3). Specimens 
must be collected within 14 days prior to the first dose of study intervention.
Table 3
Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
≥1500/µL
Platelets
≥100 000/µL
Hemoglobin
≥9.0 g/dL or ≥5.6 mmol/La
Renal
Creatinine OR
Measured or calculatedb creatinine clearance
≤1.5 × ULN OR
≥60 mL/min for participant with creatinine levels 
>1.5 × institutional ULN
Hepatic
Total bilirubin
≤1.5 ×ULN OR direct bilirubin ≤ULN for participants 
with total bilirubin levels >1.5 × ULN
AST (SGOT) and ALT (SGPT)
≤2.5 × ULN (≤5 × ULN for participants with liver 
metastases)
Coagulation
International normalized ratio (INR) OR 
prothrombin time (PT)
Activated partial thromboplastin time (aPTT)
≤1.5 × ULN unless participant is receiving 
anticoagulant therapy as long as PT or PTT is within 
therapeutic range of intended use of anticoagulants
ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT)=aspartate 
aminotransferase (serum glutamic oxaloacetic transaminase); ULN=upper limit of normal.
aCriteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) 
transfusion within last 2 weeks.
bCreatinine clearance (CrCl) should be calculated using the Cockcroft-Gault Method: Refer to Appendix 10 
for appropriate calculation. Refer to Section 6.6.2.2 for CrCl requirement prior to administration of first dose 
of cisplatin.
Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value 
requirements should be adapted according to local regulations and guidelines for the administration of 
specific chemotherapies.
5.2
Exclusion Criteria
Refer to Section 10.7 (Appendix 7) for country-specific requirements.
The participant must be excluded from the study if the participant:
Medical Conditions
1. Has had previous systemic therapy for advanced (metastatic) or unresectable (locally 
advanced) biliary tract cancer (intra-or extra hepatic cholangiocarcinoma or gallbladder 
cancer), with the exception of neoadjuvant/adjuvant therapy which is allowed. 
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Neoadjuvant/adjuvant therapy should have been completed at least 6 months prior to 
diagnosis of advanced and/or unresectable disease, and participants should not have 
received gemcitabine and/or cisplatin in the neoadjuvant/adjuvant setting. Participants 
who received prior neoadjuvant/adjuvant therapy with R2 postoperative pathology of the 
oncologic resection are excluded.
2. Has ampullary cancer.
3. Has small cell cancer, neuroendocrine tumors, lymphoma, sarcoma, mixed tumor 
histology and/or mucinous cystic neoplasms.
Note: Participants with mixed HCC/cholangiocarcinoma may be included.
4. Has an active autoimmune disease that has required systemic treatment in the past 2 years 
(ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs). 
Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic 
treatment and is allowed.
5. Has undergone major surgery and has not recovered adequately from the procedure
and/or complications from the surgery prior to starting study intervention.
6. A WOCBP who has a positive urine pregnancy test within 24 hours prior to 
administration of study intervention (see inclusion criterion 7 and Appendix 5). If the 
urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be 
required.
Prior/Concomitant Therapy
7. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an 
agent directed to another stimulatory or coinhibitory T-cell receptor (eg, CTLA-4, 
OX-40, CD137).
8. Has received prior anticancer therapy (eg, TACE, palliative surgery) for advanced 
unresectable biliary tract cancer (intra-or extra hepatic cholangiocarcinoma or gallbladder 
cancer), including investigational agents within 4 weeks prior to randomization.
9. Has not recovered (ie, AE ≤Grade 1 or baseline) from AEs due to previously 
administered anticancer therapy. Participants with ≤Grade 2 neuropathy may be eligible
based on investigator assessment.
10. Has received prior radiotherapy within 2 weeks of start of study intervention. Participants 
must have recovered from all radiation-related toxicities, not require corticosteroids, and 
have not had radiation pneumonitis. A 1-week washout is permitted for palliative 
radiation (≤2 weeks of radiotherapy) to noncentral nervous system (CNS) disease if 
deemed safe by the investigator. A 2-week washout period is required for a longer course 
of radiation (>2 weeks).
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11. Has received a live vaccine within 30 days prior to the first dose of study intervention.
Note: Examples of live vaccines include, but are not limited to, the following: measles, 
mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus
Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection 
are generally killed virus vaccines and are allowed; however, intranasal influenza 
vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed.
Prior/Concurrent Clinical Study Experience
12. Is currently participating in or has participated in a study of an investigational agent or 
has used an investigational device within 4 weeks prior to the first dose of study 
intervention.
Note: Participants who have entered the follow-up phase of an investigational study may 
participate as long as it has been 4 weeks after the last dose of the previous 
investigational agent.
Diagnostic Assessments
13. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in 
dosing exceeding 10 mg daily of prednisone equivalent) or any other form of 
immunosuppressive therapy within 7 days prior to the first dose of study intervention.
14. Has a known additional invasive malignancy that is progressing or has required active 
treatment within the past 3 years.
Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the 
skin, or carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) that have 
undergone potentially curative therapy are not excluded.
15. Has severe hypersensitivity (≥Grade 3) to pembrolizumab, gemcitabine, or cisplatin
and/or any of their excipients.
16. Has a history of (noninfectious) pneumonitis that required steroids or has current 
pneumonitis.
17. Has an active infection requiring systemic therapy, with the exception of HBV and HCV.
18. Has dual active HBV infection
 and HCV 
infection
 at study entry.
19. Has a known history of human immunodeficiency virus (HIV) infection.
Note: No HIV testing is required unless mandated by local health authority.
20. Has known active tuberculosis (TB; Bacillus tuberculosis). Note: No testing for TB is 
required unless mandated by local health authority.
CCI
CCI
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21. Has a known history of, or any evidence of, CNS metastases and/or carcinomatous 
meningitis, as assessed by local site investigator.
22. Has a history or current evidence of any condition, (eg, hearing impairment, etc.), 
therapy, or laboratory abnormality that might confound the results of the study, interfere 
with the participant's participation for the full duration of the study, or is not in the best 
interest of the participant to participate, in the opinion of the treating investigator.
23. Has a known psychiatric or substance abuse disorder that would interfere with the 
participant’s ability to cooperate with the requirements of the study.
Other Exclusions
24. Is pregnant or breastfeeding or expecting to conceive or father children within the 
projected duration of the study, starting with the screening visit through 180 days (male 
participants) or 210 days (female participants) after the last dose of chemotherapy or 
through 120 days (female participants only) after the last dose of pembrolizumab or 
placebo, whichever is greater.
25. Has had an allogenic tissue/solid organ transplant. 
5.3
Lifestyle Considerations
There are no lifestyle considerations defined for this study.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study, but 
are not subsequently randomized in the study. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any AEs or SAEs meeting reporting 
requirements as outlined in the data entry guidelines.
Rescreening is allowed in case of screen failure. Please refer to Section 8.11.1 - Screening for 
details.
5.5
Participant Replacement Strategy
A participant who discontinues from study intervention or withdraws from the study will not 
be replaced.
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6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
Clinical supplies will be packaged to support enrollment. Clinical supplies will be affixed 
with a clinical label in accordance with regulatory requirements.
6.1
Study Intervention(s) Administered
The study intervention(s) to be used in this study are outlined in Table 4.
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Table 4
Study Interventions
Arm 
Name
Arm Type
Intervention 
Name
Type
Dose 
Formu-
lation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Admini-
stration
Regimen/
Treatment 
Period/
Vaccination 
Regimen
Use
IMP/
NIMP
Sourcing
Arm A
Experimental
Pembrolizumab
Drug
Sterile 
Suspension 
(Vial)
25 mg/mL
200 mg
IV 
Infusion
Day 1 of each 
cycle, up to 
35 admini-
strations
Experimental
IMP
Central
Arm A
Experimental
Cisplatin
Drug
Vial
1 mg/mL vial, 
20 mg vial, or 
50 mg vial
25 mg/m2
IV 
Infusion
Day 1 and 
Day 8 of each 
cycle, up to 8 
cycles
Background 
Treatment
NIMP
Local or 
Central
Arm A
Experimental
Gemcitabine
Drug
Vial
1 g/ vial
1000 mg/m2
IV 
Infusion
Day 1 and 
Day 8 of each 
cycle, until 
PD or 
unacceptable 
toxicity 
Background 
Treatment
NIMP
Local or 
Central
Arm B
Active 
Comparator
Placebo (Normal 
Saline)
Drug
Sterile 
Suspension 
(Vial)
N/A
N/A
IV 
Infusion
Day 1 of each 
cycle, up to 
35 admini-
strations
Placebo
IMP
Local
Arm B
Active 
Comparator
Cisplatin
Drug
Vial
1 mg/mL vial, 
20 mg vial, or 
50 mg vial
25 mg/m2
IV 
Infusion
Day 1 and 
Day 8 of each 
cycle, up to 8 
cycles
Background 
Treatment
NIMP
Local or 
Central
Arm B
Active 
Comparator
Gemcitabine
Drug
Vial
1 g/ vial
1000 mg/m2
IV 
Infusion
Day 1 and 
Day 8 of each 
cycle, until 
PD or 
unacceptable 
toxicity
Background 
Treatment
NIMP
Local or 
Central
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Arm 
Name
Arm Type
Intervention 
Name
Type
Dose 
Formu-
lation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Admini-
stration
Regimen/
Treatment 
Period/
Vaccination 
Regimen
Use
IMP/
NIMP
Sourcing
Definition Investigational Medicinal Product (IMP) and Non-Investigational Medicinal Product (NIMP) is based on guidance issued by the European Commission. Regional 
and/or Country differences of the definition of IMP/NIMP may exist. In these circumstances, local legislation is followed. Refer to Section 10.7 (Appendix 7) for country-specific 
requirements.
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All study interventions will be administered on an outpatient basis.
All products indicated in Table 4 will be provided centrally by the Sponsor or locally by the 
study site, subsidiary or designee, depending on local country operational or regulatory 
requirements with the exception of placebo (normal saline), which will be provided locally.
For any commercially available product that is provided by the study site, subsidiary, or 
designee, every attempt will be made to source these supplies from a single lot/batch number. 
The study 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.
Refer to Section 8.1.8 for details regarding administration of the study intervention.
6.1.1
Treatment
The initial treatment or first course of pembrolizumab consists of 35 treatments. Note: The 
number of treatments is calculated starting with the first dose.
For participants who have attained a confirmed CR and have been treated for at least 8 cycles 
(at least 24 weeks), receiving 2 cycles of the combination including 2 doses of 
pembrolizumab or placebo beyond the initial CR confirmation date, treatment may be 
stopped.
These participants may be eligible for Second Course described in Section 6.1.2.
6.1.2
Second Course
All participants who have SD, PR, or CR may be eligible for up to an additional 17 cycles of 
pembrolizumab if there is BICR-verified radiographic disease progression by RECIST 1.1 
after initial treatment or first course has been completed or stopped for confirmed CR as 
specified in Section 6.1.1 after consultation with the Sponsor. This retreatment is the Second 
Course of this study.
Participants may enter the Second Course if all of the following criteria are met:
•
The participant received pembrolizumab, determined upon unblinding if applicable
•
No new anticancer treatment was administered after the last dose of study intervention
•
The participant meets all of the inclusion criteria and none of the exclusion criteria
•
The study is ongoing
The decision of whether or not to continue gemcitabine during second course will be at the 
discretion of the investigator. If continued, participants will be retreated at the same dose 
level and frequency as when they last received the combination of pembrolizumab and 
gemcitabine. Treatment with gemcitabine will continue until PD or intolerable toxicity.
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An objective response or disease progression that occurs during the Second Course will not 
be counted as an event for the primary analysis in this study.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
Details on preparation and administration of pembrolizumab or placebo are provided in the 
Pharmacy Manual. Dose preparation must be performed by separate unblinded study 
personnel. Dose administration must be performed by blinded study personnel.
Gemcitabine and cisplatin will be prepared and administered as per local product 
label/SmPC. The body surface area (BSA) in m2 should be calculated per local guidance. The 
dose of gemcitabine and cisplatin shall not be recalculated by body weight fluctuation in 
principle, but for 10% or higher fluctuation of body weight, recalculation is possible at the 
discretion of the investigator. When recalculating, BSA in m2 should be calculated per local 
guidance.
6.2.2
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study 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.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
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 study 
interventions in accordance with the protocol and any applicable laws and regulations.
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6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Intervention randomization will occur centrally using an interactive response technology 
(IRT) system. There are 2 study intervention arms. Participants will be assigned randomly in 
a 1:1 ratio to (Arm A) pembrolizumab plus gemcitabine/cisplatin and (Arm B) placebo plus 
gemcitabine/cisplatin.
6.3.2
Stratification
Intervention randomization will be stratified according to the following factors:

Region (Region 1: Asia versus Region 2: Non-Asia)

Locally Advanced versus Metastatic

Note: In the event the participant has locally advanced and metastatic BTC, the 
participant should be stratified as metastatic.

Site of Origin (gallbladder/intrahepatic/extrahepatic)
6.3.3
Blinding
A double-blinding technique with in-house blinding will be used. Pembrolizumab and 
placebo (normal saline) will be packaged identically so that blind is maintained. The 
participant, the investigator, and Sponsor personnel or delegate(s) who are involved in the 
study intervention administration or clinical evaluation of the participants are unaware of the 
intervention assignments.
6.4
Study Intervention Compliance
Administration of study intervention(s) will be monitored by the investigator and/or study 
staff, and/or qualified designee per institutional guidelines and procedures. The total volume 
of study medication infused will be compared with the total volume prepared to determine 
compliance with each dose administered.
If there are interruptions in the study intervention schedule or infusion/injection was stopped, 
the details of and reason for any interruption or infusion/injection cessation of study 
intervention will be documented in the participant’s medical record. 
Refer to Section 6.6.1 for Dose Modification and Toxicity Management Guidelines for non-
hepatic irAEs associated with pembrolizumab monotherapy, coformulations, or IO 
combinations and for other allowed dose interruptions.
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6.5
Concomitant Therapy
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing study. If there is a clinical indication for any medication or vaccination 
specifically prohibited, discontinuation from study intervention may be required. The 
investigator is to discuss any prohibited medication/vaccination with the Sponsor's Clinical 
Director. The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the participant's primary physician. However, the decision to continue the 
participant on study intervention requires the mutual agreement of the investigator, the 
Sponsor, and the participant.
Listed below are concomitant therapies that should be avoided or carefully monitored:

Hepatotoxic drugs (examples below):

Etifoxine

Isoniazid

Nitrofurantoin

Ketoconazole

Amiodarone

Phenytoin

Herbal supplements or alternative medicines should also be avoided during the 
Screening and Intervention Phase of this study.

Possible interaction between gemcitabine and warfarin has been reported and may 
occur at any time. Close monitoring is recommended (monitor INR weekly during 
gemcitabine treatment and for 1 to 2 months after discontinuing gemcitabine 
treatment).

Any use of other myelosuppressive medications should be carefully monitored for 
risk of infection.

Participants with controlled hepatitis B enrolled in the study may require close 
monitoring of liver function tests and other parameters for hepatitis reactivation if 
they are exposed to prolonged corticosteroids, anti-tumor necrosis factor (TNF)
therapy or other immunosuppressive therapy for management of irAEs.

Untreated or incompletely treated HCV participants may initiate antiviral therapy for 
HCV if liver function remains stable for at least 3 months on study intervention.

For HBV viral load over 100 IU/mL during study intervention, participants must start 
treatment for HBV.
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Listed below are concomitant therapies prohibited during the course of the study:

Antineoplastic systemic chemotherapy or biological therapy

Immunotherapy not specified in this protocol

Chemotherapy not specified in this protocol

Investigational agents other than pembrolizumab

Radiation therapy
Note: Radiation therapy to a symptomatic lesion or to the brain is allowed at the 
Investigator’s discretion. Radiation therapy to 2 symptomatic lesions may be allowed
following Sponsor Consultation. A 1-week washout is permitted for palliative 
radiation (≤2 weeks of radiotherapy) to non-CNS disease if deemed safe by the 
investigator. A 2-week washout period is required for a longer course of radiation 
(>2 weeks).

Live vaccines within 30 days prior to the first dose of study intervention and while 
participating in the study. Examples of live vaccines include, but are not limited to, 
the following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, 
and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed 
virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) 
are live attenuated vaccines and are not allowed.
Note: Any licensed COVID-19 vaccine (including for Emergency Use) in a particular 
country is allowed in the study as long as they are mRNA vaccines, adenoviral 
vaccines, or inactivated vaccines. These vaccines will be treated just as any other 
concomitant therapy.
Investigational vaccines (ie, those not licensed or approved for Emergency Use) are 
not allowed.

Any medication prohibited in combination with chemotherapy as described in the 
respective product labels for cisplatin and gemcitabine.

Any chronic immunological-suppressive treatment for any reason other than the 
management of AEs, as described in Section 6.6.1 (Table 5).
Note: Systemic glucocorticoids are permitted only for the following purposes:

To modulate symptoms of an AE that is suspected to have an immunologic 
etiology
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
As needed for the prevention of emesis; systemic steroid use as antinausea 
medication should be limited as deemed safe by the investigator due to possible 
theoretical risk of lower efficacy of pembrolizumab

Premedication for IV contrast allergies

Short-term oral or IV use in doses >10 mg/day prednisone equivalent for chronic 
obstructive pulmonary disease exacerbations

For chronic systemic replacement not to exceed 10 mg/day prednisone equivalent
In addition, the following glucocorticoid use is allowed:

For topical or ocular use

Intraarticular joint use

For inhalation in the management of asthma or chronic obstructive pulmonary 
disease.
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 eCRF including all 
prescription, over-the-counter (OTC) products, herbal supplements, and IV medications and 
fluids. If changes occur during the study period, documentation of drug dosage, frequency, 
route, and date should also be included on the eCRF.
All concomitant medications received within 28 days prior to the first dose of study 
intervention and up to 30 days after the last dose of study intervention should be recorded. If 
participants experience an SAE or ECI, all concomitant medications administered more than 
30 days after the last dose of study intervention are to be recorded for SAEs and ECIs as 
defined in Section 8.4.
Refer to Section 10.7 (Appendix 7) for country-specific requirements.
6.5.1
Rescue Medications and Supportive Care
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 along with the dose modification guidelines in
Section 6.6.1, Table 5. 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 
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guidelines are intended to be applied when the investigator determines the events to be 
related to pembrolizumab or placebo.
Note: If after the evaluation of the event, it is determined not to be related to pembrolizumab
or placebo, the investigator does not need to follow the treatment guidance. Refer to Table 5
in Section 6.6.1 for guidelines regarding dose modification and supportive care.
It may be necessary to perform additional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event.
6.6
Dose Modification (Escalation/Titration/Other)
6.6.1
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue)
If appropriate, the investigator may attribute each toxicity event to gemcitabine, cisplatin, 
pembrolizumab or placebo and use dose modification according to Table 5 and Table 6. 
(pembrolizumab) and Table 7 (gemcitabine/cisplatin). To ensure that participants can receive 
adequate SOC chemotherapy dosing, standard supportive care measures should be used first,
before dose modification, if there are no other reasons to modify SOC dosing for 
chemotherapy agents. Dose modification should be performed considering the following:
•
Treatment for each new cycle may be delayed if the scheduled off-drug periods are not 
adequate to allow for recovery to the guideline for restarting each study intervention.
•
Pembrolizumab or placebo dose reductions are not permitted. Pembrolizumab or placebo 
treatment may be interrupted or discontinued due to toxicity.
•
Chemotherapy may be interrupted for a maximum of 6 weeks from last dose in case of 
chemotherapy-related toxicity; pembrolizumab or placebo may be interrupted for a 
maximum of 12 weeks from last dose (refer to Section 6.6.1.1).
•
If a participant experiences several toxicities related to chemotherapy (gemcitabine 
and/or cisplatin) and there are conflicting recommendations, follow the most conservative 
dose adjustment recommended (dose reduction appropriate to the most severe toxicity).
•
Reduction of one chemotherapy agent and not the other agent is appropriate if, in the 
opinion of the investigator, the toxicity is clearly related to one of the study interventions. 
If, in the opinion of the investigator, the toxicity is related to the combination of both 
chemotherapy agents, both drugs should be reduced according to recommended dose 
modifications. If the toxicity is related to the combination of 3 agents, chemotherapy 
should be reduced, interrupted, or discontinued, and pembrolizumab or placebo should be 
interrupted or discontinued according to the recommended dose modifications. Both 
groups may have one or both chemotherapy agents discontinued and continue to receive 
pembrolizumab or placebo. The reverse is also allowed, ie, pembrolizumab or placebo 
can be stopped but one or both chemotherapy agents continued if the investigator 
attributes the AE to pembrolizumab or placebo.
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The CTCAE v5.0 must be used to grade the severity of AEs. All dose modifications should 
be based on the AE requiring the greatest dose modification.
If toxicity is not otherwise specified, investigators should refer to the product label or local 
guidelines for dose adjustments.
In addition, participants should receive appropriate supportive care measures as deemed 
necessary by the treating investigator. Suggested supportive care measures are included in 
Table 6 (pembrolizumab), Table 7 (gemcitabine/cisplatin) and Section 6.5.1.
6.6.1.1
Dose Modification of Pembrolizumab
Dose Modification and Toxicity Management for Non-hepatic Immune-related AEs 
Associated with Pembrolizumab
AEs associated with pembrolizumab exposure may represent an immune-related response. 
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 study data, most irAEs were reversible and could be managed with 
interruptions of pembrolizumab, administration of corticosteroids and/or other supportive 
care. For suspected irAEs, ensure adequate evaluation to confirm etiology or exclude other 
causes. Additional procedures or tests such as bronchoscopy, endoscopy, skin biopsy may be 
included as part of the evaluation.
Dose Modification and Toxicity Management Guidelines for Non-hepatic irAEs associated with 
pembrolizumab monotherapy, coformulations, or IO combinations are provided in Table 5.
For guidance related to the diagnosis and management of hepatic ECIs, refer to Section 
6.6.2.3. Refer to Section 10.7 (Appendix 7) for country-specific requirements.
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Table 5
Dose Modification and Toxicity Management Guidelines for Non-hepatic Immune-related Adverse Events Associated with 
Pembrolizumab Monotherapy, Coformulations, or IO Combinations
General instructions:
1.
Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive treatment should begin if the irAEs are not 
controlled by corticosteroids.
2.
Pembrolizumab monotherapy, coformulations or IO combinations must be permanently discontinued if the irAE does not resolve or the corticosteroid dose is not 
≤10 mg/day within 12 weeks of the last treatment.
3.
The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks.
4.
If pembrolizumab monotherapy, coformulations or IO combinations have been withheld, treatment may resume after the irAE decreased to ≤Grade 1 after corticosteroid 
taper.
irAEs
Toxicity Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or IO 
Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Pneumonitis 
Grade 2
Withhold 
Administer corticosteroids 
(initial dose of 1 to 2 mg/kg 
prednisone or equivalent) 
followed by taper
Add prophylactic antibiotics for 
opportunistic infections
Monitor participants for signs and symptoms of 
pneumonitis
Evaluate participants with suspected pneumonitis 
with radiographic imaging and initiate 
corticosteroid treatment
Recurrent 
Grade 2, 
Grade 3 or 4 
Permanently 
discontinue
Diarrhea/Colitis 
Grade 2 or 3
Withhold
Administer corticosteroids 
(initial dose of 1 to 2 mg/kg 
prednisone or equivalent) 
followed by taper
Monitor participants for signs and symptoms of 
enterocolitis (ie, diarrhea, abdominal pain, blood 
or mucus in stool with or without fever) and of 
bowel perforation (ie, peritoneal signs and ileus)
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
Recurrent Grade 
3 or Grade 4
Permanently 
discontinue
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irAEs
Toxicity Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or IO 
Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
T1DM or 
Hyperglycemia
New onset 
T1DM or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of 
-cell failure
Withhold a
Initiate insulin replacement 
therapy for participants with 
T1DM
Administer antihyperglycemic 
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 
discontinue a
Hyperthyroidism
Grade 2
Continue
Treat with nonselective beta-
blockers (eg, propranolol) or 
thionamides as appropriate
Monitor for signs and symptoms of thyroid 
disorders
Grade 3 or 4
Withhold or 
permanently 
discontinue a
Hypothyroidism
Grade 2, 3 or 4
Continue
Initiate thyroid replacement 
hormones (eg, levothyroxine or 
liothyronine) per standard of 
care
Monitor for signs and symptoms of thyroid 
disorders
Nephritis:
grading according 
to increased 
creatinine or acute 
kidney injury
Grade 2
Withhold
Administer corticosteroids 
(prednisone 1 to 2 mg/kg or 
equivalent) followed by taper
Monitor changes of renal function
Grade 3 or 4
Permanently 
discontinue
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irAEs
Toxicity Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or IO 
Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Neurological 
Toxicities
Grade 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
Myocarditis
Asymptomatic 
cardiac enzyme 
elevation with 
clinical suspicion 
of myocarditis 
(previously 
CTCAE v4.0 
Grade 1)
Withhold
Based on severity of AE 
administer corticosteroids
Ensure adequate evaluation to confirm etiology 
and/or exclude other causes
Grade 2, 3 or 4
Permanently 
discontinue
Exfoliative 
Dermatologic 
Conditions
Suspected SJS, 
TEN, or DRESS
Withhold
Based on severity of AE 
administer corticosteroids
Ensure adequate evaluation to confirm etiology or 
exclude other causes
Confirmed SJS, 
TEN, or DRESS
Permanently 
discontinue
All Other irAEs
Persistent Grade 
2
Withhold
Based on severity of AE 
administer corticosteroids
Ensure adequate evaluation to confirm etiology or 
exclude other causes
Grade 3
Withhold or 
discontinue based on 
the event b
Recurrent 
Grade 3 or 
Grade 4 
Permanently 
discontinue
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irAEs
Toxicity Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or IO 
Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
AE(s)=adverse event(s); CTCAE=Common Terminology Criteria for Adverse Events; DRESS=Drug Rash with Eosinophilia and Systemic Symptom; GI=gastrointestinal; 
IO=immuno-oncology; ir=immune-related; IV=intravenous; SJS=Stevens-Johnson Syndrome; T1DM=type 1 diabetes mellitus; TEN=Toxic Epidermal Necrolysis; 
ULN=upper limit of normal.
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations.
a
The decision to withhold or permanently discontinue pembrolizumab monotherapy, coformulations or IO combinations is at the discretion of the investigator or treating 
physician. If control achieved or ≤Grade 2, pembrolizumab monotherapy, coformulations or IO combinations may be resumed.
b
Events that require discontinuation include, but are not limited to: encephalitis and other clinically important irAEs (eg, vasculitis and sclerosing cholangitis).
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Dose Modification and Toxicity Management of Infusion Reactions Related to 
Pembrolizumab Monotherapy, Coformulations, or IO Combinations
Pembrolizumab monotherapy, coformulations, or IO combinations may cause severe or life-
threatening infusion reactions including severe hypersensitivity or anaphylaxis. Signs and 
symptoms usually develop during or shortly after drug infusion and generally resolve 
completely within 24 hours of completion of infusion. Dose modification and toxicity 
management guidelines on pembrolizumab monotherapy, coformulations, or IO 
combinations associated infusion reactions are provided in Table 6.
Table 6
Pembrolizumab Monotherapy, Coformulations, or IO Combinations Infusion 
Reaction Dose Modification and Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at Subsequent 
Dosing
Grade 1
Mild reaction: infusion 
interruption not 
indicated; intervention 
not indicated
Increase monitoring of vital signs as 
medically indicated until the 
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 (eg, 
antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated 
for ≤24 h
Stop Infusion
Additional appropriate medical therapy 
may include but is not limited to:
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Increase monitoring of vital signs as 
medically indicated until the 
participant is deemed medically stable 
in the opinion of the investigator.
If symptoms resolve within 1 hour of 
stopping drug infusion, the infusion 
may be restarted at 50% of the original 
infusion rate (eg, from 100 mL/h to 
50 mL/h). 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 study 
intervention.
Participant may be premedicated 
1.5 h (±30 min) prior to infusion 
of study intervention with:
Diphenhydramine 50 mg PO (or 
equivalent dose of 
antihistamine).
Acetaminophen 500 to 1000 mg 
PO (or equivalent dose of 
analgesic).
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NCI CTCAE Grade
Treatment
Premedication at Subsequent 
Dosing
Grades 3 or 4
Grade 3:
Prolonged (ie, not 
rapidly responsive to 
symptomatic 
medication and/or 
brief interruption of 
infusion); recurrence 
of symptoms after 
initial improvement; 
hospitalization 
indicated for other 
clinical sequelae (eg, 
renal impairment, 
pulmonary infiltrates)
Grade 4:
Life-threatening; 
pressor or ventilatory 
support indicated
Stop Infusion.
Additional appropriate medical therapy 
may include but is not limited to:
Epinephrine**
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Increase monitoring of vital signs as 
medically indicated until the 
participant is deemed medically stable 
in the opinion of the investigator.
Hospitalization may be indicated.
**In cases of anaphylaxis, epinephrine 
should be used immediately.
Participant is permanently 
discontinued from further study 
intervention.
No subsequent dosing
h=hour; IV=intravenous; CTCAE=Common Terminology Criteria for Adverse Events; NCI=National Cancer Institute; 
NSAIDs=nonsteroidal anti-inflammatory drugs.
Note: Appropriate resuscitation equipment should be available at the bedside and a physician readily available during 
the period of drug administration.
For further information, please refer to the CTCAE v5.0 at http://ctep.cancer.gov
Other Allowed Dose Interruption for Pembrolizumab Monotherapy, Coformulations, 
or IO Combinations
Pembrolizumab monotherapy, coformulations, or IO combinations may be interrupted for 
situations other than treatment-related AEs such as medical or surgical events and/or 
unforeseen circumstances not related to study intervention. However, study intervention is to 
be restarted within 3 weeks of the originally scheduled dose and within 42 days of the 
previously administered dose, unless otherwise discussed with the Sponsor. The reason for 
study intervention interruption is to be documented in the participant's study record.
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6.6.1.2
Dose Modification of Gemcitabine or Cisplatin
Dose modifications for gemcitabine and cisplatin are detailed in Table 7. The following 
serves as a guide and does not replace investigator’s clinical judgment. Follow local 
applicable product label recommendations if dosing considerations are more stringent.

CrCl will be based on the original weight-based Cockcroft and Gault formula 
(Appendix 10). If the calculated CrCl is <60 or >120 mL/min, measure EDTA 
clearance or CrCl before prescribing. CrCl must be ≥60 mL/min prior to 
administration of first dose of cisplatin and ≥40 mL/min prior to the administration 
subsequent doses of cisplatin. Cisplatin may be delayed for up to 42 days to allow the 
participant time to recover from the cisplatin-related toxicity. If a participant’s CrCl 
value has not returned to ≥40 mL/min within 42 days after the previous dose, 
cisplatin must be discontinued. Additional details for dose modifications for cisplatin 
use are listed in Table 7.

Gemcitabine should be administered with caution in participants with evidence of 
significant renal or hepatic impairment as there is insufficient information from 
clinical studies to allow clear dose recommendation for these patient populations. For 
significant renal impairment defined as CrCl <30 mL/min, consider dose reduction 
and discuss with Sponsor. For serum bilirubin >1.6 mg/dL, consider dose reduction of
gemcitabine to 800 mg/m2. Monitor carefully and discontinue gemcitabine if any 
drug-related worsening occurs [Venook, A. P., et al 2000].

Gemcitabine should be discontinued at the first signs of any evidence of 
microangiopathic hemolytic anemia, such as rapidly falling hemoglobin with 
concomitant thrombocytopenia, elevation of serum bilirubin, serum creatinine, blood 
urea nitrogen, or LDH, which may indicate development of hemolytic uremic 
syndrome. Renal failure may not be reversible, even with discontinuation of therapy, 
and dialysis may be required.

Maximal dose reduction permitted is up to 40% of starting dose of cisplatin 
(10 mg/m2) and gemcitabine (400 mg/m2). Doses below this level are not considered 
therapeutic and the participant will be discontinued from the related chemotherapy.
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Table 7
Dose Modification Guidelines for Gemcitabine/Cisplatin-related Adverse Events
Category
Toxicity
Grade
Gem
dose
Cis
dose
Timing for 
Restarting Study 
Intervention
Subsequent Dose
Hematologica
Neutrophil 
count 
decreasedb
1-2b
None
None
N/A
N/A
3
75%
None
N/A
Gemcitabine dose 
should be re-escalated 
to full dose (100%) on 
the subsequent cycles 
upon recovery of 
hematologic toxicity. 
If reduction required 
for 2 consecutive 
doses, permanently 
reduce dose of 
gemcitabine by 25%d
4c
Hold 
Hold
Neutrophil count 
recovers to 
>1000/mm3 d
Reduce gemcitabine 
dose by 25% of last 
dosed,e
Febrile 
Neutropeniab
3-4c
Hold
Hold
Toxicity resolves 
and
Neutrophil count 
recovers to 
>1000/mm3 d
Reduce gemcitabine 
dose by 25% of last 
dosed,e
Platelet count 
decreased
3
75%
100%
N/A
Gemcitabine dose 
should be re-escalated 
to full dose (100%) on 
the subsequent cycles. 
If reduction is required 
for 2 consecutive 
doses, permanently 
reduce gemcitabine 
dose by 25%d
4c
Hold 
Hold
Platelet count 
recovers to 
>50,000/mm3 d
Reduce gemcitabine 
dose by 25% of last 
dosed,e
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Category
Toxicity
Grade
Gem
dose
Cis
dose
Timing for 
Restarting Study 
Intervention
Subsequent Dose
Non-
hematologica
Renal 
dysfunction 
Serum 
creatinine 
increased 
above 
baseline 
100%f
Subsequent dosing based on CrCl (mL/min)g
Cisplatin Dose:
>60: Give 100%,
51– 60: Give 75%,
40 – 50: Give 50%,
<40 mL/min: Hold and follow modifications above on 
recovery and if not recovered to at least ≥40 mL/min 
within 42 days after the previous dose permanently 
discontinue
Peripheral 
Sensory 
Neuropathyh
2
100%
75%
N/A
Reduce cisplatin dose 
by 25% of last dose
3c
100%
Hold 
Toxicity resolves 
to ≤Grade 2a
Reduce cisplatin dose 
by 25% of last dose. 
Continue to reduce 
cisplatin by 25% for 
each additional 
episode.
4
100%
N/A
N/A
Permanently 
discontinue 
Nausea and 
vomiting 
3-4c
Hold 
Hold
Toxicity resolves
to ≤Grade 2a
Resume at 100% 
All Other
Non-
Hematologic
Toxicitiesa,f,i
3-4c
Hold 
Hold 
Toxicity resolves
to ≤Grade 2a
Follow standard of 
care guidelines 
Abbreviations: AE=adverse event; G-CSF=granulocyte colony-stimulating factor; Gem=gemcitabine; Cis=cisplatin; 
N/A=not applicable
a.
Participants with intolerable or persistent Grade 2 drug-related AE may hold at physician discretion.
b.
See the package insert of each of the G-CSF drugs for administration of G-CSF for neutropenia.
c.
Permanent discontinuation should be considered for any severe or life-threatening event. Consult Sponsor before 
restarting treatment after a Grade 4 drug-related AE.
d.
Permanently discontinue gemcitabine and cisplatin if gemcitabine-/cisplatin-related hematologic toxicity does not 
resolve to ≤Grade 2 within 6 weeks.
e.
If Day 8 study intervention is delayed by ≥2 weeks, then subsequent therapy should start with next cycle. 
Pembrolizumab should be given on Day 1 of each new cycle. There should be at minimum a 3-week interval 
between pembrolizumab doses and a minimum 1-week interval between the chemotherapy doses.
f.
Gemcitabine should be administered with caution in participants with evidence of significant renal or hepatic 
impairment as there is insufficient information from clinical studies to allow clear dose recommendation for these 
patient populations.
g.
Follow local cisplatin product label recommendations if dosing considerations are more stringent.
h.
Administration may be interrupted or reduced at the discretion of the investigator.
i.
Allow continuous treatment for laboratory AEs that are asymptomatic and deemed to be not clinically significant.
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Other Allowed Dose Interruption for Gemcitabine or Cisplatin
Gemcitabine or cisplatin may be interrupted for situations other than treatment-related AEs 
such as medical or surgical events and/or unforeseen circumstances not related to study 
intervention. However, study intervention is to be restarted within 3 weeks of the originally 
scheduled dose and within 6 weeks of the previously administered dose, unless otherwise 
discussed with the Sponsor. The reason for study intervention interruption is to be 
documented in the participant’s study record.
6.6.1.3
Guidance for Management of Hepatic Events of Clinical Interest
Hepatic ECIs include any of the following events if the events are considered not due to 
disease progression as judged by the investigator. All of these events (if not associated with 
disease progression under study) will require holding study intervention and notification of 
the event(s) to the Sponsor within 24 hours after awareness via electronic media or paper.
For dose interval modification, refer to Sections 6.6.1.1 and 6.6.1.2.
ALT:
-
Among participants with Baseline ALT <2×ULN: ALT ≥5×ULN
-
Among participants with Baseline ALT ≥2×ULN: ALT >3× the Baseline level
-
ALT >500 U/L regardless of baseline level
Total bilirubin:
-
Total bilirubin >3.0 mg/dL
Regardless of laboratory values, hepatic decompensation diagnosed clinically, including:
-
New onset clinically detectable ascites requiring intervention for >3 days
-
Hepatic encephalopathy
-
Gastrointestinal bleeding suggestive of portal hypertension (eg, esophageal or gastric 
varices)
All cases of retreatment after interruption of study intervention for HECI must be recorded in 
the database. HECIs are not the result of disease progression, and therefore the following 
evaluations are not required for these etiologies.
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Immediate assessment in case of HECI:
All Participants
All participants should be considered for evaluation according to the directions below within 
72 hours of the alert for a nonoverdose ECI. Laboratory assessments of HECIs will be 
performed locally; central laboratory is acceptable if local laboratory is not available.
Procedures:
-
Consider obtaining a consultation with a hepatologist
-
Obtain a workup for hepatitis if there is no underlying hepatitis, including hepatitis A, 
B, C, D, E, Epstein-Barr virus, and cytomegalovirus
-
Assess for ingestion of drugs/supplements with hepatotoxic potential
-
Assess for alcohol ingestion
-
Assess for potential bacterial infection, biliary obstruction, or occult gastrointestinal 
bleeding
-
Repeat ALT, AST, total bilirubin, direct bilirubin, alkaline phosphatase, γ glutamyl 
transpeptidase, INR, and complete blood count with differential
-
Measure HCV RNA viral load (applies only for participants who have current active 
HCV infection or had infection in the past)
-
HBV DNA, HBsAg, anti-HBc (total and IgM), and anti-HBs regardless of prior HBV 
status (Note: participants should be questioned about compliance with the use of 
antiviral agents)
-
Other laboratories or imaging studies as clinically indicated
-
Consider liver biopsy if indicated
BTC patients are at risk for a range of complications that can cause hepatic laboratory 
abnormalities with or without clinical decompensation. Those with a history of chronic HCV 
or HBV infection also have the potential to experience virologic flares.
The following section provides further guidance on the diagnosis and 
management of potential hepatic complications among BTC participants in this study. The 
recommendation is to hold study interventions for 1 to 2 days. If toxicity does not improve 
within 1 to 2 days or worsens, follow “Management of HECI” below.
CCI
CCI
CCI
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Table 8
Management of HECI for Pembrolizumab Monotherapy, Coformulations, or IO 
Combinations
If HECI is determined to be due to other causes, cisplatin can be restarted if infection is ruled 
out and otherwise deemed clinically appropriate by the investigator.
Diagnosis
Management
Hepatitis B 
considered flare or 
change in HBV 
immunologic 
status
Rapid elevation of ALT to >5×ULN 
and/or >3× baseline
Interrupt study intervention for up to 12 weeks.
Start antiviral therapy or check for compliance 
if HBV is detectable.
Measure safety labs for AST, ALT, ALP, total 
bilirubin, direct bilirubin, and INR on weekly 
basis.
Measure HBsAg and HBV DNA on weekly 
basis (if detected at the time of onset of ECI).
Evaluate the following every 2-3 weeks:
anti -HBs, and HBV DNA levels (if not 
detected at the onset of ECI)
Restart study intervention only if ALT returns 
to normal or Grade 1 (if normal at baseline), or 
to baseline grade (if Grade 2 at baseline) within 
12 weeks, and the participant is clinically 
stable; otherwise, the participant should be 
permanently discontinued.
Hepatitis C 
exacerbation in 
participants with 
HCV RNA 
positive
Rapid elevation of ALT to >5×ULN 
and/or >3x baseline 
Interrupt study intervention for up to 12 weeks.
Assess use of injection or inhalation drugs.
Recheck HCV genotype at the time of relapse 
of HCV RNA to rule out new infection.
Measure safety labs for AST, ALT, ALP, total 
bilirubin, direct bilirubin, and INR on weekly
basis
Measure HCV RNA levels every 2 weeks.
Please discuss benefit:risk with Sponsor prior 
to starting HCV antiviral therapy.
Restart study intervention only if ALT returns 
to normal or Grade 1 (if normal at baseline), or 
to baseline grade (if Grade 2 at baseline) within 
12 weeks, and the participant is clinically 
stable; otherwise, the participant should be 
permanently discontinued.
Relapse of HCV 
infection for 
participants with 
successfully 
treated or new 
HCV infection 
If HCV RNA was TND at baseline, 
and now has confirmed detectable 
HCV RNA (2 specimens, 1 week 
apart)
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Diagnosis
Management
Immune-related 
hepatitis
If any of the HECI criteria is met as 
defined in the protocol Section 8.4.7
Note:
Immune-related hepatitis is a 
diagnosis made after excluding other 
possible etiologies such as viral 
flare, biliary or vascular obstruction, 
infection, medications, and alcohol 
use usually immune-related hepatitis 
response to dechallenge and/or 
steroids and reoccurs with 
rechallenge
Interrupt study intervention for up to 12 weeks.
Start IV corticosteroid 60 mg/day of prednisone 
or equivalent followed by oral corticosteroid.
Monitor with biweekly laboratory tests, 
including AST, ALT, total bilirubin, direct 
bilirubin, ALP, and INR.
Restart study intervention only if:
a.
Abnormal laboratory values resolve to 
Grade ≤1 or baseline (if abnormal at 
baseline)
b.
Taper steroid over 28 days
c.
Steroid treatment is tapered to prednisone 
<10 mg/day or equivalent
Permanently Discontinue study intervention 
if:
a.
Laboratory abnormalities do not resolve 
within 3 weeks
Other Causes
Rule out infection with blood, urine, 
and ascites culture – antibiotics 
should be started if infection is 
found
If total bilirubin is elevated, imaging 
should be obtained to rule out 
vascular compromise, biliary 
obstruction, and/or tumor 
progression by imaging
Rule out alcohol use and hepatotoxic 
drugs including herbal and 
alternative medications
Restart study intervention only if laboratory 
values have returned to Grade 1 or baseline (if 
normal or Grade 1 at start) or to baseline grade 
within 6 weeks.
If biliary obstruction is present, consultation 
with a gastroenterologist and/or an 
interventional radiologist should be obtained to 
see if the obstruction may be relieved.
ALP=alkaline phosphatase; anti-HBs=hepatitis B surface antigen antibody; ALT=alanine aminotransferase; 
AST=aspartate aminotransferase; CP-C=Child-Pugh Grade C; DNA=deoxyribonucleic acid; ECI=event of clinical 
interest; HBV=hepatitis B virus; HCV=hepatitis C virus; HECI=hepatic events of clinical interest; INR=international 
normalized ratio; IV=intravenous; RNA=ribonucleic acid; TND=target not detected; ULN=upper limit of normal.
6.7
Intervention After the End of the Study
There is no study-specified intervention following the end of the study.
6.8
Clinical Supplies Disclosure
This study is blinded but supplies are provided as open label; therefore, an unblinded 
pharmacist or qualified study site personnel will be used to blind supplies. Study intervention
identity (name, strength, or potency) is included in the label text; random code/disclosure 
envelopes or lists are not provided.
The emergency unblinding call center will use the intervention/randomization schedule for 
the study to unblind participants and to unmask study intervention identity. The emergency 
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unblinding call center should only be used in cases of emergency (refer to Section 8.1.10). In 
the event that the emergency unblinding call center is not available for a given site in this 
study, the central electronic IRT should be used to unblind participants and to unmask study 
intervention identity. The Sponsor will not provide random code/disclosure envelopes or lists 
with the clinical supplies.
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
Discontinuation of study intervention does not represent withdrawal from the study.
As certain data on clinical events beyond study intervention discontinuation may be 
important to the study, they must be collected through the participant’s last scheduled follow-
up, even if the participant has discontinued study intervention. Therefore, all participants 
who discontinue study intervention prior to completion of the protocol-specified treatment 
period will still continue to be monitored in the study and participate in the study visits and 
procedures as specified in Section 1.3 and Section 8.11.3 unless the participant has 
withdrawn from the study (Section 7.2).
Participants may discontinue study intervention at any time for any reason or be discontinued 
from the study intervention at the discretion of the investigator should any untoward effect 
occur. In addition, a participant may be discontinued from study intervention by the 
investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or 
for administrative and/or other safety reasons. Specific details regarding procedures to be 
performed at study intervention discontinuation are provided in Section 8.1.9.
A participant must be discontinued from study intervention but continue to be monitored in 
the study for any of the following reasons:
•
The participant or participant’s legally acceptable representative requests to discontinue 
study intervention
•
Any prolonged interruption of study intervention beyond the permitted periods, for irAE 
management or other allowed dose interruptions, as noted in Section 6.6.2.1 require 
sponsor consultation prior to restarting treatment.  If treatment will not be restarted, the 
participant will continue to be monitored in the study and the reason for discontinuation 
of study intervention will be recorded in the medical record.
•
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 intervention
•
The participant has a confirmed positive serum pregnancy test
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•
Participant has any of the following nonoverdose hepatic ECIs:
•
ALT >20×ULN (confirmed within 1 week)
•
Drug-related total bilirubin >10 x ULN
•
CPS of >9 points
•
Unacceptable toxicity, as described in Section 6.6
Note: Participants who discontinue one or all components of chemotherapy due to 
toxicity or AEs can continue with pembrolizumab or placebo up to the full 
35 administrations
•
Prohibited concomitant medication requiring discontinuation of study intervention (refer 
to Section 6.5)
•
Radiographic disease progression outlined in Section 8.2.1.5 (after obtaining informed 
consent addendum and Sponsor communication, the investigator may elect to continue 
treatment beyond iCRO-verified disease progression)
•
Any progression or recurrence of any malignancy, or occurrence of another malignancy,
that requires active treatment
•
Discontinuation of pembrolizumab/placebo for recurrence of a severe or life-threatening
event, or of any of the laboratory abnormalities listed above (refer to Section 6.6.1.1),
that are presumed to be immune-related
For participants who are discontinued from study intervention but continue to be monitored 
in the study, all visits and procedures, as outlined in the SoA, should be completed.
7.2
Participant Withdrawal From the Study
It has been well-documented that a higher rate of withdrawal can render a study 
uninterpretable; therefore, unnecessary withdrawal of participants should be avoided. 
As clinical event data are important study endpoints, participants who discontinue study 
intervention prior to completion of the treatment period should be encouraged to continue all 
remaining study visits for follow-up and vital status assessment as outlined in the SoA and 
Section 8.11.3.
The investigator is to inform the participants that:

they may discontinue from study intervention at any time during the study, 
and

they are encouraged to continue visits in the study for follow-up, imaging, and 
vital status assessment
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If participants elect to stop study procedures, they are encouraged to continue to be followed, 
which allows periodic survival follow-up and vital status data to be collected.
If a participant fails to return for scheduled visits and/or if the study site is unable to contact 
the participant after multiple attempts (ie, lost to follow-up), the procedures to be performed 
are outlined in Section 7.3.
If a participant decides not to continue receiving study intervention, the participant is to be 
encouraged to continue visits in the study for follow-up, imaging, and vital status assessment.
Participants who withdraw consent during the study
If the participant or participant’s legally acceptable representative withdraws consent, the 
participant must be withdrawn from the study.
Section 8.1.9 delineates the specific procedures performed at the time of withdrawal and 
withdrawal from future biomedical research. Any AEs that are present at the time of 
withdrawal should be followed in accordance with the safety requirements outlined in
Section 8.4.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
•
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
•
The investigator or designee must make every effort to regain contact with the participant 
at each missed visit (eg, telephone calls and/or a certified letter to the participant’s last 
known mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
•
Note: A participant is not considered lost to follow-up until the last scheduled visit for the 
individual participant. The missing data for the participant will be managed via the 
prespecified statistical data handling and analysis guidelines.
8
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and their timing are summarized in the SoA.
•
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
•
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified (by education, training, and experience) staff. Delegation of study 
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site personnel responsibilities will be documented in the Investigator Trial File Binder (or 
equivalent).
•
All study-related medical (or dental) decisions must be made by an investigator who is a 
qualified physician (or dentist when appropriate).
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of ICF may be utilized for screening or baseline 
purposes provided the procedure met the protocol-specified criteria and were performed 
within the time frame defined in the SoA.
•
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, Hepatitis C), and thus local regulations 
may require that additional informed consent be obtained from the participant. In these 
cases, such evaluations/testing will be performed in accordance with those regulations.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
8.1
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented informed consent from each potential participant or their legally 
acceptable representative prior to participating in this clinical study or future biomedical 
research. If there is a change to the participant’s status during the study (eg, health or age of 
majority requirements), the investigator or medically qualified designee must ensure the 
appropriate documented informed consent is in place.
8.1.1.1
General Informed Consent
Informed consent given by the participant or their legally acceptable representative must be 
documented on a consent form. The form must include the trial protocol number, trial 
protocol title, dated signature, and agreement of the participant (or his/her legally acceptable 
representative) and of the person conducting the consent discussion.
A copy of the signed and dated informed consent form should be given to the participant (or 
their legally acceptable representative) before participation in the study.
The initial ICF, any subsequent revised ICF, and any written information provided to the 
participant must receive the IRB/IEC’s approval/favorable opinion in advance of use. The 
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participant or his/her legally acceptable representative should be informed in a timely manner 
if new information becomes available that may be relevant to the participant’s willingness to 
continue participation in the study. 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 participant’s or the participant’s legally acceptable representative’s dated 
signature.
If the investigator recommends continuation of study intervention beyond disease 
progression, the participant or their legally acceptable representative will be asked to provide 
documented informed consent.
Specifics about the study and the study population are to be included in the study consent 
form.
The informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, 
and Sponsor requirements.
8.1.1.2
Consent and Collection of Specimens for Future Biomedical Research
The investigator or medically qualified designee will explain the future biomedical research 
consent to the participant, or the participant’s legally acceptable representative, answer all of 
his/her questions, and obtain documented informed consent before performing any procedure 
related to future biomedical research. A copy of the informed consent will be given to the 
participant before performing any procedure related to future biomedical research.
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator, who is a qualified 
physician, to ensure that the participant qualifies for the study.
8.1.3
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant provides documented informed consent. At the time of intervention
randomization, site personnel will add the treatment/randomization number to the participant 
identification card.
The participant identification card also contains contact information for the emergency 
unblinding call center so that a healthcare provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
8.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee. The 
investigator/designee will collect all active conditions and any condition diagnosed within 
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the prior 10 years that the investigator considers to be clinically important. Details regarding 
the disease for which the participant has enrolled in this study will be recorded separately and 
not listed as medical history.
If a medical condition is diagnosed at the time of Screening due to the physical examination, 
laboratory tests, radiologic assessments, other assessments, and/or a combination of these 
evaluations, the medical condition is to be recorded as a baseline condition along with the 
participant’s other medical history unless due to any protocol-specified intervention (eg, 
procedure, washout, or run-in treatment including placebo run-in).
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
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 28 days before C1D1. Treatment for the disease for which the participant has enrolled
in this study will be recorded separately and not listed as a prior medication.
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study through the Safety Follow-up visit. In addition, new medications started 
during the Second Course through the Second Course Safety Follow-up visit should be 
recorded.
8.1.6
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur prior to randomization. Each participant 
will be assigned only 1 screening number. Screening numbers must not be re-used for 
different participants.
Any participant who is screened multiple times will retain the original screening number 
assigned at the initial screening visit. Specific details on the screening/rescreening visit 
requirements are provided in Section 8.11.1.
8.1.7
Assignment of Treatment/Randomization Number
All eligible participants will be randomly allocated and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment randomization. Once a 
treatment/randomization number is assigned to a participant, it can never be re-assigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
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8.1.8
Study Intervention Administration
Administration of study intervention will be monitored by the investigator and/or study staff
and/or qualified designee per institutional guidelines and procedures.
Study intervention should begin within 3 days of randomization.
8.1.8.1
Timing of Dose Administration
Study intervention should be administered after all procedures/assessments have been 
completed. Study intervention may be administered up to 3 days before or after the scheduled 
Day 1 of each cycle due to administrative reasons except for C1D1, where the acceptable 
window is +3 days from randomization. Pembrolizumab or placebo infusion will be 
administered first, and then administration of chemotherapy, according to local guidelines 
and practices.
8.1.8.1.1
Pembrolizumab
Pembrolizumab 200 mg or placebo will be administered as a 30-minute IV infusion, every 
3 weeks. Sites should make every effort to target infusion timing to be as close to 30 minutes 
as possible. However, given the variability of infusion pumps from site to site, a window 
of -5 minutes and + 10 minutes is permitted (ie, infusion time is 30 minutes: -5 min/+10 
min).
Every effort should be made to begin the first dose of study intervention on the day of 
randomization, but if this is not achieved, study intervention should be initiated no later than 
3 days from the date of randomization.
All subsequent pembrolizumab or placebo cycles may be administered up to 3 days before or 
3 days after the scheduled Day 1 of each cycle due to administrative reasons per the 
investigator’s judgment.
The Pharmacy Manual contains specific instructions for pembrolizumab dose calculation, 
reconstitution, preparation of the infusion fluid, and administration.
8.1.8.1.2
Gemcitabine/Cisplatin
Cisplatin will be administered as an IV infusion on Day 1 and Day 8 of a 3-week cycle and 
should be immediately preceded and followed by hydration procedures and administered 
according to local guidelines/product label procedures. Cisplatin may be administered on 
Day 2, if required per local guidelines; however, Day 1 is the preferred day for intervention
administration. Gemcitabine will be administered as an IV infusion on Days 1 and 8 of a 
3-week cycle, according to local guidelines and product label procedures.
Premedication with antiemetic therapy can be given prior to cisplatin and gemcitabine
administration. Consider following Multinational Association of Supportive Care in Cancer 
(MASCC) guidelines (http://www.mascc.org/antiemetic-guidelines) and, including a 5-HT3 
receptor antagonist, dexamethasone (or equivalent) and aprepitant (or equivalent) as per the 
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MASCC guidelines. Based on data showing potential impact of steroid use on efficacy of 
PD-1 and PD-L1 blockade, systemic steroid use as anti-nausea medication should be limited 
as deemed safe by the investigator [Arbour, K. C., et al 2018].
8.1.9
Discontinuation and Withdrawal
Participants who discontinue study intervention prior to completion of the study intervention 
period should be encouraged to continue to be followed for all remaining study visits as 
outlined in the SoA and Section 8.11.3.
Participants who withdraw from the study should be encouraged to complete all applicable 
activities scheduled for the final study visit at the time of withdrawal. Any AEs that are 
present at the time of withdrawal should be followed in accordance with the safety 
requirements outlined in Section 8.4.
8.1.9.1
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for future biomedical research. Participants may 
withdraw consent at any time by contacting the investigator for the main study. If medical 
records for the main study are still available, the investigator will contact the Sponsor using 
the designated mailbox (clinical.specimen.management@MSD.com). Subsequently, the 
participant's consent for future biomedical research will be withdrawn. A letter will be sent 
from the Sponsor to the investigator confirming the withdrawal. It is the responsibility of the 
investigator to inform the participant of completion of withdrawal. Any analyses in progress 
at the time of request for withdrawal or already performed prior to the request being received 
by the Sponsor will continue to be used as part of the overall research study data and results. 
No new analyses would be generated after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study records) 
or the specimens have been completely anonymized, there will no longer be a link between 
the participant’s personal information and their specimens. In this situation, the request for 
specimen withdrawal cannot be processed.
8.1.10
Participant Blinding/Unblinding
STUDY INTERVENTION IDENTIFICATION INFORMATION IS TO BE UNMASKED 
ONLY IF NECESSARY FOR THE WELFARE OF THE PARTICIPANT. EVERY 
EFFORT SHOULD BE MADE NOT TO UNBLIND.
For emergency situations where the investigator or medically qualified designee (consistent 
with local requirements) needs to identify the intervention used by a participant and/or the 
dosage administered, he/she will contact the emergency unblinding call center by telephone 
and make a request for emergency unblinding. As requested by the investigator or medically 
qualified designee, the emergency unblinding call center will provide the information to 
him/her promptly and report unblinding to the Sponsor. Prior to contacting the emergency 
unblinding call center to request unblinding of a participant’s intervention assignment, the 
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investigator who is a qualified physician should make reasonable attempts to enter the 
intensity/toxicity grade of the AEs observed, the relation to study intervention, the reason 
thereof, etc., in the medical chart. If it is not possible to record this assessment in the chart 
prior to the unblinding, the unblinding should not be delayed.
In the event that unblinding has occurred, the circumstances around the unblinding (eg, date, 
reason, and person performing the unblinding) must be documented promptly, and the 
Sponsor Clinical Director notified as soon as possible.
For studies that require nonemergency unblinding as part of the study design (eg, disease 
progression) to support treatment decisions, IRT should be used to unblind the participant’s 
treatment assignment. The emergency unblinding center should not be used for this purpose.
Once an emergency unblinding or a nonemergency unblinding that is part of the study design 
has taken place, the investigator, site personnel, and Sponsor personnel may be unblinded so 
that the appropriate follow-up medical care can be provided to the participant.
Treatment identification information is to be unblinded ONLY in the following situation:
1.
For the welfare of the participant, if necessary.
2.
Participants requiring second course who completed 35 cycles and stopped first 
course study intervention with SD or better including CR and had to discontinue for 
any reason other than disease progression or intolerability. Such participants must 
have experienced radiographic disease progression while off study intervention 
according to the criteria in Section 6.1.2.
Note: PD-L1 status will remain blinded to the participant and the investigator.
Participants whose treatment assignment has been unblinded by the investigator or medically 
qualified designee and/or nonstudy treating physician should continue to be monitored in the 
study.
Additionally, the investigator or medically qualified designee must go into the IRT system 
and perform the unblind in the IRT system to update drug disposition. In the event that the 
emergency unblinding call center is not available for a given site in this study, the IRT 
system should be used for emergency unblinding in the event that this is required for 
participant safety.
8.1.11
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained are reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
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8.1.12
Tumor Tissue for Biomarker Status
During the screening period, a tumor sample for each participant is required and is to be:

A newly obtained core or incisional biopsy of a tumor lesion, which was not previously 
irradiated
or

An archival tumor tissue sample if a new biopsy is unavailable (depending on protocol 
requirements)
FFPE tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived 
tissue.
Details pertaining to tumor tissue submission can be found in the Procedures Manual.
The central laboratory will use the tissue sample to ascertain PD-L1 status using the PD-L1 
IHC 22C3 pharmDx (Investigational Use Only [IUO]) diagnostic kit. The diagnostic test is 
identical to the US FDA approved PD-L1 IHC 22C3 pharmDx kit except it is labeled IUO.
The PD-L1 result will be masked to the site.
8.2
Efficacy/Immunogenicity Assessments
8.2.1
Tumor Imaging and Assessment of Disease
The process for image collection and transmission to the iCRO can be found in the Site 
Imaging Manual (SIM).
Tumor imaging by CT/MRI chest, abdomen and pelvis is required at all scheduled imaging 
time points (CT is strongly preferred). For the abdomen and pelvis, contrast-enhanced 
magnetic resonance imaging (MRI) may be used when CT with iodinated contrast is 
contraindicated, or when mandated by local practice.
Whole body radionuclide bone scan is as clinically indicated at baseline and on study. 
MRI/CT (MRI is strongly preferred) brain imaging is only as clinically indicated at baseline 
and on study.
The same imaging technique should be used in a participant throughout the study to optimize 
the reproducibility of the assessment of existing and new tumor burden and improve the 
accuracy of the response assessment based on imaging. Note: for the purposes of assessing 
tumor imaging, the term “investigator” refers to the local investigator at the site and/or the 
radiological reviewer at the site or at an offsite facility.
Participant eligibility will be determined using local assessment (investigator assessment) 
based on RECIST 1.1. All scheduled images for all study participants from the sites will be 
submitted to the iCRO. In addition, images (including via other modalities) that are obtained 
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at an unscheduled time point to determine disease progression, as well as imaging obtained 
for other reasons, but which shows radiologic progression, should also be submitted to the 
iCRO.
When the investigator identifies radiographic progression per RECIST 1.1, the iCRO will 
perform expedited verification of radiologic PD and communicate the results to the study site 
and Sponsor via email (refer to Section 8.2.1.5 and Figure 2). Treatment should continue 
until PD has been verified by BICR (if initial site-assessed PD was not verified by BICR, 
each subsequent scan must be submitted to iCRO with verification of PD request until PD 
has been verified by BICR). Regardless of whether PD is verified, if the investigator 
considers the participant has progressed, but elects to implement iRECIST, the investigator 
will assess for confirmation of progression by iRECIST at subsequent time points. Images 
should continue to be submitted to the iCRO.
8.2.1.1
Initial Tumor Imaging
The screening images must be submitted to the iCRO for retrospective review.
Tumor imaging performed as part of routine clinical management is acceptable for use as 
screening tumor imaging if it is of diagnostic quality and performed within 28 days prior to 
the date of randomization and can be assessed by the iCRO.
Tumor imaging at baseline includes the following:

CT/MRI of the chest, abdomen, and pelvis

MRI/CT of the brain when clinically indicated

Bone scan whole body when clinically indicated
8.2.1.2
Tumor Imaging During the Study
On study first scheduled imaging assessment must be performed 6 weeks (42 days +7 days) 
from the date of randomization. Subsequent tumor imaging should be performed every 6 
weeks (42 days ±7 days) through Week 54. Participants who remain on treatment beyond 
Week 54 will have imaging performed every 12 weeks (84 days ±7 days).
Imaging timing should follow calendar days and should not be adjusted for delays in cycle 
starts. Imaging should continue to be performed until disease progression is identified by the 
investigator and verified by BICR (unless the investigator elects to continue treatment and 
follow iRECIST), the start of new anticancer treatment, withdrawal of consent, or death,
whichever occurs first. All supplemental imaging must be submitted to the iCRO.
Objective response should be confirmed by a repeat imaging assessment. Tumor imaging to 
confirm PR or CR should be performed at least 4 weeks after the first indication of a 
response is observed. Participants will then return to regular scheduled imaging, starting with 
the next scheduled imaging time point. Participants who receive additional imaging for 
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confirmation do not need to undergo the next scheduled tumor imaging if it is less than 4 
weeks later; tumor imaging may resume at the subsequent scheduled imaging time point. 
Note: Response does not typically need to be verified in real time by the BICR.
Per iRECIST (Section 8.2.1.6), disease progression should be confirmed by the site 4 to 8 
weeks after site-assessed first radiologic evidence of PD in clinically stable participants. 
Participants who have unconfirmed disease progression may continue on treatment at the 
discretion of the investigator until progression is confirmed by the site provided they have 
met the conditions detailed in Section 8.2.1.6. Participants who receive confirmatory imaging 
do not need to undergo the next scheduled tumor imaging if it is less than 4 weeks later; 
tumor imaging may resume at the subsequent scheduled imaging time point, if clinically 
stable. Participants who have confirmed disease progression by iRECIST, as assessed by the 
site, will discontinue study intervention. Exceptions are detailed in Section 8.2.1.6.
8.2.1.3
End-of-Treatment and Follow-up Tumor Imaging
For participants who discontinue study intervention, tumor imaging should be performed at 
the time of treatment discontinuation (±4 week window). If previous imaging was obtained 
within 4 weeks prior to the date of discontinuation, then imaging at treatment discontinuation 
is not mandatory. For participants who discontinue study intervention due to documented 
disease progression, this is the final required tumor imaging if the investigator elects not to 
implement iRECIST.
For participants who discontinue study intervention without documented disease progression, 
every effort should be made to continue monitoring disease status by tumor imaging using 
the same imaging schedule used while on treatment calculated from the date of 
randomization (refer to Section 8.2.1.2).
Scans are to be continued until one of the following conditions are met:
disease progression as defined by RECIST 1.1 verified by BICR
the start of a new anticancer treatment
pregnancy
death
withdrawal of consent
the end of the study
Participants who are clinically stable and treated past radiographic progression may continue 
to be assessed until progression is confirmed according to the rules of iRECIST, when 
clinically appropriate.
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8.2.1.4
Second Course (Retreatment) Tumor Imaging
Tumor scans must be performed within 28  days before restarting study intervention with 
pembrolizumab.
If disease progression has been verified by BICR for the First Course, the Second Course 
may be initiated. The disease progression scan may be used as the Second Course baseline 
scan if performed within 4 weeks prior to dosing and meets scan standards.
The first scan should be performed at 6 weeks (42 days +7 days) after restarting study 
intervention. Subsequent tumor scans are to be performed every 12 weeks (84 days ±7 days) 
or more frequently, if clinically indicated.
Scans should continue to be performed until disease progression, the start of a new anticancer 
treatment, withdrawal of consent, death, completion of Second Course, or notification by the 
Sponsor, whichever occurs first. 
If participants discontinue study intervention, tumor scans are to be performed at 
discontinuation (±4 week window) unless previous scans were obtained within 4 weeks of 
discontinuation. If participants discontinue study intervention due to documented disease 
progression, this is the final required tumor scan.
If participants discontinue study intervention without documented disease progression, every 
effort is to be made to monitor disease status by acquiring tumor scans every 12 weeks (84
days ±7 days) until the start of a new anticancer treatment, disease progression, death, or the 
end of the study, whichever occurs first.
The only Second Course scan to be provided to the iCRO is the baseline scan if it is the final 
scan for the Initial Treatment or First Course.
8.2.1.5
RECIST 1.1 Assessment of Disease
RECIST 1.1 will be used 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 (eg,
discontinuation of study intervention). Although RECIST 1.1 references a maximum of 5 
target lesions in total and 2 per organ, this protocol allows a maximum of 10 target lesions in 
total and 5 per organ, if clinically relevant to enable a broader sampling of tumor burden.
Upon investigator-assessed disease progression, the indicative scans are to be submitted 
immediately to iCRO for BICR verification of progression. After submission of scan(s), the 
iCRO will email the assessment to the site and Sponsor.
If disease progression is not verified, the process continues as follows:
•
If participant is clinically stable, continue study intervention per protocol
-
resume imaging per protocol schedule (≥4 weeks to next scan)
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-
send scans to iCRO
-
continue local assessment
-
do not change investigator assessment of progression
-
if subsequent scan(s) indicate progression, submit scan(s) to iCRO to request 
verification
•
If the participant is not clinically stable, best medical practice is to be applied
Before stopping study intervention or imaging or starting new anti-cancer therapy in a 
participant who is clinically stable, communication with the Sponsor is required.
If disease progression is verified, the process continues as follows:
•
investigator judgement will determine action
•
if the participant is clinically stable and study intervention is to continue, communication 
with the sponsor is required and a reconsent addendum must be signed
•
obtain scans locally per original protocol schedule
•
do not send scans to iCRO
Figure 2 illustrates the study intervention decision process involving verification of disease 
progression for participants.
•
For the purpose of this decision process, lack of clinical stability is defined as:
-
unacceptable toxicity
-
clinical signs or symptoms indicating clinically significant disease progression
-
decline in performance status
-
rapid disease progression or threat to vital organs or critical anatomical sites (eg, CNS 
metastasis, respiratory failure due to tumor compression, spinal cord compression) 
requiring urgent alternative medical intervention
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Figure 2
Study Intervention Decision Making Process When Progression per RECIST 1.1 
is Observed by the Investigator (PFS Endpoint)
8.2.1.6
iRECIST Assessment of Disease
iRECIST is based on RECIST 1.1, but adapted to account for the unique tumor response seen 
with immunotherapeutic drugs. iRECIST will be used by the investigator to assess tumor 
response and progression, and make treatment decisions [Seymour, L., et al 2017]. When 
clinically stable, participants may continue study intervention beyond RECIST 1.1
progression with continued assessment of response according to the rules outlined in
Appendix 8. iRECIST reflects that some participants can have a transient tumor flare after 
the start of immunotherapy then experience subsequent disease response. This data will be 
captured in the clinical database.
If the participant is clinically stable (refer to Sec. 8.2.1.5), continue study intervention per 
protocol 
Perform scans 4 to 8 weeks after RECIST 1.1 progression
Continue investigator assessment per iRECIST
If progression is BICR-verified, stop sending scans to iCRO
If the participant is not clinically stable, best medical practice is to be applied.
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8.2.2
Patient-reported Outcomes
The EQ-5D-5L, EORTC QLQ-C30, and EORTC QLQ-BIL21 questionnaires will be 
administered by trained site personnel and completed electronically by participants in the 
following order: EQ-5D-5L first, then EORTC QLQ-C30, then EORTC QLQ-BIL21. See the 
SoA (Section 1.3.1) for ePRO administration schedule.
It is best practice and strongly recommended that electronic patient-reported outcomes 
(ePROs) are administered to randomized participants prior to drug administration, AE
evaluation, and disease status notification. If the participant does not complete the ePROs at a
scheduled time point, the MISSMODE form must be completed to capture the reason the 
assessment was not performed.
If at the time of enrollment of a participant, the translated version of the EQ-5D-5L, EORTC 
QLQ-C30 and/or EORTC QLQ-BIL21 questionnaires are not available for that 
language/country, and therefore cannot be completed by the participant at Cycle 1 Day 1, 
then the EORTC QLQ-C30 and/or EORTC QLQ-BIL21 will not be required for this 
participant at any point during the study. The other study PRO measures must be completed 
as scheduled.
NOTE: For some sites, the translated EORTC QLQ-C30 and/or EORTC QLQ-BIL21 might 
become available after study start-up and should be administered to participants at their time 
of enrollment; for some sites, the EORTC QLQ-C30 and/or EORTC QLQ-BIL21 translation 
might not be available for the entire duration of the study.
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided below.
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
8.3.1.1
Full Physical Examination
The investigator or qualified designee will perform a complete physical examination during 
the Screening period and at the time of study intervention discontinuation. Clinically 
significant abnormal findings should be recorded as medical history. After the first dose of 
study intervention, new clinically significant abnormal findings should be recorded as AEs.
Investigators should pay special attention to clinical signs related to previous serious illnesses
including signs of liver decompensation (eg, hepatic encephalopathy and ascites).
8.3.1.2
Directed Physical Examination
For cycles that do not require a full physical examination, as defined in Section 1.3, the 
investigator or qualified designee will perform a directed physical examination, including 
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special attention to signs of liver decompensation (eg, hepatic encephalopathy and ascites), as 
clinically indicated, prior to study intervention administration. New clinically significant 
abnormal findings should be recorded as AEs.
Day 8 directed physical examination will not be performed when both chemotherapy agents 
(gemcitabine/cisplatin) are permanently discontinued.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.3.2
Audiometry
Participants receiving cisplatin should be monitored for audiological complications.
Audiometry testing will be performed at Screening or per local standard, by the investigator 
or medically qualified designee (consistent with local requirements). Assessments may be 
repeated during the study, as clinically indicated. After the first dose of study intervention, 
new clinically significant abnormal findings should be recorded as AEs.
8.3.3
Vital Signs
The investigator or qualified designee will take vital signs at Screening, prior to the 
administration of each dose of study intervention, at study discontinuation, and during the 
Follow-up Period, as specified in the SoA (Section 1.3). Vital signs include temperature, 
pulse, respiratory rate, weight, and blood pressure. Height will be measured at the screening 
visit only.
Day 8 vital signs will not be assessed/performed when both chemotherapy agents 
(gemcitabine/cisplatin) are permanently discontinued.
8.3.4
Electrocardiograms
A standard 12-lead electrocardiogram (ECG) will be performed using local standard 
procedures once at Screening. Clinically significant abnormal findings should be recorded as 
medical history. Additional ECGs may be performed as clinically necessary.
8.3.5
Clinical Safety Laboratory Assessments
•
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the 
SoA for the timing and frequency.
•
The investigator or medically qualified designee (consistent with local requirements) 
must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the case report form 
(CRF). The laboratory reports must be filed with the source documents. Clinically 
significant abnormal laboratory findings are those which are not associated with the 
underlying disease, unless judged by the investigator to be more severe than expected for 
the participant's condition.
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•
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.
•
If laboratory values from nonprotocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).
•
For any laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 30 days after the last dose of study intervention, every 
attempt should be made to perform repeat assessments until the values return to normal or 
baseline or if a new baseline is established as determined by the investigator.
Details regarding specific laboratory procedures/assessments to be performed in this study 
are provided below. The total amount of blood/tissue to be drawn/collected over the course 
of the study (from Screening to End of Intervention), including approximate blood/tissue 
volumes drawn/collected by visit and by sample type per participant can be found in the 
Study laboratory manual. Refer to the SoA (Section 1.3) for the timing of laboratory 
assessments.
8.3.5.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
Laboratory tests for hematology, chemistry, and urinalysis are specified in Appendix 2.
Day 8 hematology, chemistry and liver panel blood samples will not be collected after both 
chemotherapy agents (gemcitabine/cisplatin) are permanently discontinued.
Repeat HBV viral load and HBsAg testing approximately every 6 weeks if HBsAg negative 
and anti-HBc positive and HBV viral load is undetectable at screening and not on antiviral
therapy and approximately every 12 weeks for participants on antiviral therapy for HBV until 
the end of study intervention and then per local standard of care. This testing should be 
aligned with study intervention visits.
8.3.5.2
Pregnancy Testing

Pregnancy testing:
-
Pregnancy testing requirements for study inclusion are described in Section 5.1.
-
Pregnancy testing (urine or serum as required by local regulations) should be 
conducted every 3 weeks during the Study Intervention Phase.
-
Pregnancy testing (urine or serum as required by local regulations) should be 
conducted approximately 240 days after the last dose of chemotherapy or 150 days 
after the last dose of pembrolizumab or placebo, whichever is greater, or 30 days after 
cessation of study intervention if the participant initiates new anticancer therapy.
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-
Additional serum or urine pregnancy tests may be performed, as determined 
necessary by the investigator or required by local regulation, to establish the absence 
of pregnancy at any time during the participant’s participation in the study.
Refer to Section 10.7 (Appendix 7) for country-specific requirements.
8.3.6
Performance Assessments
8.3.6.1
Eastern Cooperative Oncology Group (ECOG) Performance Scale
The ECOG Performance Status is standardized criteria to measure how cancer impacts level 
of functioning (performance status) in terms of ability to care for oneself, daily activity, and 
physical ability (walking, working, etc) with Grades 0 to 5.
The investigator or qualified designee will assess ECOG status (see Appendix 9) at 
Screening, prior to the administration of each dose of study intervention and during the 
Follow-up Period, as specified in the SoA (Section 1.3). If ECOG status assessment is 
performed prior to dosing on C1D1, then Screening ECOG is not mandatory.
Day 8 ECOG status will not be performed after both chemotherapy agents (gemcitabine/
cisplatin) are permanently discontinued.
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Reportable 
Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3.
Progression of the cancer under study is not considered an AE as described in Section 8.4.6
and Appendix 3.
Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant's legally authorized 
representative).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators remain responsible for following up AEs, SAEs, and other reportable safety 
events for outcome according to Section 8.4.3.
The investigator, who is a qualified physician, will assess events that meet the definition of 
an AE or SAE as well as other reportable safety events with respect to seriousness, 
intensity/toxicity and causality.
Adverse events will not be collected for participants during the prescreening period (for 
determination of archival tissue status) as long as that participant has not undergone any 
protocol-specified procedure or intervention. If the participant requires a blood draw, fresh 
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tumor biopsy, etc., the participant is first required to provide consent to the main study, and 
AEs will be captured according to guidelines for standard AE reporting.
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
All AEs, SAEs, and other reportable safety events that occur after the participant provides 
documented informed consent but before intervention randomization must be reported by the 
investigator if the participant is receiving placebo run-in or other run-in treatment, if the 
event causes the participant to be excluded from the study, or is the result of a protocol-
specified intervention, including but not limited to washout or discontinuation of usual 
therapy, diet, or a procedure.
•
All AEs from the time of intervention randomization through 30 days following cessation 
of study intervention must be reported by the investigator.
•
All AEs meeting serious criteria, from the time of intervention randomization through 90 
days following cessation of study intervention or 30 days following cessation of study 
intervention if the participant initiates new anticancer therapy, whichever is earlier, must 
be reported by the investigator.
•
All pregnancies and exposure during breastfeeding, from the time of intervention 
allocation/randomization through the time required to eliminate systemic exposure after 
cessation of study intervention as described in [Sections 5.1 and 8.3.5], or 30 days after 
cessation of study intervention if the participant initiates new anticancer therapy must be 
reported by the investigator.
•
Additionally, any SAE brought to the attention of an investigator at any time outside of 
the time period specified above must be reported immediately to the Sponsor if the event 
is considered related to study intervention.
Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 9.
Exception: A positive pregnancy test at the time of initial screening is not a reportable event 
unless the participant has received study intervention.
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Table 9
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time Period:
Consent to 
Randomization/ Allocation
Reporting Time 
Period:
Randomization/ 
Allocation 
through Protocol-
specified Follow-
up Period
Reporting Time 
Period:
After the Protocol-
specified Follow-up 
Period
Time Frame 
to Report 
Event and 
Follow-up 
Information 
to Sponsor:
Nonserious 
Adverse Event 
(NSAE) 
Report if:
- due to protocol-specified 
intervention
- causes exclusion
- participant is receiving 
placebo run-in or other run-
in treatment
Report all
Not required
Per data entry 
guidelines
Serious Adverse 
Event (SAE) 
including Cancer 
and Overdose
Report if:
- due to protocol-specified 
intervention
- causes exclusion
- participant is receiving 
placebo run-in or other run-
in treatment
Report all
Report if:
- drug/vaccine 
related.
(Follow ongoing to 
outcome)
Within 24 
hours of 
learning of 
event
Pregnancy/
Lactation 
Exposure
Report if:
- due to intervention
- causes exclusion
Exception: A positive 
pregnancy test at the time of 
initial screening is not a 
reportable event unless the 
participant has received 
study intervention.
Report all
Previously reported –
Follow to completion/
termination; report 
outcome
Within 24 
hours of 
learning of 
event
Event of Clinical 
Interest (require 
regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report
- hepatic ECIs 
- require regulatory 
reporting
Not required
Within 24 
hours of 
learning of 
event
Event of Clinical 
Interest (do not 
require regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report
- non-hepatic ECIs 
and those not 
requiring 
regulatory 
reporting
Not required
Within 5 
calendar days 
of learning of 
event
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other 
reportable safety events. Open-ended and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE occurrence.
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8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs, SAEs, and other reportable safety events,
including pregnancy and exposure during breastfeeding, events of clinical interest (ECIs), 
cancer, and overdose will be followed until resolution, stabilization, until the event is 
otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). In 
addition, the investigator will make every attempt to follow all nonserious AEs that occur in
randomized participants for outcome. Further information on follow-up procedures is given 
in Appendix 3.
8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and Sponsor policy and 
forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.4.5
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to 
the investigator or their designee), including the pregnancy of a male participant’s female 
partner, that occurs during the study are reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy. 
Any pregnancy complication will be reported as an AE or SAE.
The medical reason (example: maternal health or fetal disease) for an elective termination of 
a pregnancy will be reported as an AE or SAE. Prenatal testing showing fetus will be born 
with severe abnormalities/congenital anomalies that leads to an elective termination of a 
pregnancy will be reported as an SAE for the fetus.
Pregnancy outcomes of ectopic pregnancy, spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth 
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must be reported as serious events (Important Medical Events). If the pregnancy continues to 
term, the outcome (health of infant) must also be reported.
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
Efficacy endpoints, as outlined in this section, will not be reported to the Sponsor as AEs or 
SAEs, as described in Section 8.4.1.
Specifically, the suspected/actual events covered in this exception include any event that is
disease progression of the cancer under study.
The Sponsor (via the external data monitoring committee [eDMC]) will monitor unblinded 
aggregated efficacy endpoint events and safety data to ensure the safety of the participants in 
the study. The Sponsor will ensure that unblinded aggregated efficacy endpoint events and 
safety data are monitored to safeguard the participants in the study.
8.4.7
Events of Clinical Interest (ECIs)
Selected nonserious and SAEs are also known as ECIs and must be reported to the Sponsor. 
Events of clinical interest for this study include: 
a. An overdose of Sponsor's product, as defined in Section 8.5, that is not associated with 
clinical symptoms or abnormal laboratory results.
b. Hepatic ECIs as defined in Section 6.6.1.3. For guidance related to the diagnosis and 
management of hepatic ECIs, refer to Section 6.6.1.3.
8.5
Treatment of Overdose
For this study, an overdose of pembrolizumab will be defined as any dose of 1000 mg or 
greater.
No specific information is available on the treatment of overdose of pembrolizumab. In the 
event of overdose, the participant should be observed closely for signs of toxicity. 
Appropriate supportive treatment should be provided if clinically indicated.
An overdose for gemcitabine or cisplatin will be defined as any dose exceeding the 
prescribed dose by 20%.
Treatment of overdose of gemcitabine or cisplatin should follow the guidelines in the 
relevant product labels. In the event of overdose, the participant should be observed closely 
for signs of toxicity. Appropriate supportive treatment should be provided if clinically 
indicated.
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8.6
Pharmacokinetics
The decision as to which blood samples collected will be assayed for evaluation of 
PK/pharmacodynamics will be collaboratively determined by the Sponsor (eg, samples at 
lower doses may not be assayed if samples at higher doses reveal undetectable drug 
concentrations). If indicated, these samples may also be assayed and/or pooled for assay in an 
exploratory manner for metabolites and/or additional pharmacodynamic markers.
To further evaluate pembrolizumab immunogenicity and pembrolizumab exposure in this 
indication, and also to evaluate exposure of the proposed dosing regimen, sample collections 
for analysis of antidrug antibodies (ADA) and PK are currently planned as shown in the SoA 
(Section 1.3.1). Blood samples will be obtained to measure PK of serum pembrolizumab. 
The pembrolizumab serum maximum concentration (Cmax) and minimum concentration 
(Ctrough) at planned visits and times will be summarized. If ongoing ADA and/or PK results 
continue to be consistent with existing ADA and/or PK data from other pembrolizumab 
clinical studies, it may be decided to discontinue or reduce further sample collection in this 
study. 
8.6.1
Blood Collection for PK for MK-3475
Sample collection, storage, and shipment instructions for serum samples will be provided in 
the laboratory manual. Pharmacokinetic samples should be drawn according to the PK 
collection schedule for all participants in the SoA (Section 1.3.1).
8.6.2
Blood Collection for Anti-pembrolizumab Antibodies
Sample collection, storage, and shipment instructions for serum samples will be provided in 
the laboratory manual. Anti-pembrolizumab antibody samples should be drawn according to 
the ADA collection schedule for all participants in the SoA (Section 1.3.1). Simultaneous PK 
sampling is required for interpretation of ADA analysis.
8.6.3
Blood Collection for RNA Analyses and Plasma and Serum Biomarker 
Analyses
Blood should be collected predose for C1D1, C2D1, C5D1, and at End of Intervention (EOI).
will be stored at the end of the study for future biomedical 
research if the participant has consented (refer to Section 8.9).
Further details are provided in the laboratory manual.
8.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
CCI
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8.8
Biomarkers
Sample collection, storage, and shipment instructions for the exploratory biomarker 
specimens will be provided in the laboratory manual.
Refer to Section 10.7 (Appendix 7) for country-specific requirements.
8.8.1
Planned Genetic Analysis Sample Collection
The planned genetic analysis sample should be drawn 
 This sample will not be collected at the 
site if there is either a local law or regulation prohibiting collection, or if the IRB/IEC does 
not approve the collection of the sample for these purposes. If the sample is collected, 
will be stored for future biomedical research if the participant 
provides documented informed consent for future biomedical research. If the planned genetic
analysis is not approved, but future biomedical research is approved and consent is given, 
this sample will be collected for the purpose of future biomedical research.
Sample collection, storage, and shipment instructions for planned genetic analysis samples 
will be provided in the laboratory manual.
8.8.2
Tissue Sample
All participants must submit either a newly obtained core or excisional biopsy or archival 
tissue (fine needle aspirate is not adequate for both archival and new tissue samples) to a 
central vendor for characterization of biomarker evaluation and deemed adequate for 
evaluation prior to randomization. Submission of formalin-fixed, paraffin-embedded block 
specimens are preferred to slides. If the sample is determined to be nonevaluable prior to 
CCI
CCI
CCI
CCI
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testing by the central laboratory, a new sample must be submitted and deemed adequate by 
the central vendor prior to participant randomization. Detailed instructions for tissue 
collection, processing, and shipment are provided in the laboratory manual.
If the participant provides documented informed consent for future biomedical research, any 
leftover samples that would be ordinarily discarded at the end of the main study will be 
retained for future biomedical research.
8.9
Future Biomedical Research Sample Collection
If the participant provides documented informed consent for future biomedical research, the 
following specimens will be obtained as part of future biomedical research:
•
Leftover specimens listed in Section 8.8 Biomarkers.
8.10
Health Economics Medical Resource Utilization and Health Economics
Medical resource utilization and health economics data associated with medical encounters 
will be collected in the CRF by the investigator and study site personnel for all participants 
throughout the study. Protocol-mandated procedures, tests, and encounters are excluded.
The collected data may be used to conduct exploratory economic analyses and will include:
All-cause hospitalizations and emergency department visits must be reported in the eCRF, 
from the time of study intervention allocation/randomization through 90 days following 
cessation of study intervention, or 30 days following cessation of study intervention, if the 
participant initiates new anticancer therapy, whichever is earlier.
8.11
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.11.1
Screening
Documented informed consent must be provided prior to performing any protocol-specific 
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. Screening procedures are to be completed within 28 days prior to the 
first dose of study intervention except for the following:

Laboratory tests are to be performed within 14 days prior to the first dose of study 
intervention. An exception is hepatitis testing which may be performed up to 28 days 
prior to the first dose of study intervention. Evaluation of ECOG is to be performed 
within 3 days prior to the first dose of study intervention.

For women of reproductive potential, a urine or serum pregnancy test will be 
performed within 24 hours (urine) or 72 hours (serum) prior to the first dose of study 
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intervention. If urine pregnancy results cannot be confirmed as negative, a serum 
pregnancy test will be required (performed by the local study site laboratory).
Tumor tissue from a fresh core or excisional biopsy or archival is acceptable. Archival tissue 
must be <5 years of age from the time of sample submission.
8.11.1.1
Rescreening
Participants may be rescreened after initially failing to meet the inclusion/exclusion criteria. 
Results from assessments during the initial screening period are acceptable in lieu of a repeat 
screening test if performed within the specified time frame and the corresponding 
inclusion/exclusion criteria is met. For repeat hepatitis testing during rescreening, the site 
may proceed with randomization in certain cases after collecting hepatitis blood samples but 
before results are available only with approval by the Sponsor. Participants may not rescreen 
more than 1 time without consulting with the Sponsor. Participants who are rescreened will 
retain their original screening number.
8.11.2
Study Intervention Period
Visit requirements are outlined in the SoA (Section 1.3). Specific procedure-related details 
are provided in Section 8.1 through 8.11.
8.11.3
Post-intervention Visit
8.11.3.1
Safety Follow-up Visit
The mandatory Safety Follow-up Visit should be conducted approximately 30 days after the 
last dose of study intervention or before the initiation of a new anticancer treatment, 
whichever comes first.
Participants who are eligible for retreatment with pembrolizumab may have up to 2 safety 
follow-up visits: 1 after the Initial Treatment or First Course and 1 after the Second Course.
8.11.3.2
Efficacy Follow-up Visits
Participants who complete the protocol-required cycles of study intervention or discontinue 
study intervention for a reason other than disease progression will begin Efficacy Follow-up 
and should be assessed Q6W (42 days ±7 days) through Week 54 and Q12W (84 days ±7 
days) thereafter to monitor disease status. Every effort should be made to collect information 
regarding disease status until the start of new anticancer therapy, disease progression, death, 
end of study, or if the participant begins retreatment. Information regarding poststudy 
anticancer treatment will be collected if new treatment is initiated.
Participants who complete all efficacy assessments and/or will not have further efficacy 
assessments must enter Survival Follow-up.
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Participants who are eligible to receive retreatment with pembrolizumab according to the 
criteria in Section 6 will move from Efficacy Follow-up to Second Course when they 
experience disease progression. Details are provided in the SoA (Section 1.3).
8.11.3.3
Survival Follow-up Assessments
Participant survival follow-up status will be assessed approximately every 12 weeks until 
death, withdrawal of consent, or the end of the study, whichever occurs first.
The first survival follow-up assessment should be scheduled as described below:

For participants who discontinue treatment intervention and who will not enter 
Efficacy Follow-up, the first survival follow-up contact will be scheduled 12 weeks 
after the discontinuation visit and/or Safety Follow-up Visit (whichever is last).

For participants who completed assessments in Efficacy Follow-up, the first survival 
follow-up contact will be scheduled 12 weeks after the last efficacy assessment 
follow-up visit has been performed.
8.11.4
Vital Status
To ensure current and complete survival information (vital status) is available at the time of 
database locks, updated vital status may be requested during the study by the Sponsor. For 
example, updated vital status may be requested before but not limited to, an eDMC review, 
interim and/or final analysis. Upon Sponsor notification, all participants who do not/will not 
have a scheduled study visit or study contact during the Sponsor-defined time period will be 
contacted for their vital status.
9
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/final database lock, changes are made to 
primary and/or key secondary hypotheses, or the statistical methods related to those 
hypotheses, then the protocol will be amended (consistent with International Council for 
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use [ICH]
Guideline E-9). Changes to exploratory or other nonconfirmatory analyses made after the 
protocol has been finalized, but prior to unblinding/final database lock, will be documented 
in a supplemental SAP (sSAP) and referenced in the clinical study report (CSR) for the 
study. Post hoc exploratory analyses will be clearly identified in the CSR. Other planned 
analyses (ie, those specific to the analysis of PK data or PROs) will be documented in a sSAP 
or separate analysis plans.
Details pertaining to the statistical analyses for participants enrolled in China will be 
provided in a separate sSAP.
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9.1
Statistical Analysis Plan Summary
Key elements of the SAP are summarized below; the comprehensive plan is provided in 
Sections 9.2 through 9.12.
Study Design Overview
A Phase 3 Randomized, Double Blind Study of Pembrolizumab Plus 
Gemcitabine/Cisplatin versus Placebo Plus Gemcitabine/Cisplatin as First-
Line Therapy in Participants with Advanced and/or Unresectable Biliary 
Tract Carcinoma
Study Intervention
Assignment
Participants will be randomized in a 1:1 ratio to receive pembrolizumab
plus gemcitabine/cisplatin (experimental arm) or placebo plus 
gemcitabine/cisplatin (control arm). This is a double-blind study. Study 
Intervention allocation/randomization will be stratified according to the 
following factors:

Geographic region (Region 1: Asia versus Region 2: Non-Asia)

Locally advanced versus metastatic

Site of Origin (gallbladder/intrahepatic/extrahepatic)
Analysis Populations
Efficacy: Intention to Treat (ITT)
Safety: All Participants as Treated (APaT)
Primary
Endpoint/Hypothesis
Overall survival (OS)
Statistical Methods for
Key Efficacy Analyses
The primary and secondary hypotheses will be evaluated by comparing
pembrolizumab plus gemcitabine/cisplatin to placebo plus 
gemcitabine/cisplatin in OS and PFS using stratified log-rank tests.
Estimation of the HR will be performed using a stratified Cox regression 
model. Event rates over time will be estimated within each treatment group
using the Kaplan-Meier method. The stratified Miettinen and Nurminen
method [Miettinen, O. and Nurminen, M. 1985] with strata weighted by 
sample size will be used for analysis of ORR. 
Statistical Methods for
Key Safety Analyses
For analyses in which 95% CIs 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.
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Interim Analyses
Two interim analyses are planned in this study. Results will be reviewed 
by an external data monitoring committee. Details are provided in Section 
9.7.

Interim Analysis 1 (IA1)
o
Timing: To be performed when ~585 OS events have been 
observed and ~26 months passed since the start of 
randomization.
o
Primary purpose: Interim analysis for OS and final 
analyses for PFS and ORR.

Interim Analysis 2 (IA2)
o
Timing: To be performed when ~695 OS events have been 
observed and ~32 months passed since the start of 
randomization.
o
Primary purpose: Interim analysis for OS.

Final Analysis
o
Timing: To be performed when ~818 OS events have been 
observed and ~38 months passed since the start of 
randomization
o
Primary purpose: Final analysis for OS
Multiplicity
The overall Type I error over the primary and secondary hypotheses is 
strongly controlled at 2.5% (1-sided), with 2.5% initially allocated to OS
(H1). By using the graphical approach of Mauer and Bretz [Maurer, W., et al 
2011], if one null hypothesis is rejected, the alpha will be shifted to other 
hypotheses. The alpha value will be passed for testing PFS and ORR if the 
OS null hypothesis is rejected.
Sample Size and Power
The planned sample size was 1048 participants, but the updated power 
calculations are based on 1069 participants, which is the actual final number 
of randomized participants. It is estimated that there will be ~818 deaths at
the OS final analysis. With 818 deaths, the study has ~93% power to reject 
the null OS hypothesis under the alternative hypothesis (HR=1 for the first 2 
months from randomization followed by HR=0.75 after 2 months) at an 
initially assigned 2.5% (1-sided) significance level. 
China Extension (if
applicable)
China participants randomized during the global portion will be included in 
all global portion analyses (efficacy and safety). China participants 
randomized during the China extension portion will be excluded from all 
global portion analyses. China participants randomized during global and 
extension portion will both be included in the China-specific analyses.
9.2
Responsibility for Analyses/In-house Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
This study will be conducted as a double-blind study under in-house blinding procedures. 
The official, final database will not be unblinded until medical/scientific review has been 
performed, protocol deviations have been identified, and data have been declared final and 
complete.
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The Clinical Biostatistics department will generate the randomized allocation schedule(s) for 
study intervention assignment for this protocol, and the randomization will be implemented 
in an interactive voice response system.
The investigator and Sponsor study team (clinical, statistical, statistical programming and 
data management personnel) will be blinded to participant level PD-L1 biomarker results.
PD-L1 biomarker results will not be shared with the site staff or participants. An unblinded 
Sponsor clinical scientist, statistician, and statistical programmer will have access to 
participant level PD-L1 results for the purpose of data review and will have no other 
responsibilities associated with the study. A summary of PD-L1 biomarker prevalence may 
be provided to the Sponsor study team by the unblinded designated Sponsor statistician.
Further documentation will be provided in the sSAP. In addition, imaging will be performed 
by BICR without knowledge of treatment assignments or PD-L1 status.
Blinding procedures related to the planned IAs are described in Section 9.7. Blinding to 
treatment will be maintained at all investigational sites. Analyses or summaries generated by 
randomized treatment assignment or actual treatment received at the planned IAs will be 
provided by the external unblinded statistician to the DMC.
Extension Study in China (if applicable)
For all participants in China, including participants randomized in the global portion and the 
extension portion, participant level treatment information will be blinded to the 
statistician(s)/programmer(s) responsible for the China extension portion analysis until the 
extension portion database lock is achieved. The extent to which individuals are unblinded to 
the results will be limited. Blinded and unblinded individuals will be clearly documented.
9.3
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.
9.4
Analysis Endpoints
9.4.1
Efficacy Endpoints
Primary

Overall Survival (OS)
OS is defined as the time from randomization to death due to any cause.
Secondary

Progression-free survival (PFS)
PFS is defined as the time from randomization to the first documented PD per RECIST 
1.1 by BICR, or death due to any cause, whichever occurs first. 
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
Objective Response Rate (ORR)
The ORR is defined as the percentage of participants who achieve a confirmed CR or PR 
per RECIST 1.1 as assessed by BICR.

Duration of Response (DOR)
For participants who demonstrate confirmed CR or PR per RECIST 1.1 as assessed by 
BICR, duration of response is defined as the time from the first documented evidence of 
CR or PR until disease progression or death due to any cause, whichever occurs first.
9.4.2
Safety Endpoints
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, SAEs, fatal AEs, laboratory tests, and vital signs. Furthermore, specific events will be 
collected and designated as ECIs, as described in Section 8.4.7.
9.4.3
Patient-Reported Outcome Endpoints
The following exploratory PRO endpoints will be evaluated, as described in Section 3:

Change in patient-reported outcomes from baseline in EORTC QLQ-C30 and 
EORTC QLQ- BIL21 global health status/QOL score

Time to deterioration (TTD) in EORTC QLQ-C30 and EORTC QLQ-BIL21 global 
health status/QOL score
TTD is defined as the time from baseline to the first onset of PRO deterioration. PRO 
deterioration is defined as a PRO score decrease of 10 points or more (out of 100), with 
subsequent confirmation [Osoba, D., et al 1998]. Details will be provided in the sSAP.
9.5
Analysis Populations
Extension Portion of the Study in China (if applicable)
After the sample size required for the global portion is reached, the study may continue to 
randomize participants in China alone until the sample size for China participants reaches the 
target number of participants. The China participants randomized after the enrollment of the 
global portion is closed will not be included in the global portion primary analysis 
population. The ITT participants in China, including all participants in China randomized in 
the global portion and the extension portion, will be analyzed for China-specific analysis.
9.5.1
Efficacy Analysis Populations
The analyses of efficacy endpoints other than DOR are based on the intention to treat (ITT) 
population. All randomized participants will be included in this population. Participants will 
be analyzed in the treatment group to which they are randomized. The DOR analysis will be 
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based on the population of responders (participants that achieved complete or partial 
response). The reasons for exclusion from the ITT population (if any) will be summarized.
9.5.2
Safety Analysis Populations
Safety Analyses will be conducted in the All Participants as Treated (APaT) population, 
which consists of all randomized participants who received at least 1 dose of study 
intervention. Participants will be included in the treatment group corresponding to the study 
intervention they actually received for the analysis of safety data using the APaT population. 
This will be the treatment group to which they are randomized except for participants who 
take incorrect study intervention for the entire intervention period; such participants will be 
included in the treatment group corresponding to the study intervention actually received.
Any participant who receives the incorrect study medication for 1 cycle, but receives the 
correct study intervention 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 1 laboratory or vital sign measurement obtained after at least 1 dose of study 
intervention is required for inclusion in the analysis of each specific parameter. To assess 
change from baseline, a baseline measurement is also required.
9.5.3
PRO Analysis Populations
The analyses of PRO endpoints will be based on a quality of life-related full analysis set 
(FAS) population following ICH E9 guidelines. This population consists of all randomized 
participants who have received at least 1 dose of study intervention and have completed at 
least 1 PRO assessment for the specific endpoint. Participants will be analyzed in the 
treatment group to which they are randomized.
9.6
Statistical Methods
9.6.1
Statistical Methods for Efficacy Analyses
This section describes the statistical methods that address the primary and secondary efficacy 
objectives. Methods related to exploratory objectives will be described in the sSAP. Efficacy 
results that will be deemed to be statistically significant after consideration of the Type I 
error control strategy are described in Section 9.8. Nominal p-values will be computed for 
other efficacy analyses but should be interpreted with caution due to potential issues of 
multiplicity. The 3 stratification factors used for randomization; geographic region (Region 
1: Asia versus Region 2: Non-Asia), locally advanced versus metastatic, and site of origin 
(gallbladder/intrahepatic/extrahepatic) will be applied to all stratified efficacy analyses (in 
particular, the stratified log-rank test, stratified Cox model, and stratified Miettinen and 
Nurminen method [Miettinen, O. and Nurminen, M. 1985]). The analysis stratification will 
be based on the value of the randomization factor entered into the IVRS. If required, some of 
the small strata among the 12 strata formed by the 3 factors might be pooled for analyses; the 
pooling strategy will be documented in the sSAP prior to the database lock for the first 
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interim analysis. Decisions regarding the pooling will be based on a blinded review of 
response and event counts by stratum.
The efficacy analyses for ORR, DOR and PFS will include responses and documented 
progression events that occur before the Second Course treatment.
9.6.1.1
Overall Survival
The nonparametric Kaplan-Meier method will be used to estimate the survival curves. The 
hypotheses of treatment difference in survival will be tested by the stratified log-rank test. A 
stratified Cox proportional hazard model with Efron’s method of tie handling will be used to 
estimate the magnitude of the treatment difference (ie, the HR). The HR and its 95% CI from 
the stratified Cox model with a single treatment covariate will be reported. With a piecewise
constant HR (as is the case with the delayed effect working model), the HR estimate from the 
Cox model is approximately equal on the log scale to the average of the HRs in each period 
weighted proportionally to the number of events in the period. The stratification factors used 
for randomization (Section 6.3.2) will be applied to both the stratified log-rank test and the 
stratified Cox model. Participants without documented death at the time of analysis will be 
censored at the date of last known contact.
9.6.1.2
Progression-free Survival
The nonparametric Kaplan-Meier method will be used to estimate the PFS curve in each 
treatment arm. The hypotheses of treatment difference in PFS will be tested by the stratified 
log-rank test. A stratified Cox proportional hazard model with Efron’s method of tie handling 
will be used to estimate the magnitude of the treatment effect (ie, 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 randomization (Section 6.3.2) will be applied to both the 
stratified log-rank test and the stratified Cox model.
Since disease progression is assessed periodically, progressive disease (PD) can occur any 
time in the time interval between the last assessment where PD was not documented and the 
assessment when PD is documented. The true date of disease progression will be 
approximated by the earlier of the date of the first assessment at which PD is objectively 
documented per RECIST 1.1 by BICR and the date of death. Additional analyses will be 
performed for comparison of PFS based on investigator’s assessment.
For the primary analysis, any participant who experiences an event (PD or death) 
immediately after 2 or more missed disease assessments will be censored at the last disease 
assessment prior to the missed visits. In addition, any participant who initiates new 
anticancer therapy prior to documented progression will be censored at the last disease 
assessment prior to the initiation of new anticancer therapy. Participants who do not start new 
anticancer therapy and who do not experience an event will be censored at the last disease 
assessment. If a participant meets multiple criteria for censoring, the censoring criterion that 
occurs earliest will be applied.
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In order to evaluate the robustness of the PFS endpoint per RECIST 1.1 by BICR, 
2 sensitivity analyses with different sets of censoring rules will be performed. The first 
sensitivity analysis follows the intention to treat principle. That is, PDs/deaths are counted as 
events regardless of missed study visits or initiation of new anticancer therapy. The second 
sensitivity analysis considers discontinuation of study intervention due to reasons other than 
complete response or initiation of new anticancer treatment, whichever occurs later, to be a 
PD event for participants without documented PD or death. If a participant meets multiple 
criteria for censoring, the censoring criterion that occurs earliest will be applied. The 
censoring rules for the primary and sensitivity analyses are summarized in Table 10.
Table 10
Censoring Rules for Primary and Sensitivity Analyses of PFS
Situation
Primary Analysis
Sensitivity Analysis 1
Sensitivity Analysis 2
PD or death documented 
after ≤1 missed disease 
assessment, and before 
new anticancer therapy, 
if any
Progressed at date of 
documented PD or death 
Progressed at date of 
documented PD or 
death
Progressed at date of 
documented PD or death
Death or progression 
immediately after 
≥2 consecutive missed 
disease assessments, or 
after new anticancer
therapy
Censored at last disease 
assessment prior to 
the earlier date of ≥2 
consecutive missed 
disease assessment and 
new anticancer therapy, 
if any
Progressed at date of 
documented PD or 
death
Progressed at date of 
documented PD or death
No PD and no death; and 
new anticancer treatment 
is not initiated
Censored at last disease 
assessment 
Censored at last 
disease assessment 
Progressed at treatment 
discontinuation due to 
reasons other than 
complete response; 
otherwise censored at last 
disease assessment if still 
on study treatment or 
completed study treatment.
No PD and no death; 
new anticancer treatment 
is initiated
Censored at last disease 
assessment before new 
anticancer treatment 
Censored at last 
disease assessment
Progressed at date of new 
anticancer treatment
Abbreviations: PD=progressive disease; PFS=progression-free survival.
9.6.1.3
Objective Response Rate
The Stratified Miettinen and Nurminen method [Miettinen, O. and Nurminen, M. 1985] with 
weights proportional to the stratum size will be used for comparison of the ORRs between 
the treatment arms. The same stratification factors used for randomization (Section 6.3.2) 
will be used as stratification factors in the analysis. A 95% CI for the difference in response 
rates between the treatment arms will be provided. Additional supportive unstratified 
analyses may also be provided. An additional analysis will be performed for the comparison 
of ORR based on the investigator’s assessment.
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The point estimate of ORR will be provided by treatment group, together with a 95% CI 
using the exact binomial method proposed by Clopper and Pearson (1934) [Clopper, C. J. 
1934].
9.6.1.4
Duration of Response
If sample size permits, DOR will be summarized descriptively using Kaplan-Meier medians 
and quartiles. Only the subset of participants who show a confirmed CR or PR will be 
included in this analysis.
Censoring rules for DOR are summarized in Table 11. For the DOR analysis, a 
corresponding summary of the reasons responding participants are censored will also be 
provided. Responding participants who are alive, have not progressed, have not initiated new 
anticancer treatment, have not been determined to be lost to follow-up, and have had a 
disease assessment within ~5 months of the data cutoff date are considered ongoing 
responders at the time of analysis. If a participant meets multiple criteria for censoring, the 
censoring criterion that occurs earliest will be applied.
Table 11
Censoring Rules for DOR
Situation
Date of Progression or Censoring
Outcome
No progression nor death, no new 
anticancer therapy initiated
Last adequate disease assessment
Censor
(non-event)
No progression nor death, new 
anticancer therapy initiated
Last adequate disease assessment 
before new anticancer therapy initiated
Censor
(non-event)
Death or progression immediately after 
≥2 consecutive missed disease 
assessments or after new anticancer
therapy, if any
Earlier date of last adequate disease 
assessment prior to ≥2 missed adequate 
disease assessments and new anticancer
therapy, if any
Censor
(non-event)
Death or progression after ≤1 missed 
disease assessments and before new 
anticancer therapy, if any
PD or death
End of response
(Event)
A missed disease assessment includes any assessment that is not obtained or is considered inadequate for 
evaluation of response.
Abbreviations: DOR=duration of response; PD=progressive disease.
9.6.1.5
Analysis Strategy for Key Efficacy Endpoints
A summary of the primary analysis strategy for the key efficacy endpoints is provided in
Table 12.
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Table 12
Analysis Strategy for Key Efficacy Endpoints
Endpoint/Variable
Statistical Method
Analysis 
Population
Missing 
Data
Approach
Primary Analyses
OS
Testing: Stratified Log-rank test 
Estimation: Stratified Cox model with 
Efron’s tie handling method
ITT
Censored at last 
known alive date
or data cutoff date, 
whichever is the 
earliest
Key Secondary Analyses
PFS per RECIST 1.1 by BICR
Testing: Stratified Log-rank test 
Estimation: Stratified Cox model with 
Efron’s tie handling method
ITT
Censored 
according to 
rules in Table 10
ORR per RECIST 1.1 by 
BICR
Testing and estimation:
stratified Miettinen and Nurminen method
[Miettinen, O. and Nurminen, M. 1985]
ITT
Participants with 
missing response 
data are 
considered non-
responders.
Abbreviations: BICR=blinded independent central review; ITT=intention to treat; ORR=objective 
response rate; OS=overall survival; PFS=progression-free survival; RECIST 1.1=Response Evaluation 
Criteria in Solid Tumors 1.1.
The strategy to address multiplicity issues with regard to multiple endpoints and interim 
analyses is described in Section 9.7 – Interim Analyses and Section 9.8 – Multiplicity.
9.6.2
Statistical Methods for Safety Analyses
The primary safety analyses will include only events that occur before the Second Course 
Treatment. Safety and tolerability will be assessed by clinical review of all relevant 
parameters, including AEs and laboratory tests.
The analysis of safety results will follow a tiered approach (Table 13). The tiers differ with 
respect to the analyses that will be performed. Adverse events (specific terms as well as 
system organ class terms) are either prespecified as “Tier 1” endpoints, or will be classified 
as belonging to “Tier 2” or “Tier 3” based on the number of events observed.
Tier 1 Events
AEs that are immune mediated or potentially immune mediated are well documented and 
will be evaluated separately; however, these events have been characterized consistently 
throughout the pembrolizumab clinical development program and determination of statistical 
significance is not expected to add value to the safety evaluation. Similarly, the combination 
of pembrolizumab and gemcitabine/cisplatin has not been associated with any new safety 
signals. Therefore, there are no Tier 1 events defined for this study.
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Tier 2 Events
Tier 2 parameters will be assessed via point estimates with 95% CIs provided for differences 
in the proportion of participants with events using the Miettinen and Nurminen (M&N) 
method [Miettinen, O. and Nurminen, M. 1985], an unconditional, asymptotic method.
Membership in Tier 2 requires that at least 10% of participants in any treatment group exhibit 
the event; all other adverse experiences will belong to Tier 3. The threshold of at least 10% 
of participants was chosen for Tier 2 event because the population enrolled in this study are 
in critical conditions and usually experience various AEs of similar types regardless of 
treatment; events reported less frequently than 10% of participants would obscure the 
assessment of overall safety profile and add little to the interpretation of potentially 
meaningful treatment differences. In addition, Grade 3 to 5 AE (≥5% of participants in one of 
the treatment groups) and SAE (≥5% of participants in one of the treatment groups) will be 
considered Tier 2 endpoints. Because many 95% CIs may be provided without adjustment for 
multiplicity, the CIs should be regarded as a helpful descriptive measure to be used in safety 
review, not a formal method for assessing the statistical significance of the between-group 
differences.
Tier 3 Events
Safety endpoints that are not Tier 1 or 2 events are considered Tier 3 events. Only point 
estimates by treatment group are provided for Tier 3 safety parameters.
Continuous Safety Measures
Continuous measures such as changes from baseline in laboratory parameters that are not 
prespecified 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.
Table 13
Analysis Strategy for Safety Parameters
Safety 
Tier
Safety Endpoint
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 2
Any AEs (≥10% of participants in one of the 
treatment groups)
X
X
Any Grade 3 to 5 AE (≥5% of participants in one 
of the treatment groups)
X
X
Any serious AE (≥5% of participants in one of the 
treatment groups)
X
X
Tier 3
Any AEs
X
Discontinuation due to AE
X
Change from baseline results (laboratory test 
toxicity grade)
X
Abbreviations: AE=adverse event; CI=confidence interval; X=results will be provided.
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9.6.3
Statistical Methods for Patient-reported Outcome Analyses
To evaluate the treatment effect on the health-related QOL outcomes at prespecified time 
points (provided in the sSAP), a constrained longitudinal data analysis (cLDA) model will be 
applied, with the PRO score as the response variable, and the treatment by time interaction 
and stratification factors as covariates. Least square mean (LS mean) change from baseline 
will be summarized. Groupwise comparisons will be performed and model-based LS mean 
score will be provided by treatment group and study visit.
Participants postbaseline EORTC QLQ-C30 scores will be classified as “improvement,” 
“stable,” or “deterioration” according to a predefined threshold (eg, 10-point or greater 
change from baseline). The number and proportion of participants with “improved,” “stable,” 
or “deteriorated” symptoms/scales will be summarized by treatment group.
Time to deterioration is defined as the time from the baseline PRO assessment to 
deterioration or death, whichever occurs first [Yang, J. C., et al 2013]. The Kaplan-Meier 
method will be used to estimate times to deterioration survival curve for each treatment arm.
Stratification factors used for allocation will be used in the stratified Cox proportional 
hazards models. The HR, 95% CI, and nominal p-value will be reported.
Details of PRO analyses will be described in the sSAP.
9.6.4
Statistical Methods for Pharmacokinetics (PK) Analyses
Plasma concentration versus time data will be pooled with data from existing studies and will 
be analyzed using a population PK approach to estimate population PK parameters. The 
detailed methods will be included in a separate analysis plan prior to the planned first interim 
efficacy analysis.
9.6.5
Summaries of Baseline Characteristics and Demographics
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 randomized and the primary 
reason for discontinuation will be displayed. Demographic variables (such as age), baseline 
characteristics, primary and secondary diagnoses, and prior and concomitant therapies will be 
summarized by treatment either by descriptive statistics or categorical tables.
9.7
Interim Analyses
9.7.1
Efficacy Interim Analyses
The eDMC will serve as the primary reviewer of the unblinded results of the efficacy and 
safety analyses and will make recommendations for discontinuation of the study or 
modification to an EOC (refer to Section 10.1.4.2) of the 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 
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study, the EOC and limited additional Sponsor personnel may be unblinded to results at the 
treatment level in order to act on these recommendations. Additional logistical details will be 
provided in the eDMC Charter.
Two interim analyses are planned in addition to the final analysis for this study. Results of 
the interim analyses will be reviewed by the eDMC. Details on the boundaries for 
establishing statistical significance with regard to efficacy are discussed further in Section 
9.8.
The analyses planned, endpoints evaluated, and drivers of timing are summarized in 
Table 14.
Table 14
Summary of Interim and Final Analyses Strategy
Analyses
Key Endpoints
Timing
Primary Purpose of Analysis
IA1
OS
~585 OS events have been 
observed and ~26 months passed 
since the start of randomization.

Interim OS analysis

Final PFS and ORR analyses 
if OS superiority is established
IA2
OS
~695 OS events have been 
observed and ~32 months passed 
since the start of randomization.

Interim OS analysis
FA
OS
~818 OS events have been 
observed and ~38 months passed 
since the start of randomization.
Final OS analysis
Abbreviations: FA=final analysis; IA1=interim analysis 1; IA2=interim analysis 2; OS=overall survival.
9.7.2
Safety Interim Analyses
The eDMC will conduct regular safety monitoring. The timing of the safety monitoring will 
be specified in the eDMC charter.
9.8
Multiplicity
The study uses the graphical method of Maurer and Bretz [Maurer, W., et al 2011] to control 
multiplicity for multiple hypotheses as well as interim analyses. According to this approach, 
study hypotheses may be tested more than once, and when a particular null hypothesis is 
rejected, the alpha allocated to that hypothesis can be reallocated to other hypotheses.
Figure 3 shows the initial one-sided α allocation for each hypothesis in the ellipse
representing the hypothesis. The weights for reallocation from each hypothesis to the others 
are represented in the boxes on the lines connecting hypotheses.
The initial α assigned to OS will be 0.025. If OS hypothesis is rejected, the corresponding 
alpha will be reallocated equally to PFS and ORR. If the PFS hypothesis is rejected, the 
corresponding alpha will be reallocated to ORR. If the ORR hypothesis is rejected, the 
corresponding alpha will be reallocated to PFS.
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Within each endpoint, the Type I error control across the interim and final analyses will be 
maintained by the use of the Lan-DeMets spending function approach with O’Brien-Fleming 
boundaries.
Figure 3
Multiplicity Diagram for Type I Error Control
Abbreviations: ORR=objective response rate; OS=overall survival; PFS=progression-free survival
9.8.1
Overall Survival
The initial α-level for testing OS is 0.025. Under the alternative hypothesis, the treatment 
effect will be delayed by 2 months, with OS HR=1 in the first 2 months, and HR=0.75 after 2 
months.CCI
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 At the time of an analysis, the 
observed number of events may differ substantially from the expected. To avoid 
overspending at an interim analysis and leave reasonable alpha for the FA, the minimum 
alpha spending strategy will be adopted. At an IA, the information fraction used in Lan-
DeMets spending function to determine the alpha spending at the IA will be based on the 
minimum of the expected information fraction and the actual information fraction at each 
analysis. Specifically,

In the scenario that the events accrue slower than expected and the observed number of 
events is less than the expected number of events at a given analysis, the information 
fraction will be calculated as the observed number of events at the IA over the target 
number of events at FA.

In the scenario that the events accrue faster than expected and the observed number of 
events exceeds the expected number of events at a given analysis, then the information 
CCI
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fraction will be calculated as the expected number of events at the IA over the target 
number of events at FA.
The FA will use the remaining Type I error that has not been spent at the earlier analyses. 
The event counts for all analyses will be used to compute the correlations.
Of note, while the information fraction used for alpha spending calculation will be the 
minimum of the actual information fraction and the expected information fraction, the 
correlations required for deriving the bounds will still be computed using the actual 
information fraction based on the observed number of events at each analysis over the target 
number of events at the FA.
The minimum spending approach assumes timing is not based on any observed Z-value and 
thus the Z test statistics used for testing conditioned on timing are multivariate normal. Given 
the probabilities derived with the proposed spending method, the correlations based on actual 
event counts are used to compute bounds that control the Type I error at the specified alpha 
level for a given hypothesis conditioned on the IA timing. Since this is true regardless of 
what is conditioned on, the overall Type I error for a given hypothesis unconditionally is 
controlled at the specified level. By using more conservative spending early in the study, 
power can be retained to detect situations where the treatment effect may be delayed.
9.8.2
Progression-free Survival
The PFS hypothesis is not allocated any α initially and can only be tested when the OS is 
successful. The study will test PFS at IA1 (final PFS analysis). The p-value based on PFS 
data observed at IA1 will be calculated and compared to its corresponding p-value bound 
when OS demonstrates superiority and α for PFS test becomes available (which might 
happen at OS IA1, IA2 or FA). A descriptive analysis of PFS may also be provided at the
IA2 or FA data cutoff when superiority in OS is demonstrated.
Following the multiplicity strategy as outlined in Figure 3, the PFS hypothesis may be tested 
at α=0.0125 (if the OS null hypothesis is rejected), or at α=0.025 (if both the OS and ORR 
null hypotheses are rejected). Under the alternative, the treatment effect will be delayed by 2 
months, with PFS HR=1 in the first 2 months, and HR=0.7 after 2 months. Table 16 shows 
the boundary properties and power for each of these α levels for the PFS analysis.
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Table 16
Efficacy Boundaries and Properties for Progression-free Survival Analyses
Analysis
Value
α = 0.0125
α = 0.025
IA1 (Final PFS analysis)
Z
2.2414
1.9600
N: 1069
p (1-sided)a
0.0125
0.0250
Events: 786
HR at boundb
0.8554
0.8695
Month: ~26
P(Cross) if HR = 1c
0.0125
0.0250
P(Cross) under the alternative hypothesisd,e
0.9176
0.9518
Abbreviations: HR=hazard ratio; IA1=interim analysis 1; PFS=progression-free survival.
The number of events is estimated.
a The nominal α for testing.
b The approximate HR required to reach an efficacy bound.
c P(Cross if HR = 1) is the probability of crossing a bound under the null hypothesis.
d The alternative hypothesis is HR=1 for the first 2 months and HR=0.7 after 2 months.
e P(Cross) under the alternative hypothesis is the probability of crossing a bound under the alternative 
hypothesis.
9.8.3
Objective Response
The ORR hypothesis is not allocated any α initially and can only be tested when the OS is 
successful. The study will test ORR at IA1 (final ORR analysis). The p-value based on ORR 
data observed at IA1 will be calculated and compared to its corresponding p-value bound 
when OS demonstrates superiority and α for ORR test becomes available (which might 
happen at OS IA1, IA2 or FA). A descriptive analysis of ORR may also be provided at the 
IA2 or FA data cutoff when superiority in OS is demonstrated.
Table 17 shows the boundary properties for 2 possible 1-sided α-levels as well as the 
approximate treatment difference required to reach the boundary (ORR difference) which 
were derived using a Lan-DeMets O’Brien-Fleming spending function. Note that the final 
row indicates the total power to reject the null hypothesis for ORR.
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Table 17
Efficacy Boundaries and Properties for Objective Response Analyses
Analysis
Value
α level=0.0125
α level=0.025
IA1
N: 1069
Z
2.2414
1.9600
p (1-sided) a
0.0125
0.0250
delta at bound b
0.0627
0.0548
P(Cross) if delta=0 c
0.0125
0.0250
P(Cross) if delta=0.1d
0.9088
0.9470
Abbreviations: IA1=interim analysis 1; ORR=objective response rate.
a The nominal α for testing.
b Delta at bound is the approximate delta required to reach an efficacy bound.
c P(Cross if delta=0) is the probability of crossing a bound under the null hypothesis, with an 
underlying ORR of 25% in both treatment groups.
d P(Cross if delta=0.1) is the probability of crossing a bound under the alternative hypothesis.
9.8.4
Safety Analyses
The DMC has responsibility for assessment of overall risk/benefit. When prompted by safety 
concerns, the DMC can request corresponding efficacy data. DMC review of efficacy data to 
assess the overall risk/benefit to study participants will not require a multiplicity adjustment 
typically associated with a planned efficacy interim analysis. However, to account for any 
multiplicity concerns raised by the DMC review of unplanned efficacy data prompted by 
safety concerns, a sensitivity analysis for OR, PFS, and OS adopting a conservative 
multiplicity adjustment will be prespecified in the sSAP.
9.9
Sample Size and Power Calculations
The study enrollment has been completed with 1069 participants randomized in a 1:1 ratio 
into the pembrolizumab plus gemcitabine/cisplatin or placebo plus gemcitabine/cisplatin
arms. OS is the sole primary endpoint for the study, with PFS and ORR as the key secondary 
endpoints.
CCI
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9.10
Subgroup Analyses
To determine whether the treatment effect is consistent across various subgroups, the 
between-group treatment effect for OS, PFS, and ORR (with a nominal 95% CI) will be 
estimated and plotted by treatment group within each category of the following classification 
variables:

Geographic region (Region 1: Asia versus Region 2: Non-Asia)

Locally advanced versus metastatic

Site of origin (gallbladder/intrahepatic/extrahepatic)

Age category (<65, ≥65 years)

Gender (female, male)

Biliary stent and or a biliary drain (yes, no)

Antibiotics within 1 month of study start (yes, no)

Prior therapy (radiation, chemotherapy, PDT)

Smoking status (never, former, current)

Microsatellite instability-high (MSI-H) (yes, no, indeterminate)

PD-L1 expression (CPS ≥1 versus <1)

PD-L1 expression (CPS≥10 versus <10)

ECOG performance status at randomization (0 vs. 1)
The consistency of the treatment effect will be assessed using descriptive statistics for each 
category of the subgroup variables listed above. If the number of participants in a category of 
a subgroup variable is less than 5% of the ITT population, the subgroup analysis will not be 
performed for this category of the subgroup variable, and this subgroup variable will not be 
displayed in the forest plot. The subgroup analyses for PFS and OS will be conducted using 
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an unstratified Cox model, and the subgroup analyses for ORR will be conducted using the
unstratified Miettinen and Nurminen method.
9.11
Compliance (Medication Adherence)
Drug accountability data for study intervention will be collected during the study. Any 
deviation from protocol-directed administration will be reported.
9.12
Extent of Exposure
Extent of exposure for a participant is defined as number of cycles in which the participant 
receives the study intervention. Summary statistics will be provided on extent of exposure for 
the APaT population.
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Code of Conduct for Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, 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 participants in clinical trials is the 
overriding concern in the design and conduct of clinical trials. In all cases, MSD clinical trials will be conducted 
in compliance with local and/or national regulations, and International Council for Harmonisation Good Clinical 
Practice (ICH-GCP), and also in accordance with the ethical principles that have their origin in the Declaration of 
Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD 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 that are observational in nature, or 
which are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the 
full control of MSD.
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 MSD or comparator products. Alternatively, MSD
may conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to 
determine patient preferences, etc.
The design (i.e., participant population, duration, statistical power) must be adequate to address the specific
purpose of the trial. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
MSD selects investigative sites based on medical expertise, access to appropriate participants, adequacy of 
facilities and staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial 
initiation, sites are evaluated by MSD personnel (or individuals acting on behalf of MSD) to assess the ability 
to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and Good Clinical Practice
(GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data are verified versus 
source documentation according to standard operating procedures. Per MSD policies and procedures, if fraud, 
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scientific/research misconduct or serious GCP-non-compliance is suspected, the issues are investigated. 
When necessary, the clinical site will be closed, the responsible regulatory authorities and ethics review 
committees notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the pre-specified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important 
to patients, physicians, and payers. 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 such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). 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. MSD funding of a trial will be acknowledged in 
publications.
III. Participant Protection
A. Regulatory Authority and Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics 
Committee [IEC])
All protocols and protocol amendments will be submitted by MSD for regulatory authority 
acceptance/authorization prior to implementation of the trial or amendment, in compliance with local and/or 
national regulations.
The protocol, protocol amendment(s), informed consent form, investigator’s brochure, and other relevant trial 
documents must be reviewed and approved by an IRB/IEC before being implemented at each site, in compliance 
with local and/or national regulations. Changes to the protocol that are required urgently to eliminate an 
immediate hazard and to protect participant safety may be enacted in anticipation of ethics committee approval.  
MSD will inform regulatory authorities of such new measures to protect participant safety, in compliance with 
local and/or national regulations.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance. 
Potential participants 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.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Participants may withdraw from an MSD 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
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible. Unless required by 
law, only the investigator, Sponsor (or individuals acting on behalf of MSD), ethics committee, and/or regulatory 
authorities will have access to confidential medical records that might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
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IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD does not pay incentives to 
enroll participants in its trials. However, when enrollment is particularly challenging, additional payments may be 
made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent 
on chart review and medical evaluation to identify potentially eligible participants.
B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may 
wish to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD 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.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
10.1.2
Financial Disclosure
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required. It is the investigator's/subinvestigator's 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
10.1.3
Data Protection
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information that would make the participant identifiable will not be transferred.
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The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
10.1.3.1
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 IRB, IEC, 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 study will be 
considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol.
10.1.3.2
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF data. By signing the consent form, the participant agrees to this 
process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant 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 participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules 
and regulations.
10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
10.1.4
Committees Structure
10.1.4.1
Scientific Advisory Committee (SAC)
This study was developed in collaboration with a SAC. The SAC is comprised of both 
Sponsor and non-Sponsor scientific experts who provide input with respect to study design, 
interpretation of study results, and subsequent peer-reviewed scientific publications.
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10.1.4.2
Executive Oversight Committee
The EOC is comprised of members of Sponsor Senior Management. The EOC will receive 
and decide upon any recommendations made by the eDMC regarding the study.
10.1.4.3
External Data Monitoring Committee
To supplement the routine study monitoring outlined in this protocol, an external DMC will 
monitor the interim data from this study. The voting members of the committee are external 
to the Sponsor. The members of the DMC must not be involved with the study in any other 
way (eg, they cannot be study investigators) and must have no competing interests that could 
affect their roles with respect to the study.
The DMC will make recommendations to the EOC regarding steps to ensure both participant 
safety and the continued ethical integrity of the study. Also, the DMC will review interim 
study results, consider the overall risk and benefit to study participants (Section 9.7 – Interim 
Analysis) and recommend to the EOC whether the study 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 study governance structure; and requirements for and proper documentation 
of DMC reports, minutes, and recommendations will be described in the DMC charter that is 
reviewed and approved by all the DMC members.
10.1.5
Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments.
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
10.1.6
Compliance with Study 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 study is solely responsible for determining whether the study and its results are subject
to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries. MSD, as Sponsor of this study, will 
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review this protocol and submit the information necessary to fulfill these requirements. MSD 
entries are not limited to FDAAA or the EMA clinical trial directive mandated trials. 
Information posted will allow participants to identify potentially appropriate studies for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate study locations and study 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 study or its results to those 
registries.
10.1.7
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of GCP
(eg, International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals for Human Use GCP: Consolidated Guideline and other generally 
accepted standards of GCP); and all applicable federal, state and local laws, rules and 
regulations relating to the conduct of the clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Studies.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority. 
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
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10.1.8
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including participants’ documented informed consent, pertaining to 
the conduct of this study must be retained by the investigator for 15 years after study 
completion unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor.
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10.1.9
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
of the site’s participants. Source documents and data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained if necessary (eg, via 
an audit trail). Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.
10.1.10
Study and Site Closure
The Sponsor or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor or 
designee will promptly notify that study site’s IRB/IEC as specified by applicable regulatory 
requirement(s).
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10.2
Appendix 2: Clinical Laboratory Tests
•
The tests detailed in Table 18 will be performed by the local laboratory with the 
exception of hepatitis testing, which will be performed by the central laboratory.
•
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5.1 and Section 5.2 of the protocol.
•
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations.
Table 18
Protocol-required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count 
WBC count with Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Chemistry
Blood Urea 
Nitrogen 
(BUN)a
Potassium
Aspartate 
Aminotransferase
(AST)/ Serum Glutamic
Oxaloacetic 
Transaminase (SGOT)
Total bilirubin (and 
direct bilirubin, if 
total bilirubin is 
elevated above the 
upper limit of 
normal)
Albumin
Carbon Dioxide (CO2) 
or Bicarbonateb
Chloride
Phosphorous
Creatininec
Sodium
Alanine 
Aminotransferase
(ALT)/ Serum Glutamic
Pyruvic Transaminase 
(SGPT)
Total Protein
Glucose 
Calcium
Alkaline phosphatase
Magnesium
Uric acid
Lactic Acid 
Dehydrogenase (LDH)
Routine 
Urinalysis
•
Specific gravity
•
pH, glucose, protein, blood, ketones by dipstick
•
Microscopic examination (if blood or protein is abnormal)
Other Tests
•
Follicle stimulating hormone (as needed in women of nonchildbearing potential only)
•
Serum or urine β human chorionic gonadotropin (β hCG) pregnancy test (as needed for 
WOCBP
•
Serology: Anti- HCV, HCV viral load, HBsAg, Anti-HBc (total and IgM), and HBV 
viral load, per local guidelines. See Appendix 7 for Country-Specific Requirements e
•
Serology HIV antibody (if required by local regulation)
•
Coagulation panel (PT/INR, aPTT) f
•
Thyroid function tests (T3 [or free T3d], free T4, and TSH)
•
Tuberculosis, if applicable (refer to Section 10.7 [Appendix 7] for country-specific 
requirements)
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Laboratory 
Assessments
Parameters
Abbreviations: ALT=alanine aminotransferase; Anti-HBc = hepatitis B core antibody; Anti-HCV= hepatitis 
C virus antibody; aPTT=activated partial thromboplastin time; AST=aspartate aminotransferase; BUN=blood 
urea nitrogen; HBsAg=hepatitis B surface antigen; HBV = hepatitis B virus; HCV = hepatitis C virus;
HIV=human immunodeficiency virus; INR=International Normalized Ratio; PT=prothrombin time; 
RBC=red blood cell; RNA=ribonucleic acid; SGOT=serum glutamic oxaloacetic transaminase; SGPT=serum 
glutamic pyruvic transaminase; T3=triiodothyronine; T4=thyroxine; TSH=thyroid-stimulating hormone; 
WBC=white blood cell; WOCBP=women of childbearing potential
a.
Urea is acceptable if BUN is not available as per institutional standard.
b.
If the test is considered part of standard of care.
c.
Creatinine clearance can be used in place of creatinine (see Appendix 10 for calculation using Cockcroft 
and Gault Formula).
d.
T3 is preferred over free T3. If not available, free T3 may be tested.
e.
All study-required laboratory assessments will be performed by a local laboratory, with the exception of 
hepatitis testing (anti- HCV, HCV viral load, HCV genotype, HBsAg, Anti-HBc [total and IgM], and 
HBV viral load,) which will be performed centrally or locally as indicated in the protocol.
f.
PT/INR should be tested as needed for participants on warfarin-based anticoagulation therapy.
The investigator (or medically qualified designee) must document their review of each 
laboratory safety report.
Laboratory/analyte results that could unblind the study will not be reported to investigative 
sites or other blinded personnel until the study has been unblinded.
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definition of AE
AE definition
•
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.
•
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.
•
NOTE: For purposes of AE definition, study intervention (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, diagnostic 
agent, or protocol specified procedure whether investigational or marketed (including 
placebo, active comparator product, or run-in intervention), manufactured by, licensed 
by, provided by, or distributed by the Sponsor for human use in this study.
Events meeting the AE definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.
•
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.
•
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.
•
For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”
•
Any new cancer (that is not a condition of the study). Progression of the cancer under 
study is not a reportable event. Refer to Section 8.4.6 for additional details.
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Events NOT meeting the AE definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
•
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
•
Surgery planned prior to informed consent to treat a pre-existing condition that has not 
worsened.
•
Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.2
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b. Is life-threatening
•
The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing 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 an SAE.) A pre-existing condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
d. Results in persistent or significant disability/incapacity
•
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
•
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
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and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
•
In offspring of participant taking the product regardless of time to diagnosis.
f.
Other important medical events
•
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.
•
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.3.3
Additional Events Reported in the Same Manner as SAE
Additional events that require reporting in the same manner as SAE
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor in the same time frame 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
10.3.4
Recording AE and SAE
AE and SAE recording
•
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.
•
The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.
•
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
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•
There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.
•
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity/toxicity
•
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
•
The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) according to the NCI Common Terminology for Adverse Events 
(CTCAE), version 5.0. Any AE that changes CTCAE grade over the course of a given 
episode will have each change of grade recorded on the AE CRFs/worksheets.
-
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated.
-
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (ADL).
-
Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care ADL.
-
Grade 4: Life threatening consequences; urgent intervention indicated.
-
Grade 5: Death related to AE.
Assessment of causality
•
Did the Sponsor’s product cause the AE?
•
The determination of the likelihood that the Sponsor’s product caused the AE 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 product and the AE 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 
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their respective elements (in number and/or intensity), the more likely the Sponsor’s 
product caused the AE:
-
Exposure: Is there evidence that the participant 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 studies 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.
-
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; (3) the study is a single-dose drug study; or (4) Sponsor’s product(s) is/are 
only used 1 time.)
-
Rechallenge: Was the participant 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 study is a single-dose drug study; or (3) Sponsor’s 
product(s) is/are used only 1 time.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE SPONSOR’S PRODUCT, OR IF RE-EXPOSURE 
TO THE SPONSOR’S PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR AS PER DOSE 
MODIFICATION GUIDELINES IN THE PROTOCOL, AND IF REQUIRED, THE 
INIRB/IEC.
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•
Consistency with study intervention 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.
•
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:
◦
Participant 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 participant with overdose without an associated AE.)
•
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.
•
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.
•
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.
•
For studies in which multiple agents are administered as part of a combination regimen, 
the investigator may attribute each AE causality to the combination regimen or to a single 
agent of the combination. In general, causality attribution should be assigned to the 
combination regimen (ie, to all agents in the regimen). However, causality attribution 
may be assigned to a single agent if in the investigator’s opinion, there is sufficient data 
to support full attribution of the AE to the single agent.
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Follow-up of AE and SAE
•
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
•
New or updated information will be recorded in the CRF.
•
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool
•
The primary mechanism for reporting to the Sponsor will be the electronic data collection 
(EDC) tool.
•
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
•
If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper AE Reporting form.
•
Reference Section 8.4.1 for reporting time requirements.
•
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
•
After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.
•
If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).
•
Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
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SAE reporting to the Sponsor via paper CRF
•
If the EDC tool is not operational, facsimile transmission or secure e-mail of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.
•
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
•
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
•
Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
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10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation
Not applicable.
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10.5
Appendix 5: Contraceptive Guidance
10.5.1
Definitions
Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below):
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
•
Premenarchal
•
Premenopausal female with 1 of the following:
-
Documented hysterectomy
-
Documented bilateral salpingectomy
-
Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
•
Postmenopausal female
-
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
◦
A high follicle stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormone replacement therapy (HRT). However, in the absence 
of 12 months of amenorrhea, confirmation with two FSH measurements in the 
postmenopausal range is required.
-
Females on HRT and whose menopausal status is in doubt will be required to use one 
of the nonhormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
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10.5.2
Contraception Requirements
•
Contraceptives allowed during the study includea:
Highly Effective Contraceptive Methods That Have Low User Dependency
Failure rate of <1% per year when used consistently and correctly.
•
Progestogen-only subdermal contraceptive implantb,c
•
Intrauterine hormone-releasing system (IUS)c
•
Intrauterine device (IUD)
•
Bilateral tubal occlusion
•
Azoospermic partner (vasectomized or secondary to medical cause)
This is a highly effective contraception method provided that the partner is the sole male sexual partner 
of the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective 
method of contraception should be used. A spermatogenesis cycle is approximately 90 days.
Note: Documentation of azoospermia can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
Sexual Abstinence
•
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study intervention. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the 
preferred and usual lifestyle of the participant.
a.
Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for participants of clinical studies.
b.
If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable 
contraceptive implants are limited to those which inhibit ovulation
c.
IUS is a progestin releasing IUD.
Note: The following are not acceptable methods of contraception:
-
Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhea method (LAM).
-
Male condom with cap, diaphragm, or sponge with spermicide.
-
Male and female condom should not be used together (due to risk of failure with friction).
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
1. Definitions
a. Biomarker: A biological molecule found in blood, other body fluids, or tissues that is
a sign of a normal or abnormal process or of a condition or disease. A biomarker may
be used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics: The investigation of variations of DNA and RNA characteristics 
as related to drug/vaccine response.2
c. Pharmacogenetics: A subset of pharmacogenomics, pharmacogenetics is the influence 
of variations in DNA sequence on drug/vaccine response.2
d. DNA: Deoxyribonucleic acid.
e. RNA: Ribonucleic acid.
2. Scope of Future Biomedical Research
The specimens consented and/or collected in this study as outlined in Section 8.8 will be 
used in various experiments to understand:




The specimen(s) may be used for 
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need. All specimens will be used by the Sponsor or those working for or 
with the Sponsor.
3. Summary of Procedures for Future Biomedical Research.
a. Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in 
future biomedical research
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b. Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all participants or legal guardians, at a 
study visit by the investigator or his or her designate. Informed consent for future 
biomedical research should be presented to the participants on the visit designated in 
the SoA. If delayed, present consent at next possible Participant Visit. Consent forms 
signed by the participant will be kept at the clinical study site under secure storage for 
regulatory reasons.
A template of each study site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.
c. eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for future biomedical research will be captured 
in the eCRFs. Any specimens for which such an informed consent cannot be verified 
will be destroyed.
d. Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as outlined 
in the SoA. In general, if additional blood specimens are being collected for future 
biomedical research, these will usually be obtained at a time when the participant is 
having blood drawn for other study purposes.
4. Confidential Participant 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 participant’s clinical information with future test results. In 
fact little or no research can be conducted without connecting the clinical study data to 
the specimen. The clinical data allow specific analyses to be conducted. Knowing 
participant characteristics like gender, age, medical history and intervention outcomes are 
critical to understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for future 
biomedical research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below.
At the clinical study site, unique codes will be placed on the future biomedical research 
specimens. This code is a random number which does not contain any personally 
identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers will 
appear on the specimen tube.
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5. Biorepository Specimen Usage
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses utilizing the future biomedical research specimens may be performed 
by the Sponsor, or an additional third party (eg, a university investigator) designated by 
the Sponsor. The investigator conducting the analysis will follow the Sponsor’s privacy 
and confidentiality requirements. Any contracted third party analyses will conform to the 
specific scope of analysis outlined in future biomedical research protocol and consent. 
Future biomedical research specimens remaining with the third party after specific 
analysis is performed will be reported to the Sponsor.
6. Withdrawal From Future Biomedical Research
Participants may withdraw their consent for future biomedical research and ask that their 
biospecimens not be used for future biomedical research. Participants may withdraw 
consent at any time by contacting the investigator for the main study. If medical records 
for the main study are still available, the investigator will contact the Sponsor using the 
designated mailbox (clinical.specimen.management@MSD.com). Subsequently, the 
participant’s specimens will be flagged in the biorepository and restricted to main study 
use only. If specimens were collected from study participants specifically for future 
biomedical research, these specimens will be removed from the biorepository and 
destroyed. Documentation will be sent to the investigator confirming withdrawal and/or 
destruction, if applicable. It is the responsibility of the investigator to inform the 
participant of completion of the withdrawal and/or destruction, if applicable. Any 
analyses in progress at the time of request for withdrawal/destruction or already 
performed prior to the request being received by the Sponsor will continue to be used as 
part of the overall research study data and results. No new analyses would be generated 
after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the participant’s personal information and their specimens. In this situation, 
the request for withdrawal of consent and/or destruction cannot be processed.
7. Retention of Specimens
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being 
answered. In this special circumstance, specimens will be stored until these questions 
have been adequately addressed.
Specimens from the study site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
study, the study site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility which 
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operates to assure the integrity of the specimens. Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated study administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Participants
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include: Lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and participants. Participants will not be 
identified by name in any published reports about this study or in any other scientific 
publication or presentation.
10. Future Biomedical Research Study Population
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical studies for future biomedical research.
11. Risks Versus Benefits of Future Biomedical Research
For future biomedical research, risks to the participant have been minimized and are 
described in the future biomedical research informed consent.
The Sponsor has developed strict security, policies, and procedures to address participant 
data privacy concerns. Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality. In this highly unlikely situation, there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be emailed directly to 
clinical.specimen.management@MSD.com.
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13. References
1. National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2. International Conference on Harmonization [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample 
Coding Categories. Available from 
http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/definitions-
for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-genomic-data-and-
sample-cod.html 
3. Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, 
Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/ 
4. Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at 
http://i-pwg.org/
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10.7
Appendix 7: Country-specific Requirements
CCI
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CCI
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CCI
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10.8
Appendix 8: Description of the iRECIST Process for Assessment of Disease 
Progression
iRECIST is based on RECIST 1.1 but adapted to account for the unique tumor response seen 
with immunotherapeutic drugs. iRECIST will be used by the investigator to assess tumor 
response and progression, and to guide decisions about changes in management.
Assessment at screening and before RECIST 1.1 Progression
Until radiographic disease progression based on RECIST 1.1, there is no distinct iRECIST 
assessment.
Assessment and Decision at RECIST 1.1 Progression
For participants who show radiological disease progression by RECIST 1.1, the investigator 
will decide whether to continue a participant on study intervention until repeat scans 4 to 8 
weeks later are obtained, as described in Section 8.2.1.6.
Tumor flare may manifest as any factor causing radiographic progression per RECIST 1.1, 
including:
•
Increase in the sum of diameters of target lesion(s) identified at baseline to ≥20% and 
≥5 mm from nadir
Note: The iRECIST publication uses the terminology “sum of measurements,” but “sum 
of diameters” will be used in this protocol, consistent with the original RECIST 1.1 
terminology.
•
Unequivocal progression of nontarget lesion(s) identified at baseline
•
Development of new lesion(s)
iRECIST defines new response categories, including iUPD (unconfirmed progressive 
disease) and iCPD (confirmed progressive disease). For purposes of iRECIST assessment, 
the first visit showing progression according to RECIST 1.1 will be assigned a visit (overall) 
response of iUPD, regardless of which factors caused the progression.
At this visit, target and nontarget lesions identified at baseline by RECIST 1.1 will be 
assessed as usual.
New lesions will be classified as measurable or nonmeasurable, using the same size 
thresholds and rules as for baseline lesion assessment in RECIST 1.1. From measurable new 
lesions, up to 5 lesions total (up to 2 per organ), may be selected as New Lesions – Target. 
The sum of diameters of these lesions will be calculated, and kept distinct from the sum of 
diameters for target lesions at baseline. All other new lesions will be followed qualitatively 
as New Lesions – Non-target.
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Assessment at the Confirmatory Scans
On the confirmatory scans, the participant will be classified as progression confirmed (with 
an overall response of iCPD), or as showing persistent unconfirmed progression (with an 
overall response of iUPD), or as showing disease stability or response (iSD/iPR/iCR).
Confirmation of Progression
Progression is considered confirmed, and the overall response will be iCPD, if ANY of the 
following occurs:
•
Any of the factors that were the basis for the iUPD at the previous visit show worsening
-
For target lesions, worsening is a further increase in the sum of diameters of ≥5 mm, 
compared to any prior iUPD time point
-
For nontarget lesions, worsening is any significant growth in lesions overall, 
compared to a prior iUPD time point; this does not have to meet the “unequivocal” 
standard of RECIST 1.1
-
For new lesions, worsening is any of these:
◦
An increase in the new lesion sum of diameters by ≥5 mm from a prior iUPD time 
point
◦
Visible growth of new nontarget lesions
◦
The appearance of additional new lesions
•
Any new factor appears that would have triggered PD by RECIST 1.1
Persistent iUPD
Progression is considered not confirmed, and the overall response remains iUPD, if:
-
None of the progression-confirming factors identified above occurs AND
-
The target lesion sum of diameters (initial target lesions) remains above the initial PD 
threshold (by RECIST 1.1)
Additional scans for confirmation are to be scheduled 4 to 8 weeks from the scans on which 
iUPD is seen. This may correspond to the next visit in the original visit schedule. The 
assessment of the subsequent confirmation scan proceeds in an identical manner, with 
possible outcomes of iCPD, iUPD, and iSD/iPR/iCR.
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Resolution of iUPD
Progression is considered not confirmed, and the overall response becomes iSD/iPR/iCR, if:
-
None of the progression-confirming factors identified above occurs, AND
-
The target lesion sum of diameters (initial target lesions) is not above the PD 
threshold.
The response is classified as iSD or iPR (depending on the sum of diameters of the target 
lesions), or iCR if all lesions resolve.
In this case, the initial iUPD is considered to be pseudo-progression, and the level of 
suspicion for progression is “reset.” This means that the next visit that shows radiographic 
progression, whenever it occurs, is again classified as iUPD by iRECIST, and the 
confirmation process is repeated before a response of iCPD can be assigned.
Management Following the Confirmatory Scan
If repeat scans do not confirm PD and the participant continues to be clinically stable, study 
intervention is to continue, the regular imaging schedule is followed. If PD is confirmed, 
participants may be discontinued from study intervention.
NOTE: If a participant has confirmed radiographic progression (iCPD) and clinically 
meaningful benefit, study intervention may be continued after consultation with the Sponsor. 
If study intervention is continued, tumor scans are to be performed following the intervals as 
outlined in Section 1.3.
Detection of Progression at Visits After Pseudo-progression Resolves
After resolution of pseudo-progression (ie, after iSD/iPR/iCR), iUPD is indicated by any of 
the following events:
Target lesions
- Sum of diameters reaches the PD threshold (≥20% and ≥5 mm increase from nadir) 
either for the first time, or after resolution of previous pseudo-progression. The nadir is 
always the smallest sum of diameters seen during the entire study, either before or 
after an instance of pseudo-progression.
Nontarget lesions
- If nontarget lesions have never shown unequivocal progression, their doing so for the 
first time results in iUPD.
- If nontarget lesions have shown previous unequivocal progression, and this 
progression has not resolved, iUPD results from any significant further growth of non-
target lesions, taken as a whole.
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New lesions
- New lesions appear for the first time
- Additional new lesions appear
- Previously identified new target lesions show an increase of ≥5 mm in the new lesion 
sum of diameters, from the nadir value of that sum
- Previously identified non-target lesions show any significant growth
If any of the events above occur, the overall response for that visit is iUPD, and the iUPD 
evaluation process (see Assessment at the Confirmatory Scan above) is repeated. Progression 
must be confirmed before iCPD can occur.
The decision process on the subsequent iUPD is identical to the iUPD confirmation process 
for the initial disease progression, with one exception, which can occur if new lesions had 
occurred at a prior instance of iUPD, had not resolved, then worsened (increase in size or 
number) leading to the second iUPD. If new lesion worsening has not resolved at the 
confirmatory scan, then iUPD cannot resolve to iSD or iPR. It will remain iUPD until either a 
decrease in the new lesion burden allows resolution to iSD or iPR, or until new or worsening 
cause of progression indicates iCPD.
Additional details about iRECIST are provided in the iRECIST publication [Seymour, L., et 
al 2017].
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10.9
Appendix 9: ECOG Performance Status
Developed by the Eastern Cooperative Oncology Group, Robert L. Comis, MD, Group 
Chair.*
GRADE
ECOG PERFORMANCE STATUS
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, eg, light housework, office work
2
Ambulatory and capable of all selfcare but unable to carry out any work 
activities; up and about more than 50% of waking hours
3
Capable of only limited selfcare; confined to bed or chair more than 50% of 
waking hours
4
Completely disabled; cannot carry on any selfcare; totally confined to bed or 
chair
5
Dead
*Oken M, Creech R, Tormey D, et al. Toxicity and response criteria of the Eastern Cooperative 
Oncology Group. Am J Clin Oncol. 1982;5:649-655
http://ecog-acrin.org/resources/ecog performance status
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10.10 Appendix 10: Calculated Creatinine Clearance
Original, Weight-Based Cockcroft and Gault Formula for Calculated Creatinine
Clearance for Men
For serum creatinine concentration in mg/dL:
CrCl =
(mL/min)
(140 – agea) (wtb) 1.0 72
serum creatinine (mg/dL)
For serum creatinine concentration in mol/L:
CrCl =
(mL/min)
(140 – agea) (wtb) 1.0
0.81 serum creatinine (mol/L)
Abbreviations: CrCl=creatinine clearance; wt=weight
a.
Age in years.
b.
Weight (wt) in kilograms.
Source: Cockcroft and Gault 1976. [Cockcroft, D. W. and Gault, M. H. 1976].
Original, Weight-Based Cockcroft and Gault Formula for Calculated Creatinine
Clearance for Women
For serum creatinine concentration in mg/dL:
CrCl =
(mL/min)
(140 – agea) (wtb) 0.85
72 serum creatinine (mg/dL)
For serum creatinine concentration in mol/L:
CrCl =
(mL/min)
(140 – agea) (wtb) 0.85
0.81 serum creatinine (mol/L)
Abbreviations: CrCl=creatinine clearance; wt=weight
a.
Age in years.
b.
Weight (wt) in kilograms.
Source: Cockcroft and Gault 1976. [Cockcroft, D. W. and Gault, M. H. 1976].
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10.11 Appendix 11: Abbreviations
Abbreviation
Expanded Term
ADA
antidrug antibodies
ADL
activities of daily living 
AE
adverse event 
ALT
alanine aminotransferase
Anti-HBe
hepatitis B e antibody
Anti-HBs
hepatitis B surface antibody
Anti-HCV
hepatitis C antibody
APaT
All Participants as Treated
ASC
active symptom control
AST
aspartate aminotransferase
BCG
Bacillus Calmette Guérin
BICR
blinded independent central review(er)
BSA
body surface area
BTC
biliary tract cancer
C
cycle
CCA
cholangiocarcinoma
CD
cluster of differentiation
CDE
Center for Drug Evaluation
CI
confidence interval
CMV
cytomegalovirus
CNS
central nervous system 
CPS
combined positive score
CR
complete response
CrCl
creatinine clearance
CRF
Case Report Form 
CSR
Clinical Study Report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTFG
Clinical Trial Facilitation Group 
CTLA-4
cytotoxic T-lymphocyte-associated protein 4
D
day
D/C
discontinuation
DC
disease control
DCR
disease control rate
DILI
drug-induced liver injury
DMC
Data Monitoring Committee 
dMMR
mismatch repair deficient
DNA
deoxyribonucleic acid 
DOR
duration of response
EBV
Epstein-Barr virus
ECG
electrocardiogram 
ECI
event of clinical interest
ECOG
Eastern Cooperative Oncology Group;
eCRF
electronic Case Report Form
eCTA
exploratory Clinical Trial Application
EDC
electronic data collection 
eDMC
external Data Monitoring Committee
EDTA
ethylenediaminetetraacetic acid
EMA
European Medicines Agency
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Abbreviation
Expanded Term
EOC
Executive Oversight Committee 
EOI
end of intervention
EORTC
European Organisation for the Research and Treatment of Cancer
ePRO
electronic patient-reported outcome
EQ-5D-5L
European Quality of Life 5-dimension, 5-level Questionnaire
ESMO
European Society for Medical Oncology
FA
final analysis
FAS
full analysis set
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FFPE
formalin-fixed, paraffin-embedded
FOLFOX
folinic acid, fluorouracil, and oxaliplatin
FSH
follicle stimulating hormone 
FU
follow-up
GBC
gallbladder cancer
GCP
Good Clinical Practice 
Gem/cis
gemcitabine/cisplatin
GEMOX
gemcitabine with oxaliplatin
H
hypothesis
HBc
hepatitis B core antibody
HBeAg
hepatitis B early antigen
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCC
Hepatocellular cancer
HCV
hepatitis C virus
HECI
hepatic events of clinical interest
HGRAC
Human Genetics Resources Administration of China
HIV
human immunodeficiency virus
HR
hazard ratio
HRT
hormone replacement therapy
IA1
Interim analysis 1
IA2
Interim analysis 2
IB
Investigator’s Brochure 
ICF
Informed Consent Form 
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
iCPD
confirmed progressive disease per iRECIST
iCR
complete response per iRECIST
iCRO
imaging contract research organization
IDH1
isocitrate dehydrogenase 1
IEC
Independent Ethics Committee
Ig
immunoglobulin
IHC
immunohistochemistry
IMP
Investigational Medicinal Product
IND
Investigational New Drug 
INR
international normalized ratio
IO
immuno-oncology
iPR
partial response per iRECIST
irAE
Immune-related adverse event
IRB
Institutional Review Board 
iRECIST
Modified Response Evaluation Criteria in Solid Tumors 1.1 for immune-based 
therapeutics
0880QN


PRODUCT:  MK-3475  
186
PROTOCOL/AMENDMENT NO.:  966-06  
MK-3475-966-06 FINAL PROTOCOL
16-JUN-2022
Abbreviation
Expanded Term
IRT
interactive response technology
iSD
stable disease per iRECIST
ITT
intention to treat
IUD
intrauterine device
IUO
investigational use only
iUPD
unconfirmed progressive disease per iRECIST
IUS
intrauterine hormone-releasing system
IV
intravenous
IVRS
interactive voice response system
LDH
lactic acid dehydrogenase
LS
least squares
MASCC
Multinational Association of Supportive Care in Cancer
MMR
mismatch repair
M&N
Miettinen and Nurminen
MRI
magnetic resonance imaging
mRNA
messenger ribonucleic acid
MSI
microsatellite instability
MSI-H
microsatellite instability-high
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NIMP
Non-investigational Medicinal Product
NSCLC
non-small cell lung cancer
OR
objective response
ORR
objective response rate
OS
overall survival
PCR
polymerase chain reaction
PD
progressive disease
PD-1
programmed cell death 1
PD-L1
programmed cell death ligand 1
PD-L2
programmed cell death ligand 2
PDT
photodynamic therapy
PFS
progression-free survival
PK
pharmacokinetic
PO
per os (by mouth)
PR
partial response
PRO 
patient-reported outcomes
PS
performance score
Q3/6/12W
every 3/6/12 weeks
QLQ
quality of life questionnaire
QOL
quality of life
R2
macroscopic residual tumor
RECIST 1.1
Response Evaluation Criteria in Solid Tumors version 1.1
RNA
ribonucleic acid
S-1
oral fluoropyrimidine containing tegafur, gimeracil, and oteracil
SAC
Scientific Advisory Committee
SAE
serious adverse event 
SAP
statistical analysis plan
SD
stable disease
SIM
Site Imaging Manual
SmPC
Summary of Product Characteristics
SNP
single nucleotide polymorphism
SoA
schedule of activities
0880QN


PRODUCT:  MK-3475  
187
PROTOCOL/AMENDMENT NO.:  966-06  
MK-3475-966-06 FINAL PROTOCOL
16-JUN-2022
Abbreviation
Expanded Term
SOC
standard of care
sSAP
supplemental statistical analysis plan
SUSAR
suspected unexpected serious adverse reaction
TACE
transarterial chemoembolization
TARE
transarterial radioembolization
TB
tuberculosis
TILs
tumor-infiltrating lymphocytes
TSH
thyroid-stimulating hormone
TTD
time to deterioration
TTP
time-to-progression 
UK
United Kingdom
ULN
upper limit of normal
US
United States
WOCBP
woman/women of childbearing potential 
0880QN


PRODUCT:  MK-3475  
188
PROTOCOL/AMENDMENT NO.:  966-06  
MK-3475-966-06 FINAL PROTOCOL
16-JUN-2022
11
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0880QN


PRODUCT:  MK-3475  
191
PROTOCOL/AMENDMENT NO.:  966-06  
MK-3475-966-06 FINAL PROTOCOL
16-JUN-2022
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0880QN


PRODUCT:  MK-3475  
192
PROTOCOL/AMENDMENT NO.:  966-06  
MK-3475-966-06 FINAL PROTOCOL
16-JUN-2022
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0880QN


PRODUCT:  MK-3475  
193
PROTOCOL/AMENDMENT NO.:  966-06  
MK-3475-966-06 FINAL PROTOCOL
16-JUN-2022
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0880QN


PRODUCT:  MK-3475  
194
PROTOCOL/AMENDMENT NO.:  966-06  
MK-3475-966-06 FINAL PROTOCOL
16-JUN-2022
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0880QN


PRODUCT:  MK-3475  
195
PROTOCOL/AMENDMENT NO.:  966-06  
MK-3475-966-06 FINAL PROTOCOL
16-JUN-2022
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0880QN


PRODUCT:  MK-3475  
196
PROTOCOL/AMENDMENT NO.:  966-06  
MK-3475-966-06 FINAL PROTOCOL
16-JUN-2022
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PRODUCT:  MK-3475  
197
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MK-3475-966-06 FINAL PROTOCOL
16-JUN-2022
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0880QN


PRODUCT:  MK-3475  
198
PROTOCOL/AMENDMENT NO.:  966-06  
MK-3475-966-06 FINAL PROTOCOL
16-JUN-2022
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