Clinical trial NCT03062358
Conditions: Carcinoma, Hepatocellular
Keywords: Programmed Cell Death Receptor 1 (PD-1) Programmed Cell Death Receptor Ligand 1 (PD-L1) Programmed Cell Death Receptor Ligand 2 (PD-L2) PD1 PD-1 PDL1 PD-L1 PDL2
Sponsor: Merck Sharp & Dohme LLC
Start date: 2017-04-27; Completion date: 2024-10-15
Enrollment: 453 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine the efficacy and safety of pembrolizumab or placebo given with best supportive care (BSC) in Asian participants with previously systemically treated advanced hepatocellular carcinoma (HCC). The primary hypothesis of this study is that overall survival is prolonged in participants who receive pembrolizumab compared to those who receive placebo.

Detailed description:

Arms: arm 1: Participants receive pembrolizumab by intravenous (IV) infusion on Day 1 of each 3-week cycle for up to 35 cycles of treatment plus BSC. arm 2: Participants receive placebo by intravenous (IV) infusion on Day 1 of each 3-week cycle for up to 35 cycles of treatment plus BSC.
Interventions: intervention 1: pembrolizumab intervention 2: placebo intervention 3: best supportive care (BSC)
Intervention descriptions: intervention 1: Administered as an intravenous (IV) infusion every 3 weeks (Q3W) intervention 2: Normal saline solution administered as an IV infusion Q3W intervention 3: BSC will include pain management and management of other potential complications including ascites per local standards of care.

Protocol documents:
Prot_000.pdf: 
Official Protocol Title: 
NCT number: 
Document Date: 
A Phase III Randomized Double-blind Study of Pembrolizumab 
plus Best Supportive Care vs. Placebo plus Best Supportive Care 
as Second-Line Therapy in Asian Subjects with
Previously Systemically Treated Advanced Hepatocellular 
Carcinoma (KEYNOTE-394)
19-April-2021
NCT03062358


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THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., 
WHITEHOUSE STATION, NJ, U.S.A.
SPONSOR:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. 
(hereafter referred to as the Sponsor or Merck)
One Merck Drive
P.O. Box 100
Whitehouse Station, New Jersey, 08889-0100, U.S.A.
Protocol-specific Sponsor Contact information can be found in the Investigator Trial File 
Binder (or equivalent).
TITLE:
A Phase III Randomized Double-blind Study of Pembrolizumab plus Best Supportive Care 
vs. Placebo plus Best Supportive Care as Second-Line Therapy in Asian Subjects with 
Previously Systemically Treated Advanced Hepatocellular Carcinoma (KEYNOTE-394)
EudraCT NUMBER:  Not Applicable
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TABLE OF CONTENTS
DOCUMENT HISTORY ..................................................................................................... 11
SUMMARY OF CHANGES................................................................................................ 12
1.0
TRIAL SUMMARY.................................................................................................. 13
2.0
TRIAL DESIGN........................................................................................................ 14
Trial Design ........................................................................................................... 14
Trial Diagram........................................................................................................ 16
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 17
Primary Objective(s) & Hypothesis(es).............................................................. 17
Secondary Objective(s) & Hypothesis(es)........................................................... 17
Exploratory Objectives......................................................................................... 17
4.0
BACKGROUND & RATIONALE.......................................................................... 18
Background ........................................................................................................... 18
Pharmaceutical and Therapeutic Background .................................................... 19
Pre-clinical and Clinical Trials ........................................................................... 20
Ongoing Clinical Trials....................................................................................... 21
Information on Other Trial-Related Therapy...................................................... 21
Rationale................................................................................................................ 22
Rationale for the Trial and Selected Subject Population .................................... 22
Rationale for Dose Selection/Regimen/Modification......................................... 22
Rationale for the Use of Comparator/Placebo ............................................. 23
Rationale for Endpoints ...................................................................................... 24
Efficacy Endpoints....................................................................................... 24
4.2.3.1.1
Primary Efficacy Endpoints.................................................................. 24
4.2.3.1.2
Secondary Efficacy Endpoints.............................................................. 24
4.2.3.1.3
Exploratory Endpoints .......................................................................... 24
Immune-related RECIST (irRECIST) ......................................................... 25
Patient Reported Outcomes.......................................................................... 25
Medical Resource Utilization and Health Economics ................................. 26
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Safety Endpoints.......................................................................................... 26
Biomarker Research..................................................................................... 27
Future Biomedical Research........................................................................ 28
Benefit/Risk ........................................................................................................... 28
5.0
METHODOLOGY ................................................................................................... 29
Entry Criteria........................................................................................................ 29
Diagnosis/Condition for Entry into the Trial...................................................... 29
Subject Inclusion Criteria.................................................................................... 29
Subject Exclusion Criteria .................................................................................. 31
Trial Treatment(s) ................................................................................................ 34
Dose Selection/Modification .............................................................................. 34
Dose Selection (Preparation) ....................................................................... 34
Dose Modification (Escalation/Titration/Other).......................................... 35
5.2.1.2.1
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue).......................................................................................... 35
Guidance for Diagnosis and Management of Hepatic Events of Clinical 
Interest ......................................................................................................... 40
Timing of Dose Administration.......................................................................... 45
Trial Blinding...................................................................................................... 46
Randomization ...................................................................................................... 46
Stratification.......................................................................................................... 46
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 46
Acceptable Concomitant Medications ................................................................ 47
Prohibited Concomitant Medications.................................................................. 47
Rescue Medications & Supportive Care............................................................. 48
Supportive Care Guidelines ................................................................................ 48
Diet/Activity/Other Considerations..................................................................... 49
Diet...................................................................................................................... 49
Contraception...................................................................................................... 49
Pregnancy............................................................................................................ 50
Use in Nursing Women....................................................................................... 51
Subject Withdrawal/Discontinuation Criteria................................................... 51
Discontinuation of Treatment ............................................................................. 51
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Withdrawal from the Trial .................................................................................. 52
Subject Replacement Strategy............................................................................. 52
Beginning and End of the Trial ........................................................................... 52
Clinical Criteria for Early Trial Termination ................................................... 53
6.0
TRIAL FLOW CHART ........................................................................................... 54
Initial Treatment with Study Drug ..................................................................... 54
Second Course Treatment.................................................................................... 59
7.0
TRIAL PROCEDURES ........................................................................................... 62
Trial Procedures ................................................................................................... 62
Administrative Procedures.................................................................................. 62
Informed Consent......................................................................................... 62
7.1.1.1.1
General Informed Consent.................................................................... 62
7.1.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research................................................................................................ 63
Inclusion/Exclusion Criteria ........................................................................ 63
Subject Identification Card .......................................................................... 63
Medical History ........................................................................................... 63
Prior and Concomitant Medications Review............................................... 63
7.1.1.5.1
Prior Medications.................................................................................. 63
Prior Treatment Details for HCC ................................................... 64
7.1.1.5.2
Concomitant Medications..................................................................... 64
Subsequent Anti-Cancer Status.................................................................... 64
Assignment of Screening Number............................................................... 64
Assignment of Treatment/Randomization Number..................................... 64
Trial Compliance (Medication/Diet/Activity/Other)................................... 64
Clinical Procedures/Assessments........................................................................ 65
Adverse Event Monitoring........................................................................... 65
Physical Exam.............................................................................................. 65
7.1.2.2.1
Full Physical Exam ............................................................................... 65
7.1.2.2.2
Directed Physical Exam........................................................................ 65
Height, Weight, and Vital Signs .................................................................. 65
12-Lead Electrocardiogram ......................................................................... 66
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Eastern Cooperative Oncology Group Performance Status......................... 66
Child-Pugh Score......................................................................................... 66
Patient Reported Outcomes (PROs)............................................................. 66
Laboratory Procedures/Assessments .................................................................. 66
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) .. 66
7.1.3.1.1
Pregnancy Tests .................................................................................... 67
Central Laboratory Assessments.................................................................. 68
Tumor Tissue ............................................................................................... 68
Blood Collection for RNA Analysis, Plasma Biomarker Analysis and 
Serum Biomarker Analysis.......................................................................... 68
Planned Genetic Analysis Sample Collection.............................................. 68
Future Biomedical Research Sample Collection ......................................... 69
Efficacy Measurements....................................................................................... 69
Tumor Imaging and Assessment of Disease................................................ 69
Initial Tumor Imaging.................................................................................. 69
Tumor Imaging During the Trial ................................................................. 70
End of Treatment and Follow-up Tumor Imaging....................................... 70
Second Course (Retreatment) Tumor Imaging............................................ 70
RECIST 1.1 Assessment of Disease............................................................ 71
irRECIST Assessment of Disease................................................................ 71
Other Procedures................................................................................................. 76
Withdrawal/Discontinuation........................................................................ 76
7.1.5.1.1
Withdrawal From Future Biomedical Research ................................... 76
7.1.5.1.2
Lost to Follow-up.................................................................................. 76
Blinding/Unblinding .................................................................................... 77
Calibration of Critical Equipment................................................................ 77
Visit Requirements.............................................................................................. 78
Screening...................................................................................................... 78
Treatment Period Visit................................................................................. 78
Post-Treatment Visits................................................................................... 80
7.1.6.3.1
Safety Follow-up Visits ........................................................................ 80
7.1.6.3.2
Follow-up Visits ................................................................................... 80
7.1.6.3.3
Survival Follow-up ............................................................................... 80
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7.1.6.3.4
Survival Status...................................................................................... 81
Assessing and Recording Adverse Events .......................................................... 81
Definition of an Overdose for This Protocol and Reporting of Overdose to 
the Sponsor.......................................................................................................... 82
Reporting of Pregnancy and Lactation to the Sponsor ....................................... 82
Immediate Reporting of Adverse Events to the Sponsor.................................... 83
Serious Adverse Events ............................................................................... 83
Events of Clinical Interest............................................................................ 84
Protocol-Specific Exceptions to Serious Adverse Event Reporting............ 85
Evaluating Adverse Events................................................................................. 85
Sponsor Responsibility for Reporting Adverse Events ...................................... 88
TRIAL GOVERNANCE AND OVERSIGHT................................................... 88
Executive Oversight Committee......................................................................... 88
Data Monitoring Committee............................................................................... 88
8.0
STATISTICAL ANALYSIS PLAN ........................................................................ 88
Statistical Analysis Plan Summary ..................................................................... 89
Responsibility for Analyses/In-House Blinding ................................................. 90
Hypotheses/Estimation......................................................................................... 91
Analysis Endpoints ............................................................................................... 91
Efficacy Endpoints.............................................................................................. 91
Primary......................................................................................................... 91
Secondary..................................................................................................... 91
Safety Endpoints ................................................................................................. 91
Analysis Populations............................................................................................. 92
Efficacy Analysis Populations ............................................................................ 92
Safety Analysis Populations ............................................................................... 92
Statistical Methods................................................................................................ 93
Statistical Methods for Efficacy Analyses.......................................................... 93
Overall Survival (OS) .................................................................................. 93
Progression-Free Survival (PFS).................................................................. 94
Objective Response Rate (ORR) ................................................................. 95
Disease Control Rate (DCR)........................................................................ 96
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Time to Progression (TTP) .......................................................................... 96
Duration of Response (DOR)....................................................................... 97
Statistical Methods for Safety Analyses ............................................................. 98
Summaries of Demographic and Baseline Characteristics ................................. 99
Interim Analyses ................................................................................................. 100
Efficacy Interim Analyses................................................................................. 100
Safety Interim Analyses.................................................................................... 101
Multiplicity .......................................................................................................... 101
Sample Size and Power Calculations ................................................................ 105
Subgroup Analyses and Effect of Baseline Factors.......................................... 106
Compliance (Medication Adherence)................................................................ 106
Extent of Exposure.............................................................................................. 106
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ............................................................................................................... 107
Investigational Product ...................................................................................... 107
Packaging and Labeling Information ............................................................... 107
Clinical Supplies Disclosure............................................................................... 107
Storage and Handling Requirements................................................................ 108
Discard/Destruction/Returns and Reconciliation ............................................ 108
Standard Policies................................................................................................. 108
10.0
ADMINISTRATIVE AND REGULATORY DETAILS..................................... 109
Confidentiality..................................................................................................... 109
Confidentiality of Data ..................................................................................... 109
Confidentiality of Subject Records................................................................... 109
Confidentiality of Investigator Information...................................................... 109
Confidentiality of IRB/IEC Information........................................................... 110
Compliance with Financial Disclosure Requirements..................................... 110
Compliance with Law, Audit and Debarment ................................................. 110
Compliance with Trial Registration and Results Posting Requirements...... 112
Quality Management System............................................................................. 112
Data Management............................................................................................... 112
Publications ......................................................................................................... 113
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11.0
LIST OF REFERENCES....................................................................................... 114
12.0
APPENDICES......................................................................................................... 119
Merck Code of Conduct for Clinical Trials...................................................... 119
Collection and Management of Specimens for Future Biomedical 
Research............................................................................................................... 121
Understanding the Intent, Scope and Public Health Benefits of 
Exploratory Biomarker Research: A Guide for IRBs/IECs and 
Investigational Site Staff .................................................................................... 125
Approximate Blood/Tissue Volumes Drawn/Collected by Trial Visit and 
by Sample Types ................................................................................................. 136
Hepatitis B Definitions and Treatment Considerations .................................. 137
Common Terminology Criteria for Adverse Events ....................................... 138
Child-Pugh Score................................................................................................ 139
Barcelona Clinic Liver Cancer Staging System............................................... 141
List of Abbreviations .......................................................................................... 142
13.0
SIGNATURES......................................................................................................... 145
Sponsor's Representative ................................................................................... 145
Investigator.......................................................................................................... 145
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LIST OF TABLES
Table 1
Adequate Organ Function Laboratory Values..................................................... 31
Table 2
Trial Treatment.................................................................................................... 34
Table 3
Dose Modification and Toxicity Management Guidelines for Non-hepatic 
Immune-related 
Adverse 
Events 
Associated 
with 
Pembrolizumab 
Monotherapy, Coformulations or IO Combinations ........................................... 36
Table 4
Pembrolizumab Infusion Reaction Dose modification and Treatment 
Guidelines............................................................................................................ 39
Table 5
Laboratory Tests.................................................................................................. 67
Table 6
Imaging and Treatment after First Radiologic Evidence of PD.......................... 74
Table 7
Evaluating Adverse Events ................................................................................. 86
Table 8
Statistical Analysis Plan...................................................................................... 89
Table 9
Censoring rules for Primary and Sensitivity Analyses of PFS............................ 95
Table 10
Censoring rules for TTP...................................................................................... 96
Table 11
Censoring Rules for DOR ................................................................................... 97
Table 12
Analysis Strategy for Key Efficacy Hypotheses ................................................. 98
Table 13
Analysis Strategy for Safety Parameters............................................................. 99
Table 14
Summary of Interim and Final Analyses Strategy ............................................ 101
Table 15
Summary of Timing, Sample Size and Decision Guidance for the Interim 
Analyses and Final Analysis of Overall Survival ............................................. 103
Table 16
Summary of Timing, Sample Size and Decision Guidance for the Interim 
Analysis and Final Analysis of Progression Free Survival............................... 104
Table 17
Efficacy Boundaries for Testing the ORR Hypothesis ..................................... 105
Table 18
Product Descriptions ......................................................................................... 107
Table 19
Hepatitis B Definitions and Treatment Considerations..................................... 137
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LIST OF FIGURES
Figure 1
Trial Diagram ...................................................................................................... 16
Figure 2
Imaging and Treatment for Clinically Stable Subjects after First Radiologic 
Evidence of Progressive Disease Assessed by Site............................................. 75
Figure 3
Multiplicity Strategy.......................................................................................... 102
Figure 4
Barcelona Clinic Liver Cancer staging system ................................................. 141
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
3475-394-05
19-APR-2021
To update the dose modification and toxicity management 
guidelines for irAEs.
3475-394-04
25-OCT-2018
OS HR assumption was changed to take into account the potential 
diluted OS effect due to increased trend of using more effective 
post-study anti-cancer therapies in the near future.
3475-394-03
29-AUG-2018
To add an interim analysis for ORR for earlier data analysis for a 
potential early filing.
3475-394-02
07-DEC-2017
Revised dose modification table to align with the most current label 
and safety information for pembrolizumab.
3475-394-01
14-JUL-2017
Prohibited concomitant medication and exclusion criteria revised to 
be consistent with other MK-3475 China/AP studies.
3475-394-00
30-SEP-2016
NA
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SUMMARY OF CHANGES
PRIMARY REASON(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title(s)
Description of Change (s)
Rationale
5.2.1.2.1
Immune-Related Events and 
Dose Modification (Withhold, 
Treat, Discontinue)
The dose modification and 
toxicity management guidelines 
for irAEs and table were 
updated.
The dose modification and 
toxicity management guidelines 
for irAEs and table were 
updated as requested by the 
U.S. FDA in an effort to 
harmonize the presentation of 
safety information across all 
FDA-approved PD-1/L1 
antibody prescribing 
information.
ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
No additional changes.
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1.0 TRIAL SUMMARY
Abbreviated Title
A Phase III Randomized Double-blind Study of Pembrolizumab plus 
Best Supportive Care vs. Placebo plus Best Supportive Care as 
Second-Line Therapy in Asian Subjects with Previously Systemically 
Treated Advanced Hepatocellular Carcinoma (KEYNOTE-394)
Sponsor Product Identifiers
MK-3475
Pembrolizumab
Trial Phase
Phase III
Clinical Indication
Advanced Hepatocellular carcinoma
Trial Type
Interventional
Type of control
Placebo Plus Best Supportive Care (BSC)
Route of administration
Intravenous (IV)
Trial Blinding
Double-blind
(Select Groups)
Pembrolizumab plus BSC or placebo plus BSC
Number of trial subjects
Approximately 450 subjects will be enrolled.
Estimated duration of trial
The Sponsor estimates that the trial will require approximately 37
months from the time the first subject signs the informed consent until 
the last subject’s last study-related phone call or visit.
Duration of Participation
Each subject will participate in the trial from the time the subject signs 
the informed consent form (ICF) through the final contact.  After a 
screening phase of up to 28 days, each eligible subject will be 
randomized to receive pembrolizumab 200 mg intravenously or 
placebo beginning on Day 1 of each 3-week dosing cycle.  Treatment 
will continue until progressive disease, unacceptable adverse events, 
intercurrent illness that prevents further administration of treatment, 
investigator’s decision to withdraw the subject, subject withdrawal of 
consent, pregnancy of the subject, noncompliance with trial treatment 
or procedure requirements, subject having received 35 treatments 
(approx. 2 years) of study drug, or administrative reasons requiring 
cessation of treatment. Subjects who stop study drug as a result of 
obtaining an investigator-determined confirmed complete response 
(CR) or those subjects who stop after receiving 35 trial treatments 
may be eligible, at the discretion of the investigator, for an additional 
17 trial treatments (approx. 1 year) after progressive disease if they 
meet the criteria for re-treatment (Second Course Phase) and the study 
is ongoing.
Subjects who discontinue for reasons other than 
progressive disease will have post-treatment follow-up visits for 
monitoring disease status as if they were still on treatment until 
progressive disease, initiating a non-study anti-cancer treatment;
withdraw of consent from study participation, or becoming lost to 
follow-up. All subjects will be followed (by telephone or visit) for 
survival until death, withdrawal of consent from study participation, 
or the end of the study. After the end of study treatment, each subject 
will be followed for 30 days for adverse event monitoring. Serious 
adverse events will be collected for 90 days after the end of treatment 
or for 30 days after the end of treatment if the subject initiates new 
anticancer therapy, whichever is earlier.
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A list of abbreviations used in this document can be found in Section 12.9.
2.0 TRIAL DESIGN
Trial Design
This is a double-blind randomized phase III trial of pembrolizumab plus best supportive care 
(BSC) versus placebo plus BSC in Asian subjects with previously systemically treated 
advanced hepatocellular carcinoma (HCC). To be eligible, subjects must have documented 
objective radiographic progression of disease (PD) on or after stopping treatment with 
sorafenib or oxaliplatin-based chemotherapy, or else be intolerant of sorafenib or oxaliplatin-
based chemotherapy as defined in Section 5.1.2.  They also must have disease not amenable 
to a curative treatment approach (e.g., transplant, surgery, or ablation). In order to be eligible, 
subjects must have at least one measurable lesion that is confirmed by the investigator per 
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 prior to randomization. Subjects 
will be enrolled regardless of tissue programmed death ligand 1 (PD-L1) biomarker status.  
Subjects will not be required to provide a tumor tissue sample for biomarker analysis, but are 
strongly urged to do so if tissue is available. Available samples will be evaluated at a central 
laboratory for expression status of PD-L1 by immunohistochemistry (IHC). Approximately 
450 subjects will be randomized at a 2:1 ratio to receive pembrolizumab 200 mg 
intravenously (IV) every 3 weeks (Q3W) or placebo (IV administration of saline) Q3W.  
Subjects from both arms can receive BSC as per local standard of care.
The primary objective of this trial is to compare the overall survival (OS) in subjects who 
receive pembrolizumab plus BSC and those who receive placebo plus BSC. On-study 
imaging assessments will be performed Q6W calculated from the date of randomization and 
independent of treatment delays.  RECIST 1.1 will be used by the site for treatment decisions 
until the first radiologic evidence of progressive disease (PD). 
Following the first radiologic evidence of PD by RECIST 1.1, treatment decisions may be 
made by the adaption of RECIST 1.1 as described in Section 4.2.3.2 termed immune-related 
RECIST (irRECIST) to accommodate the tumor response patterns seen with pembrolizumab 
treatment (e.g., tumor flare).  This was first described by Nishino, et al. 2013 [1], but is 
further modified for the pembrolizumab program.  For a clinically stable subject with first 
radiologic evidence of PD, it is at the discretion of the site investigator to continue treating 
the subject with study drug until PD is confirmed at least 4 weeks after the date of the first 
tumor imaging suggesting PD per the site investigator and subsequently confirmed by the 
central imaging vendor.  If radiologic PD is confirmed by the site investigator, the subject 
should be discontinued from treatment unless, in the opinion of the investigator, the subject is 
achieving a clinically meaningful benefit; an exception for continued treatment may be 
considered following consultation with the Sponsor.  PD will also be assessed by blinded 
independent central review (BICR).
Subjects should continue on study treatment until PD is confirmed by RECIST 1.1, 
unacceptable adverse events (AEs), intercurrent illness that prevents further administration of 
Randomization Ratio
Pembrolizumab plus BSC versus placebo plus BSC 
at a 2:1
randomization ratio
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treatment, the investigator decides to withdraw the subject, the subject withdraws consent, 
pregnancy of the subject, noncompliance with trial treatment or procedure requirements, 
administrative reasons requiring discontinuation, or the subject received 35 trial treatments 
(approx. 2 years).  Subjects who discontinue trial treatment for a reason other than disease 
progression will move into the Follow-Up Phase and should be assessed Q6W (42±7 days) 
by radiologic imaging to monitor disease status.  Disease status will continue to be monitored 
until:  the start of new anti-cancer treatment, disease progression, death, or the end of the 
study, whichever occurs first.  All subjects will be followed Q12W for OS until death, 
withdrawal of consent from participation in the study, or the end of the study, whichever 
occurs first.  
Subjects who attain an investigator-determined confirmed complete response (CR) and who 
have received at least 8 trial treatments (approximately 6 months of therapy) may discontinue 
treatment at the discretion of the investigator after receiving at least 2 treatments beyond the 
initial determination of a CR.  Subjects who stop study drug after receiving 35 trial 
treatments (approximately 2 years) for reasons other than PD or intolerability or who stop 
after attaining a CR may be eligible for retreatment with up to an additional 17 treatments 
(second course of treatment, approximately 1 year) after they have experienced radiographic 
PD.  The decision to retreat will be at the discretion of the investigator only if no other cancer 
treatment was administered since the last dose of study drug, the subject still meets the 
parameters listed in the inclusion and exclusion criteria, and the trial remains open.
Adverse events will be monitored throughout the trial and graded in severity according to the 
guidelines outlined in the National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 (see Section 12.6).  After the end of treatment, each 
subject will be followed for 30 days for AE monitoring.  Serious adverse events (SAEs) will 
be collected for 90 days after the end of treatment or 30 days after the end of treatment if the 
subject initiates new anticancer therapy, whichever is earlier.  
Prior to verification of PD by blinded independent central review, switching to another 
treatment is discouraged. Following verification of PD, subjects may switch to another anti-
cancer treatment.  
This study will be conducted in conformance with Good Clinical Practices (GCP).
Specific procedures to be performed during the trial, as well as their prescribed times and 
associated visit windows, are outlined in the Trial Flow Chart - Section 6.0. Details of each 
procedure are provided in Section 7.0 – Trial Procedures.
Group allocation will be implemented via the interactive voice response system / integrated 
web response system (IVRS/IWRS).
This trial will use a group sequential design. There will be two efficacy interim analyses for 
ORR, PFS and OS (the first interim at approximately Month 17 after study start, when the 
first 163 randomized subjects have at least 24 weeks follow up; the second interim at 
approximately Month 31 after study start with approximately 276 OS events accumulated
(See section 8.7). Results of the interim analyses will be reviewed by the external Data 
Monitoring Committee (eDMC), which will make recommendations to the Sponsor to 
continue, modify or end the trial according to the plan described briefly in Section 2.2 - Trial 
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Diagram and in detail in Section 8.0 - Statistical Analysis Plan. The role of the eDMC will be 
clearly elicited in the eDMC charter.
Trial Diagram
The trial design is depicted in Figure 1.
Figure 1
Trial Diagram
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Stratification Factors: Prior treatment (sorafenib vs. chemotherapy); Macrovascular invasion: 
(Yes vs. No); Etiology (HBV vs. others (HCV, non-infected))
3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
Compare pembrolizumab to placebo in Asian subjects with previously systemically treated
advance HCC:
Primary Objective(s) & Hypothesis(es)
Objective:  To compare overall survival (OS) between two treatment arms
(pembrolizumab plus BSC versus placebo plus BSC)
Hypothesis:  Pembrolizumab prolongs OS compared to placebo
Secondary Objective(s) & Hypothesis(es)
1) Objective: To compare progression-free survival (PFS) per RECIST 1.1 as assessed 
by blinded independent central review (BICR) between two treatment arms
(pembrolizumab plus BSC versus placebo plus BSC)
Hypothesis: Pembrolizumab prolongs PFS per RECIST 1.1, as assessed by BICR
compared to placebo
2) Objective:  To compare the objective response rate (ORR) per RECIST 1.1 as 
assessed by BICR between two treatment arms (pembrolizumab plus BSC versus 
placebo plus BSC)
Hypothesis:  Pembrolizumab increases ORR per RECIST 1.1, as assessed by BICR
compared to placebo
3) Objective:  To compare the duration of response (DOR), disease control rate (DCR) 
and time to progression (TTP), per RECIST 1.1 as assessed by BICR between two 
treatment arms (pembrolizumab plus BSC versus placebo plus BSC)
4) Objective:  To evaluate the safety and tolerability profile of pembrolizumab-treated 
subjects compared with placebo-treated subjects
Exploratory Objectives
1) Objective:  To evaluate PFS, ORR, DOR, DCR, and TTP per irRECIST as assessed 
by BICR between two treatment arms (pembrolizumab plus BSC versus placebo plus 
BSC).  
2) Objective:  To explore the relationship between PD-L1 immunohistochemistry (IHC) 
and response to study drug. 
3) Objective:  To evaluate score changes from baseline in health related quality of life 
using the European Organization for Research and Treatment of Cancer (EORTC) 
Quality of Life Questionnaire—Core (QLQ-C30). 
4) Objective:  To characterize utilities using EuroQol-5 Dimension (EuroQol EQ-5D).
5) Objective:  To explore the relationship between genomic variation and response to 
the treatment administered.  Variation across the human genome will be analyzed for 
association with clinical data collected in this study.
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4.0 BACKGROUND & RATIONALE
Background
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background 
information on MK-3475.
Liver cancer is the third leading cause of cancer deaths worldwide [2]. In 2012, there were 
approximately 782,000 new cases of HCC and 746,000 deaths worldwide. Around 83% HCC 
cases occur in less developed regions, with approximately 50% from China. In China, HCC 
is one of the most common malignancies, ranking third in incidence and second in mortality.
Approximately 400,000 new cases (51% of the world) and 383,200 deaths (49% of the 
world) occurred in China in 2012 [3]. Most HCC arises in the setting of liver cirrhosis from 
varied causes, including viral hepatitis, excessive alcohol consumption, hemochromatosis, 
and metabolic syndrome [4]. Worldwide, chronic hepatitis B virus (HBV) infection accounts 
for approximately 50% of the total cases of HCC, and it is the dominant risk factor in most 
areas of Asia that have a high incidence of HCC, particularly in China [5]. Around 60–80% 
of HCC cases in China are associated with HBV infection and 6–11% with HCV infection
[6]. Aflatoxin B1 is another major risk factor for HCC in China [7]. As a consequence of 
these different etiologies, HCC is a heterogeneous malignancy. Despite advances in early 
detection, liver transplantation and liver-directed therapies, about 70% of HCC patients 
present with advanced disease. As HCC is resistant to most traditional chemotherapy agents, 
the median survival for patients with advanced disease is typically 6–9 months without 
therapy.
The multi-targeted tyrosine kinase inhibitor sorafenib is the current standard of care 
worldwide for the treatment of patients with advanced HCC and preserved liver function 
based on a large Phase III trial in a Western population. In this trial, TTP was 5.5 months, 
and OS was 10.7 months in the treatment arm, compared with 2.8 and 7.9 months in the 
control arm respectively [8]. A similar study conducted in the Asia-Pacific region showed an 
almost identical hazard ratio for sorafenib of 0.68 [95% CI 0.50-0.93], p=0.014, although 
overall survival was shorter in this trial (6.5months vs. 4.2 months) [9]. In parts of Asia, the 
FOLFOX regimen (folinic acid, 5-fluorouracil, and oxaliplatin) has also been approved, 
based on a randomized trial comparing FOLFOX with doxorubicin [10]. In this trial, there 
was a non-significant trend toward improved OS in the FOLFOX arm (6.4 months vs. 4.97
months, HR of 0.8 [95% CI 0.63-1.02]), but in a pre-specified Chinese substudy, the 
FOLFOX arm was superior to doxorubicin (5.7 months vs. 4.3 months, HR of 0.74 [95% CI 
0.55-0.98]; p=0.03) [11]. Based on comparable survival data with sorafenib, the FOLFOX 
regimen is recommended for 1st line treatment of advanced HCC by China liver cancer 
guidelines [12]. In Thailand, oxaliplatin was also approved for advanced HCC in 2014. 
Oxaliplatin-based regimens are also included in the Korea Practice Guideline for the 
management of HCC [13]. Despite these advances, continued investigation of additional 
agents for advanced HCC patients remains crucial.
In the second-line setting, there is no approved agent for treatment of advanced HCC in 
China and other Asian regions.  Several large randomized trials failed to show a significant 
survival advantage of various agents against placebo in the second line, including brivanib 
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[14], everolimus [15] and ramucirumab [16]. Smaller studies have suggested the possible 
efficacy for MET inhibitors and regorafenib in advanced HCC [17][18].  Chemotherapy 
drugs including capecitabine and the gemcitabine/oxaliplatin (GEMOX) combination have 
also been used in the second line in small trials [19][20].  However, there are no agents or 
combinations yet approved for second-line HCC, underscoring the high unmet medical need 
for this disease. The standard of care for second-line treatment for advanced HCC is still 
best supportive care in Asian countries
Pharmaceutical and Therapeutic Background
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of 
the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its 
ligands, PD-L1 and PD-L2.  KEYTRUDA (pembrolizumab, MK-3475) has recently been 
approved in the United States for the treatment of patients with unresectable or metastatic 
melanoma and disease progression following treatment with ipilimumab or a BRAF 
inhibitor, if BRAF V600 mutation-positive.  Pembrolizumab was also recently approved for 
the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors 
express PD-L1 as determined by an FDA-approved test, with disease progression on or after 
platinum-containing chemotherapy.  
The importance of intact immune surveillance in controlling neoplastic growth has been 
known for decades [21].  Accumulating evidence shows a correlation between tumor-
infiltrating lymphocytes (TILs) in cancer tissue and a favorable prognosis in various 
malignancies [22][23][24][25][26].  In particular, the presence of CD8+ T-cells and the ratio 
of CD8+ effector T-cells to FoxP3+ regulatory T-cells seem to correlate with improved 
prognosis and long-term survival in many solid tumors.
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 Ig 
superfamily member related to CD28 and CTLA-4 which has been shown to negatively 
regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2) 
[27][28].  
The structure of murine PD-1 has been identified [29].  PD-1 and family members are type I 
transmembrane glycoproteins containing an Ig variable-type (V-type) domain responsible for 
ligand binding and a cytoplasmic tail which is responsible for the binding of signaling 
molecules.  The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an 
immunoreceptor tyrosine-based inhibition motif (ITIM) and an immunoreceptor tyrosine-
based switch motif (ITSM).  
Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases SHP-1 and SHP-2 to 
the ITSM motif within its cytoplasmic tail, leading to the dephosphorylation of effector 
molecules such as CD3ζ, PKCθ, and ZAP70 which are involved in the CD3 T-cell signaling 
cascade [28][30][31][32].  The mechanism by which PD-1 down modulates T-cell responses 
is similar to, but distinct from, that of CTLA-4 as both molecules regulate an overlapping set 
of signaling proteins [33][34].  PD-1 was shown to be expressed on activated lymphocytes 
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including peripheral CD4+ and CD8+ T-cells, B-cells, T-regulatory cells, and natural killer 
cells [35][36].  Expression has also been shown during thymic development on CD4-/CD8-
(double negative) T-cells as well as subsets of macrophages and dendritic cells [37].  
The ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed or can be induced in a 
variety of cell types, including non-hematopoietic tissues as well as in various tumors 
[38][39][40][34].  Both ligands are type I transmembrane receptors containing both IgV- and 
IgC-like domains in the extracellular region and contain short cytoplasmic regions with no 
known signaling motifs.  Binding of either PD-1 ligand (PD-L1 or PD-L2) to the PD-1 
receptor on T-cells inhibits T-cell activation.  PD-L1 is expressed at low levels on various 
non-hematopoietic tissues, most notably on vascular endothelium, whereas PD-L2 protein is 
only detectably expressed on antigen-presenting cells found in lymphoid tissue or chronic 
inflammatory environments.  PD-L2 is thought to control immune T-cell activation in 
lymphoid organs, whereas PD-L1 serves to attenuate excessive T-cell function in peripheral 
tissues [34].  Although healthy organs express little (if any) PD-L1, a variety of cancers were 
demonstrated to express abundant levels of this T-cell inhibitor.  PD-1 has been suggested to 
regulate tumor-specific T-cell expansion in subjects with melanoma [41]
Pre-clinical and Clinical Trials
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 or anti-mouse PD-L1 antibodies have demonstrated 
anti-tumor responses as a 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 IFN-γ, granzyme B and 
perforin, indicating that the mechanism of action involves local infiltration and activation of 
effector T-cell function in vivo[42][43][44][45][46][47]. Experiments have confirmed the in 
vivo efficacy of PD-1 blockade as a monotherapy as well as in combination with 
chemotherapy in syngeneic mouse tumor models (see the IB).
Clinical trials have demonstrated efficacy using pembrolizumab in subjects with advanced 
melanoma, NSCLC, head and neck cancer, bladder cancer, Hodgkin’s lymphoma, triple-
negative breast cancer, and gastric adenocarcinoma. In addition, recent data demonstrates 
emerging evidence of single-agent activity in additional tumor types such as mesothelioma, 
urothelial cancer, ovarian cancer, neuroendocrine carcinoma, and small cell lung cancer.
Pre-clinical data indicates PD-1 pathway is very important for HCC. In a mouse model of 
HCC, blockage of PD-1 and with immunostimulatory monoclonal antibodies extended 
survival [48]. 
Clinical data shows that Hepatocellular carcinoma (HCC) patients with higher expression of
tumoral PD-L1 had a significantly poorer prognosis than patients with lower expression and 
tumor expression of PD-L1 has also been shown to be an independent predictor for 
postoperative recurrence in HCC patients [49]. High expression levels of PD-1 on T-cells, 
both in tumor-infiltrating lymphocytes (TILs) and peripheral blood mononuclear cells 
(PBMCs) were also correlated with poor prognosis in HCC patients after surgical resection 
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[50]. 
The relationship between PD-1 pathway and HCC prognosis is still under 
investigation.
Nivolumab is also a humanized monoclonal antibody (mAb) to block the interaction between 
PD-1 and its ligands, PD-L1 and PD-L2. There is a phase I/II trial of nivolumab 
(CheckMate-040) in previously systemically treated patients with HCC regardless of PD-L1 
IHC expression .The interim analysis demonstrated that the estimated survival rate in 
evaluable patients (n=47) was 62% at 12 months. Results also show the safety profile of 
nivolumab is generally consistent with that previously reported in other tumor types [51].
While the relationship between the PD-L1 expression on tumor cells and responses to anti-
PD-1 treatment is still under investigation. The interim results of the dose-escalation phase of 
CheckMate-040 from 2016 ASCO shows that PD-L1 expression was observed in 8/41 
patients (20%) and overall responses occurred regardless of PD-L1 status (2/8 in PD-L1-
positive and 5/33 in PD-L1-negative patients)[52]. The interim results from the dose-
expansion phase of this study shows PD-L1 IHC was quantifiable in 128 patients and 
responses occurred regardless of PD-L1 status (ORR = 5/26 [19%] patients with PD-L1 ≥ 1% 
and 20/102 [20%] patients with PD-L1 < 1%). For patients without evaluable PD-L1 
expression data, the ORR was 10/86 (12%) [53].
Based on similar mechanisms of action with nivolumab, pembrolizumab is also being 
investigated for HCC. KEYNOTE-224 is a non-randomized, multicenter, open-label, phase 2 
trial of pembrolizumab in patients with advanced HCC who have previously been treated 
with sorafenib. An objective response was recorded in 18(17%) of 104 participants (95% CI 
11-26) who had received at least one dose of pembrolizumab, 46 (44%) patients had stable 
disease. The safety and toxicity profile of pembrolizumab in these patients was manageable 
and generally similar to that of pembrolizumab in other tumor types. The results of 
KEYNOTE-224 show clinical activity and manageable safety of pembrolizumab in patients 
with advanced hepatocellular carcinoma. There is an on-going clinical trial, KEYNOTE-240, 
for previously systemically treated HCC patients.
KEYNOTE-240 is double-blind 
randomized phase III trial of pembrolizumab plus BSC versus placebo plus BSC in subjects 
from US, EU and some Asian countries with previously systemically treated advanced HCC. 
The primary objectives of this trial are to determine PFS and OS as dual-primary endpoints. 
Adverse events will be monitored throughout the trial. In this study, Merck defined hepatic 
events of clinical interest (hepatic ECI), and developed guidance for diagnosis and 
management of hepatic ECIs accordingly.
Ongoing Clinical Trials
Ongoing clinical trials of pembrolizumab are being conducted in advanced melanoma, non-
small cell lung cancer, HCC, and a number of other advanced solid tumor indications and 
hematologic malignancies.  For study details refer to the IB.
Information on Other Trial-Related Therapy
There is no standard second-line therapy for advanced HCC. Best supportive care will 
include pain management and management of other potential complications including ascites 
per local standards of care.
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Rationale
Rationale for the Trial and Selected Subject Population
HCC often develops in the setting of inflammation of various types, including viral 
infections. In a gene-expression profiling study, non-tumoral tissue from patients with HCC 
with an inflammatory signature predicted a worse overall survival [54]. HCC patients with 
higher tumor expression of PD-L1 have a significantly poorer prognosis than patients with 
lower expression, and tumor expression of PD-L1 is an independent predictor for 
postoperative recurrence in HCC [49].  In addition, high expression levels of PD-1 on T-
cells, both in TILs and PBMCs, also correlate with increased stage and higher recurrence 
rates in HCC patients after surgical resection [50].  
Recently, immunotherapy has been shown to produce antitumor effects in HCC, a tumor 
which has shown resistance to traditional forms of chemotherapy.  CTLA-4 inhibition with 
tremelimumab was evaluated in HCV-associated HCC patients[55].  Seventeen patients were 
evaluable for response, and 3 partial responses were seen lasting for 3.6, 9.2 and 15.8 months.
Almost half of the stable disease patients were stable for over 6 months, and toxicity was 
manageable, despite early elevations in transaminases.  The interim analysis of a Phase I/II 
trial of the anti–PD-1 antibody, nivolumab, in subjects with advanced HCC demonstrated an 
estimated survival rate in evaluable patients (n=47) of 62% at 12 months with several durable 
responses.  Responses were seen both in viral-mediated cancers and those without an 
underlying viral etiology.  Results also show the safety profile of nivolumab in HCC to be 
generally consistent with that previously reported in other tumor types [51].  
Immunotherapy has been shown to produce promising antitumor effects in HCC. In addition,
the safety profile of anti-PD-1 treatment has been shown to be favorable in HCC, consistent 
with that previously reported in other tumor types [51].  Thus, from the scientific and ethical 
point of view, a randomization of 2:1 is reasonable. Compared to the 1:1 randomization ratio,
2:1 randomization enables Asian subjects to have higher chance to receive treatment in this 
placebo-controlled study. Furthermore, this will also help to facilitate recruitment and 
mitigate the risk of patient withdrawal.
Rationale for Dose Selection/Regimen/Modification
The dose of pembrolizumab planned to be studied in this trial is 200 mg Q3W.  The dose 
recently approved in the United States and several other countries for treatment of melanoma 
and NSCLC subjects is 2 mg/kg Q3W.  Information on the rationale for selecting 200 mg 
Q3W is summarized below.
KEYNOTE-001 is an open-label Phase I study being conducted to evaluate the safety, 
tolerability, pharmacokinetics (PK), pharmacodynamics, and anti-tumor activity of single-
agent pembrolizumab.  The dose escalation portion of this trial evaluated three dose levels, 1 
mg/kg, 3 mg/kg and 10 mg/kg, administered every 2 weeks (Q2W) and dose expansion 
cohorts evaluated 2 mg/kg Q3W and 10 mg/kg Q3W in subjects with advanced solid tumors.  
All dose levels were well tolerated and no dose-limiting toxicities were observed.  This first-
in-human study of pembrolizumab showed evidence of target engagement and objective 
evidence of tumor size reduction at all dose levels.  No maximum tolerated dose (MTD) was
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identified.  In addition, two randomized cohort evaluations of melanoma subjects receiving 
pembrolizumab at a dose of 2 mg/kg versus 10 mg/kg Q3W have been completed, and one 
randomized cohort evaluating 10 mg/kg Q3W versus 10 mg/kg Q2W has also been 
completed.  The clinical efficacy and safety data demonstrate lack of important differences in 
efficacy or safety profile across doses. 
An integrated body of evidence suggests that 200 mg every 3 weeks (Q3W) is expected to 
provide similar response to that seen with 2 mg/kg Q3W, 10 mg/kg Q3W and 10 mg/kg 
Q2W.  Previously, a flat pembrolizumab exposure-response relationship for efficacy and 
safety was seen in subjects with melanoma at doses ranging from 2 mg/kg to 10 mg/kg.  
Exposures for 200 mg Q3W are expected to lie within this range and will be close to those 
obtained with 2 mg/kg Q3W dose.  
A population PK model, which characterized the influence of body weight and other patient 
covariates on exposure, has been developed.  The PK profile of pembrolizumab is consistent 
with that of other humanized monoclonal antibodies, which typically have low clearance and 
a limited volume of distribution.  The distribution of exposures from the 200 mg fixed dose 
are predicted to considerably overlap those obtained with the 2 mg/kg dose and importantly 
will maintain individual patient exposures within the exposure range established in 
melanoma and NSCLC as associated with maximal clinical response.  The PK properties of 
pembrolizumab, and specifically the weight-dependency in clearance and volume of 
distribution are consistent with the absence of a meaningful advantage to weight-based 
dosing relative to fixed dosing.  
In translating to other tumor indications, similarly flat exposure-response relationships for 
efficacy and safety as observed in subjects with melanoma can be expected, as the anti-tumor 
effect of pembrolizumab is driven through immune system activation rather than through a 
direct interaction with tumor cells, rendering it independent of the specific tumor type.  In 
addition, available PK results in subjects with melanoma, NSCLC, and other tumor types 
support a lack of meaningful difference in pharmacokinetic exposures obtained at tested 
doses among tumor types.  Thus the 200 mg Q3W fixed-dose regimen is considered an 
appropriate fixed dose for other tumor indications as well.  
A fixed dose regimen will simplify the dosing regimen to be more convenient for physicians 
and to reduce potential for dosing errors.  A fixed dosing scheme will also reduce complexity 
in the logistical chain at treatment facilities and reduce wastage. The existing data suggest 
200 mg Q3W as the appropriate dose for pembrolizumab.
Rationale for the Use of Comparator/Placebo
This is a double-blinded trial .Subjects will be randomized to receive IV pembrolizumab or 
placebo. Both treatment arms are eligible to receive BSC based on the discretion of the 
investigator. 
In the second-line setting, there is no clear standard of care for HCC-directed therapy.  
Several large randomized trials failed to show a significant survival advantage against 
placebo in the second line setting, including brivanib [14], everolimus [15], and ramucirumab 
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[16].  Smaller studies have suggested the possible efficacy for MET inhibitors and 
regorafenib in advanced HCC, and larger randomized trials are underway to investigate these 
drugs [17][18].  Chemotherapy drugs including capecitabine and the gemcitabine/oxaliplatin 
combination have also been used in the second line, and retrospective reviews suggest some 
possible effects [19][20].  However, there are no agents or combinations yet approved for 
second-line HCC, underscoring the high unmet need for this disease, and the rationale for a 
placebo arm.  Subjects randomized to pembrolizumab and to the placebo arm will be treated 
with BSC at the investigator’s discretion.  
Rationale for Endpoints
Efficacy Endpoints
4.2.3.1.1 Primary Efficacy Endpoints
The primary efficacy objective of this study is to evaluate the anti-tumor activity of 
pembrolizumab in Asian subjects with HCC. OS is the primary endpoint. The endpoint of OS 
is the gold standard for demonstrating superiority of antineoplastic therapy in clinical studies 
in the area of oncology.
4.2.3.1.2 Secondary Efficacy Endpoints
The secondary efficacy objectives of this study are to: 
1) To compare PFS per RECIST 1.1 as assessed by BICR
2) To compare ORR per RECIST 1.1 as assessed by BICR
3) To evaluate DOR, DCR and TTP per RECIST 1.1 as assessed by BICR
Measurable disease will be confirmed by the investigator at enrollment, prior to subject 
randomization, to ensure that the assessment of measurable disease is accurate. These 
endpoints have been chosen as ancillary markers of efficacy in a population with few 
treatment options.
4.2.3.1.3 Exploratory Endpoints
Exploratory efficacy objectives of this study are to explore ORR, DOR, DCR, TTP and PFS 
per irRECIST assessed by the central imaging vendor to assess different evaluations in HCC 
population.  
Since the association between PD-L1 IHC and responses in HCC is still not clear. This study 
will collect tumor tissue for PD-L1 IHC testing. It will explore the association between PD-
L1 IHC and response in subjects with HCC treated with pembrolizumab plus BSC versus 
placebo plus BSC to determine whether PD-L1 expression may predict response to 
pembrolizumab.
Quality of life and health utilities will be examined between groups. EORTC QLQ-C30 will 
be used for evaluating changes in health related quality of life from baseline; and EuroQol 
EQ-5D will used to characterize utilities between two treatment arms.
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Immune-related RECIST (irRECIST)
RECIST 1.1 will be adapted to account for the unique tumor response characteristics seen 
with treatment of pembrolizumab. Immunotherapeutic agents such as pembrolizumab may 
produce antitumor effects by potentiating endogenous cancer-specific immune responses.  
The response patterns seen with such an approach may extend beyond the typical time course 
of responses seen with cytotoxic agents, and can manifest a clinical response after an initial 
increase in tumor burden or even the appearance of new lesions.  Standard RECIST 1.1 may, 
thus, not provide an accurate response assessment of immunotherapeutic agents such as 
pembrolizumab. 
Based on an analysis of patients with melanoma enrolled in KEYNOTE-001, 7% of 
evaluable patients experienced delayed or early tumor pseudoprogression.  Of note, patients 
who had progressive disease by RECIST 1.1 but not by immune-related response criteria had 
longer OS than patients with progressive disease by both criteria.  Additionally, the data 
suggest that RECIST 1.1 may underestimate the benefit of pembrolizumab in approximately 
15% of patients.  These findings support the need to apply a modification to RECIST 1.1 that 
takes into account the unique patterns of atypical response in immunotherapy and enable 
treatment beyond initial radiographic progression as described above (Section 2.1). 
Immune-related RECIST (irRECIST) is RECIST 1.1 adapted to account for the unique tumor 
response seen with immuno-therapeutics as described in Nishino et al., [1].  The assessment 
of unidimensional target lesions and response categories per irRECIST are identical to 
RECIST 1.1.  However, Merck has implemented an adaptation related to new lesions, non-
target lesions and tumor burden assessment in order to confirm radiographic progression.  
Therefore, irRECIST will be used by local site investigators to assess tumor response and 
progression, and make treatment decisions as well as by the central imaging vendor in 
support of all secondary and exploratory response endpoints.  Confirmation of PD for 
irRECIST endpoints will be taken from the central imaging review retrospectively, according 
to the irRECIST definition.
For further information on irRECIST, see Section 7.1.4.7
Patient Reported Outcomes
As part of an exploratory analysis, subjects will provide information regarding their health-
related quality of life (HRQoL) via the following EORTC assessment tools: EORTC 
QLQ-C30 and EuroQol-5D3L (EQ5D-3L) questionnaires.  These measures are not pure 
efficacy or safety endpoints because they are affected by both disease progression and 
treatment tolerability. 
EORTC QLQ-C30 
The EORTC QLQ-C30 is the most widely used cancer specific HRQoL instrument. It 
contains 30 items and measures 5 functioning dimensions (physical, role, cognitive, 
emotional, and social), 3 symptom items (fatigue, nausea/vomiting, pain), 6 single items 
(dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, and financial impact), and a 
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global health and quality of life scale [56].  This instrument has been translated and validated
into 81 languages and used in more than 3000 studies worldwide.
EuroQoL-5D
The EuroQol-5D-3L (EQ5D-3L) is a standardized instrument for use as a measure of health 
outcome.  The EQ5D-3L will provide data for use in economic models and analyses 
including developing health utilities or quality adjusted life years (QALYs).  The 5 health 
state dimensions in this instrument include the following:  mobility, self-care, usual 
activities, pain/discomfort, and anxiety/depression.  Each dimension is rated on a three point 
scale from 1 (extreme problem) to 3 (no problem).  The EQ5D-3L also includes a graded (0 
to 100) vertical visual analog scale on which the subject rates his or her general state of 
health at the time of the assessment.  The EQ5D-3L will always be completed by subjects 
first before completing the EORTC QLQ-C30 and is to be completed at various time points 
as specified in the Trial Flow Chart, beginning with Cycle 1 until 30 days post-treatment 
discontinuation. 
See flow chart for Patient Reported Outcome (PRO) administration schedule (Section 6.1).
Medical Resource Utilization and Health Economics
All-cause hospitalizations and emergency room visits must be reported in the eCRF, from the
time of treatment allocation/randomization through 90 days following cessation of study
treatment, or 30 days following cessation of study treatment, if the participant initiates new
anticancer therapy, whichever is earlier.
Safety Endpoints
The safety objective of this trial is to characterize the safety and tolerability of 
pembrolizumab in Asian subjects with previously systemically treated HCC.  The primary 
safety analysis will be based on subjects who have toxicities as defined by NCI-CTCAE, 
v4.0 (see Section 12.6). 
The attribution to drug, time-of-onset, duration of the event, its resolution, and any 
concomitant medications administered will be recorded.  Safety parameters to be analyzed 
include, but are not limited to, AEs, SAEs, fatal AEs, and laboratory changes.  Furthermore, 
specific events will be collected and designated as events of clinical interest (ECIs) as 
described in Section 7.2.3.  
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the 
last dose of trial treatment or before the initiation of a new anti-neoplastic treatment, 
whichever comes first. All AEs that occur prior to the Safety Follow-Up Visit should be 
recorded. Subjects with an AE of Grade >1 will be followed until the resolution of the AE to 
Grade 0-1 or until the beginning of a new anti-neoplastic therapy, whichever occurs first.  All 
SAEs that occur within 90 days following cessation of treatment, or 30 days following 
cessation of treatment if the subject initiates new anticancer therapy, whichever is earlier, 
should be followed and recorded.
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Biomarker Research
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Future Biomedical Research
Benefit/Risk
Subjects in clinical trials generally cannot expect to receive direct benefit from treatment 
during participation, as clinical trials are designed to provide information about the safety 
and effectiveness of an investigational medicine. However, experience with this approved 
drug in other indications, as well as similar drugs in hepatocellular carcinoma suggests that 
study subjects may receive a clinical benefit (see Section 4.1.1).  
The benefit-risk profile for pembrolizumab in HCC population is unknown since these
subjects have not been previously reported. The safety and efficacy data generated to date 
provide a favorable risk-benefit assessment for the continued use of pembrolizumab as a 
treatment for advanced/metastatic melanoma and NSCLC, and as an investigational 
medicinal product in subjects with triple negative breast cancer, squamous cell carcinoma of 
the head and neck, urothelial tract cancer, colorectal cancer, adenocarcinoma of the 
stomach/gastroesophageal junction, renal cell carcinoma, hematologic malignancies, multiple 
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myeloma, and other advanced solid tumors. Based on pembrolizumab data from other 
indications and data in HCC patients, as well as data from other agents in the class, a 
favorable benefits-risk profile is anticipated. No unexpected risks have been reported in HCC 
with other immune check point inhibitors other than transient elevations in alanine 
aminotransferase (ALT) and aspartate aminotransferase (AST).
Additional details regarding specific benefits and risks for subjects participating in this 
clinical trial may be found in the accompanying IB and Informed Consent documents.
5.0 METHODOLOGY
Entry Criteria
Diagnosis/Condition for Entry into the Trial
Male/Female Asian subjects with advanced HCC after progression on or intolerance to
sorafenib or oxaliplatin-based chemotherapy with no curative option will be enrolled in this 
trial.
Subject Inclusion Criteria
In order to be eligible for participation in this trial, the subject must:
1. Be willing and able to provide written informed consent for the trial.  The subject 
may also provide consent for Future Biomedical Research (FBR).  However, the 
subject may participate in the main trial without participating in FBR.
2. Be 18 years of age on day of signing informed consent.
3. Have a HCC diagnosis confirmed by radiology, histology, or cytology (fibrolamellar, 
and mixed hepatocellular/cholangiocarcinoma subtypes are not eligible).
Note: Radiologic confirmation diagnosis is provided by the study site.  Definition of 
radiological confirmation:  Clinical findings consistent with the diagnosis of liver 
cirrhosis and a liver mass measuring at least 2 cm with characteristic vascularization 
(intense enhancement seen in the hepatic arterial-dominant phase and contrast 
washout in the late portal venous phase) seen in either triphasic computed 
tomography (CT) scan or magnetic resonance imaging (MRI).
4. Have Barcelona Clinic Liver Cancer (BCLC) Stage C diseases or BCLC Stage B 
disease not amenable to locoregional therapy or refractory to locoregional therapy
and not amenable to a curative treatment approach (see Appendix 12.8). 
5. Have a Child-Pugh A liver score within 7 days prior to first dose of study drug.
6. Have a predicted life expectancy of >3 months.
7. Have at least one measurable lesion based on RECIST 1.1 as determined by 
investigator.  Target lesions situated in a previously irradiated or post locoregional 
treatment area are considered measurable if progression has been demonstrated in 
such lesions
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Note: the same image acquisition and processing parameters should be used 
throughout the study for a given subject.
8. Have a performance status of 0 or 1 using the Eastern Cooperative Oncology Group 
(ECOG) Performance Scale within 7 days of first dose of study drug.
9. Have documented objective radiographic progression during or after treatment with 
sorafenib
or oxaliplatin-based chemotherapy,
or intolerance to sorafenib
or 
oxaliplatin-based chemotherapy. 
Note: (1) Sorafenib intolerance definition: Any Grade ≥2 drug-related AE which, 
despite supportive therapy, recurred after a sorafenib treatment interruption of at least 
7 days and dose reduction resulting in the subject requesting, or the physician 
recommending discontinuation of medication due to toxicity.  
(2) Oxaliplatin-based chemotherapy intolerance definition: 1) having had at least one 
dose of chemotherapy and 2) having a Grade ≥2 drug-related AE which both a) 
persisted in spite of comprehensive supportive therapy according to institutional 
standards and b) persisted or recurred after dose reduction and resulted in the subject 
requesting or the physician recommending discontinuation of medication due to the 
toxicity
10. Female subjects of childbearing potential must have a negative urine or serum 
pregnancy test within 72 hours prior to receiving the first dose of study medication 
(Cycle 1, Day 1). If the urine test is positive or cannot be confirmed as negative, a 
serum pregnancy test will be required.  
11. Female subjects of childbearing potential (Section 5.7.2) must be willing to use an 
adequate method of contraception as outlined in Section 5.7.2 – Contraception for the 
course of the study, starting with the first dose of study medication through at least 
120 days or longer based on local regulation after the last dose of study medication .
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception 
for the subject.
12. Male subject of childbearing potential (Section 5.7.2) must agree to use an adequate 
method of contraception as outlined in Section 5.7.2 - Contraception, starting with the 
first dose of study medication (Cycle 1, Day 1) through 120 days after the last dose of 
study medication 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception 
for the subject.
13. Demonstrate adequate organ function as defined in Table 1.  All screening laboratory 
tests should be performed within 7 days prior to first dose of study drug.
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Table 1
Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
≥1200/µL
Platelets
≥60,000/µL
Hemoglobin
≥8 g/dL without transfusion or EPO dependency within 7 
days.
Renal
Creatinine OR
Measured or calculated creatinine clearance
(GFR can also be used in place of creatinine 
or creatinine clearance)
≤1.5×ULN OR
≥60 mL/min for subject with creatinine levels >1.5 × 
institutional ULN
Note:  Creatinine clearance should be calculated per 
institutional standard
Hepatic
Total bilirubin
≤2 mg/dL, or direct bilirubin ≤ULN for those with total 
bilirubin > 2mg/dL
AST (SGOT) and ALT (SGPT)
≤5×ULN 
Albumin
≥3.0 g/dL
Note: No albumin supplement (or BCAA) allowed within 
the last 14 days.
Coagulation
INR or PT
≤1.5×ULN unless subject is receiving anticoagulant 
therapy
as long as PT is within therapeutic range of intended use 
of anticoagulants
ALT = alanine aminotransferase; AST = aspartate aminotransferase; EPO = erythropoietin; GFR = glomerular filtration 
rate; INR = international normalized ratio; PT = prothrombin time; SGOT = serum glutamic oxaloacetic transaminase; 
SGPT = serum glutamic pyruvic transaminase; ULN = upper limit of normal.  
Subject Exclusion Criteria
The subject must be excluded from participating in the trial if the subject:
1. Is currently participating, or has participated in any study of an investigational agent 
and received its study therapy, or used an investigation device within 4 weeks prior to 
the first dose of our study treatment. Has received herbal/complementary oral or IV 
medicine used as systemic anti-cancer therapy within 2 weeks prior to the first dose 
of our study treatment. Subjects must also have recovered from associated therapy 
(i.e., to Grade ≤1 or baseline) and from adverse events due to any prior therapy. 
2. Has received sorafenib or oxaliplatin-based chemotherapy within 14 days of first dose 
of study medication, or received more than one systemic anticancer drug in the 
advanced hepatocellular cancer setting.
3. Has had esophageal or gastric variceal bleeding within the last 6 months. 
4. Has clinically apparent ascites on physical examination.  
Note: ascites detectable on imaging studies only IS allowed.
5. Portal vein invasion at the main portal branch (Vp4), inferior vena cava, or cardiac 
involvement of HCC based on imaging.  
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6. Has had clinically diagnosed hepatic encephalopathy in the last 6 months.  Subjects 
on rifaximin or lactulose to control their encephalopathy are not allowed.
7. Has had a solid organ or hematologic transplant.
8. Had prior systemic therapy for HCC in the advanced (incurable) setting other than 
sorafenib or oxaliplatin-based chemotherapy, prior to start study drug.
9. Has a known severe hypersensitivity (≥Grade 3) to pembrolizumab, its active
substance and/or any of its excipients. (Refer to the respective Investigator’s
Brochure for a list of excipients.)
10. Has active autoimmune disease that has required systemic treatment in past 2 years 
(i.e., with use of disease-modifying agents, corticosteroids, or immunosuppressive 
drugs).  Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a 
form of systemic treatment.
11. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any 
other form of immunosuppressive therapy within 7 days prior to the first dose of trial 
treatment.  The use of physiologic doses of corticosteroids may be approved after 
consultation with the Sponsor.
Physiologic dose of corticosteroid definition: ≤10 mg/day prednisone or equivalent
12. Has received locoregional therapy to liver (transcatheter chemoembolization [TACE], 
transcatheter embolization [TAE],
hepatic arterial infusion [HAI], radiation, 
radioembolization, or ablation) within 4 weeks prior to the first dose of study drug.  
Subject is not eligible if aforementioned treatments were administered between last 
dose of sorafenib or oxaliplatin-based chemotherapy and first dose of study 
medication.
13. Has had major surgery to liver or other site within 4 weeks prior to the first dose of
study drug.
14. Has had a minor surgery (e.g., simple excision, tooth extraction) ≤7 days prior to the 
first dose of study treatment (Cycle 1, Day 1).  
15. Has not recovered adequately (i.e., Grade ≤1 or baseline) from the toxicity and/or
complications from any intervention prior to starting therapy.
16. Has a diagnosed additional malignancy within 3 years prior to first dose of study 
treatment with the exception of curatively treated basal cell carcinoma of the skin, 
squamous cell carcinoma of the skin and/or curatively resected in situ cancers.
17. Has a known history of, or any evidence of, central nervous system (CNS) metastases
and/or carcinomatous meningitis as assessed by local site investigator.
18. Has a history of (non-infectious) pneumonitis that required steroids or current 
pneumonitis.
19. Has an active infection requiring systemic therapy.
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20. Has a history or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the trial, interfere with the subject’s participation
for the full duration of the trial, or is not in the best interest of the subject to
participate, in the opinion of the treating investigator, including dialysis.
21. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial.
22. Is pregnant or breastfeeding, or expecting to conceive or father children within the
projected duration of the trial, starting with the first dose of study medication through
120 days or longer based on local regulation after the last dose of trial treatment.
23. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or 
with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, 
CTLA-4, OX-40, CD137), or if the subject has previously participated in Merck 
pembrolizumab clinical trials.
24. Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies).
No HIV testing is required unless mandated by local health authority
25. Has untreated active Hepatitis B. (Please refer to Table 19)
Note:  Controlled (treated) hepatitis B subjects will be allowed if they meet the
following criteria:
Antiviral therapy for HBV must be given for at least 4 weeks prior to first dose of 
study drug, and HBV viral load must be maintained less than 2000 IU/mL 
(104copies/ml) for at least 4 weeks prior to first dose of study drug.  Those on active 
HBV therapy with viral loads under 2000 IU/mL (104copies/ml) should stay on the 
same therapy throughout study treatment.
Those subjects who are anti-HBc (+) and negative for HBsAg, anti-HBs and HBV 
viral load do not require HBV prophylaxis, but need close monitoring for reactivation 
as described
26. Subjects with chronic HCV infection with less than 4 weeks between completion of 
HCV therapy and start of study drug.
Note: Subjects with chronic infection with HCV who are untreated or non-curatively 
treated HCV are allowed on study.
27. Has received a live vaccine within 30 days of planned start of study therapy (Cycle 1, 
Day 1).
Note: The killed virus vaccines used for seasonal influenza vaccines for injection are 
allowed; however intranasal influenza vaccines (e.g., FluMist®) are live attenuated 
vaccines and are not allowed.
28. Any subject who cannot receive MRI or triphasic, contrast-enhanced CT for 
evaluation of HCC.
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Trial Treatment(s)
Study treatment to be used in this trial is outlined below in Table 2. BSC will vary with local 
treatment practices.
Table 2
Trial Treatment
Drug
Dose/Potency
Dose 
Frequency
Route of 
Administration
Regimen
Use 
Pembrolizumab
(MK-3475)
200 mg
Q3W
IV infusion
IV infusion
Experimental
Placebo
0.90% 
w/v 
NaCI
Q3W
IV infusion
IV infusion
Control
Trial Treatment should begin within 3 days of randomization. However, every effort should 
be made to begin trial treatment on the day of randomization.
All supplies indicated in Table 2 above will be provided centrally by the Sponsor or locally 
by the trial site, subsidiary or designee, depending on local country operational or regulatory 
requirements.
For any commercially available product that is provided by the trial site, subsidiary or 
designee every attempt will be made to source these supplies from a single lot/batch number. 
The trial site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product as per local guidelines unless otherwise instructed by the 
Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of trial 
treatments in accordance with the protocol and any applicable laws and regulations.
Dose Selection/Modification
Dose Selection (Preparation)
The rationale for selection of the dose of pembrolizumab to be used in this trial is provided in 
Section 4.0, Background and Rationale.  Details on preparation and administration of study 
drug are provided in the Pharmacy Manual. 
Administration of BSC should follow local treatment guidelines.
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Dose Modification (Escalation/Titration/Other)
5.2.1.2.1 Immune-Related 
Events 
and 
Dose 
Modification 
(Withhold, 
Treat, 
Discontinue)
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. Based on the severity of irAEs, withhold or permanently 
discontinue pembrolizumab and administer corticosteroids. 
Dose Modification and Toxicity Management Guidelines for Non-hepatic irAEs associated 
with pembrolizumab monotherapy, coformulations, or IO combinations are provided in 
Table 3.
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Table 3
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 
(CTCAEv4.0)
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 1-2 mg/kg 
prednisone or equivalent) 
followed by taper

Monitor participants for signs and symptoms of 
pneumonitis

Evaluate participants with suspected pneumonitis 
with radiographic imaging and initiate 
corticosteroid treatment

Add prophylactic antibiotics for opportunistic 
infections
Recurrent Grade 2 
or Grade 3 or 4 
Permanently 
discontinue
Diarrhea / Colitis 
Grade 2 or 3
Withhold

Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper

Monitor participants for signs and symptoms of 
enterocolitis (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 
(CTCAEv4.0)
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 β-cell 
failure
Withhold a

Initiate insulin replacement 
therapy for participants 
with T1DM

Administer anti-
hyperglycemic in 
participants with 
hyperglycemia

Monitor participants for hyperglycemia or other 
signs and symptoms of diabetes
Hypophysitis
Grade 2
Withhold

Administer corticosteroids 
and initiate hormonal 
replacements as clinically 
indicated

Monitor for signs and symptoms of hypophysitis 
(including hypopituitarism and adrenal 
insufficiency)
Grade 3 or 4
Withhold or 
permanently 
discontinue a
Hyperthyroidism 
Grade 2
Continue

Treat with non-selective 
beta-blockers (eg, 
propranolol) or thionamides 
as appropriate

Monitor for signs and symptoms of thyroid 
disorders
Grade 3 or 4
Withhold or 
Permanently 
discontinue a
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irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Hypothyroidism
Grade 2-4
Continue

Initiate thyroid replacement 
hormones (eg, 
levothyroxine or 
liothyronine) per standard 
of care

Monitor for signs and symptoms of thyroid 
disorders
Nephritis and 
renal dysfunction
Grade 2
Withhold

Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by 
taper

Monitor changes of renal function
Grade 3 or 4
Permanently 
discontinue
Myocarditis
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
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 b
Recurrent Grade 3 
or Grade 4 
Permanently 
discontinue
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: Guillain-Barre Syndrome, encephalitis, myelitis, DRESS, SJS, TEN 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
Pembrolizumab may cause severe or life threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion. 
Dose modification and toxicity management guidelines on pembrolizumab associated 
infusion reaction are provided in Table 4. 
Table 4
Pembrolizumab Infusion Reaction Dose modification and Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at 
Subsequent Dosing
Grade 1
Mild reaction; infusion 
interruption 
not 
indicated; 
intervention 
not indicated
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator.
None
Grade 2
Requires 
therapy 
or 
infusion interruption but 
responds promptly to 
symptomatic treatment 
(e.g., 
antihistamines, 
NSAIDs, narcotics, IV 
fluids); 
prophylactic 
medications 
indicated 
for ≤24 hrs
Stop Infusion.
Additional appropriate medical therapy may 
include but is not limited to:
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator.
If symptoms resolve within 1 hour of stopping 
drug infusion, the infusion may be restarted at 
50% of the original infusion rate (e.g. from 100 
mL/hr to 50 mL/hr).  Otherwise dosing will be 
held until symptoms resolve and the subject 
should be premedicated for the next scheduled 
dose.
Subjects who develop Grade 2 toxicity despite 
adequate premedication should be permanently 
discontinued from further study drug treatment
Subject may be premedicated 
1.5h (± 30 minutes) prior to 
infusion of study treatment 
with:
Diphenhydramine 50 mg po 
(or 
equivalent 
dose 
of 
antihistamine).
Acetaminophen 500-1000 mg 
po (or equivalent dose of 
analgesic).
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NCI CTCAE Grade
Treatment
Premedication at 
Subsequent Dosing
Grades 3 or 4
Grade 3:
Prolonged 
(i.e., 
not 
rapidly responsive to 
symptomatic medication 
and/or brief interruption 
of infusion); recurrence 
of symptoms following 
initial 
improvement; 
hospitalization indicated 
for 
other 
clinical 
sequelae 
(e.g., 
renal 
impairment, pulmonary 
infiltrates)
Grade 4:
Life-threatening; 
pressor or ventilatory 
support indicated
Stop Infusion.
Additional appropriate medical therapy may 
include but is not limited to:
Epinephrine**
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator.
Hospitalization may be indicated.
**In cases of anaphylaxis, epinephrine should be 
used immediately.
Subject is permanently discontinued from 
further study drug treatment.
No subsequent dosing
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during 
the period of drug administration.
For further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) at 
http://ctep.cancer.gov
Other allowed dose interruption for pembrolizumab 
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as 
medical / surgical events or logistical reasons not related to study therapy. Subjects should be 
placed back on study therapy within 3 weeks of the scheduled interruption, unless otherwise 
discussed with the Sponsor. The reason for interruption should be documented in the patient's 
study record.
Guidance for Diagnosis and Management of Hepatic Events of Clinical Interest 
In addition to overdose, hepatic ECIs will include any of the following events.  All of these 
events will require holding study treatment, notification of the Sponsor within 24 hours, and 
a hepatologist consultation (if necessary).  All cases of retreatment and permanent 
discontinuation must be reported to the Sponsor and recorded in the database.  Refer to 
Section 7.2.3.2 for reporting guidelines and the definition of hepatic ECIs.
a.
ALT:
i. Among subjects with baseline ALT <2×ULN:  ALT ≥5×ULN
ii. Among subjects with baseline ALT ≥2×ULN:  ALT >3× the baseline
level
iii. ALT >500 U/L regardless of baseline level
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b. AST:
i. Among subjects with baseline AST <2×ULN:  AST ≥5×ULN
ii. Among subjects with baseline AST ≥2×ULN:  AST >3× the baseline
level
iii. AST >500 U/L regardless of baseline level
c.
Total Bilirubin:
i. Among subjects with baseline levels <1.5 mg/dL:  a value of 
>2.0 mg/dL
ii. Among subjects with baseline levels that are ≥1.5 mg/dL:  a value ≥2× 
the baseline level 
iii. Total bilirubin >3.0 mg/dL regardless of baseline level
d. Regardless of laboratory values, hepatic decompensation diagnosed clinically, 
including:
i. New onset clinically detectable ascites
ii. Gastrointestinal bleeding suggestive of portal hypertension (e.g.,
esophageal or gastric varices)
iii. Encephalopathy
Immediate assessment
All subjects

All subjects should be evaluated according to directions below within 
72 hours of alert for non-overdose hepatic ECI 

Procedures:
o
Obtain a consultation with a hepatologist (if necessary)
o
Obtain a work-up for hepatitis if there is no underlying hepatitis, including 
hepatitis A, B,C, D, E, Epstein-Barr virus, and cytomegalovirus
o
Assess for ingestion of drugs/supplements with hepatotoxic potential 
o
Assess for alcohol ingestion
o
Assess for potential bacterial infection, biliary obstruction, or occult 
gastrointestinal bleeding
o
Repeat ALT, AST, T-bil, D-bil, ALP, -glutamyl transpeptidase, INR, and 
complete blood count (CBC) with differential 
o
Other laboratories or imaging studies as clinically indicated
o
Consider liver biopsy if indicated by hepatologist
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Hepatitis C-Infected Subjects (including subjects who previously achieved sustained 
virologic response for 12 weeks [SVR 12] or sustained virologic response for 24 
weeks [SVR24]

In addition to the above, measure HCV RNA viral load
Hepatitis B-infected Subjects

In addition to the above, measure HBV DNA, HBsAg, HBeAg, anti-HBc, 
anti-HBe antibody, and anti-HBs antibody

Subjects should be questioned about compliance with the use of anti-viral 
agents.
Permanent Discontinuation Criteria for Subjects with Non-overdose Hepatic ECI
Therapy should also be permanently discontinued for: 

ALT >20×ULN

Child-Pugh (CP) score of ≥9 points

Gastrointestinal bleeding suggestive of portal hypertension (e.g., esophageal 
or gastric varices)

New onset clinically detectable ascites

Hepatic encephalopathy or

Recurrence of a severe or life-threatening event, or of any of the laboratory 
abnormalities listed above, that are presumed to be immune-related.
Diagnosis and Management of Non-Overdose Hepatic ECIs
HCC subjects 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.  Immune-related hepatitis has been observed in ~1% of subjects who 
received pembrolizumab.  The following section provides further guidance on the 
diagnosis and management of potential hepatic complications among HCC subjects. 
a.
Hepatitis B Flare
Hepatitis B flares are characterized by rapid elevations of ALT and AST to 
>5×ULN and/or >3× baseline.  ALT elevation to ≥10×ULN is common.  In the 
absence of hepatic decompensation, ALT/AST elevations are typically isolated 
(i.e., limited/no elevations of bilirubin/ALP).  Subjects who are compliant with 
anti-viral therapy should have continued suppression of HBV DNA at the time of 
flare; thus, detection of HBV DNA should prompt questioning of subjects for 
compliance.  Laboratory abnormalities secondary to flare are typically observed 
for 3-5 weeks.  
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Among subjects with HBV, a flare should be considered if this pattern is observed 
and there is no evidence of an alternative etiology.  Guidelines for subjects with a 
diagnosis of HBV flare are as follows:

Care should be instituted in consultation with a hepatologist (if necessary).

For subjects who have detectable HBV DNA, re-institute anti-viral therapy.

If the subject is clinically stable, pembrolizumab dosing may be interrupted 
for up to 12 weeks.  Subjects should undergo weekly laboratory tests 
including: AST, ALT, ALP, T-bil, D-bil, INR, HBsAg, HBV DNA (if 
detected at the onset of the flare).  Obtain anti-HBe antibody, anti-HBs 
antibody, and HBV DNA levels (if not detected at the onset of the flare) every 
2-3 weeks.

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 subjects are clinically 
stable, subjects may restart pembrolizumab treatment.  If these conditions are 
not met, then pembrolizumab treatment should be permanently discontinued.
b. Hepatitis C Recurrence or Flare
Subjects who achieved SVR 12 or SVR 24 and subjects with ongoing HCV 
infection are eligible for enrollment.  In rare circumstances, HCV subjects who 
achieve SVR 12 or SVR 24 may relapse at later time points.  Relapse is 
characterized by detection of HCV RNA, often accompanied by ALT elevations 
to >5×ULN.  In the absence of hepatic decompensation, ALT/AST elevations are 
typically isolated (i.e., limited/no elevations of bilirubin/ALP).
Among subjects with uncontrolled hepatitis C, virologic flares are possible.  
Hepatitis C flares are characterized by rapid elevations of ALT and AST to 
>5×ULN and/or >3× baseline along with a rise in HCV RNA.  ALT elevation to 
≥10×ULN and a 1 log elevation in HCV RNA level are common.  In the absence 
of hepatic decompensation, ALT/AST elevations are typically isolated (i.e., 
limited/no elevations of bilirubin/ALP).  Laboratory abnormalities secondary to 
flare or recurrence are typically observed for 3-5 weeks.  
Guidelines for subjects with recurrent HCV infection or an HCV flare are 
described below:
i. Recurrent HCV infection:
If the subject entered the study with an HCV RNA test of “Target not 
Detected” and has confirmed detectable HCV RNA (2 specimens, 1 week 
apart), then the subject has experienced a late HCV relapse or a recurrent 
infection. 

Question the subject about use of injection or inhalation drugs

At the time of first detection of HCV RNA, send a specimen for HCV 
genotyping

Measure AST, ALT, ALP, T-bil, D-bil, and INR weekly
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
Measure HCV RNA levels every 2 weeks

Therapy with HCV anti-viral treatments should be strongly considered.
i. HCV Flare:

At the time of first detection of HCV RNA, send a specimen for HCV 
genotyping

Measure AST, ALT, ALP, T-bil, D-bil, INR weekly

Measure HCV RNA levels every 2 weeks

Therapy with HCV anti-viral treatments should be strongly considered. 
ii. For both recurrent infection and HCV flare:  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 subjects are clinically stable, subjects may restart 
pembrolizumab treatment.  If these conditions are not met, then 
pembrolizumab treatment should be permanently discontinued.
c.
Immune-related hepatitis 
i. Description:  Immune-related hepatitis due to pembrolizumab should be 
suspected if:

AST or ALT baseline values are less than 2×ULN, and AST or ALT 
laboratory values increase to ≥5×ULN

Among subjects with baseline ALT or AST ≥2×ULN, levels increase to 
>3× the baseline level

AST/ALT >500 U/L regardless of baseline level

Among subjects with baseline T-bil levels <1.5 mg/dL:  a value of 
>2.0 mg/dL

Among subjects with baseline T-bil levels that are ≥1.5 mg/dL:  a value of 
≥2× the baseline level, OR

Total bilirubin >3.0 mg/dL regardless of baseline level.
Immune-related hepatitis is a diagnosis made after excluding other possible 
etiologies for the change.  Viral flare (if applicable), biliary or vascular 
obstruction, infection, medications, and alcohol use must be ruled out (see 
below).
ii. Management

Interrupt pembrolizumab treatment and alert the sponsor as per ECI 
criteria above for ALT, AST, bilirubin, and hepatic decompensation.  

For Grade 2 AST / ALT elevation or increased bilirubin, administer 
corticosteroids (initial dose of 0.5-1mg/kg prednisone or equivalent) 
followed by taper.
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
For Grade 3-4 AST / ALT elevation or increased bilirubin, administer 
corticosteroids (initial dose of 1-2mg/kg prednisone or equivalent) 
followed by taper.

Monitor with liver function tests (consider weekly or more frequently until 
liver enzyme value returned to baseline or is stable).

If symptoms and laboratory tests resolve to Grade ≤1 or baseline (if 
abnormal at baseline), taper steroids over 28 days. Study treatment may be 
restarted after steroid treatment has been tapered to prednisone ≤10 
mg/day (or equivalent dose of another agent).  Treatment and laboratory 
results must be reported on a case report form (CRF).

If laboratory abnormalities do not resolve within 3 weeks, or steroids 
cannot be lowered to ≤10 mg/day (or prednisone equivalent) within 
12 weeks, or subjects show evidence of decompensation to Child-Pugh 
score C (CP C) status or have esophageal or variceal bleeding at any point, 
treatment must be permanently discontinued.  This must be reported on a 
CRF.
d. Other Hepatic Events of Clinical Interest

Infection needs to be ruled out with cultures of blood, urine, and ascites (if 
possible), as well as chest x-ray and abdominal imaging if relevant.  If an 
infection is found, antibiotics should be started.  

If T-bili is elevated above baseline, imaging assessment should be obtained to 
rule out vascular compromise, biliary obstruction, and/or tumor progression.  
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. 

A careful review of drugs, including herbal and alternative medications, 
should be obtained, and alcohol use should be ruled out.  See Section 5.5.2 for 
drugs which may interfere with hepatic function. 

For all of these cases, subjects may resume pembrolizumab treatment if they 
are clinically stable after appropriate therapy or discontinue the causative 
agent, as long as laboratory values have returned to Grade 1 or baseline (if 
normal or Grade 1 at start) or to baseline grade within 3 weeks.  

Treatment must be permanently discontinued if the subject is off study 
treatment therapy for infection, obstruction, or drug/alcohol-related toxicity 
for more than 3 weeks, or if they have esophageal bleeding, or become CP C 
at any point.
Timing of Dose Administration
Cycle 1, Day 1 treatment with study drug should begin on the day of randomization, but no 
later than 3 days from the date the subject is randomized to study treatment.  However, every 
effort should be made to begin trial treatment on the day of randomization.  
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For all additional cycles of study treatment, treatment 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.  
All study treatments will begin on Day 1 of each cycle after all pre-dose study procedures 
and assessments have been completed as detailed on the Trial Flow Chart –Section 6.0.
Study treatment 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 min and 
+10 min is permitted (i.e., infusion time is 30 minutes: –5 min/+10 min).
The Pharmacy Manual contains specific instructions for the preparation of the study 
treatment infusion fluid and administration of infusion solution.
Trial Blinding 
A double-blinding technique with in-house blinding will be used.  Pembrolizumab and 
placebo will be packaged identically so that blind is maintained. The subject, the investigator 
and Sponsor personnel or delegate(s) who are involved in the treatment or clinical evaluation 
of the subjects are unaware of the group assignments.
See Section 7.1.5.2, Blinding/Unblinding, for a description of the method of unblinding a 
subject during the trial, should such action be warranted.
Randomization
Treatment allocation/randomization will occur centrally using an interactive voice response 
system / integrated web response system (IVRS/IWRS).
There are 2 treatment arms.  
Subjects will be assigned randomly in a 2:1 ratio to pembrolizumab and placebo, 
respectively.
Stratification
Treatment allocation/randomization will be stratified according to the following factors:
1) Prior treatment  (sorafenib vs. chemotherapy)
2) Macrovascular invasion: (Yes vs. No)
3) Etiology (HBV vs. others (HCV, non-infected))
Concomitant Medications/Vaccinations (Allowed & Prohibited)
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for any medication or vaccination 
specifically prohibited during the trial, discontinuation from trial therapy or vaccination may 
be required.  The investigator should discuss any questions regarding this with the Sponsor 
Clinical Director.  The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the subject's primary physician.  However, the decision to continue the 
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subject on trial therapy or vaccination schedule requires the mutual agreement of the 
investigator, the Sponsor and the subject.
Acceptable Concomitant Medications
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.  All concomitant medication will be recorded on the case report form (CRF) 
including all prescription, over-the-counter (OTC), and IV medications and fluids.  If 
changes occur during the trial period, documentation of drug dosage, frequency, route, and 
date may also be included on the CRF.
All medications received within 28 days before the first dose of trial treatment and within 
30 days after the last dose of trial treatment should be recorded.  Medications administered 
more than 30 days after the last dose of trial treatment should be recorded for SAEs and 
events of clinical interest (ECIs) as defined in Section 7.2.3.  
Prohibited Concomitant Medications
Subjects are prohibited from receiving the following therapies during the Treatment Phase 
(including retreatment for post-CR relapse) of this trial:

Antineoplastic systemic chemotherapy or biological therapy

Immunotherapy not specified in this protocol

Chemotherapy not specified in this protocol

Investigational agents other than pembrolizumab

Radiation therapy.  
o
Note: Radiation therapy to a symptomatic solitary lesion or to the brain 
may be allowed with sponsor approval as long as it is not a target lesion.

Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited to, 
the following:  measles, mumps, rubella, chickenpox, yellow fever, rabies, 
β-human chorionic gonadotropin, and typhoid (oral) vaccine.  The killed virus 
vaccines used for seasonal influenza vaccines for injection are allowed; however 
live attenuated intranasal influenza vaccines (e.g., FluMist®) are not allowed.

Glucocorticoids (inhaled steroids as part of a stable regimen for the treatment of 
asthma/chronic obstructive pulmonary disease are permitted) for any purpose 
other than to modulate symptoms from an adverse event.  The use of physiologic 
doses of corticosteroids may be approved after consultation with the Sponsor.
o
Note:  Use of prophylactic corticosteroids to avoid allergic reactions (e.g., 
IV contrast dye) is permitted.
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Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be discontinued from study 
treatment.  Subjects may receive other medications that the investigator deems to be 
medically necessary.  
It is important for investigators to review each medication (prescription and non-prescription) 
the subject is taking before starting the study and at each study visit. 

At each visit, subjects should be questioned about any new drug they are taking. 

To minimize the risk of adverse drug interactions, every effort should be made to 
limit the number of concomitant drugs to those that are truly essential. 

Drugs known to be hepatotoxic (i.e., drugs with a warning of hepatotoxicity in the 
package insert) should be avoided during the dosing period.  Investigators are 
encouraged to review each medication for potential hepatotoxicity by searching the 
www.livertox.nih.gov website.
Listed below are specific restrictions for concomitant therapy during the course of the trial.
The following medications/therapies should be avoided during the dosing period and for 
14 days thereafter:
Known hepatotoxic drugs, including but not limited to: 

Etifoxine

Isoniazid

Nitrofurantoin

Ketoconazole

Amiodarone

Phenytoin
The exclusion criteria describe other medications that are prohibited in this trial.  
There are no prohibited therapies during the post-treatment follow-up phase.
Rescue Medications & Supportive Care
No rescue or supportive medications are specified to be used in this trial.
Supportive Care Guidelines
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of adverse 
events with potential immunologic etiology are outlined along with the dose modification 
guidelines in Section 5.2.1.2, [Table 3].  Where appropriate, these guidelines include the use 
of oral or intravenous treatment with corticosteroids as well as additional anti-inflammatory 
agents if symptoms do not improve with administration of corticosteroids.  Note that several 
courses of steroid tapering may be necessary as symptoms may worsen when the steroid dose 
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is decreased. For each disorder, attempts should be made to rule out other causes such as 
metastatic disease or bacterial or viral infection, which might require additional supportive 
care.  The treatment guidelines are intended to be applied when the investigator determines 
the events to be related to study treatment. 
Note: if after the evaluation the event is determined not to be related, the investigator does 
not need to follow the treatment guidance (as outlined below). Refer to Table 3 in Section 
5.2.1.2 for dose modification and supportive care. 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event. 
Diet/Activity/Other Considerations
Diet
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea, or vomiting.
Contraception
Pembrolizumab may have adverse effects on a fetus in utero.  Furthermore, it is not known if 
pembrolizumab has transient adverse effects on the composition of sperm.  
For this trial, male subjects will be considered to be of non-reproductive potential if they 
have azoospermia (whether due to having had a vasectomy or due to an underlying medical 
condition).  
Female subjects will be considered of non-reproductive potential if they meet 1 of the 
following criteria:

She is postmenopausal, defined as at least 12 months with no menses without an 
alternative medical cause; in women <45 years of age who are not using hormonal 
contraception or hormonal replacement therapy, a high follicle-stimulating hormone 
(FSH) level in the postmenopausal range may be used to confirm a post-menopausal 
state.  In the absence of 12 months of amenorrhea, a single FSH measurement is 
insufficient.

She had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy, or 
bilateral tubal ligation/occlusion at least 6 weeks prior to screening; 

She has a congenital or acquired condition that prevents childbearing.
Female and male subjects of reproductive potential must agree to avoid becoming pregnant 
or impregnating a partner, respectively, while receiving study drug and for 120 days after the 
last dose of study drug by complying with one of the following:  

Practice abstinence from heterosexual activity.
Abstinence (relative to heterosexual activity) can be used as the sole method of contraception 
if it is consistently employed as the subject’s preferred and usual lifestyle and if considered 
acceptable 
by 
local 
regulatory 
agencies 
and 
European 
Research 
Councils 
(ERCs)/Institutional Review Boards (IRBs).  Periodic abstinence (eg, calendar, ovulation, 
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symptothermal, post-ovulation methods, etc.) and withdrawal are not acceptable methods of 
contraception.

Use (or have their partner use) acceptable contraception during heterosexual activity.  
Acceptable methods of contraception are‡:

Single method (one of the following is acceptable):
• Intrauterine device (IUD)
• Vasectomy of a female subject’s male partner 
• Contraceptive rod implanted into the skin
Combination method (requires use of two of the following):
• Diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide)
• Cervical cap with spermicide (nulliparous women only)  
• Contraceptive sponge (nulliparous women only) 
• Male condom or female condom (cannot be used together)
• Hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or progestin-
only pill), contraceptive skin patch, vaginal contraceptive ring, or subcutaneous 
contraceptive injection
‡If a contraceptive method listed above is restricted by local regulations/guidelines, then it 
does not qualify as an acceptable method of contraception for subjects participating at sites in 
this country/region.
Subjects should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate 
in the study subjects of childbearing potential must adhere to the contraception requirement 
(described above) from the day of study medication initiation (or 14 days prior to the 
initiation of study medication for oral contraception) throughout the study period up to 
120 days after the last dose of trial medication.  If there is any question that a subject of 
childbearing potential will not reliably comply with the requirements for contraception, that 
subject should not be entered into the study.
Pregnancy
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, the 
subject will be immediately discontinued from trial treatment. The site will contact the 
subject at least monthly and document the subject’s status until the pregnancy has been 
completed or terminated.  The outcome of the pregnancy will be reported to the Sponsor 
without delay and within 24 hours if the outcome is a serious adverse experience (e.g., death, 
abortion, congenital anomaly, or other disabling or life-threatening complication to the 
mother or newborn).  The study investigator will make every effort to obtain permission to 
follow the outcome of the pregnancy and report the condition of the fetus or newborn to the 
Sponsor.  If a male subject impregnates his female partner, the study personnel at the site 
must be informed immediately and the pregnancy must be reported to the Sponsor and 
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followed as described in Section 7.2.2 (Reporting of Pregnancy and Lactation to the 
Sponsor).
Use in Nursing Women
It is unknown whether pembrolizumab is excreted in human milk.  Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the 
nursing infant, subjects who are breast-feeding are not eligible for enrollment.
Subject Withdrawal/Discontinuation Criteria
Discontinuation of Treatment
Discontinuation of treatment does not represent withdrawal from the trial.
As certain data on clinical events beyond treatment discontinuation may be important to the 
study, they must be collected through the subject’s last scheduled follow-up, even if the 
subject has discontinued treatment.  Therefore, all subjects who discontinue trial treatment
prior to completion of the treatment period will still continue to participate in the trial as 
specified in Section 6.0 - Trial Flow Chart and Section 7.1.6.3 –Post-Treatment Visits.
Subjects may discontinue treatment at any time for any reason or be dropped from treatment
at the discretion of the investigator should any untoward effect occur.  In addition, a subject 
may be discontinued from treatment by the investigator or the Sponsor if treatment is 
inappropriate, the trial plan is violated, or for administrative and/or other safety reasons.  
Specific details regarding procedures to be performed at treatment discontinuation are 
provided in Section 7.1.5 – Other Procedures.
A subject must be discontinued from treatment but continue to be monitored in the trial for 
any of the following reasons:
○
The subject or subject’s legally acceptable representative requests to discontinue 
treatment.
o
The subject is lost to follow-up.
o
Confirmed radiographic disease progression per the terms outlined in Section 7.1.4
o
Unacceptable adverse events as described in Section 7.2.
o
Any progression or recurrence of any malignancy, or any occurrence of another 
malignancy that requires active treatment
o
Intercurrent illness that prevents further administration of treatment
o
Recurrent Grade 2 pneumonitis
o
Investigator’s decision to withdraw the subject
o
The subject has a confirmed positive serum pregnancy test.
o
Noncompliance with trial treatment or procedure requirements
o
Administrative reasons
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o
The subject has a medical condition or personal circumstance which, in the opinion of the 
investigator and/or Sponsor, placed the subject at unnecessary risk from continued 
administration of study drug.
o
Completed 35 treatments with study drug
Note: 35 treatments (approx. 2 years) are calculated from the first dose. Subjects who stop 
study treatment after receiving 35 treatments may be eligible for retreatment if they progress 
after stopping study treatment provided they meet the requirements detailed in Section 7.1.6.  
Subjects may be retreated in the Second Course Phase with up to 17 (approx. 1 year) 
additional trial treatments.
For subjects who are discontinued from treatment but continue to be monitored in the trial, 
all visits and procedures, as outlined in the trial flowchart, should be completed.
Subjects may be allowed to begin treatment again if deemed medically appropriate, unless 
the subjects/s treatment assignment has been unblinded by the investigator/delegate and/or 
non-study treating physician.
Withdrawal from the Trial
A subject must be withdrawn from the trial if the subject or subject’s legally acceptable 
representative withdraws consent from the trial.
If a subject withdraws from the trial, they will no longer receive treatment or be followed at 
scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the trial 
including the procedures to be performed should a subject repeatedly fail to return for 
scheduled visits and/or if the study site is unable to contact the subject, as well as specific 
details regarding withdrawal from Future Biomedical Research are outlined in Section 7.1.5
– Other Procedures.
Subject Replacement Strategy
A subject who discontinues from the trial will not be replaced.
Beginning and End of the Trial
The overall trial begins when the first subject signs the informed consent form.  The overall 
trial ends when the last subject completes the last study-related phone-call or visit,
discontinues from the trial or is lost to follow-up (i.e. the subject is unable to be contacted by 
the investigator).
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Clinical Criteria for Early Trial Termination
Early trial termination will be the result of the criteria specified below:
1. Quality or quantity of data recording is inaccurate or incomplete
2.
Poor adherence to protocol and regulatory requirements
3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential 
health hazard to subjects
4. Plans to modify or discontinue the development of the study drug. 
In the event of Sponsor decision to no longer supply study drug, ample notification will 
be provided so that appropriate adjustments to subject treatment can be made.
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6.0 TRIAL FLOW CHART
Initial Treatment with Study Drug
Trial Period:
Screening 
Phase
Treatment Cycles (3-Week Cycles)
End of 
Treatment
Post-treatment
Treatment Cycle/Title:
Screening
1
2
3
4
5
6
7
≥8
Discon
Safety 
Follow-up
Follow-Up 
Visits
Survival 
Follow-
Upa
At time of 
discon
30 days 
post last 
dose
Every 
6 weeks 
post-discon
Every 12
weeks
Scheduling Window (Days)b
-28 to -1
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±7
Administrative Procedures
Informed consent
X
Informed consent for future biomedical 
research (optional)
X
Inclusion/exclusion criteria
X
Subject identification card
X
Demographics and medical history
X
Prior and concomitant medication 
review
X
X
X
X
X
X
X
X
X
X
X
Post-study anticancer therapy status
X
X
X
Survival statusa
X
Clinical Procedures/Assessments
Review adverse events c
X
X
X
X
X
X
X
X
X
X
X
X
Full physical examination
X
X
Directed physical examination
X
X
X
X
X
X
X
X
X
Child-Pugh Score d
X
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Trial Period:
Screening 
Phase
Treatment Cycles (3-Week Cycles)
End of 
Treatment
Post-treatment
Treatment Cycle/Title:
Screening
1
2
3
4
5
6
7
≥8
Discon
Safety 
Follow-up
Follow-Up 
Visits
Survival 
Follow-
Upa
At time of 
discon
30 days 
post last 
dose
Every 
6 weeks 
post-discon
Every 12
weeks
Scheduling Window (Days)b
-28 to -1
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±7
Heightq, weight, and vital signs (T, P,
RR, BP)
X
X
X
X
X
X
X
X
X
X
12-Lead electrocardiogram
X
ECOG performance status e
X
X
X
X
X
X
X
X
X
X
EQ-5D, EORTC QLQ-C30f
X
X
X
X
X
X
X
X
X
Pembrolizumab/placebo administration
X
X
X
X
X
X
X
X
LOCAL Laboratory Assessmentsn
Pregnancy test g
X
PT/INR h
Xe
X
X
X
X
X
X
X
X
X
CBC with differentialh
Xe
X
X
X
X
X
X
X
X
X
Chemistry panel and liver panelh
Xe
X
X
X
X
X
X
X
X
X
Urinalysisi
X
X
X
X
X
X
T3, FT4, and TSHi.J
X
X
X
X
X
X
X
AFPjk
Xe
X
X
X
X
X
X
X
X
X
Anti-HCV antibodyl
X
If Anti-HCV positive
HCV viral loadl
X
X
X
X
X
X
X
X
X
X
HBsAg , HBsAb, Anti-HBc,
HBV e antigen, Anti-HBe, HBV viral 
load
X
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Trial Period:
Screening 
Phase
Treatment Cycles (3-Week Cycles)
End of 
Treatment
Post-treatment
Treatment Cycle/Title:
Screening
1
2
3
4
5
6
7
≥8
Discon
Safety 
Follow-up
Follow-Up 
Visits
Survival 
Follow-
Upa
At time of 
discon
30 days 
post last 
dose
Every 
6 weeks 
post-discon
Every 12
weeks
Scheduling Window (Days)b
-28 to -1
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±7
If (1) HBsAg+ or (2) anti-HBc+ and 
HBsAg- and HBV viral load
<2000IU/ml (104copies/ml)
HBsAgm HBV viral loadm
X
X
X
X
X
X
X
X
Anti-HBcm, HBeAbm, HBV e 
antigenm HBsAbm
X
X
CENTRAL Laboratory Assessments
Efficacy Measurements
Tumor imagingp
X
X
X
X
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Trial Period:
Screening 
Phase
Treatment Cycles (3-Week Cycles)
End of 
Treatment
Post-treatment
Treatment Cycle/Title:
Screening
1
2
3
4
5
6
7
≥8
Discon
Safety 
Follow-up
Follow-Up 
Visits
Survival 
Follow-
Upa
At time of 
discon
30 days 
post last 
dose
Every 
6 weeks 
post-discon
Every 12
weeks
Scheduling Window (Days)b
-28 to -1
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±7
AFP = alpha fetoprotein; BP = blood pressure; CBC = complete blood count; Discon = discontinuation; ECOG = Eastern Cooperative Oncology Group; FBR = future biomedical 
research; FT4 = free thyroxine; HBsAb = Hepatitis B Surface antibody; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HCV = hepatitis C virus; INR = 
international normalized ratio; P = pulse; Q3W = every 3 weeks; PRO = patient-reported outcomes; RR = respiratory rate; T = temperature; PT = prothrombin time; T3 = 
triiodothyronine; TSH = thyroid-stimulating hormone. 
a.
In subjects who experience PD or starts a new anti-cancer therapy contact should be made (example; by telephone) approximately Q12W to assess for survival status.
Updated survival status may be requested by the Sponsor at any time during the course of the study. Upon Sponsor notification, all participants who do not/will not have 
a scheduled study visit or study contact during the Sponsor defined time period will be contacted for their survival status (excluding participants that have a death event 
previously recorded).
b.
Cycle 1 treatment must be given within 3 days of randomization.  The window for each visit is ±3 days unless otherwise noted.  If dosing is delayed due to 
administrative reasons, the subsequent dosing visit should be re-calculated to account for the every 3 week dosing visits.
c.
SAEs will be followed through 90 days following cessation of treatment, or 30 days following cessation of treatment if the subject initiates new anticancer therapy, 
whichever is earlier. All protocol specific hepatic ECIs will be collected throughout the study as listed in Section 7.2.3.2.  If any of the hepatic ECI criteria are met, 
collect the Child-Pugh score until the hepatic ECIs resolve.
d.
If any of the hepatic ECI criteria are met, document the Child Pugh score with each visit until the hepatic ECIs resolve. 
e.
ECOG Performance Status, Child-Pugh Score, and laboratory tests for screening and determining eligibility are to be performed within 7 days prior to the first dose of 
trial treatment except hepatitis and thyroid tests, which may be performed within 28 days.  
f.
See Section 4.2.3.3 for details regarding administration of Patient Reported Outcomes (PROs).  All PROs are to be performed at Cycle 1, Cycle 2, Cycle 3, Cycle 4, 
Cycle 5 and Cycle 7.  After Cycle 7 (Week 18), PROs are to be performed every 9 weeks (e.g., Week 27, Week 36, Week 45).  PROs are to be performed up to a year or 
End of Treatment, whichever comes first, at treatment discontinuation, and at the 30-day post-treatment discontinuation follow-up visit.  A visit window of ±7 days will 
apply to PRO visit assessment.  See Section 7.1.2.7 for timing and order of PROs at each visit.  
g.
For women of reproductive potential, a urine or serum pregnancy test should be performed within 72 hours prior to receiving the first dose of study medication (Cycle 1 
Day 1).  A serum test can be done if urine is not appropriate.  Additionally, if urine test is positive or is not evaluable, a serum test is required.  Subjects must be 
excluded/discontinued in the event of a positive test result.  Pregnancy tests (serum and/or urine tests) should be repeated if required by local guidelines. 
h.
After Cycle 1, laboratory samples can be collected up to 72 hours prior to the scheduled time point. PT/INR, CBC with differential, chemistry panel, and liver panel to 
be performed every cycle.  Details for collection can be found in Section 7.1.3 Laboratory Procedure/Assessments.  Liver panel to include albumin, ALT, AST, total 
bilirubin, alkaline phosphatase, direct bilirubin, and total protein.  
i.
While on treatment, UA and thyroid function tests will be performed every other cycle.
j.
After Cycle 1, subject will be dosed even if AFP and thyroid evaluations are not available prior to dosing; however, the results must be available and reviewed before 
the next scheduled visit.
k.
AFP will be measured every 3 weeks (21±3 days) calculated from the date of randomization, or earlier if clinically indicated.
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Trial Period:
Screening 
Phase
Treatment Cycles (3-Week Cycles)
End of 
Treatment
Post-treatment
Treatment Cycle/Title:
Screening
1
2
3
4
5
6
7
≥8
Discon
Safety 
Follow-up
Follow-Up 
Visits
Survival 
Follow-
Upa
At time of 
discon
30 days 
post last 
dose
Every 
6 weeks 
post-discon
Every 12
weeks
Scheduling Window (Days)b
-28 to -1
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±7
l.
Anti-HCV antibody to be performed at the screening visit. For subjects who are positive, HCV viral loads will be measured every 3 weeks (21±3 days) from the date of 
randomization, or earlier if clinically indicated.
m.
HBsAg, HBV viral load to be performed at baseline and every 3 weeks (21±7 days) during treatment, or earlier if clinically indicated.  At screening, subjects must have 
results within 28 days of first dose, at each subsequent visit, the values must be checked by the next visit (3 weeks later).  Anti-HBc, HBeAb, HBV e antigen, and 
HBsAb to be performed every 12 weeks (84±7 days) during treatment, or earlier if clinically indicated.  Additional tests to be performed for ECIs are described in 
Section 5.2.1.3.      
n.
Details for collection can be found in Section 7.1.3 Laboratory Procedures/Assessments.
o.
p.
Screening tumor imaging will be performed within 21 days prior to randomization.  Imaging at screening should include the chest, abdomen, and pelvis, as detailed in 
the image acquisition manual. The first on-study imaging time point will be performed at 6 weeks (42±7 days) calculated from the date of randomization and will 
continue to be performed Q6W (42±7 days), or earlier if clinically indicated. Imaging details can be found in the Site Imaging Manual.
q.
Height will be measured at Visit 1 only.
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Second Course Treatment
Trial Period:
Treatment Cycles
End of 
Treatment
Post-treatment
Treatment Cycle/Title:
1
2
3
4
5
6
7
8 and 
Beyond
Discon
Safety 
Follow-up
Follow Up 
Visits
Survival 
Follow-Upa
At time of 
Discon
30 Days Post-
discon
Every 6 
Weeks Post-
discon
Every 12 Weeks
Scheduling Window (Days)b
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 7
± 7
± 7
Administrative Procedures
Eligibility criteria
X
Concomitant medication review
X
X
X
X
X
X
X
X
X
X
Clinical Procedures/Assessments
Review adverse events
X
X
X
X
X
X
X
X
X
X
Xc
Full physical examination
X
X
Directed physical examination
X
X
X
X
X
X
X
Weight, and vital signs (T, P, RR, BP)
X
X
X
X
X
X
X
X
X
ECOG performance statusd
X
X
X
X
X
X
X
X
X
Post-study anticancer therapy status
X
X
X
Survival statusa
X
Trial Treatment Administration
Pembrolizumab/placebo administration
X
X
X
X
X
X
X
X
LOCAL Laboratory Assessments
Pregnancy teste
X
PT/INR 
Xd
X
X
X
X
X
X
X
X
X
CBC with differentialf
Xd
X
X
X
X
X
X
X
X
X
Chemistry and liver panelsf
Xd
X
X
X
X
X
X
X
X
X
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Trial Period:
Treatment Cycles
End of 
Treatment
Post-treatment
Treatment Cycle/Title:
1
2
3
4
5
6
7
8 and 
Beyond
Discon
Safety 
Follow-up
Follow Up 
Visits
Survival 
Follow-Upa
At time of 
Discon
30 Days Post-
discon
Every 6 
Weeks Post-
discon
Every 12 Weeks
Urinalysisg
Xd
X
X
X
X
X
T3, FT4, and TSHg
Xd
X
X
X
X
X
X
AFPd
X
X
X
X
X
X
X
X
X
If Anti-HCV positive:
HCV viral loadi
X
X
X
X
X
X
X
X
X
HBsAg , HBsAb, Anti-HBc, 
HBV e antigen, Anti-HBe, HBV viral load
X
If (1) HBsAg+ or (2) anti-HBc+ and HBV 
viral load <2000IU/ml(104copies/ml):
HBsAg and HBV viral loadj
X
X
X
X
X
X
X
X
Anti-HBcj, HBeAbj, HBe antigenj , HBsAbj
X
X
Efficacy Measurements
Tumor imagingh
Xh
Xh
Xh
X
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Trial Period:
Treatment Cycles
End of 
Treatment
Post-treatment
Treatment Cycle/Title:
1
2
3
4
5
6
7
8 and 
Beyond
Discon
Safety 
Follow-up
Follow Up 
Visits
Survival 
Follow-Upa
At time of 
Discon
30 Days Post-
discon
Every 6 
Weeks Post-
discon
Every 12 Weeks
AFP = alpha-fetoprotein; BP = blood pressure; CBC = complete blood count; Discon = discontinuation; ECOG = Eastern Cooperative Oncology Group; FT4 = free thyroxine; 
INR = international normalized ratio; P = pulse; RR = respiratory rate; T = temperature; PT = prothrombin time; T3 = triiodothyronine; TSH = thyroid-stimulating hormone. 
a.
In subjects who experience PD or starts a new anti-cancer therapy contact should be made (by telephone or visit) approximately Q12W to assess for survival status. Updated 
survival status may be requested by the Sponsor at any time during the course of the study. Upon Sponsor notification, all participants who do not/will not have a scheduled 
study visit or study contact during the Sponsor defined time period will be contacted for their survival status (excluding participants that have a death event previously 
recorded).
b.
In general, the window for each visit is ±3 days unless otherwise noted.  
c.
SAEs will be followed through 90 days following cessation of treatment, or 30 days following cessation of treatment if the subject initiates new anticancer therapy, 
whichever is earlier. All protocol specified hepatic ECIs will be collected throughout the study as listed in Section 7.2.3.2. If any of the hepatic ECI criteria are met, collect 
the Child Pugh score with each visit until the hepatic ECIs resolve.
d.
Laboratory and ECOG tests for determining eligibility are to be performed within 7 days prior to the first retreatment dose of study drug. AFP will be measured every 3 
weeks (21±7 days) calculated from the date of randomization.
e.
For women of reproductive potential, a urine or serum pregnancy test should be performed within 72 hours prior to receiving the first dose of study medication (Cycle 1 Day 
1).  A serum test can be done if urine is not appropriate.  Additionally, if urine test is positive or is not evaluable, a serum test is required.  Subjects must be 
excluded/discontinued in the event of a positive test result.  Pregnancy tests (serum and/or urine tests) should be repeated if required by local guidelines.  
f.
After Cycle 1, laboratory samples can be collected up to 72 hours prior to the scheduled time point.  CBC, chemistry, and liver panel to be performed every cycle.  Liver 
panel to include albumin, ALT, AST, total bilirubin, alkaline phosphatase, direct bilirubin, and total protein. 
g.
Urinalysis and thyroid function tests to be performed every other cycle.  
h.
Tumor imaging should be performed within 21 days prior to starting or restarting study treatment and continue to be performed every 6 weeks (42±7 days) calculated from 
the first dose of retreatment, or more frequently if clinically indicated.   
i.
If anti-HCV was negative prior to first dose of retreatment, anti-HCV must be performed within 28days prior to retreatment in the Second Course Phase. For subjects with
positive anti-HCV antibody, HCV viral loads will be measured every 3 weeks (21±7 days) during treatment, or earlier if clinically indicated.  
j.
HBsAg, HBV viral load are to be performed within 28days prior to first dose of retreatment and every 3 weeks (21±7 days) during treatment, or earlier if clinically indicated.  
Anti-HBc, HBeAb, HBV e antigen, and HBsAb to be performed within 28days prior to first dose of retreatment and every 12 weeks (84±7 days) during treatment, or earlier 
if clinically indicated.  Additional tests to be performed for ECIs are described in Section 5.2.1.3.   
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7.0 TRIAL PROCEDURES
Trial Procedures
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to 
perform these procedures at unscheduled time points if deemed clinically necessary by the 
investigator.
Furthermore, additional evaluations/testing may be deemed necessary by the investigator and 
or the Sponsor for reasons related to subject safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations 
may require that additional informed consent be obtained from the subject.  In these cases, 
such evaluations/testing will be performed in accordance with those regulations.
Administrative Procedures
Informed Consent
The investigator or qualified designee must obtain documented consent from each potential 
subject or each subject’s legally acceptable representative prior to participating in a clinical 
trial or Future Biomedical Research. If there are changes to the subject’s status during the 
trial (e.g., health or age of majority requirements), the investigator or qualified designee must 
ensure the appropriate consent is in place. 
7.1.1.1.1 General Informed Consent
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion. 
A copy of the signed and dated consent form should be given to the subject before 
participation in the trial.
The initial informed consent form, any subsequent revised written informed consent form 
and any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The subject or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the trial.  The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the subject’s dated signature or 
by the subject’s legally acceptable representative’s dated signature.
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.  
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements.
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7.1.1.1.2 Consent and Collection of Specimens for Future Biomedical Research
The investigator or qualified designee will explain the Future Biomedical Research consent 
to the subject, answer all of his/her questions, and obtain written informed consent before 
performing any procedure related to the Future Biomedical Research sub-trial.  A copy of the 
informed consent will be given to the subject.
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.
Subject Identification Card
All subjects will be given a Subject Identification Card identifying them as participants in a 
research trial. The card will contain trial site contact information (including direct telephone 
numbers) to be utilized in the event of an emergency. The investigator or qualified designee 
will provide the subject with a Subject Identification Card immediately after the subject 
provides written informed consent. At the time of treatment allocation/randomization, site 
personnel will add the treatment/randomization number to the Subject Identification Card.
The subject identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about trial 
medication/vaccination in emergency situations where the investigator is not available.
Medical History
A medical history will be obtained by the investigator or qualified designee.  Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
is considered to be clinical significant by the investigator.  Disease details regarding the 
subject’s HCC will be recorded separately and not listed as medical history.  
If the subject has lost at least 6.8 kg over the 3 months prior to screening, “weight loss” 
should be entered as an active condition on the medical history.  Any autoimmune disorders, 
regardless of onset date, should be recorded.  
The investigator or qualified designee will obtain prior and current details regarding the 
subject’s HCC.  
Prior and Concomitant Medications Review
7.1.1.5.1 Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject 
within 30 days of the first dose of trial medication, including alternative/complementary 
medications. Prior anti-cancer treatment for HCC will be recorded separately and not listed 
as a prior medication.
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Prior Treatment Details for HCC
The investigator or qualified designee will review all prior anti-cancer treatments including 
systemic treatments, radiation, local therapy, and surgeries.  
7.1.1.5.2 Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial from the time of signing the informed consent form until the Safety Follow-
up Visit.  In addition, new medications started during the Second Course Phase through the 
Second Course Safety Follow-up Visit should be recorded. 
All medications related to reportable SAEs and ECIs should be recorded as defined in 
Section 7.2.
Subsequent Anti-Cancer Status
The investigator or qualified designee will review all new anti-cancer therapy initiated after 
the last dose of trial treatment.  If a subject initiates a new anti-cancer therapy within 30 days 
after the last dose of trial treatment, the 30 day Safety Follow-up visit must occur before the 
first dose of the new therapy.  
Once new anti-cancer therapy has been initiated the subject will move into survival follow-
up.  Details regarding survival status follow-up are outlined in 7.1.6.3.3 – Survival Follow 
Up.  
Assignment of Screening Number
All consented subjects will be given a unique screening number that will be used to identify 
the subject for all procedures that occur prior to randomization or treatment allocation.  Each 
subject will be assigned only one screening number.  Screening numbers must not be re-used 
for different subjects.
Specific details on the screening visit requirements are provided in Section 7.1.6.1.  
Assignment of Treatment/Randomization Number
All eligible subjects will be randomly allocated and will receive a treatment/randomization 
number.  The treatment/randomization number identifies the subject for all procedures 
occurring after treatment allocation/randomization.  Once a treatment/randomization number 
is assigned to a subject, it can never be re-assigned to another subject.
A single subject cannot be assigned more than 1 treatment/randomization number.
Trial Compliance (Medication/Diet/Activity/Other)
Interruptions from the protocol specified treatment plan for greater than 12 weeks between 
doses for non-drug–related or administrative reasons require consultation between the 
investigator and the Sponsor and written documentation of the collaborative decision on 
subject management.
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The total volume of study treatment infused will be compared to the total volume prepared to 
determine compliance with each dose administered.  The instructions for preparing and 
administering study treatment are provided in the Pharmacy Manual.  
Administration of trial medication will be witnessed by the investigator and/or trial staff or 
qualified designee per institutional guidelines and procedures. .
Clinical Procedures/Assessments
Adverse Event Monitoring
The investigator or qualified designee will assess each subject to evaluate for potential new 
or worsening AEs as specified in the Trial Flow Chart and more frequently if clinically 
indicated.  Adverse events will be graded and recorded throughout the trial and during the 
follow-up period according to NCI CTCAE Version 4.0 (see Section 12.6).  Toxicities will 
be characterized in terms regarding seriousness, causality, toxicity grading, and action taken 
with regard to trial treatment.  
All AEs of unknown etiology associated with study treatment exposure should be evaluated 
to determine if it is possibly an event of a potentially immunologic etiology; see
Section 5.6.1.
Please refer to Section 7.2 for detailed information regarding the assessment and recording of 
AEs.
Physical Exam
7.1.2.2.1 Full Physical Exam
The investigator or clinical designee will perform a complete physical exam during the 
screening period.  Clinically significant abnormal findings should be recorded as medical 
history.  Additional full physical exams should be performed as specified in the Trial Flow 
Chart - Section 6.0 Assessment for possible ascites and hepatic encephalopathy should be
noted on every examination. After the first dose of trial treatment new clinically significant 
abnormal findings should be recorded as AEs.  
7.1.2.2.2 Directed Physical Exam
For cycles that do not require a full physical exam per the Trial Flow Chart - Section 6.0, the 
investigator or qualified designee will perform a directed physical exam as clinically 
indicated prior to dosing on Day 1 of each treatment cycle. Assessment for possible ascites 
and hepatic encephalopathy should be noted on every examination. New clinically significant 
abnormal findings should be recorded as AEs.  
Height, Weight, and Vital Signs
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment, and at treatment discontinuation as specified in 
the Trial Flow Chart - Section 6.0 - Height will be measured at Visit 1 only.  
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Vital signs should include temperature, pulse, respiratory rate, blood pressure, height, and 
weight.  
12-Lead Electrocardiogram
A standard 12-lead electrocardiogram (ECG) will be performed one time during screening 
using local standard procedures. Clinically significant abnormal findings should be recorded 
as medical history. Additional time points may be performed as clinically necessary.
Eastern Cooperative Oncology Group Performance Status
The investigator or qualified designee will assess ECOG Performance Status (see
Section 12.5) at Screening, prior to dosing on Day 1 of each treatment cycle, and at 
discontinuation of trial treatment as specified in the Trial Flow Chart – Section 6.0.  
Child-Pugh Score
Originally developed in 1973, the Child-Pugh score was used to estimate the risk of operative 
mortality in patients with bleeding esophageal varices.  It has since been modified, refined, 
and become a widely used tool to assess prognosis in patients with chronic liver disease and 
cirrhosis.  The score considers 5 factors, 3 of which assess the synthetic function of the liver 
(i.e., total bilirubin level, serum albumin, and coagulation parameters [INR or PT]) and 2 of 
which are based on clinical assessment (i.e., degree of ascites and degree of hepatic 
encephalopathy).
Patient Reported Outcomes (PROs)
It is strongly recommended that Patient Reported Outcomes (PROs) are administered prior to 
drug administration, adverse event evaluation, and disease status notification starting with the 
EQ-5D-3L, followed by EORTC QLQ-C30; an exception to this recommendation may occur 
at the treatment discontinuation visit where patients may have already been notified of their 
disease status or an AE evaluation is known prior to them arriving to the clinic.  All PROs 
are to be performed as specified in the Trial Flow Chart – Section 6. If the subject does not 
complete the PROs, the MISS_MODE form must be completed to capture the reason the 
assessment was not performed. A visit window of ±7 days will apply to PRO visit 
assessments.  
Laboratory Procedures/Assessments
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below. The total amount of blood/tissue to be drawn/collected over the course of 
the trial (from pre-trial to post-trial visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per subject can be found in in the Procedures 
Manual.  Refer to the Trial Flow Chart - Section 6 for the schedule of laboratory assessments.
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
Laboratory tests for hematology, chemistry and urinalysis are specified in Table 5.
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Table 5
Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Hematocrit
Albumin
Blood
Pregnancy test (serum or
urine) a
Hemoglobin
Alkaline phosphatase
Glucose
AFP
Platelet count
Alanine aminotransferase
Protein
PT/INR
WBC (total and 
differential)
Aspartate aminotransferase
Specific gravity 
Total triiodothyronine (T3) 
or free T3, FT4, and TSHb,d
RBC
Bicarbonatec
Microscopic 
exam, 
if 
abnormal 
results 
are 
noted
Anti-HCV antibody d
Calcium
HCV viral load d
Chloride
HBsAg d
Creatinine
HBV viral load d
Glucose
Anti-HBc antibody d
Phosphorus
HBV e antigen d
Potassium
HBeAb d
Sodium
HBsAb d
Total bilirubin  
Direct bilirubin
Total protein
Blood urea nitrogen or Urea
AFP = α-fetoprotein;; FT4 = free thyroxine; HBc = hepatitis core antigen ; HBeAg = hepatitis B e antigen; HBeAb = anti-
HBe antibody; HBV = hepatitis B virus; HBsAb = hepatitis B surface antibody; HBsAg = hepatitis B surface antigen; 
HCV = hepatitis C virus; INR = international normalized ratio; PT = prothrombin time; RBC= red blood cell; 
T3 = triiodothyronine; TSH = thyroid-stimulating hormone; WBC = white blood cell.
a
Perform on women of childbearing potential 72 hours prior to Day 1 of Cycle 1. 
b.   T3 is preferred; if not available free T3 may be tested.
c.    If this test is not done as part of local standard of care, this test does not need to be performed.
d.
If the local laboratory is unable to perform these tests, the site should submit the sample to the central laboratory for 
testing; details are provided in the Procedure Manual.
Laboratory tests for screening should be performed within 7 days prior to the first dose of 
study treatment. An exception is hepatitis, AFP, and thyroid serologies, which may be 
performed within 28 days prior to first dose. Subjects eligible for study retreatment should 
have laboratory tests performed within 7 days prior to the first dose of study treatment in the 
Second Course Phase. After Cycle 1, in both the Initial Treatment Phase and the Second 
Course Phase, pre-dose laboratory safety tests can be conducted up to 72 hours prior to 
dosing unless otherwise noted on the flow charts. 
Laboratory test results must be reviewed by the investigator or qualified designee and found 
to be acceptable prior to administration of each dose of trial treatment, unless otherwise 
specified in the flow chart. Unresolved abnormal laboratory values that are drug-related AEs 
should be followed until resolution.  Laboratory tests do not need to be repeated after the end 
of treatment if laboratory results are within normal range.  
7.1.3.1.1 Pregnancy Tests
All women who are being considered for participation in the trial, and who are not surgically 
sterilized or postmenopausal, must be tested for pregnancy within 72 hours prior to Day 1 of 
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Cycle 1.  If a urine test is positive or not evaluable a serum test will be required. Subjects 
must be excluded/discontinued from the study in the event of a positive or borderline-
positive test result.  
Central Laboratory Assessments
Sample collection timing, storage and shipment instructions for the central laboratory 
assessments will be provided in the Laboratory Manual.
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Future Biomedical Research Sample Collection
Efficacy Measurements
Tumor Imaging and Assessment of Disease
The process for image collection and transmission to the blinded central imaging vendor can 
be found in the Site Imaging Manual (SIM).  Tumor imaging should be acquired by 
computed tomography (CT).  Magnetic resonance imaging (MRI) is also acceptable as a 
primary imaging modality for objective evaluation of and measurement of tumor lesions if it’s the 
local standard of care..  The same imaging technique regarding modality and use of contrast 
should be used in a subject throughout the trial to optimize the visualization of existing and 
new tumor burden.  
Measurable disease by the investigator per RECIST 1.1 is required prior to subject 
randomization. Although RECIST 1.1 references a maximum of 5 target lesions in total and 
2 per organ, Merck allows a maximum of 10 target lesions in total and 5 per organ.  
All scheduled images for all study subjects from the sites will be submitted to the central 
imaging vendor.  In addition, additional imaging (including other modalities) that are 
obtained at an unscheduled time point to determine disease progression, as well as imaging 
obtained for other reasons but captures radiologic progression, should be submitted to the 
central imaging vendor as well.  
After the local site investigator-assessed first radiologic evidence of PD, the central imaging 
vendor will verify PD during the study.  Expedited verification of radiologic PD by the 
central imaging vendor will be communicated to the study site and sponsor.
Initial Tumor Imaging
Initial tumor imaging at screening must be performed within 21 days prior to the date of 
randomization.  The site study team must review screening images to confirm the subject has 
measurable disease per RECIST 1.1.  
Scans performed as part of routine clinical management are acceptable for use as screening
tumor imaging if they are of diagnostic quality, were performed within 21 days prior to the 
date of randomization, and can be assessed by the site study team. 
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Tumor Imaging During the Trial
The first on-study imaging assessment should be performed at 6 weeks (42±7 days) from the 
date of allocation.  Subsequent tumor imaging should be performed Q6W (42±7 days) or 
more frequently if clinically indicated.  Imaging timing should follow calendar days and 
should not be adjusted for delays in cycle starts. Imaging should continue to be performed 
until disease progression is verified by BICR (unless site PI elects to continue treatment and 
follow irRECIST, the start of new anti-cancer treatment, withdrawal of consent, death, or 
notification by the Sponsor, whichever occurs first).  All supplemental imaging must be 
submitted to the central imaging vendor.
Per RECIST 1.1 partial response (PR) and complete response (CR) should be confirmed by a 
repeat tumor imaging assessment ≥4 weeks from the date the response was first documented.  
The tumor imaging for confirmation of response may be performed at the earliest 4 weeks 
after the first indication of response, or at the next scheduled scan (i.e., 6 weeks later), 
whichever is clinically indicated.  Subjects will then return to regular scheduled imaging 
every 6 weeks, starting with the next scheduled imaging time point.  Subjects who obtain a 
confirmation scan do not need to undergo the next scheduled tumor imaging if it is <4 weeks 
later; tumor imaging may resume at the subsequent scheduled imaging time point.
Per irRECIST (Section 7.1.4.7), disease progression should be confirmed by the site at least 
4 weeks after central verification of site-assessed first radiologic evidence of PD in clinically 
stable subjects.  Subjects who have unconfirmed disease progression may continue on 
treatment at the discretion of the site investigator until progression is confirmed by the site
provided they have met the conditions detailed in Section 7.1.4.7. Subjects who have 
confirmed disease progression as assessed by the site will discontinue the treatment.  
Exceptions are detailed in Section 7.1.4.7.  
End of Treatment and Follow-up Tumor Imaging
In subjects who discontinue trial treatment, tumor imaging should be performed at the time 
of treatment discontinuation (±4 week window).  If a previous scan was obtained within 
4 weeks prior to the date of discontinuation, then a scan at treatment discontinuation is not 
mandatory. 
In subjects who discontinue trial treatment due to documented disease 
progression, this is the final required tumor imaging.  
In subjects who discontinue trial treatment without documented disease progression, every 
effort should be made to continue monitoring their disease status by tumor imaging using the 
same imaging schedule used while on treatment (every 6 weeks) to monitor disease status 
until the start of new anticancer treatment, disease progression, death, or the end of the study, 
whichever occurs first.  
Second Course (Retreatment) Tumor Imaging
A scan must be performed within 21 days prior to restarting treatment with pembrolizumab.  
Local reading (investigator assessment with site radiology reading) will be used to determine 
eligibility.  Imaging should be submitted to the blinded central imaging vendor for 
retrospective review.  
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The first on-study imaging assessment should be performed 6 weeks (42 days ±7 days) after 
the restart of treatment.  Subsequent tumor imaging should be performed every 6 weeks 
(42 days ±7 days) or more frequently if clinically indicated.  
Per irRECIST (Section 7.1.4.7), if tumor imaging shows initial PD per RECIST 1.1, tumor 
assessment should be repeated ≥4 weeks later in order to confirm PD with the option of 
continuing treatment while awaiting radiologic confirmation of progression.  Subjects who 
obtained a confirmation scan do not need to undergo scheduled tumor imaging if it is <4 
weeks later and may wait until the next scheduled imaging time point in clinically stable.  
Imaging should continue to be performed until disease progression, the start of new 
anticancer treatment, withdrawal of consent, death, or notification by the Sponsor, whichever 
occurs first.  Disease progression may be confirmed at least 4 weeks after the first tumor 
imaging indicating PD in clinically stable subjects.  Additional irRECIST detail is described 
in Section 7.1.4.7.
In subjects who discontinue trial treatment, tumor imaging should be performed at the time 
of treatment discontinuation (±4 week window).  If a previous scan was obtained within 
4 weeks prior to the date of discontinuation, then a scan at treatment discontinuation is not 
mandatory. 
In subjects who discontinue trial treatment due to documented disease 
progression, this is the final required tumor imaging.  
In subjects who discontinue trial treatment without documented disease progression, every 
effort should be made to continue monitoring their disease status by radiologic imaging every 
6 weeks (42 days ±7 days) until the start of new anticancer treatment, disease progression, 
death, or the end of the study, whichever occurs first.  
RECIST 1.1 Assessment of Disease
RECIST 1.1 will be applied by the blinded central imaging vendor as the primary measure 
for assessment of tumor response, date of disease progression, and as a basis for all protocol 
guidelines related to disease status (e.g., discontinuation of study therapy).  Initial tumor 
imaging showing site-assessed PD should be submitted to the central imaging vendor 
immediately. The site will be notified if the central imaging vendor verifies PD using 
RECIST 1.1. Figure 2 illustrates the imaging flow involving verification of PD for clinically 
stable subjects.
irRECIST Assessment of Disease
irRECIST is RECIST 1.1 adapted as described below to account for the unique tumor 
response seen with immunotherapeutic
drugs.  irRECIST
will be used by site 
investigator/local radiology review to assess tumor response and progression, and make 
treatment decisions.  This data will be collected in the clinical database.  Treatment efficacy 
based on irRECIST as assessed by BICR will be evaluated retrospectively.
When feasible, subjects should not be discontinued until progression is confirmed by the 
local site investigator/radiology assessment.  This allowance to continue treatment despite 
initial radiologic progressive disease (PD) takes into account the observation that some 
subjects can have a transient tumor flare in the first few months after the start of 
immunotherapy, and then experience subsequent disease response.  Subjects that are deemed 
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clinically unstable are not required to have repeat tumor imaging for confirmation of PD. 
Tumor flare includes any of the following scenarios:

Worsening of existing target lesion(s)

Worsening of existing non-target lesion(s)

Development of new lesion(s)
In subjects who have shown initial evidence of radiological PD by RECIST 1.1 as verified by 
the central imaging vendor, it is at the discretion of the PI whether to continue a subject on 
study treatment until repeat imaging is obtained (using irRECIST for subject management, 
see Table 6 and Figure 2).  This clinical judgment decision by the site investigator should be 
based on the subject’s overall clinical condition, including performance status, clinical 
symptoms, and laboratory data. Subjects may receive study treatment and tumor assessment 
should be repeated ≥4 weeks later to confirm PD by irRECIST per site assessment.  Clinical 
stability is defined as the following: 
1) Absence of symptoms and signs indicating clinically significant progression of 
disease, including worsening of laboratory values,
2) No decline in ECOG performance status,
3) Absence of rapid progression of disease, and
4) Absence of progressive tumor at critical anatomical sites (e.g., cord compression) 
requiring urgent alternative medical intervention.   
Any subject deemed clinically unstable should be discontinued from trial treatment at central 
verification of site-assessed first radiologic evidence of PD and is not required to have repeat 
imaging for PD confirmation.
In determining whether or not the tumor burden has increased or decreased per irRECIST,
the local site investigator should consider all target and non-target lesions as well as any 
incremental new lesion(s).
Scenarios where PD is not confirmed at repeat imaging if ALL of the following occur by 
irRECIST: 

Target lesion sum of diameters is <20% or <5 mm absolute increase compared to 
nadir,

Non-target disease resulting in initial PD is qualitatively stable or improved,

New lesion resulting in initial PD is qualitatively stable or improved,

No incremental new lesion(s) since last evaluation, and

No incremental new non-target lesion progression since last evaluation.  
If repeat imaging does not confirm PD by irRECIST as assessed by the local site investigator
and the subject continues to be clinically stable, treatment may continue and follow the 
regular imaging schedule. 
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Scenarios where PD is confirmed at repeat imaging if ANY of the following occur by 
irRECIST:

Target lesion sum of diameters remains ≥20% and at least 5 mm absolute increase 
compared to nadir,

Non-target disease resulting in initial PD is qualitatively worse,

New lesion resulting in initial PD is qualitatively worse,

Additional new lesion(s) since last evaluation,

Additional new non-target lesion progression since last evaluation.  
NOTE: If a subject has confirmed radiographic progression (i.e., 2 scans at least 4 weeks 
apart demonstrating progressive disease) per irRECIST, but the subject is achieving a 
clinically meaningful benefit and there is no further increase in the tumor burden at the 
confirmatory tumor imaging, an exception to continue treatment may be considered
following consultation with the Sponsor.
In this case, if treatment is continued, tumor 
imaging should continue to be performed following the intervals as outlined in Section 6.0 –
Trial Flow Chart and be submitted to the central imaging vendor.  
Additional details about irRECIST are referenced in Merck Tip Sheet for RECIST 1.1 and 
irRECIST.  
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Table 6
Imaging and Treatment after First Radiologic Evidence of PD
Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
First 
radiologic 
evidence of PD 
by RECIST 1.1 
which has been 
verified by the 
BICR
Repeat 
imaging 
at >4 weeks at 
site to confirm 
PD
May continue study 
treatment 
at 
the 
local 
site 
Investigator’s 
discretion 
while 
awaiting 
confirmatory tumor 
imaging by site by 
irRECIST.
Repeat imaging at 
>4 weeks 
to 
confirm 
PD 
per 
physician 
discretion only
Discontinue treatment
Repeat 
tumor 
imaging 
confirms PD by 
irRECIST at the 
local site
No 
additional 
imaging required
Discontinue 
treatment (exception 
is 
possible 
upon 
consultation 
with 
sponsor)
No 
additional 
imaging required
N/A
Repeat 
tumor 
imaging 
shows 
SD, PR or CR by 
irRECIST by the 
local site
Continue 
regularly 
scheduled 
imaging 
assessments 
Continue 
study 
treatment 
at 
the 
local 
site 
Investigator’s 
discretion
Continue regularly 
scheduled imaging 
assessments 
May 
restart 
study 
treatment if condition 
has improved and/or 
clinically 
stable 
per 
Investigator’s 
discretion. Next tumor 
image 
should 
occur
according to the regular 
imaging 
schedule 
outlined in the protocol
CR = complete response; irRECIST = immune-related Response Evaluation Criteria in Solid Tumors; N/A = not applicable; 
PD = progressive disease; PR= partial response; RECIST = Response Evaluation Criteria in Solid Tumors; SD = stable 
disease.  
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Figure 2
Imaging and Treatment for Clinically Stable Subjects after First Radiologic 
Evidence of Progressive Disease Assessed by Site
BICR = blinded independent central review; irRECIST = immune-related Response Evaluation Criteria In Solid 
Tumors; PD = progressive disease; PI = principal investigator; RECIST = Response Evaluation Criteria In Solid 
Tumors; SFU = survival follow-up.  
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Other Procedures
Withdrawal/Discontinuation
Subjects who discontinue/withdraw from treatment prior to completion of the treatment  
should be encouraged to continue to be followed for all remaining study visits.
When a subject discontinues/withdraws from participation in the trial, all applicable activities 
scheduled for the end of treatment visit should be performed at the time of discontinuation.  
Any adverse events which are present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements outlined in Section 7.2 - Assessing and 
Recording Adverse Events Subjects who attain a CR or complete 35 trial treatments 
(approximately 2 years) may discontinue treatment with the option of restarting treatment if 
they meet the criteria specified in Section 7.1.6.2. After discontinuing treatment following 
assessment of a CR or the 35 trial treatments, subjects should return to the site for a Safety 
Follow-up visit (Section 7.1.6.3.1) and then proceed to the Follow-up Period of the study 
(Section 7.1.6.3.2)..
7.1.5.1.1 Withdrawal From Future Biomedical Research
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   Subjects may withdraw consent at any time by 
contacting the principal investigator for the main trial.  If medical records for the main trial 
are still available, the investigator will contact the Sponsor using the designated mailbox 
(clinical.specimen.management@merck.com), and a form will be provided by the Sponsor to 
obtain appropriate information to complete specimen withdrawal.  Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed.  A letter will 
be sent from the Sponsor to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for destruction or already performed prior to the 
request being received by the Sponsor will continue to be used as part of the overall research 
trial data and results.   No new analyses would be generated after the request is received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial records) or 
the specimens have been completely anonymized, there will no longer be a link between the 
subject’s personal information and their specimens.  In this situation, the request for 
specimen destruction cannot be processed.
7.1.5.1.2 Lost to Follow-up
If a subject fails to return to the clinic for a required study visit and/or if the site is unable to 
contact the subject, the following procedures are to be performed:

The site must attempt to contact the subject and reschedule the missed visit..  If 
the subject is contacted, the subject should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
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
The investigator or designee must make every effort to regain contact with the 
subject at each missed visit (e.g. phone calls and/or a certified letter to the 
subject’s last known mailing address or locally equivalent methods). These 
contact attempts should be documented in the subject’s medical record.

Note:  A subject is not considered lost to follow up until the last scheduled visit 
for the individual subject.  The amount of missing data for the subject will be 
managed via the pre-specified data handling and analysis guidelines
Blinding/Unblinding
STUDY TREATMENT IDENTIFICATION INFORMATION IS TO BE UNMASKED 
ONLY IF NECESSARY FOR THE WELFARE OF THE SUBJECT. EVERY EFFORT 
SHOULD BE MADE NOT TO UNBLIND THE SUBJECT UNLESS NECESSARY.
For emergency situations where the investigator or delegate needs to identify the drug used 
by a subject 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 delegate 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 subject’s treatment assignment, the 
investigator or delegate must enter the intensity/toxicity grade of the AEs observed, the 
relation to study drug, the reason thereof, etc., in the medical chart etc.
Section 5.8 outlines the criteria for allowing subjects who are discontinued from treatment to 
continue to be monitored in the trial.
Additionally, the investigator must go into the IVRS system and perform the unblind in the 
IVRS system to update drug disposition.  In the event that the emergency unblinding call 
center is not available for a given site in this trial, IVRS/IWRS should be used for emergency 
unblinding in the event that this is required for subject safety.
IVRS/IWRS should be used for emergency unblinding in the event that this is required for 
subject safety. Subjects whose treatment assignment has been unblinded must be 
discontinued from study drug.
Study treatment identification information is to be unmasked ONLY if necessary for the 
welfare of the subject. Every effort should be made not to unblind the subject unless 
necessary. 
In the event that unblinding has occurred, the circumstances around the unblinding (eg, date, 
reason and person performing the unblinding) must be documented promptly, and the 
Sponsor Clinical Director notified as soon as possible. Once an emergency unblinding has 
taken place, the principal investigator, site personnel, and Sponsor personnel may be 
unblinded so that the appropriate follow-up medical care can be provided to the participant.
At the end of the trial, unblinding logs are to be returned to the Sponsor or designee
Calibration of Critical Equipment
The investigator or qualified designee has the responsibility to ensure that any critical device
or instrument used for a clinical evaluation/test during a clinical trial that provides important 
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information about inclusion/exclusion criteria and/or safety or efficacy parameters shall be 
suitably calibrated and maintained to ensure that the data obtained is reliable and/or 
reproducible.  Documentation of equipment calibration must be retained as source 
documentation at the trial site.
Critical Equipment for this trial includes:

Laboratory equipment – as required for inclusion labs and trial assessments

Imaging equipment – as required for study objectives
See protocol-specified guidance in the Trial Administrative Binder, Procedures Manual, and 
Site Imaging Manual.
Visit Requirements
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures.
Screening
Approximately 28 days prior to treatment, potential subjects will be evaluated to determine 
that they fulfill the entry requirements as set forth in Section 5.1.  Screening procedures may 
be repeated.
Subjects may be rescreened after initially failing to meet the inclusion/exclusion criteria. 
Subjects who are rescreened will retain their original screening number. Results of a test 
performed prior to the subject signing consent as part of routine clinical management are 
acceptable in lieu of a screening test if performed within the specified time frame.  
Screening procedures are to be completed within 28 days prior to the first dose of trial 
treatment except for the following:  
•
Laboratory tests and ECOG PS are to be performed within 7 days prior to the first dose of 
trial treatment.
•
For women of reproductive potential, a urine or serum pregnancy test will be performed 
within 72 hours prior to the first dose of trial treatment.    
Treatment Period Visit
Visit requirements are outlined in the Trial Flow Chart (Section 6.0).  Specific procedure-
related details are provided above in the Trial Procedures (Section 7.0).
Subjects who stop study drug with SD or better may be eligible for up to 17 additional trial 
treatments (approximately 1 year) if they progress after stopping study treatments.  
Retreatment with study drug is termed the Second Course Phase and is only available if the 
trial remains open and the subject meets the following conditions:

Either 
o
Stopped initial treatment with study treatment after attaining an investigator-
determined CR according to RECIST 1.1
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
Was treated with at least 8 trial treatments (approximately 6 months) 
with study treatment before discontinuing therapy

Received at least two study treatments beyond the date when the initial 
CR was declared
OR
o
Had SD, PR or CR and stopped study treatment after 35 treatments 
(approximately 2 years) for reasons other than disease progression or 
intolerability

AND
o
Experienced an investigator-determined confirmed radiographic disease 
progression after stopping their initial study treatment
o
Did not receive any anti-cancer treatment since the last dose of study 
treatment
o
Has a performance status of 0 or 1 on the ECOG Performance Scale
o
Demonstrates adequate organ function as detailed in Section 5.1.2
o
Female subject of childbearing potential should have a negative serum or 
urine pregnancy test within 72 hours prior to receiving retreatment with study 
medication (Cycle 1, Day 1).  
o
Female subjects of childbearing potential must be willing to use an adequate 
method of contraception as outlined in Section 5.7.2 – Contraception, starting 
with the dose of study medication through at least 120 days or longer based on 
local regulation.  

Note: Abstinence is acceptable if this is the usual lifestyle and 
preferred contraception for the subject.
o
Male subjects of child bearing potential must agree to use an adequate method 
of contraception as outlined in Section 5.7.2 – Contraception and not to donate 
sperm starting with the first dose of study therapy through at least 120 days or 
longer based on local regulation after the last dose of study therapy.

Note: Abstinence is acceptable if this is the usual lifestyle and 
preferred contraception for the subject.
o
Does not have a history or current evidence of any condition, therapy, or 
laboratory abnormality that might interfere with the subject’s participation for 
the full duration of the trial or is not in the best interest of the subject to 
participate, in the opinion of the treating investigator.
Subjects who enter the Second Course Phase will be retreated with the same treatment as 
when they last received study treatment.  Study treatment will be administered for up to an 
additional 17 trial treatments (approximately 1 year).
Visit requirements for the second course phase are outlined in the Second Course Phase Trial 
Flow Chart (Section 6.2).
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Post-Treatment Visits
7.1.6.3.1 Safety Follow-up Visits
The mandatory Safety Follow-up Visit should be conducted approximately 30 days after the 
last dose of trial treatment or before the initiation of a new anti-cancer treatment, whichever 
comes first.  
All AEs that occur prior to the Safety Follow-Up Visit should be recorded.  Subjects with an 
AE of Grade >1 will be followed until the resolution of the AE to Grade 0-1 or until the 
beginning of a new anti-cancer therapy, whichever occurs first.  SAEs that occur within 
90 days of the end of or within 30 days of the end of treatment if the subject initiates new 
anticancer therapy, whichever is earlier should also be followed and recorded.  
Subjects who are eligible for retreatment may have up to two safety follow-up visits, one 
after the Initial Treatment Period and one after the Second Course Treatment Phase.
7.1.6.3.2 Follow-up Visits
Subjects who discontinue trial treatment for reasons other than disease progression will move 
into the Follow-up Phase and should be assessed Q6W by radiologic imaging to monitor 
disease status. Every effort should be made to collect information regarding disease status 
until the start of new anti-cancer therapy, disease progression, death, end of trial [or if the 
subject begins retreatment with pembrolizumab as detailed in [Section 7.1.4.5]. Information 
regarding post-trial anticancer treatment will be collected if new treatment is initiated.
Subjects who are eligible to receive retreatment with pembrolizumab according to the criteria 
in Section 7.1.4.5 will move from the Follow-up Phase to the Second Course Phase when 
they experience disease progression. Details are provided in the Trial Flow Chart (Section 6) 
for retreatment with pembrolizumab.
7.1.6.3.3 Survival Follow-up
Subjects who experience confirmed disease progression or start a new anti-cancer therapy, 
will move into the Survival Follow-Up Phase and should be contacted by telephone 
approximately every 12 weeks to assess for survival status until death, withdrawal of 
consent, or the end of the trial, whichever occurs first.    

For patients who discontinue Treatment due to PD
o
Date of the first survival follow-up contact should be 12 weeks from the date of 
the 30 day safety FU Visit
o
Note: if a subject does not have a 30-day safety follow up visit the date is 
calculated from the discontinuation visit. 
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
For subjects who discontinue treatment for reasons other than PD
o
Undergo a 30-day safety follow-up visit and continue with imaging follow-up 
o
The date of the first survival follow-up contact should be based either on the date 
that the subject has first radiologic evidence of progressive disease, or on the 
date the subject starts a new anti-cancer therapy.
7.1.6.3.4 Survival Status
To ensure current and complete survival data is available at the time of database locks, 
updated survival status may be requested during the course of the study by the Sponsor.  For
example, updated survival status may be requested prior to but not limited to an external Data 
Monitoring Committee (eDMC) review, interim and/or final analysis.  Upon Sponsor 
notification, all participants who do not/will not have a scheduled study visit or study contact 
during the Sponsor defined time period, will be contacted for their survival status (excluding 
participants that have a previously recorded death event in the collection tool).
Assessing and Recording Adverse Events
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavourable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the 
use of the Sponsor’s product, is also an adverse event.
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  
Examples of this may include, but are not limited to, teething, typical crying in infants and 
children and onset of menses or menopause occurring at a physiologically appropriate time.
Sponsor's product includes any pharmaceutical product, biological product, device, 
diagnostic agent or protocol-specified procedure, whether investigational (including placebo 
or active comparator medication) or marketed, manufactured by, licensed by, provided by or 
distributed by the Sponsor for human use.
Adverse events may occur during clinical trials, or as prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal.
Progression of the cancer under study is not considered an adverse event.
All adverse events that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure. From the time of treatment allocation/randomization through 30 days following 
cessation of treatment, all adverse events must be reported by the investigator. Such events 
will be recorded at each examination on the Adverse Event case report forms/worksheets.  
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The reporting timeframe for adverse events meeting any serious criteria is described in 
section 7.2.3.1. The investigator will make every attempt to follow all subjects with non-
serious adverse events for outcome.
Electronic reporting procedures can be found in the Electronic Data Capture (EDC) data 
entry guidelines. Paper reporting procedures can be found in the Investigator Trial File 
Binder (or equivalent).
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor
In this trial, an overdose is any dose higher than ≥1000 mg (5 times the protocol defined
dose) of pembrolizumab. No specific information is available on the treatment of over dose 
of pembrolizumab.  In the event of overdose, study treatment should be discontinued and the 
subject should be observed closely for signs of toxicity.  Appropriate supportive treatment 
should be provided if clinically indicated.
If an adverse event(s) is associated with (“results from”) the overdose of Sponsor's product or 
vaccine, the adverse event(s) is reported as a serious adverse event, even if no other 
seriousness criteria are met.
If a dose of Sponsor's product or vaccine meeting the protocol definition of overdose is taken 
without any associated clinical symptoms or abnormal laboratory results, the overdose is 
reported as a non-serious Event of Clinical Interest (ECI), using the terminology “accidental 
or intentional overdose without adverse effect.”
All reports of overdose with and without an adverse event must be reported by the 
investigator within 24 hours to the Sponsor either by electronic media or paper. Electronic 
reporting procedures can be found in the EDC data entry guidelines. Paper reporting 
procedures can be found in the Investigator Trial File Binder (or equivalent).
Reporting of Pregnancy and Lactation to the Sponsor
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them) that occurs during the trial.
Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure.  Pregnancies and lactations that occur from the time of treatment 
allocation/randomization through 120 days following cessation of Sponsor’s product, or 30 
days following cessation of treatment if the subject initiates new anticancer therapy, 
whichever is earlier, must be reported by the investigator.  All reported pregnancies must be 
followed to the completion/termination of the pregnancy. Pregnancy outcomes of 
spontaneous abortion, missed abortion, benign hydatidiform mole, blighted ovum, fetal 
death, intrauterine death, miscarriage and stillbirth must be reported as serious events 
(Important Medical Events). If the pregnancy continues to term, the outcome (health of 
infant) must also be reported.
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Such events must be reported within 24 hours to the Sponsor either by electronic media or 
paper. Electronic reporting procedures can be found in the EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
Immediate Reporting of Adverse Events to the Sponsor
Serious Adverse Events
An serious adverse event is any adverse event occurring at any dose or during any use of 
Sponsor's product that:

Results in death;

Is life threatening;

Results in persistent or significant disability/incapacity;

Results in or prolongs an existing inpatient hospitalization;

Is a congenital anomaly/birth defect;

Is an other important medical event. 
Note: In addition to the above criteria, adverse events meeting either of the below criteria, 
although not serious per ICH definition, are reportable to the Sponsor in the same timeframe 
as SAEs to meet certain local requirements. Therefore, these events are considered serious by 
the Sponsor for collection purposes.

Is a new cancer (that is not a condition of the study);

Is associated with an overdose.
Refer to Table 7 for additional details regarding each of the above criteria.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any serious adverse event, or follow up to a serious adverse event, 
including death due to any cause other than progression of the cancer under study (refer to 
[Section 7.2.3.3] for additional details), that occurs to any subject must be reported within 24 
hours to the Sponsor if it causes the subject to be excluded from the trial, or is the result of a 
protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment randomization through 90 days following 
cessation of trial treatment, or 30 days following cessation of trial treatment if the subject 
initiates new anticancer therapy, whichever is earlier, any serious adverse event, or follow up 
to a serious adverse event, including death due to any cause, other than progression of the 
cancer under study (reference Section 7.2.3.3 for additional details) whether or not related to 
the Sponsor's product, must be reported within 24 hours to the Sponsor either by electronic 
media or paper. Electronic reporting procedures can be found in the EDC data entry 
guidelines. Paper reporting procedures can be found in the Investigator Trial File Binder (or 
equivalent).
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to the Sponsor's product that is brought to the attention of the 
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investigator at any time following consent through the end of the specified safety follow-up 
period specified in the paragraph above, or at any time outside of the time period specified in 
the previous paragraph also must be reported immediately to the Sponsor. 
All subjects with serious adverse events must be followed up for outcome.
Events of Clinical Interest
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI)  and must be reported to the Sponsor.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any subject must be 
reported within 24 hours to the Sponsor if it causes the subject to be excluded from the trial, 
or is the result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 14 days 
following cessation of treatment, any ECI, or follow up to an ECI, whether or not related to 
the Sponsor’s product, must be reported within 24 hours to the Sponsor, either by electronic 
media or paper.  Electronic reporting procedures can be found in the EDC data entry 
guidelines.  Paper reporting procedures can be found in the Investigator Trial File Binder (or 
equivalent).
Events of clinical interest for this trial include:
1) An overdose of Sponsor's product, as defined in Section 7.2.1 - Definition of an 
Overdose for This Protocol and Reporting of Overdose to the Sponsor, that is not 
associated with clinical symptoms or abnormal laboratory results. 
2) Hepatic ECIs include any of the following events.  All of these events will require 
holding study treatment, notification of the event(s) to the Sponsor within 24 hours 
via electronic media or paper, and a hepatology consultation if necessary.  For dose 
interval modification, refer to Section 5.2.1.2.  For guidance related to the diagnosis 
and management of hepatic ECIs, refer to Section 5.2.1.3.  
a.
ALT:
i. Among subjects with baseline ALT <2×ULN:  ALT ≥5×ULN
ii. Among subjects with baseline ALT ≥2×ULN:  ALT >3× the baseline
level
iii. ALT >500 U/L regardless of baseline level
b. AST:
i. Among subjects with baseline AST <2×ULN:  AST ≥5×ULN
ii. Among subjects with baseline AST ≥2×ULN:  AST >3× the baseline
level
iii. AST >500 U/L regardless of baseline level
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c.
Total Bilirubin:
i. Among subjects with baseline levels <1.5 mg/dL:  a value of 
>2.0 mg/dL
ii. Among subjects with baseline levels that are ≥1.5 mg/dL:  a value ≥2× 
the baseline level 
iii. Total bilirubin >3.0 mg/dL regardless of baseline level
d. Regardless of laboratory values, hepatic decompensation diagnosed clinically, 
including:
i. New onset clinically detectable ascites
ii. Gastrointestinal bleeding suggestive of portal hypertension (e.g., 
esophageal or gastric varices)
iii. Hepatic Encephalopathy
Protocol-Specific Exceptions to Serious Adverse Event Reporting
Efficacy endpoints as outlined in this section will not be reported to the Sponsor as described 
in Section 7.2.3.
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study. 
The Sponsor will monitor unblinded aggregated efficacy endpoint events and safety data to 
ensure the safety of the subjects in the trial. Any suspected endpoint which upon review is 
not progression of the cancer under study will be forwarded to global safety as a SAE within 
24 hours of determination that the event is not progression of the cancer under study.
Evaluating Adverse Events
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 4.0. Any adverse event 
which changes CTCAE grade over the course of a given episode will have each change of 
grade recorded on the adverse event case report forms/worksheets.
All adverse events regardless of CTCAE grade must also be evaluated for seriousness.
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Table 7
Evaluating Adverse Events
An investigator who is a qualified physician, will evaluate all adverse events as to:
V4.0 CTCAE 
Grading
Grade 1
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated.
Grade 2
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL.
Grade 3
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or hospitalization indicated; 
disabling; limiting self-care ADL.
Grade 4
Life threatening consequences; urgent intervention indicated.
Grade 5
Death related to AE
Seriousness
A serious adverse event is any adverse event occurring at any dose or during any use of Sponsor’s product that:
†Results in death; or
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include an 
adverse event that, had it occurred in a more severe form, might have caused death.); or
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation. (Note: Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not a serious adverse event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of a Merck product and is documented in 
the patient’s medical history.); or
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or
Is a new cancer (that is not a condition of the study) (although not serious per ICH definition, is reportable to the Sponsor within 24 hours to meet certain local 
requirements); or
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event for collection purposes. An 
overdose that is not associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 hours.
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes 
listed previously (designated above by a †).
Duration
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units
Action taken 
Did the adverse event cause the Sponsor’s product to be discontinued?
Relationship to 
Sponsor’s 
Product
Did the Sponsor’s product cause the adverse event? The determination of the likelihood that the Sponsor’s product caused the adverse event will be provided by an 
investigator who is a qualified physician. The investigator’s signed/dated initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed document must be retained for the required regulatory time frame. The 
criteria below are intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the adverse event 
based upon the available information.
The following components are to be used to assess the relationship between the Sponsor’s product and the AE; the greater the correlation with the components 
and their respective elements (in number and/or intensity), the more likely the Sponsor’s product caused the adverse event (AE):
Exposure
Is there evidence that the subject was actually exposed to the Sponsor’s product such as: reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen?
Time Course
Did 
the 
AE 
follow 
in 
a 
reasonable 
temporal 
sequence 
from 
administration 
of 
the 
Sponsor’s 
product? 
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)?
Likely Cause
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental factors
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Relationship
The following components are to be used to assess the relationship between the test drug and the AE: (continued)
to Sponsor's 
Product
(continued) 
Dechallenge
Was the Sponsor’s product discontinued or dose/exposure/frequency reduced?
If yes, did the AE resolve or improve?
If yes, this is a positive dechallenge. If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite continuation of 
the Sponsor’s product; or (3) the trial is a single-dose drug trial); or (4) Sponsor’s product(s) is/are only used one time.)
Rechallenge
Was the subject re-exposed to the Sponsor’s product in this study?
If yes, did the AE recur or worsen?
If yes, this is a positive rechallenge. If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose drug trial); or 
(3) Sponsor’s product(s) is/are used only one time).
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN 
CAUSED BY THE SPONSOR'S PRODUCT, OR IF REEXPOSURE TO THE SPONSOR'S PRODUCT POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR 
CLINICAL DIRECTOR AS PER DOSE MODIFICATION GUIDELINES IN THE PROTOCOL.
Consistency 
with Trial 
Treatment 
Profile
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the Sponsor’s product or drug class pharmacology 
or toxicology?
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements.
Record one of the following
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a Sponsor’s product relationship).
Yes, there is a reasonable 
possibility of Sponsor's product 
relationship.
There is evidence of exposure to the Sponsor's product.  The temporal sequence of the AE onset relative to the administration of the Sponsor's 
product is reasonable.  The AE is more likely explained by the Sponsor's product than by another cause.
No, there is not a reasonable 
possibility of Sponsor's product 
relationship
Subject did not receive the Sponsor's product OR temporal sequence of the AE onset relative to administration of the Sponsor's product is not 
reasonable OR the AE is more likely explained by another cause than the Sponsor’s product.  (Also entered for a subject with overdose without an 
associated AE.)
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Sponsor Responsibility for Reporting Adverse Events
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations, i.e., per ICH Topic E6 (R1) 
Guidelines for Good Clinical Practice.
TRIAL GOVERNANCE AND OVERSIGHT
Executive Oversight Committee
The Executive Oversight Committee (EOC) comprises members of Sponsor Senior 
Management. The EOC will receive and decide upon any recommendations made by the 
external data monitoring committee (eDMC) regarding the trial.
Data Monitoring Committee
To supplement the routine trial monitoring outlined in this protocol, an eDMC (external Data 
Monitoring Committee) will monitor the interim data from this trial.  The voting members of 
the committee are external to the Sponsor.  The voting members of the eDMC must not be 
involved with the trial in any other way (e.g., they cannot be trial investigators) and must 
have no competing interests that could affect their roles with respect to the trial. 
The eDMC will make recommendations to the EOC regarding steps to ensure both subject 
safety and the continued ethical integrity of the trial.  Also, the eDMC will review interim 
trial results, consider the overall risk and benefit to trial participants (see Section 8.7 -
Interim Analyses) and recommend to the EOC if the trial should continue in accordance with 
the protocol.
Specific details regarding composition, responsibilities, and governance, including the roles 
and responsibilities of the various members and the sponsor protocol team; meeting 
facilitation; the trial governance structure; and requirements for and proper documentation of 
eDMC reports, minutes, and recommendations will be described in a separate charter that is 
reviewed and approved by the eDMC.  The eDMC will monitor the trial at an appropriate 
frequency, as described in the detailed eDMC charter.  The eDMC will also make 
recommendations to the sponsor protocol team regarding steps to ensure both subject safety 
and the continued ethical integrity of the trial.
8.0 STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study. If, after the 
study has begun, 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 ICH Guideline E-9).  Changes to exploratory or other non-confirmatory analyses made 
after the protocol has been finalized, but prior to the conduct of any analysis, will be 
documented in a supplemental statistical analysis plan (sSAP) and referenced in the Clinical 
Study Report (CSR) for the study. There will be a separate biomarker analysis plan. Post hoc 
exploratory analyses will be clearly identified in the CSR. The PRO analysis plan will be 
included in the sSAP.
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Unless specified otherwise, the type I error in Section 8 indicates one-sided type I error.
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized in Table 8 below; the 
comprehensive plan is provided in Sections 8.2 through 8.12.
Table 8
Statistical Analysis Plan
Study Design Overview
A Randomized Double Blind Phase III Study of Single Agent Pembrolizumab 
plus BSC vs. placebo plus BSC as Second-Line Therapy in Asian Subjects with 
Previously Systemically Treated Advanced Hepatocellular Carcinoma after 
Progression on Sorafenib or Oxaliplatin-based Chemotherapy
Treatment Assignment
Subjects will be randomized in a 2:1 ratio to receive blinded treatment with
pembrolizumab plus BSC or placebo plus BSC (Control Arm). Stratification 
factors are in Section 5.4.  This is a double-blinded study. 
Analysis Populations
Efficacy: Intention to Treat (ITT)
Safety: All Subjects as Treated (ASaT)
Primary
Endpoints/Hypotheses
Pembrolizumab improves overall survival (OS) compared to placebo.
Statistical Methods for
Key Efficacy Analyses
The primary hypothesis will be evaluated by comparing pembrolizumab to the 
control on OS using a stratified log-rank test.  Estimation of the hazard ratio
will be done using a stratified Cox regression model.  Event rates over time
will be estimated within each treatment group using the Kaplan-Meier method. 
PFS will be analyzed using the same method for OS. Stratified Miettinen and 
Nurminen’s method [57] with weights proportional to the stratum size will be 
used for comparison of the objective response rates (ORR) between the 
treatment arms.  
Statistical Methods for
Key Safety Analyses
The analysis of safety results will follow a tiered approach.  The tiers differ 
with respect to the analyses that will be performed.  There are no Tier 1 events 
in this trial.  Tier 2 parameters will be assessed via point estimates with 95% 
confidence intervals provided for between-group comparisons; only point 
estimates by treatment group are provided for Tier 3 safety parameters.  The
95% confidence intervals for the between-treatment differences in percentages 
will be provided using the Miettinen and Nurminen method[57]
Interim Analyses
Two interim analyses will be performed in this study. Results will be 
reviewed by an external data monitoring committee. Details are provided in
Section 8.7.
IA1(ORR-driven):

Timing: to be performed when 163 randomized subjects have at least 
24 weeks follow-up (which is estimated to happen at approximately 
17 months after study start). Approximately 174 PFS events and 100
OS events are expected to be accumulated.

Purpose: estimate treatment effect and evaluate consistency with 
global data, interim analysis for ORR, PFS and OS.
IA2 (event-driven):

Timing: to be performed when approximately 276 OS events have 
been observed and enrollment is complete, estimated to be 
approximately 31 months after study start. Approximately 395 PFS 
events are expected to be accumulated at IA2.

Purpose: interim efficacy analysis for OS and ORR, primary efficacy 
analysis for PFS. 
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Final analysis (event-driven)

Timing: to be performed when approximately 345 OS events have 
been observed, estimated to be approximately 37 months after study 
start

Purpose: final analysis for OS, final analysis for ORR.  
Multiplicity
The multiplicity strategy in this study will be applied to the primary hypothesis 
(superiority of pembrolizumab in OS to placebo) and the secondary hypotheses 
of superiority of pembrolizumab to placebo in PFS and ORR. The overall Type 
I error across the three hypotheses above is strongly controlled at 2.5% (one-
sided) by the graphical approach of Maurer and Bretz [58] as described in 
Section 8.8. Initially, α=2.3% will be allocated to the OS hypothesis and 
α=0.2% will be allocated to the PFS hypothesis. Following a group sequential 
approach, the Type I error rates for the two interim and final analyses will be
controlled through the alpha-spending function as described in Section 8.8.
Sample Size and Power
The sample size is approximately 450.
The analyses of OS endpoint is event driven (i.e., the testing of the OS
hypothesis is conducted upon accumulating a preset number of events). The 
study is designed and will be conducted to accumulate approximately 345 OS 
events (unless superiority in OS is proven at the interim analysis).
For primary endpoint OS, the trial has ~87% power to demonstrate that 
pembrolizumab is superior to the control at a one-sided 2.3% alpha-level, if the 
underlying hazard ratio of OS is 0.7.  
Responsibility for Analyses/In-House Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the SPONSOR.
The SPONSOR will generate the randomized allocation schedule(s) for study treatment 
assignment for this protocol, and the randomization will be implemented in IVRS. 
Since the trial is double-blinded with in-house blinding, the Sponsor, the investigators, site 
staffs, and subjects will be blinded to the treatment assignment. In addition, the blinded 
central imaging vendor will perform the central imaging review without knowledge of 
treatment group assignment.
The eDMC will serve as the primary reviewer of the unblinded results of the interim analyses 
and will make recommendations for discontinuation of the study or modification to an 
executive oversight committee of the SPONSOR. An external unblinded statistician and 
statistical programmer will be responsible for generating unblinded data summaries and 
presenting them to the eDMC. Depending on the recommendation of the eDMC, the Sponsor 
may prepare a regulatory submission. If the eDMC recommends modifications to the design 
of the protocol or discontinuation of the study, this executive oversight committee and 
limited additional SPONSOR personnel may be unblinded to results at the treatment level in 
order to act on these recommendations. The extent to which individuals are unblinded with 
respect to results of interim analyses will be documented. Additional logistical details will be 
provided in the eDMC Charter. 
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Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.0.
Analysis Endpoints
Efficacy Endpoints
Primary
Overall Survival
OS is defined as the time from randomization to death due to any cause. Subjects without
documented death at the time of the final analysis will be censored at the date of the last
follow-up.
Secondary
Progression-Free Survival (PFS) – RECIST 1.1 by BICR
PFS is defined as the time from randomization to the first documented disease progression 
per RECIST 1.1 based on blinded central imaging vendor review or death due to any cause, 
whichever occurs first.  See Section 8.6.1 for the censoring rules.
Objective Response Rate (ORR) – RECIST 1.1 by BICR
Objective response rate is defined as the proportion of the subjects in the analysis population 
who have a complete response (CR) or partial response (PR) per RECIST 1.1.
Disease Control Rate (DCR) - RECIST 1.1 by BICR
DCR is defined as the percentage of subjects who have achieved CR, PR, or have 
demonstrated SD for at least 6 weeks prior to any evidence of progression based on 
assessments by the central imaging vendor per RECIST 1.1.
Time to Progression (TTP) – RECIST 1.1 by BICR
TTP is defined as the time from randomization to the first documented disease progression
per RECIST 1.1. See Section 8.6.1 for the censoring rules.
Duration of Response (DOR) - RECIST 1.1 by BICR
For subjects who demonstrate CR or PR, duration of response is defined as the time from 
first documented evidence of CR or PR per RECIST 1.1 until disease progression per 
RECIST 1.1 or death due to any cause, whichever occurs first.
Safety Endpoints
Safety measurements are described in Section 4.2.3.4 Safety Endpoints and Section 7.
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
adverse events (AEs), laboratory tests, and vital signs. Safety parameters to be analyzed include, 
but are not limited to, AEs, SAEs, fatal AEs, and laboratory changes.  Furthermore, specific 
events will be collected and designated as events of clinical interest (ECIs) as described in 
Section 7.2.3. 
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Events of clinical interest for this trial include:
1.
An overdose of Sponsor's product, as defined in Section 7.2.1 - Definition of an 
Overdose for This Protocol and Reporting of Overdose to the Sponsor, that is not 
associated with clinical symptoms or abnormal laboratory results. 
2.
Hepatic ECIs as defined in Section 7.2.3.  
There are no “Tier 1” events in this trial. In addition, the broad clinical and laboratory AE 
categories consisting of the percentage of subjects with any AE, any drug related AE, any 
Grade 3-5 AE, any serious AE, any AE which is both drug-related and Grade 3-5, any AE 
which is both serious and drug-related, dose modification due to AE, and who discontinued 
due to an AE, and death will be considered Tier 2 endpoints. AEs (specific terms as well as 
system organ class terms) will be classified as belonging to "Tier 2" or "Tier 3", based on the 
number of events observed.  Membership in Tier 2 requires that at least 4 subjects in any 
treatment group exhibit the event; all other AEs and predefined limits of change will belong to 
Tier 3.
Analysis Populations
Efficacy Analysis Populations
The Intention-to-Treat (ITT) population will serve as the population for primary efficacy 
analysis. All randomized subjects will be included in this population. Subjects will be 
included in the treatment group to which they are randomized.
Details on the approach to handling missing data are provided in Section 8.6 Statistical
Methods.
Safety Analysis Populations
The All Subjects as Treated (ASaT) population will be used for the analysis of safety data in 
this study. The ASaT population consists of all randomized subjects who received at least 
one dose of study treatment. Subjects will be included in the treatment group corresponding 
to the study treatment they actually received for the analysis of safety data using the ASaT 
population. For most subjects this will be the treatment group to which they are randomized. 
Subjects who take incorrect study treatment for the entire treatment period will be included in 
the treatment group corresponding to the study treatment actually received. Any subject who 
receives the incorrect study medication for one cycle but receives the correct treatment for all 
other cycles will be analyzed according to the randomized treatment group and a narrative
will be provided for any events that occur during the cycle for which the subject is incorrectly
dosed.
At least one laboratory or vital sign measurement obtained subsequent to at least one dose of 
study treatment is required for inclusion in the analysis of each specific parameter. To assess 
change from baseline, a baseline measurement is also required.
Details on the approach to handling missing data for safety analyses are provided in Section
8.6 Statistical Methods.
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Statistical Methods
Statistical Methods for Efficacy Analyses
This section describes the statistical methods that address the primary and secondary 
objectives. Methods related to exploratory objectives will be described in the supplemental 
SAP.
Efficacy results that will be deemed to be statistically significant after consideration of the 
Type I error control strategy are described in Section 8.8, Multiplicity. Nominal p-values 
may be computed for other efficacy analyses, but should be interpreted with caution due to 
potential issues of multiplicity. In the event that there are a small number of responses in one 
or more strata, for the purpose of analysis strata will be combined to ensure sufficient number 
of responses in each stratum.  Details regarding the combining of strata will be specified in 
the sSAP prior to database lock based on a blinded review of response counts by stratum.
Overall Survival (OS)
The non-parametric Kaplan-Meier method will be used to estimate the survival curves. The 
superiority hypothesis 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 (i.e., the hazard ratio). The
hazard ratio and its 95% confidence interval from the stratified Cox model with a single
treatment covariate will be reported. The stratification factors applied to both the stratified
log-rank test and the stratified Cox model will be: macrovascular invasion (Yes, No), α-
fetoprotein (ng/mL) (<200, ≥200) and region (China, ex-China).
Due to the small number in the stratum of presence of macrovascular invasion, subjects from 
any region or with any level of α-fetoprotein will be combined in this stratum. Thus, the 
following 5 strata will be used in the stratified log-rank test and the stratified Cox model:

Macrovascular invasion (No) + Region (China) + α-Fetoprotein (ng/mL) (<200)

Macrovascular invasion (No) + Region (ex-China) + α-Fetoprotein (ng/mL) (<200)

Macrovascular invasion (No) + Region (China) + α-Fetoprotein (ng/mL) (≥200)

Macrovascular invasion (No) + Region (ex-China) + α-Fetoprotein (ng/mL) (≥200)

Macrovascular invasion (Yes) 
In the event that there are a small number of responses in one or more strata, for the purpose 
of analysis strata may be further combined to ensure sufficient number of responses in each 
stratum.  Details regarding the combining of strata will be specified in the sSAP prior to 
database lock based on a blinded review of response counts by stratum.
Prior to verification of PD by blinded independent central review, switching to another 
treatment is discouraged. Following verification of PD, subjects may switch to another anti-
cancer treatment. Exploratory analyses to adjust for the effect of crossover to other PD-1 
therapies on OS may be performed based on recognized methods, e.g. the Rank Preserving 
Structural Failure Time (RPSFT) model proposed by Robins and Tsiatis [59], two stage 
model, etc., based on an examination of the appropriateness of the data to the assumptions 
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required by the methods. In case the proportional hazards assumption doesn’t hold, 
supportive analysis using Fleming and Harrington’s weighted log-rank test, Restricted Mean 
Survival Time (RMST) method or other methods, as appropriate, may be conducted, possibly 
after proper adjustment of the crossover effect over time.
Progression-Free Survival (PFS)
The non-parametric Kaplan-Meier method will be used to estimate the PFS curve in each 
treatment group. The superiority hypothesis 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 difference (i.e., hazard
ratio) between the treatment arms. The hazard ratio and its 95% confidence interval from the
stratified Cox model with Efron's method of tie handling and with a single treatment
covariate will be reported. The stratification factors and strata applied to both the stratified
log-rank test and the stratified Cox model will be the same as those factors and strata used in 
the stratified analysis for overall survival.
Since disease progression is assessed periodically, progressive disease (PD) can occur any 
time in the time interval between the last assessment where PD was not documented and the 
assessment when PD is documented. For the primary analysis, for the subjects who have PD, 
the true date of disease progression will be approximated by the date of the first assessment 
at which PD is objectively documented per RECIST 1.1 by blinded independent central 
review, regardless of discontinuation of study drug. Death is always considered as a 
confirmed PD event. Sensitivity analyses may be performed for comparison of PFS based on 
investigator's assessment per RECIST and PFS analysis for PD per irRECIST by blinded 
independent central review.
In order to evaluate the robustness of the PFS endpoint per RECIST 1.1 by blinded 
independent central review, we will perform two sensitivity analyses with a different set of 
censoring rules. The first sensitivity analysis is the same as the primary analysis except that 
(1) the date of documented PD or death will be the progression date, regardless of whether or 
not new anti-cancer treatment is initiated and (2) it censors at the last disease assessment, 
regardless of whether or not new anti-cancer treatment is initiated if no PD and no death 
occur. The second sensitivity analysis is the same as the first sensitivity analysis, except that 
it considers discontinuation of treatment due to reasons other than complete response or 
initiation of an anti-cancer treatment subsequent to discontinuation of study specified
treatment, whichever occurs later, to be a PD event for subjects without documented PD or 
death. The censoring rules for primary and sensitivity analyses are summarized in Table 9. 
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Table 9
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
PD or death documented 
after 
≥2 consecutive 
missed 
disease 
assessments or after new 
anticancer therapy, if any
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
The proportional hazards assumption on PFS will be examined using both graphical and 
analytical methods if warranted. The log[ -log] of the survival function vs. time for PFS will 
be plotted for the comparison between pembrolizumab and the control arm. If the curves are 
not parallel, indicating that hazards are not proportional, supportive analyses may be 
conducted to account for the possible non-proportional hazards effect associated with 
immunotherapies: for example, using the Restricted Mean Survival Time (RMST) method 
[60], parametric method [61], etc. Further details of the sensitivity analyses will be described 
in supplemental SAP.
The PFS analyses are described in Section 8.7 Interim Analyses and Section 8.8 Multiplicity.   
The supportive analysis of the PFS data available at the time of the final OS analysis will be 
also conducted. 
Objective Response Rate (ORR)
Stratified Miettinen and Nurminen’s method [57] with weights proportional to the stratum 
size will be used for the comparison of the objective response rates between the treatment 
arms. A 95% confidence interval for the difference in response rates between the 
pembrolizumab arm and the control arm will be provided. The stratification factors and strata 
applied to the analysis will be the same as those factors and strata used in the stratified 
analysis for overall survival.
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The ORR analysis will be conducted according to the hypotheses testing plan as described in 
Section 8.7 Interim Analyses and Section 8.8 Multiplicity. 
Disease Control Rate (DCR)
Stratified Miettinen and Nurminen’s method [57] with weights proportional to the stratum 
size will be used for the comparison of the DCR between the treatment arms. A 95% 
confidence interval for the difference in response rates between the pembrolizumab arm and 
the control arm will be provided. The stratification factors and strata applied to the analysis
will be the same as those factors and strata used in the stratified analysis for overall survival.
Time to Progression (TTP)
The non-parametric Kaplan-Meier method will be used to estimate the TTP curve in each 
treatment group. A stratified Cox proportional hazard model with Efron's method of tie
handling will be used to estimate the magnitude of the treatment difference (i.e., hazard
ratio) between the treatment arms. The hazard ratio and its 95% confidence interval from
the stratified Cox model with Efron's method of tie handling and with a single treatment
covariate will be reported. The stratification factors and strata applied to both the stratified
log-rank test and the stratified Cox model will be the same as those factors and strata used in 
the stratified analysis for overall survival.
Since disease progression is assessed periodically, progressive disease (PD) can occur any 
time in the time interval between the last assessment where PD was not documented and the
assessment when PD is documented. For the analysis, for the subjects who have PD, the true
date of disease progression will be approximated by the date of the first assessment at
which PD is objectively documented per RECIST 1.1 by blinded independent central review, 
regardless of discontinuation of study drug. Unlike in PFS analysis, death is not considered 
as an event.
The censoring rules for TTP are summarized in Table 10.
Table 10
Censoring rules for TTP
Situation
Primary Analysis
Death
without a preceding disease 
progression
Censored at date of randomization or 
date of last non-PD disease assessment, 
whichever is later
No PD and no death;
new anticancer treatment is not initiated
Censored
at
last
non-PD 
disease 
assessment
No PD and no death;
new anticancer treatment is initiated
Censored at last non-PD disease
assessment
before
new 
anticancer
PD documented after ≤1 missed disease 
assessment
Progressed at date of documented  PD
PD documented after ≥2 missed disease 
assessments
Censored 
at 
last 
non-PD 
disease 
assessment prior to the ≥2 consecutive 
missed disease assessments
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Duration of Response (DOR) 
Subjects who achieved CR or PR and are alive, have not progressed, have not initiated new 
anti-cancer treatment, have not missed ≥2 consecutive disease assessments and have not been 
determined to be lost to follow-up are considered ongoing responders at the time of analysis.  
The non-parametric Kaplan-Meier method will be used to estimate the DOR curve in
each treatment group; estimates and 95% CIs at specific duration time points will be 
provided. 
Censoring rules for DOR are summarized in Table 11.
Table 11
Censoring Rules for DOR
Situation
Date of Progression or Censoring
Outcome
No progression nor death, no new 
anti-cancer therapy initiated
Last adequate disease assessment
Censor
(non-event)
No progression nor death, new anti-
cancer therapy initiated
Last adequate disease assessment 
before new anti-cancer therapy 
initiated
Censor
(non-event)
Death or progression after ≥2 
consecutive missed adequate disease 
assessments or after new anti-cancer
therapy
Earlier date of last adequate disease
assessment prior to ≥2 missed
adequate disease assessments and
new anti-cancer therapy, if any
Censor
(non-event)
Death or progression after ≤1 
missed 
adequate 
disease 
assessments and before new anti-
cancer therapy, if any
PD or death
End of response
(Event)
Subjects are considered to have an ongoing response if censored, alive, have not progressed, have not started a 
new anti-cancer therapy, have not missed ≥2 consecutive disease assessments, and have not been determined to 
be lost to follow-up.
Table 12 summarizes the primary analysis approach for key efficacy endpoints. Sensitivity 
analysis methods are described above for each endpoint.
Analyses of the DCR, TTP, and DOR data will be performed at the time of the interim and 
final analyses of OS. 
The strategy to address multiplicity issues with regard to multiple efficacy endpoints, 
multiple populations, and interim analyses is described in Section 8.7 Interim Analyses and 
in Section 8.8 Multiplicity.
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Table 12
Analysis Strategy for Key Efficacy Hypotheses
Endpoint/Variable
(Description, Time Point)
†
Statistical Method
Analysis Population
Missing Data
Approach
Primary Hypothesis
OS
Test: Stratified Log-
rank 
test 
Estimation: 
Stratified 
Cox 
model 
with 
Efron’s tie handling 
method.
ITT
Censored at the last 
date the subject was 
known to be alive
Secondary Endpoints
PFS per RECIST 1.1 by BICR
Test: Stratified Log-
rank 
test 
Estimation: 
Stratified 
Cox 
model 
with 
Efron’s tie handling 
method
ITT
Primary 
censoring 
rule
Sensitivity analysis 1
Sensitivity analysis 2 
(More details are in 
Table 9)
ORR per RECIST 1.1 by BICR
Stratified 
M 
& 
N 
method‡
ITT
Subjects 
with 
missing 
data 
are 
considered 
non-
† Statistical models are described in further detail in the text. For stratified analyses, the stratification factors applied 
to the analysis model will be: macrovascular invasion (Yes, No), α-fetoprotein (ng/mL) (<200, ≥200) and region (China, ex-
China), with all cells that correspond to macrovascular invasion=Yes combined.
‡  Miettinen and Nurminen method.
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
adverse events (AEs), laboratory tests, and vital signs.
Tiered Approach
The analysis of safety results will follow a tiered approach (Table 13).  The tiers differ with 
respect to the analyses that will be performed. For this protocol, there are no Tier 1 events. 
Tier 2 parameters will be assessed via point estimates with 95% confidence intervals 
provided for between-group comparisons; only point estimates by treatment group are 
provided for Tier 3 safety parameters.
AEs (specific terms as well as system organ class terms) will be classified as belonging to 
"Tier 2" or "Tier 3", based on the number of events observed. Membership in Tier 2 requires 
that at least 4 subjects in any treatment group exhibit the event; all other AEs and predefined 
limits of change will belong to Tier 3.
The threshold of at least 4 events was chosen because the 95% confidence interval for the 
between-group difference in percent incidence will always include zero when treatment 
groups of equal size each have less than 4 events and thus would add little to the 
interpretation of potentially meaningful differences.  Because many 95% confidence intervals 
may be provided without adjustment for multiplicity, the confidence intervals should be 
regarded as a helpful descriptive measure to be used in review, not a formal method for 
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assessing the statistical significance of the between-group differences in AEs and predefined
limits of change.
Continuous measures such as changes from baseline in laboratory values and vital signs, that 
are not pre-specified as Tier-1 endpoints will be considered Tier 3 safety parameters.  
Summary statistics for baseline, on-treatment, and change from baseline values will be 
provided by treatment group in table format.
In addition, the broad clinical and laboratory AE categories consisting of the percentage of 
subjects with any AE, any drug related AE, any Grade 3-5 AE, any serious AE, any AE 
which is both drug-related and Grade 3-5, any AE which is both serious and drug-related, 
dose modification due to AE, and who discontinued due to an AE, and death will be 
considered Tier 2 endpoints. 
The 95% confidence intervals will be provided for between- treatment differences in the 
percentage of subjects with Tier 2 events; these analyses will be performed using the 
Miettinen and Nurminen method [55], an unconditional, asymptotic method. Safety analyses 
will not be stratified.
Table 13
Analysis Strategy for Safety Parameters
Safety 
Tier
Safety Endpoint†
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 2
Any AE
X
X
Any Serious AE 
X
X
Any Grade 3-5 AE
X
X
Any Drug-Related AE
X
X
Any Serious and Drug-Related AE
X
X
Any Grade 3-5 and Drug-Related AE
X
X 
Dose Modification due to AE
X
X
Discontinuation due to AE
X
X
Death
Specific AEs, SOCs, or PDLCs‡ (incidence ≥4 
of subjects in one of the treatment groups)
X
X
Tier 3
Specific AEs, SOCs or PDLCs‡ (incidence <4 
of subjects in all of the treatment groups)
X
Change from Baseline Results (Labs, ECGs, 
Vital Signs)
X
Summaries of Demographic and Baseline Characteristics
The comparability of the treatment groups for each relevant characteristic will be assessed by 
the use of tables and/or graphs. No statistical hypothesis tests will be performed on these 
characteristics. The number and percentage of subjects screened, randomized, the primary 
reasons for screening failure, and the primary reason for discontinuation will be displayed. 
Demographic variables (e.g., age), baseline characteristics, primary and secondary diagnoses, 
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and prior and concomitant therapies will be summarized by treatment either by descriptive 
statistics or categorical tables.
Interim Analyses
An external data monitoring committee (eDMC) will be convened to review the unblinded 
efficacy results and accumulating safety at the planned IAs. 
Efficacy Interim Analyses
Two interim analyses and one final analysis are planned in this trial. The timing and the 
purpose of each analysis are summarized in Table 14. A detailed description of the 
multiplicity adjustment and hypotheses testing plan is provided in Section 8.8 Multiplicity.
The first interim analysis will be performed at approximately Month 17, at which time the 
first 163 randomized subjects have at least 24 weeks follow-up. The main purpose of this 
interim analysis is to conduct the analysis for ORR on the first 163 randomized subjects, 
evaluate the consistency of efficacy and safety in this study to the reference global data, and 
to conduct an interim testing for efficacy on the PFS and OS endpoints for all the subjects 
randomized at that time (superiority only). Consistency of efficacy will be evaluated by 
comparing the treatment effect observed in this study to the reference global data (based on 
point estimates). Approximately 225 subjects will be enrolled at the first interim analysis 
cutoff, with approximately 174 PFS events and 100 OS events projected to be accumulated. 
The main purpose of the second interim analysis is to conduct the primary testing for efficacy 
on the PFS hypothesis and to conduct an interim testing for efficacy on the OS hypothesis 
(superiority only).  It will be performed when enrollment is complete and approximately 276
OS events (~80% of the target 345 total OS events) are observed.  It is projected that this 
event count will be accumulated at approximately 31 months after the start of the study. 
Approximately 395 PFS events are expected to be accumulated by then. Under assumptions 
specified in Section 8.9 sample size and power calculation, at the time of the secondary 
interim analysis: 1) a total of approximately 395 PFS events for testing the PFS hypothesis at 
Type I error =0.2% provides approximately 88% power to successfully demonstrate the 
PFS hypothesis; and 2) a total of approximately 276 OS events for testing the OS hypothesis 
at Type I error =1.10% provides approximately 70% power to successfully demonstrate the 
OS hypothesis. 
If superiority of PFS or OS (pembrolizumab vs. placebo) is demonstrated at one of the 
interim analyses, the ORR hypothesis will be tested according to the group-sequential 
boundaries for ORR analysis (see Table 17 in Section 8.8 Multiplicity).  
The final analysis (FA) will be performed when approximately 345 OS events are observed
which is expected at Month 37.
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Table 14
Summary of Interim and Final Analyses Strategy
Analysis
Endpoint(s)
Criteria for Conduct of Analysis
Estimated Time after 
First Participant 
Randomized
Primary 
Purpose of 
Analysis
IA 1
ORR, DOR, PFS, 
OS 
First 163 randomized subjects 
have at least 24 weeks follow-up 
~17 months
Descriptive 
ORR analysis, 
consistency 
evaluation
IA 2
ORR, PFS, OS
~276 OS events observed
~31 months
PFS FA
OS IA
FA
OS, ORR
~345 OS events observed
~37 months
OS FA
Abbreviations: FA = final analysis; IA = interim analysis; PFS = progression-free survival; ORR = overall response rate; 
OS = overall survival
The eDMC will serve as the primary reviewer of the unblinded results of the interim analyses 
and will make recommendations. Depending on the recommendation of the eDMC, the 
Sponsor may prepare a regulatory submission. NOTE: no futility test is planned in the 
interim analysis. 
Safety Interim Analyses
As noted in Section 7.3.2 – Data Monitoring Committee, the eDMC will be responsible for 
periodic interim safety reviews as specified in the DMC charter.
Multiplicity
The multiplicity strategy specified in this section will be applied to the primary hypothesis
(superiority of pembrolizumab to placebo in OS) and the secondary hypotheses of superiority 
of pembrolizumab in PFS or ORR.
The overall Type-I error across the testing of the OS, PFS, and ORR hypotheses is strongly 
controlled at =2.5% (one-sided). The multiplicity strategy will follow the graphical 
approach of Mauer and Bretz [58].  Figure 3 provides the multiplicity strategy diagram of the 
study. 
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Figure 3
Multiplicity Strategy
In the diagram shown in Figure 3, when a particular null hypothesis is rejected, the arrows 
leading to it are removed, and the Type I error allocated to the null hypothesis that was 
rejected are re-distributed to other hypotheses.  The arrows on the diagram show how the 
Type I error allocated to a hypothesis that was successfully tested will be re-distributed.
Initially, =2.3% (23/25 of the overall total =2.5% for testing the OS, PFS and ORR) is 
allocated to the OS hypothesis and =0.2% is allocated to the PFS hypothesis.
In detail, if PFS and OS hypotheses are both rejected on the initial alpha, then ORR 
hypothesis will be tested on the 2.5% alpha level. If PFS hypothesis is rejected on the initial 
alpha level 0.2% while OS is NOT rejected on the initial alpha 2.3%, then ORR hypothesis 
will be tested on the 0.2% alpha level. If ORR hypothesis can be rejected on the 0.2% alpha 
level, then OS hypothesis will be retested on the 2.5% alpha level. If PFS hypothesis is NOT
rejected on the initial alpha level 0.2% but OS hypothesis is rejected on the initial alpha 
2.3%, then PFS hypothesis can be re-tested on the 1.35% alpha level and ORR hypothesis 
can be tested on the 1.15% level. After that, we will follow the same procedure of hypothesis 
testing and type-I error re-distribution as illustrated in Figure 3.
OS hypothesis: The OS hypothesis will be tested following a group sequential approach. 
The testing of the OS hypothesis will be based on an OS test statistic calculated from study 
data at the first interim analysis. If unsuccessful at the first IA, the OS hypothesis will be 
tested at the second interim analysis time and, if unsuccessful at the second IA, the OS 
hypothesis will be tested at the final analysis time.  No futility test is planned at the interim 
analyses. The nominal Type I error rates for the two interim analyses and final analysis that 
will allow tight control of the overall Type I error for testing the OS hypothesis will be 
derived using the alpha-spending function approach based on the overall Type I error 
allocated to the OS hypothesis. The group sequential testing of the OS hypothesis will be 
conducted with efficacy boundaries (superiority test only). The OS efficacy boundary will be 
set using the Lan-DeMets spending function that approximates an O’Brien-Fleming 
boundary. The OS hypothesis will initially be tested at the overall Type I error =2.3%. If 
both the PFS and ORR null hypotheses have been rejected at the =0.2% level, the OS 
hypothesis will be tested at Type I error level of =2.5%. 
Table 15 summarizes the timing, sample size and decision guidance of the interim analyses
and final OS analysis. Interim analysis spending for OS analyses will be based on the 
expectation of 345 OS events at the final analysis and the final analysis spending will be 
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updated based on spending alpha using the actual number of OS events at times of analysis 
using spending functions as noted above.
Table 15
Summary of Timing, Sample Size and Decision Guidance for the Interim 
Analyses and Final Analysis of Overall Survival
Type I Error 
(Overall )
Analysis
Study 
Calendar 
Time
N§
Events
Information 
Fraction
Efficacy Boundary Crossing†
Nominal 

Hazard 
Ratio
Power
2.3%
IA1
IA2
Month 17
Month 31
225
450
100
276
0.30
0.80
<0.01%
1.10%
~0.42
~0.75
0.9%
70%
Final
Month 37
450
345
1.00
1.98%
~0.79
87%
2.5%
IA1
IA2
Month 17
Month 31
225
450
100
276
0.30
0.80
<0.01%
1.22%
~0.43
~0.75
1.1%
72%
Final
Month 37
450
345
1.00
2.14%
~0.79
88%
† Based on Lan-DeMets spending function that approximates an O’Brien-Fleming boundary. 
§ Expected number of subjects randomized into the study at the time of analysis.
PFS hypothesis: The PFS hypothesis will be tested following a group sequential approach. 
The testing of the PFS hypothesis will be at the first interim analysis time. If unsuccessful at 
the first IA, the PFS hypothesis will be tested at the second interim analysis time, and this 
will be final analysis for PFS. No futility test is planned at this interim analysis. The primary 
testing of the PFS hypothesis will initially be tested at one-sided Type I error =0.2%.
Depending on the results of testing of the OS and ORR hypothesis, the PFS hypothesis can 
be tested at a one-sided Type I error level of =1.35% or =2.5%. At the second interim 
analysis, it is expected that approximately 395 PFS events would have been accumulated 
assuming 1) a hazard ratio of 0.65; 2) Progression-free survival follows an exponential 
distribution with a median of 1.5 months in the control arm; 3) an enrollment time of 31
months with a recruitment rate of 16 subjects per month and a 6-month ramp up time, and 4) 
a monthly drop-out rate of ~1%. The corresponding power is expected to be over 88% when 
testing at a Type I error =0.2%.
Table 16 summarizes the timing, sample size and decision guidance of the interim and final
PFS analyses. Interim analysis spending for PFS analysis will be based on the expectation of 
395 PFS events at the final analysis and the final analysis spending will be updated on 
spending alpha using the actual number of PFS events at times of analysis when the criteria 
for triggering the final PFS analysis is complete.
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Table 16
Summary of Timing, Sample Size and Decision Guidance for the Interim 
Analysis and Final Analysis of Progression Free Survival
Type I Error 
(Overall )
Analysis
Study 
Calendar 
Time
N§
Events
Information 
Fraction
Efficacy Boundary Crossing†
Nominal 

Hazard 
Ratio
Power
0.2%
IA
FA
Month 17
Month 31
225
450
174
395
0.44
1.00
<0.01%
0.2%
~0.48
~0.74
3.4%
88%
1.35%
IA
FA
Month 17
Month 31
225
450
174
395
0.44
1.00
0.02%
1.34%
~0.57
~0.79
20%
97%
2.5%
IA
FA
Month 17
Month 31
225
450
174
395
0.44
1.00
0.07%
2.5%
~0.60
~0.81
31%
98%
† Based on Lan-DeMets spending function that approximates an O’Brien-Fleming boundary. 
§ Expected number of subjects randomized into the study at the time of analysis.
ORR hypothesis: ORR by treatment group will be estimated at each interim analysis and 
the final analysis. The initial alpha allocated to ORR is zero. If PFS or OS null hypothesis is 
rejected, depending on the results of testing of the OS and PFS hypothesis, the ORR 
hypothesis can be tested at a one-sided Type I error level of =0.2%, =1.15%, or =2.5%.
The ORR hypothesis will be tested following a group sequential approach. The testing of the 
ORR hypotheses will be at the first interim analysis time. If unsuccessful at the first IA, the 
ORR hypotheses will be tested at the second interim analysis time, and, if unsuccessful, at 
the final analysis time. Subjects who will be included in the ORR analysis are those who 
have “mature ORR information”, defined as subjects who were enrolled at least 24 weeks 
prior to the interim data cutoff dates and thus had an opportunity to have at least 4 scheduled 
scans if not discontinued. For the first interim analysis, 163 subjects with at least 24 weeks 
follow up will be included for ORR analysis and information fraction is expected to be about 
0.36. It is projected that there will be approximately 362 such subjects at the second interim 
analysis time point and the information fraction is expected to be about 0.80 (362 with 
“mature ORR information” of 450 enrolled). The nominal Type I error rates for the interim 
analyses and final analysis that will allow tight control of the overall Type I error for testing 
the ORR hypothesis will be derived using the alpha-spending function approach. The group 
sequential testing of the ORR hypothesis will be conducted with an efficacy boundary only. 
The efficacy boundary for the ORR will be set using an Exponential spending function 
[62] with parameter =0.25, which yields a Pocock-like boundary. The ORR 
hypothesis is initially allocated a Type I error =0% and thus, cannot be tested unless one or 
both of the PFS or OS null hypotheses have been rejected. Depending on the results of the 
OS and PFS hypotheses testing, the ORR hypothesis can be tested at Type I error levels of 
=0.2%, 1.15%, or 2.5%.
Table 17 shows the boundary thresholds corresponding to a group sequential testing of the 
ORR hypothesis at each of these Type I error levels. The interim analysis information 
fractions will be adjusted according to the proportion of the total number of subjects actually 
randomized (which will be known at the time of the interim analyses) who were enrolled at 
least 24 weeks prior to the interim data cutoff dates and thus had an opportunity to have at 
least 4 scheduled scans if not discontinued by the time of interim analysis.  The Exponential 
spending function will then be used to update the boundary thresholds in Table 17. 
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Table 17
Efficacy Boundaries for Testing the ORR Hypothesis
Type I 
Error 
(Overall 
)
Analysis
Study 
Calendar 
Time
N‡
Information 
Fraction
Efficacy Boundary Crossing†
Nominal 

ORR §
Power
0.2%
IA1
Month 17
163
0.36
0.03%
~16.77%
17%
IA2
Month 31
362
0.80
0.12%
~10.05%
73%
Final
Month 37
450
1.00
0.11%
~9.07%
85%
1.15%
IA1
Month 17
163
0.36
0.31%
~12.95%
42%
IA2
Month 31
362
0.80
0.67%
~7.85%
91%
Final
Month 37
450
1.00
0.58%
~7.18%
96%
2.50%
IA1
Month 17
163
0.36
0.86%
~11.09%
58%
IA2
Month 31
362
0.80
1.45%
~6.80%
96%
Final
Month 37
450
1.00
1.23%
~6.28%
98%
† Based on Exponential (=0.25) spending function. ORR is tested for superiority only.
‡ Expected number of subjects who were enrolled at least 24 weeks prior to the data cutoff date and thus 
had an opportunity to have at least 4 scheduled scans at the time of ORR analysis. 
§= ORR in pembrolizumab group – ORR in control group. The assumed expected ORR in 
pembrolizumab and control groups are 15% and 3%, respectively.
The spending function planned to be used for the testing of the OS and ORR hypotheses 
satisfy the requirements laid out in Maurer and Bretz [58]. More details will be included in 
the sSAP.
Sample Size and Power Calculations
The study will randomize subjects in a 2:1 ratio into the pembrolizumab plus BSC arm and 
the control arm (placebo plus BSC).  
The final analysis is event driven (i.e., the testing of the OS and PFS hypotheses will be 
conducted upon accumulation of a preset number of events). The study is designed and will 
be conducted to accumulate approximately 345 OS events unless superiority in OS is proven 
at the interim analyses.
OS Analysis: A total of approximately 345 OS events are required to test the OS hypothesis 
at Type I error rate of =2.3% with ~87% power (see Table 15) if the underlying OS 
hazard ratio (pembrolizumab/control) is 0.7. A total of approximately 450 subjects are 
needed to be enrolled into the study in order to accumulate approximately 345 OS events at 
approximately Month 37 after study start.
The sample size and power calculation is based on the following assumptions: 1) a hazard 
ratio of 0.7; 2) overall survival follows an exponential distribution with a median of 6.0
months in the control arm; 3) an enrollment rate of 16 subjects per month with a 6-month 
ramp up time; and 4) a monthly dropout rate of ~0.2% . 
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PFS Analysis: As described in Section 8.7 Interim Analysis, the primary PFS analysis will 
be conducted at the same time as the OS interim analysis at approximately Month 31 after
study start. It is projected that approximately 395 PFS events will be accumulated at this 
time. With 395 PFS events, the testing of the PFS hypothesis at Type I error =0.2% has 
approximately 88% power to demonstrate that pembrolizumab is superior to the control with 
respect to PFS if the underlying PFS hazard ratio (pembrolizumab/control) is 0.65.
The sample size and power calculation is based on the following assumptions: 1) a hazard 
ratio of 0.65; 2) progression-free survival follows an exponential distribution with a median 
of 1.5 months in the control arm; 3) an enrollment rate of 16 subjects per month with a 6-
month ramp up time; and 4) a monthly dropout rate of ~1%.
The sample size and power calculation were performed in the software EAST and R 
(package “gsDesign”).
Subgroup Analyses and Effect of Baseline Factors
To determine whether the treatment effect is consistent across various subgroups, the 
estimate of the between-group treatment effect (with a nominal 95% CI) for the primary 
endpoint will be estimated and plotted within each category of the following classification 
variables:

Prior treatment (Sorafenib, chemotherapy) 

Macrovascular invasion (Yes, No)

Etiology (HCV, HBV, and uninfected)

α-Fetoprotein (ng/mL) (<200, ≥200)

Reason for discontinuation of prior treatment (progressive disease, intolerance)

ECOG performance status (0, 1)

Age (<65 years, ≥65 years)

Extrahepatic spread (Yes, No)

Region (China, ex-China)
Compliance (Medication Adherence)
Drug accountability data for trial treatment will be collected during the study. Any deviation 
from protocol-directed administration will be reported.
Extent of Exposure
The extent of exposure will be summarized as duration of treatment in cycles.
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9.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES
Investigational Product
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations.
Clinical Supplies will be provided by the Sponsor as summarized in Table 18.
Clinical supplies will be packaged to support enrollment and replacement subjects as 
required.  When a replacement subject is required, the Sponsor or designee needs to be 
contacted prior to dosing the replacement supplies.
Table 18
Product Descriptions
Product Name & 
Potency
Dosage Form
Source/Additional Information
Pembrolizumab, 100 mg/ 
4 mL
Injection
Provided centrally by the Sponsor
All supplies indicated in Table 18 will be provided per the “Source/Additional Information” 
column depending on local country operational requirements.
Any commercially available product not included in Table 18 will be provided by the trial 
site, subsidiary or designee. Every attempt should be made to source these supplies from a 
single lot/batch number. The trial site is responsible for recording the lot number, 
manufacturer, and expiry date for any locally purchased product as per local guidelines 
unless otherwise instructed by the Sponsor.
Packaging and Labeling Information
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
Site pharmacies will receive open label kits of study drug.
Clinical Supplies Disclosure
This trial is blinded but provided open label; therefore, an unblinded pharmacist or qualified 
trial site personnel will be used to blind supplies. Treatment identity (name, strength or 
potency) is included in the label text; random code/disclosure envelopes or lists are not 
provided.
The emergency unblinding call center will use the treatment/randomization schedule for the 
trial to unblind subjects and to unmask treatment identity.  The emergency unblinding call 
center should only be used in cases of emergency (see Section 7.1.5.2). In the event that the 
emergency unblinding call center is not available for a given site in this trial, the central 
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electronic treatment allocation/randomization system (IVRS/IWRS) should be used in order 
to unblind subjects and to unmask treatment/vaccine identity. The Sponsor will not provide 
random code/disclosure envelopes or lists with the clinical supplies.
Treatment identification information is to be unmasked ONLY if necessary for the welfare of
the subject. Every effort should be made not to unblind the subject unless necessary.
In the event that unblinding has occurred, the circumstances around the unblinding (e.g.,
date, reason and person performing the unblinding) must be documented promptly, and the
Sponsor Clinical Director notified as soon as possible. Once an emergency unblinding has 
taken place, the principal investigator, site personnel, and Sponsor personnel may be 
unblinded so that the appropriate follow-up medical care can be provided to the subject.
Section 5.8 outlines the criteria for allowing subjects who are discontinued from treatment to 
continue to be monitored in the trial.
Storage and Handling Requirements
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.  
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site.
Clinical supplies may not be used for any purpose other than that stated in the protocol.
Discard/Destruction/Returns and Reconciliation
The investigator is responsible for keeping accurate records of the clinical supplies received 
from the Sponsor or designee, the amount dispensed to and returned by the subjects and the 
amount remaining at the conclusion of the trial. For all trial sites, the local country Sponsor 
personnel or designee will provide appropriate documentation that must be completed for 
drug accountability and return, or local discard and destruction if appropriate.   Where local 
discard and destruction is appropriate, the investigator is responsible for ensuring that a local 
discard/destruction procedure is documented.
Standard Policies
Trial 
site 
personnel 
will 
have 
access 
to 
a 
central 
electronic 
treatment 
allocation/randomization system (IVRS/IWRS system) to allocate subjects, to assign 
treatment to subjects and to manage the distribution of clinical supplies. Each person 
accessing the IVRS system must be assigned an individual unique PIN.  They must use only 
their assigned PIN to access the system, and they must not share their assigned PIN with 
anyone.
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10.0 ADMINISTRATIVE AND REGULATORY DETAILS
Confidentiality
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the institutional review board, ethics review committee (IRB/ERC) or similar 
or expert committee; affiliated institution and employees, only under an appropriate 
understanding of confidentiality with such board or committee, affiliated institution and 
employees.  Data generated by this trial will be considered confidential by the investigator, 
except to the extent that it is included in a publication as provided in the Publications section 
of this protocol.
Confidentiality of Subject Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/ERC, or regulatory authority representatives may consult and/or copy trial documents in 
order to verify worksheet/case report form data.  By signing the consent form, the subject 
agrees to this process.  If trial documents will be photocopied during the process of verifying 
worksheet/case report form information, the subject will be identified by unique code only; 
full names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all subject data used and disclosed in 
connection with this trial in accordance with all applicable privacy laws, rules and 
regulations.
Confidentiality of Investigator Information
By signing this protocol, the investigator recognizes that certain personal identifying 
information with respect to the investigator, and all subinvestigators and trial site personnel, 
may be used and disclosed for trial management purposes, as part of a regulatory 
submissions, and as required by law.  This information may include:
1. name, address, telephone number and e-mail address;
2. hospital or clinic address and telephone number;
3. curriculum vitae or other summary of qualifications and credentials; and
4. other professional documentation.
Consistent with the purposes described above, this information may be transmitted to the 
Sponsor, and subsidiaries, affiliates and agents of the Sponsor, in your country and other 
countries, including countries that do not have laws protecting such information.  
Additionally, the investigator’s name and business contact information may be included 
when reporting certain serious adverse events to regulatory authorities or to other 
investigators.  By signing this protocol, the investigator expressly consents to these uses and 
disclosures.
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If this is a multicenter trial, in order to facilitate contact between investigators, the Sponsor 
may share an investigator’s name and contact information with other participating 
investigators upon request.
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this trial.  The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
Compliance with Financial Disclosure Requirements
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54).  It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required.  It is the investigator's/subinvestigator's 
responsibility to comply with any such request.  
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements.  
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes.  This may involve the 
transmission of information to countries that do not have laws protecting personal data.
Compliance with Law, Audit and Debarment
By signing this protocol, the investigator agrees to conduct the trial in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of Good 
Clinical Practice (e.g., International Conference on Harmonization of
Technical 
Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice: 
Consolidated Guideline and other generally accepted standards of good clinical practice); and 
all applicable federal, state and local laws, rules and regulations relating to the conduct of the 
clinical trial.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by Merck, is provided in Section 12.1 -
Merck Code of Conduct for Clinical Trials.
The investigator also agrees to allow monitoring, audits, IRB/ERC review and regulatory 
authority inspection of trial-related documents and procedures and provide for direct access 
to all trial-related source data and documents.
The investigator agrees not to seek reimbursement from subjects, their insurance providers or 
from government programs for procedures included as part of the trial reimbursed to the 
investigator by the Sponsor.
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The investigator shall prepare and maintain complete and accurate trial documentation in 
compliance with Good Clinical Practice standards and applicable federal, state and local 
laws, rules and regulations; and, for each subject participating in the trial, provide all data, 
and, upon completion or termination of the clinical trial, submit any other reports to the 
Sponsor as required by this protocol or as otherwise required pursuant to any agreement with 
the Sponsor.
Trial documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the trial site upon request for inspection, 
copying, review and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities.  The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor as a result of an audit to cure deficiencies in the trial documentation 
and worksheets/case report forms.
The investigator must maintain copies of all documentation and records relating to the 
conduct of the trial in compliance with all applicable legal and regulatory requirements.  This 
documentation includes, but is not limited to, the protocol, worksheets/case report forms, 
advertising for subject participation, adverse event reports, subject source data, 
correspondence with regulatory authorities and IRBs/ERCs, consent forms, investigator’s 
curricula vitae, monitor visit logs, laboratory reference ranges, laboratory certification or 
quality control procedures and laboratory director curriculum vitae.  By signing this protocol, 
the investigator agrees that documentation shall be retained until at least 2 years after the last 
approval of a marketing application in an ICH region or until there are no pending or 
contemplated marketing applications in an ICH region or until at least 2 years have elapsed 
since the formal discontinuation of clinical development of the investigational product.  
Because the clinical development and marketing application process is variable, it is 
anticipated that the retention period can be up to 15 years or longer after protocol database 
lock. The Sponsor will determine the minimum retention period and notify the investigator 
when documents may be destroyed.  The Sponsor will determine the minimum retention 
period and upon request, will provide guidance to the investigator when documents no longer 
need to be retained.  The sponsor also recognizes that documents may need to be retained for 
a longer period if required by local regulatory requirements. All trial documents shall be 
made available if required by relevant regulatory authorities. The investigator must consult 
with and obtain written approval by the Sponsor prior to destroying trial and/or subject files.  
ICH Good Clinical Practice guidelines recommend that the investigator inform the subject’s 
primary physician about the subject’s participation in the trial if the subject has a primary 
physician and if the subject agrees to the primary physician being informed.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this trial.
Persons debarred from conducting or working on clinical trials by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s trials.  The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the trial is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will 
promptly notify that trial site’s IRB/IEC.
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According to European legislation, a Sponsor must designate an overall coordinating 
investigator for a multi-center trial (including multinational).  When more than one trial site 
is open in an EU country, Merck, as the Sponsor, will designate, per country, a national 
principal coordinator (Protocol CI), responsible for coordinating the work of the principal 
investigators at the different trial sites in that Member State, according to national 
regulations.  For a single-center trial, the Protocol CI is the principal investigator.  In 
addition, the Sponsor must designate a principal or coordinating investigator to review the 
trial report that summarizes the trial results and confirm that, to the best of his/her 
knowledge, the report accurately describes the conduct and results of the trial [Clinical Study 
Report (CSR) CI].  The Sponsor may consider one or more factors in the selection of the 
individual to serve as the Protocol CI and or CSR CI (e.g., availability of the CI during the 
anticipated review process, thorough understanding of clinical trial methods, appropriate 
enrollment of subject cohort, timely achievement of trial milestones).  The Protocol CI must 
be a participating trial investigator.
Compliance with Trial Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements 
for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov.  Merck, as 
Sponsor of this trial, will review this protocol and submit the information necessary to fulfill 
these requirements.  Merck entries are not limited to FDAMA/FDAAA mandated trials. 
Information posted will allow subjects to identify potentially appropriate trials for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate trial locations and trial site contact information.    
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAMA/FDAAA are that of the Sponsor and agrees not to submit any information about this 
trial or its results to the Clinical Trials Data Bank.
Quality Management System
By signing this protocol, the Sponsor agrees to be responsible for implementing and 
maintaining a quality management system with written development procedures and 
functional area standard operating procedures (SOPs) to ensure that trials are conducted and 
data are generated, documented, and reported in compliance with the protocol, accepted 
standards of Good Clinical Practice, and all applicable federal, state, and local laws, rules and 
regulations relating to the conduct of the clinical trial.
Data Management
The investigator or qualified designee is responsible for recording and verifying the accuracy 
of subject data. 
By signing this protocol, the investigator acknowledges that his/her 
electronic signature is the legally binding equivalent of a written signature.  By entering 
his/her electronic signature, the investigator confirms that all recorded data have been 
verified as accurate.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
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Publications
This trial is intended for publication, even if terminated prematurely. Publication may include 
any or all of the following: posting of a synopsis online, abstract and/or presentation at a 
scientific conference, or publication of a full manuscript.  The Sponsor will work with the 
authors to submit a manuscript describing trial results within 12 months after the last data 
become available, which may take up to several months after the last subject visit in some 
cases such as vaccine trials.  However, manuscript submission timelines may be extended on 
OTC trials.  For trials intended for pediatric-related regulatory filings, the investigator agrees 
to delay publication of the trial results until the Sponsor notifies the investigator that all 
relevant regulatory authority decisions on the trial drug have been made with regard to 
pediatric-related regulatory filings. Merck will post a synopsis of trial results for approved 
products on www.clinicaltrials.gov by 12 months after the last subject's last visit for the 
primary outcome, 12 months after the decision to discontinue development, or product 
marketing (dispensed, administered, delivered or promoted), whichever is later.
These timelines may be extended for products that are not yet marketed, if additional time is 
needed for analysis, to protect intellectual property, or to comply with confidentiality 
agreements with other parties.  Authors of the primary results manuscript will be provided 
the complete results from the Clinical Study Report, subject to the confidentiality agreement. 
When a manuscript is submitted to a biomedical journal, the Sponsor's policy is to also 
include the protocol and statistical analysis plan to facilitate the peer and editorial review of 
the manuscript.  If the manuscript is subsequently accepted for publication, the Sponsor will 
allow the journal, if it so desires, to post on its website the key sections of the protocol that 
are relevant to evaluating the trial, specifically those sections describing the trial objectives 
and hypotheses, the subject inclusion and exclusion criteria, the trial design and procedures, 
the efficacy and safety measures, the statistical analysis plan, and any amendments relating to 
those sections.  The Sponsor reserves the right to redact proprietary information.
For multicenter trials, subsequent to the multicenter publication (or after public disclosure of 
the results online at www.clinicaltrials.gov if a multicenter manuscript is not planned), an 
investigator and his/her colleagues may publish their data independently.  In most cases, 
publication of individual trial site data does not add value to complete multicenter results, 
due to statistical concerns.  In rare cases, publication of single trial site data prior to the main 
paper may be of value.  Limitations of single trial site observations in a multicenter trial 
should always be described in such a manuscript.
Authorship credit should be based on 1) substantial contributions to conception and design, 
or acquisition of data, or analysis and interpretation of data; 2) drafting the article or revising 
it critically for important intellectual content; and 3) final approval of the version to be 
published. Authors must meet conditions 1, 2 and 3.  Significant contributions to trial 
execution may also be taken into account to determine authorship, provided that 
contributions have also been made to all three of the preceding authorship criteria.  Although 
publication planning may begin before conducting the trial, final decisions on authorship and 
the order of authors’ names will be made based on participation and actual contributions to 
the trial and writing, as discussed above. The first author is responsible for defending the 
integrity of the data, method(s) of data analysis and the scientific content of the manuscript.
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The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or 
presentations regarding this trial 45 days prior to submission for publication/presentation. 
Any information identified by the Sponsor as confidential must be deleted prior to 
submission; this confidentiality does not include efficacy and safety results. Sponsor review 
can be expedited to meet publication timelines.
11.0 LIST OF REFERENCES
1. Mizuki Nishino, Anita Giobbie-Hurder, Maria Gargano et al. Developing a Common 
Language for Tumor Response to Immunotherapy: Immune-Related Response Criteria 
Using Unidimensional Measurements. Clin Cancer Res. 2013 July; 19(14) :3936-3943
2. Alejandro Forner, Josep M Llovet, Jordi Bruix. Hepatocellular carcinoma. Lancet 
2012;379:1245-55
3. GLOBOCAN. 
Cancer 
incidence 
and 
mortality 
worldwide 
in 
2012. 
http://globocan.iarc.fr/
4. Jacques Ferlay, Isabelle Soerjomataram, Rajesh Dikshit, Sultan Eser, Colin Mathers, 
Marise Rebelo. Cancer incidence and mortality worldwide: Sources, methods and major 
patterns in GLOBOCAN 2012. International Journal of Cancer;136: E359-386
5. Hashem B. El-Serag. Epidemiology of Viral Hepatitis and Hepatocellular Carcinoma. 
Gastroenterology. 2012 May; 142(6): 1264–1273.
6. Hillary Lin, Nghiem B. Ha, Aijaz Ahmed et al. Both HCV and HBV are Major Causes 
of Liver Cancer in Southeast Asians. J Immigrant Minority Health (2013) 15:1023–
1029
7. Hashem B. El-Serag. Epidemiology of Viral Hepatitis and Hepatocellular Carcinoma. 
Gastroenterology. 2012 May; 142(6): 1264–1273.e1
8. Josep M. Llovet, Sergio Ricci, Vincenzo Mazzaferro, et al. Sorafenib in Advanced 
Hepatocellular Carcinoma. N Engl J Med 2008;359:378-90
9. Ann-Lii Cheng, Yoon-Koo Kang, Zhengdong Chen et al. Efficacy and Safety of 
sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: 
a phase III randomized, double-blind, placebo-controlled trial.2009;10:25-34
10. Shukui Qin, Yuxian Bai, Ho Yeong Lim et al. Randomized, Multicenter, Open-Label 
Study of Oxaliplatin Plus Fluorouracil/Leucovorin Versus Doxorubicin As Palliative 
Chemotherapy in Patients With Advanced Hepatocellular Carcinoma From Asia;J Clin 
Oncol 2013;31:3501-3508
11. Shukui Qin, Ying Cheng, Jun Liang et al. Efficacy and Safety of the FOLFOX4 
Regimen Versus Doxorubicin in Chinese PatientsWith Advanced Hepatocellular 
Carcinoma: A Subgroup Analysis of the EACH Study. The Oncologist 2014;19:1–10
12. China Ministry of Health. Diagnosis and Treatment Guideline for Primary Liver 
Cancer. Chinese Clinical Oncology.2011;16(10):929-946
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13. Korean Liver Cancer Study Group (KLCSG), National Cancer Center, Korea (NCC). 
2014 Korean Liver Cancer Study Group-National Cancer Center Korea Practice 
Guideline for the Management of Hepatocellular Carcinoma. Korean Journal of 
Radiology.2015; 16(3): 465-522
14. Josep M. Llovet, Thomas Decaens, Jean-Luc Raoul, Eveline Boucher, Masatoshi Kudo 
et al. Brivanib in Patients With Advanced Hepatocellular Carcinoma Who Were 
Intolerant to Sorafenib or for Whom Sorafenib Failed: Results From the Randomized 
Phase III BRISK-PS Study. J Clin Oncol. 2013;31:3509-3516
15. Andrew X. Zhu, Masatoshi Kudo,Eric Assenat, et al. Effect of Everolimus on Survival 
in Advanced Hepatocellular Carcinoma After Failure of Sorafenib The EVOLVE-1 
Randomized Clinical Trial. JAMA. 2014;312(1):57-67
16. Andrew X Zhu, Joon Oh Park, Baek-Yeol Ryoo,et al. Ramucirumab versus placebo as 
second-line treatment in patients with advanced hepatocellular carcinoma following 
first-line therapy with sorafenib (REACH): a randomised, double-blind, multicentre, 
phase 3 trial. Lancet Oncol 2015; 16: 859–70
17. Armando Santoro, Lorenza Rimassa, Ivan Borbath,et al. Tivantinib for second-line 
treatment of advanced hepatocellular carcinoma: a randomised, placebo-controlled 
phase 2 study. Lancet Oncol 2013; 14: 55–63
18. Jordi Bruix, Won-Young Tak, Antonio Gasbarrini,et al. Regorafenib as second-line 
therapy for intermediate or advanced hepatocellular carcinoma: Multicentre, open-label, 
phase II safety study. European Journal of Cancer 2013;49: 3412– 3419
19. Alessandro Granito, Sara Marinellia, Eleonora Terzia, et al. Metronomic capecitabine as 
second-line treatment in hepatocellular carcinoma after sorafenib failure. Digestive and 
Liver Disease 2015;47: 518–522
20. Anna Patrikidou ,Isabelle Sinapi, Hélène Regnault et al. Gemcitabine and oxaliplatin 
chemotherapy for advanced hepatocellular carcinoma after failure of anti-angiogenic 
therapies. Invest New Drugs 2014; 32:1028–1035
21. Disis ML. Immune regulation of cancer. J Clin Oncol 2010;28(29):4531-8.
22. Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, et al. Tumor-
associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. 
Nat Med 2002;8(8):793-800.
23. Sharpe AH, Freeman GJ. The B7-CD28 superfamily. Nature 2002;2:116-26
24. Brown JA, Dorfman DM, Ma F-R, Sullivan EL, Munoz O, Wood CR, et al. Blockade of 
programmed death-1 ligands on dendritic cells enhances T cell activation and cytokine 
production. J Immunol 2003;170:1257-66.
25. Brown JA, Dorfman DM, Ma F-R, Sullivan EL, Munoz O, Wood CR, et al. Blockade of 
programmed death-1 ligands on dendritic cells enhances T cell activation and cytokine 
production. J Immunol 2003;170:1257-66.
26. Thompson RH, Dong H, Lohse CM, Leibovich BC, Blute ML, Cheville JC, et al. PD-1 
expressed by tumor-infiltrating immune cells and is associated with poor outcome for 
patients with renal cell carcinoma. Clin Caner Res 2007;13(6):1757-61.
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27. Talmadge JE, Donkor M, Scholar E. Inflammatory cell infiltration of tumors: Jekyll or 
Hyde. Cancer Metastasis Rev 2007;26:373-400
28. Usubütün A, Ayhan A, Uygur MC, Özen H, Toklu C, Ruacan S. Prognostic factors in 
renal cell carcinoma. J Exp Clin Cancer Res 1998;17(1):77-81
29. Al-Shibli K, Al-Saad S, Andersen S, Donnem T, Bremnes RM, Busund L-T. The 
prognistic value of intraepithelial and stromal CD3-, CD117- and CD138-positive cells 
in non-small cell lung carcinoma. APMIS 2010;118:371-82.
30. Deschoolmeester V, Baay M, Van Marck E, Weyler J, Vermeulen p, Lardon F, et al. 
Tumor infiltrating lymphocytes: an intriguing player in the survival of colorectal cancer 
patients. BMC Immunol 2010;11:19.
31. Diez M, Pollán M, Enriquez JM, Dominguez P, Santana A, Tobaruela E, et al. 
Histopathologic prognostic score in colorectal adenocarcinomas. Anticancer Res 
1998;18:689-94
32. Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pagès C, et al. 
Type, density, and location of immune cells within human colorectal tumors predict 
clinical outcome. Science 2006;313:1960-4.
33. Hiraoka N. Tumor-infiltrating lymphocytes and hepatocellular carcinoma: molecular 
biology. Int J Clin Oncol 2010;15:544-51.
34. Nobili C, Degrate L, Caprotti R, Franciosi C, Leone BE, Trezzi R, et al. Prolonged 
survival of a patient affected by pancreatic adenocarcinoma with massive lymphocyte 
and dendritic cell infiltration after interleukin-2 immunotherapy. Report of a case. 
Tumori 2008;94:426-30
35. Chemnitz JM, Parry RV, Nichols KE, June CH, Riley JL. SHP-1 and SHP-2 associate 
with immunoreceptor tyrosine-based switch motif of programmed death 1 upon primary 
human T cell stimulation, but only receptor ligation prevents T cell activation. J 
Immunol 2004;173:945-54
36. Kloor M. Lymphocyte infiltration and prognosis in colorectal cancer. Lancet 
2009;10(840):841.
37. Hillen F, Baeten CIM, van de Winkel A, Creytens D, van der Schaft DWJ, 
Winnepenninckx V, et al. Leukocyte infiltration and tumor cell plasticity are parameters 
of aggressiveness in primary cutaneous melanoma. Cancer Immunol Immunother 
2008;57:97-106.
38. Lee HE, Chae SW, Lee YJ, Kim MA, Lee HS, Lee BL, et al. Prognostic implications of 
type and density of tumour-infiltrating lymphocytes in gastric cancer. Br J Cancer 
2008;99(10):1704-11.
39. Leffers N, Gooden MJM, de Jong RA, Hoogeboom B-N, ten Hoor KA, Hollema H, et 
al. Prognostic significance of tumor-infiltrating T-lymphocytes in primary and 
metastatic lesions of advanced stage ovarian cancer. Cancer Immunol Immunother 
2009;58:449-59.
40. Nishimura H, Honjo T, Minato N. Facilitation of ßselection and modification of positive 
selection in the thymus of PD-1-deficient mice. J Exp Med 2000;191(5):891-7
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41. Liotta F, Gacci M, Frosali F, Querci V, Vittori G, Lapini A, et al. Frequency of 
regulatory T cells in peripheral blood and in tumour-infiltrating lymphocytes correlates 
with poor prognosis in renal cell carcinoma. BJU Intern 2010;107:1500-6
42. Ropponen KM, Eskelinen MJ, Lipponen PK, Alhava E, Kosma V-M. Prognostic value 
of tumour-infiltrating lynmphocytes (TILs) in colorectal cancer. J Pathol 1997;182:318-
24.
43. Dudley ME, Wunderlich JR, Yang JC, Sherry RM, Topalian SL, Restifo NP, et al. 
Adoptive cell transfer therapy following non-myeloablative but lymphodepleting 
chemotherapy for the treatment of patients with refractory metastatic melanoma. J Clin 
Oncol 2005;23(10):2346-57.
44. Hunder NN, Wallen H, Cao J, Hendricks DW, Reilly JZ, Rodmyre R, et al. Treatment 
of metastatic melanoma with autologous CD4+ T cells against NY-ESO-1. N Engl J 
Med 2008;358(25):2698-703.
45. Pölcher M, Braun M, Friedrichs N, Rudlowski C, Bercht E, Fimmers R, et al. Foxp3+
cell infiltration and granzyme B+/ Foxp3+ cell ratio are associated with outcome in 
neoadjuvant chemotherapy-treated ovarian carcinoma. Cancer Immunol Immunother 
2010;59:909-19.
46. Okazaki T, Maeda A, Nishimura H, Kurosaki T, Honjo T. PD-1 immunoreceptor 
inhibits B cell receptor-mediated signaling by recruiting src homology 2-domain-
containing tyrosine phosphatase 2 to phosphotyrosine. Proc Natl Acad Sci U S A 
2001;98(24):13866-71.
47. Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisted. Annu Rev Immunol 
2005;23:515-48.
48. Aizea Morales-Kastresana, Miguel F. Sanmamed, Inmaculada Rodriguez,et al. 
Combined Immunostimulatory Monoclonal Antibodies Extend Survival in an 
Aggressive Transgenic Hepatocellular Carcinoma Mouse Model. Clin Cancer Res; 
2013;(22): 6151–62
49. Qiang Gao, Xiao-Ying Wang, Shuang-Jian Qiu, et al. Overexpression of PD-
L1SignificantlyAssociates with Tumor Aggressiveness and Postoperative Recurrence in 
Human Hepatocellular Carcinoma. Clin Cancer Res .2009;15:971-979
50. Feng Shi, Ming Shi, Zhen Zeng, et al. PD-1 and PD-L1 upregulation promotes CD81 T-
cell apoptosis and postoperative recurrence in hepatocellular carcinoma patients. Int. J. 
Cancer.2011; 128: 887–896
51. Anthony B, EI-Khoueiry,Ignacio Melero,et al. Phase1/2 Safety and Antitumor Activity 
of Nivolumab in Patients with Advanced Hepatocellular Carcinoma(HCC):CA2019-
040. ASCO Annual Meeting.2015.Abstract LBA 101
52. Anthony B, EI-Khoueiry, Bruno Sangro,et al. Phase I/II safety and antitumor activity of 
nivolumab (nivo) in patients (pts) with advanced hepatocellular carcinoma (HCC): 
Interim analysis of the CheckMate-040 dose escalation study. ASCO Annual 
Meeting.2016.Abstract 4012
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53. Bruno Sangro, Ignacio Melero, Thomas Yau,,et al. Safety and antitumor activity of 
nivolumab (nivo) in patients (pts) with advanced hepatocellular carcinoma (HCC): 
Interim analysis of dose expansion cohorts from the phase 1/2 CheckMate-040 study. 
ASCO Annual Meeting.2016.Abstract 4078
54. Yujin Hoshida , Augusto Villanueva, Masahiro Kobayashi, et al. Gene Expression in 
Fixed Tissues and Outcome in Hepatocellular Carcinoma. N Engl J Med 
2008;359:1995-2004
55. Bruno Sangro, Carlos Gomez-Martin, Manuel de la Mata, et al. A clinical trial of 
CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and 
chronic hepatitis C. Journal of Hepatology. 2013; 59: 81–88
56. Neil K. Aaronson, Sam Ahmedzai, Bengt Bergman et al. The European Organization 
for Research and Treatment of Cancer QLQ-C30: A Quality-of-Life Instrument for Use 
in International Clinical Trials in Oncology. J Natl Cancer Inst 1993;85:365–376
57. Olli Miettinen, Markku Nurminen. Comparative Analysis of Two Rate. Statistics in 
Medicine. 1985; 4: 213-226
58. Willi Maurer, Frank Bretz. Multiple Testing in Group Sequential Trials Using Graphical 
Approaches.  Statistics in Biopharmaceutical Research.  2013,  5(4): 311-320
59. James M.Robins, Anastasions A.Tsiatis. Correcting For Non-Compliance in 
Randomized Trials Using Rank Preserving Structural Failure Time Models.  
Commun.Statist.-Theory Meth, 1991;20(8):2609-2631
60. Hajime Uno, Brian Claggett, Lu Tian, et al. Moving Beyond the Hazard Ratio in 
Quantifying the Between-Group Difference in Survival Analysis. J Clin Oncol 32:2380-
2385.
61. Patricia M. Odell, Keaven M, Anderson. New Models For Predicting Cardiovascular 
Events. J Clin Epidemiol , 1994; 47(6). 583-592
62. Keaven M. Anderson, Jason B. Clark. Fitting spending functions. Statist. 
Med,2010;29:321-327
63. Llovet JM, Di Bisceglie AM, Bruix J, Kramer BS, Lencioni R, Zhu AX, et al. Design 
and endpoints of clinical trials in hepatocellular carcinoma. J Natl Cancer Inst. 2008 
May 21;100(10):698-711.
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12.0 APPENDICES
Merck Code of Conduct for Clinical Trials
Merck*
Code of Conduct for Clinical Trials
I.
Introduction
A. Purpose
Merck, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing and reporting these trials in 
compliance with the highest ethical and scientific standards. Protection of subject safety is the overriding concern in 
the design of clinical trials. In all cases, Merck clinical trials will be conducted in compliance with local and/or 
national regulations and in accordance with the ethical principles that have their origin in the Declaration of Helsinki. 
B. Scope
Such standards shall be endorsed for all clinical interventional investigations sponsored by Merck irrespective of the 
party (parties) employed for their execution (e.g., contract research organizations, collaborative research efforts). This 
Code is not intended to apply to trials which are observational in nature, or which are retrospective. Further, this Code 
does not apply to investigator-initiated trials which are not under the control of Merck.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of Merck or comparator products.  Alternatively, Merck may 
conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to determine 
subject preferences, etc.  
The design (i.e., subject population, duration, statistical power) must be adequate to address the specific purpose 
of the trial.  Research subjects must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
Merck selects investigative sites based on medical expertise, access to appropriate subjects, adequacy of facilities 
and staff, previous performance in Merck trials, as well as budgetary considerations.  Prior to trial initiation, sites 
are evaluated by Merck personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Trial sites are monitored to assess compliance with the trial protocol and general principles of Good Clinical 
Practice.  Merck reviews clinical data for accuracy, completeness and consistency. Data are verified versus source 
documentation according to standard operating procedures.  Per Merck policies and procedures, if fraud, 
misconduct or serious GCP-non-Compliance are suspected, the issues are promptly investigated. When necessary, 
the clinical site will be closed, the responsible regulatory authorities and ethics review committees notified and 
data disclosed accordingly. 
B. Publication and Authorship
To the extent scientifically appropriate, Merck seeks to publish the results of trials it conducts.  Some early phase or 
pilot trials are intended to be hypothesis-generating rather than hypothesis testing.  In such cases, publication of results 
may not be appropriate since the trial may be underpowered and the analyses complicated by statistical issues of 
multiplicity.
Merck’s policy on authorship is consistent with the requirements outlined in the ICH-Good Clinical Practice 
guidelines. In summary, authorship should reflect significant contribution to the design and conduct of the trial, 
performance or interpretation of the analysis, and/or writing of the manuscript.  All named authors must be able to 
defend the trial results and conclusions.  Merck funding of a trial will be acknowledged in publications. 
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III. Subject Protection
A. IRB/ERC review
All clinical trials will be reviewed and approved by an independent IRB/ERC before being initiated at each site.  
Significant changes or revisions to the protocol will be approved by the IRB/ERC prior to implementation, except that 
changes required urgently to protect subject safety and well-being may be enacted in anticipation of IRB/ERC 
approval. For each site, the IRB/ERC and Merck will approve the subject informed consent form. 
B. Safety
The guiding principle in decision-making in clinical trials is that subject welfare is of primary importance.  Potential 
subjects will be informed of the risks and benefits of, as well as alternatives to, trial participation. At a minimum, trial 
designs will take into account the local standard of care.  Subjects are never denied access to appropriate medical care 
based on participation in a Merck clinical trial. 
All participation in Merck clinical trials is voluntary.  Subjects are enrolled only after providing informed consent for 
participation.  Subjects may withdraw from a Merck trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
Merck is committed to safeguarding subject confidentiality, to the greatest extent possible.  Unless required by law, 
only the investigator, sponsor (or representative) and/or regulatory authorities will have access to confidential medical 
records that might identify the research subject by name.  
D. Genomic Research
Genomic Research will only be conducted in accordance with informed consent and/or as specifically authorized by 
an Ethics Committee.
IV.Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive.  It is Merck’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of Merck trials.   Merck does not pay incentives to 
enroll subjects in its trials.  However, when enrollment is particularly challenging, additional payments may be made 
to compensate for the time spent in extra recruiting efforts.
Merck does not pay for subject referrals.  However, Merck may compensate referring physicians for time spent on 
chart review to identify potentially eligible subjects.
B. Clinical Research Funding 
Informed consent forms will disclose that the trial is sponsored by Merck, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial.  However, the local IRB/ERC may wish to alter 
the wording of the disclosure statement to be consistent with financial practices at that institution.  As noted above, 
publications resulting from Merck trials will indicate Merck as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices including, in the U.S., those established by the American Medical 
Association (AMA). 
V. Investigator Commitment
Investigators will be expected to review Merck’s Code of Conduct as an appendix to the trial protocol, and in signing 
the protocol, agree to support these ethical and scientific standards.
* In this document, "Merck" refers to Merck Sharp & Dohme Corp. and Schering Corporation, each of which is a 
subsidiary of Merck & Co., Inc.  Merck is known as MSD outside of the United States and Canada.  As warranted by 
context, Merck also includes affiliates and subsidiaries of Merck & Co., Inc."
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Collection and Management of Specimens for Future Biomedical Research
1. Definitions
a.
Biomarker:  A biological molecule found in blood, other body fluids, or tissues that is a 
sign of a normal or abnormal process or of a condition or disease.  A biomarker may be 
used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics:  The investigation of variations of DNA and RNA characteristics as 
related to drug/vaccine response.2
c.
Pharmacogenetics:  A subset of pharmacogenomics, pharmacogenetics is the influence of 
variations in DNA sequence on drug/vaccine response.2
d. DNA:  Deoxyribonucleic acid.
e.
RNA:  Ribonucleic acid.
2. Scope of Future Biomedical Research
The specimens collected in this trial as outlined in Section 7.1.3.3 – Future Biomedical 
Research Sample Collection will be used to study various causes for how subjects may 
respond to a drug/vaccine.  Future biomedical research specimen(s) will be stored to 
provide a resource for future trials conducted by the Sponsor focused on the study of 
biomarkers responsible for how a drug/vaccine enters and is removed by the body, how a 
drug/vaccine works, other pathways a drug/vaccine may interact with, or other aspects of 
disease. The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need.  All specimens will be used by the Sponsor or those working for 
or with the Sponsor.
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6. Withdrawal From Future Biomedical Research 
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   Subjects may withdraw consent at any time by 
contacting the principal investigator for the main trial. If medical records for the main 
trial are still available, the investigator will contact the Sponsor using the designated 
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mailbox (clinical.specimen.management@merck.com) and a form will be provided to 
obtain appropriate information to complete specimen withdrawal. Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed. 
Documentation will be sent to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for destruction or already performed prior to 
the request being received by the Sponsor will continue to be used as part of the overall 
research trial data and results. No new analyses would be generated after the request is 
received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the subject’s personal information and their specimens. In this situation, the 
request for specimen destruction can not be processed. 
7. Retention of Specimens 
Future Biomedical Research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being 
answered. In this special circumstance, specimens will be stored until these questions 
have been adequately addressed.
Specimens from the trial site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
trial, the trial site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility which 
operates to assure the integrity of the specimens.  Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated trial administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards (e.g., ISO17799) to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Subjects
No information obtained from exploratory laboratory studies will be reported to the 
subject, family, or physicians. Principle reasons not to inform or return results to the 
subject include: Lack of relevance to subject health, limitations of predictive capability, 
and concerns regarding misinterpretation.
If any exploratory results are definitively associated with clinical significance for subjects 
while the clinical trial is still ongoing, investigators will be contacted with information. 
After the clinical trial has completed, if any exploratory results are definitively associated 
with clinical significance, the Sponsor will endeavor to make such results available 
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through appropriate mechanisms (e.g., scientific publications and/or presentations). 
Subjects 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 subjects diagnosed and treated on Sponsor clinical 
trials for Future Biomedical Research.
11. Risks Versus Benefits of Future Biomedical Research 
For future biomedical research, risks to the subject have been minimized. No additional 
risks to the subject have been identified as no additional specimens are being collected for 
Future Biomedical Research (i.e., only leftover samples are being retained). 
The Sponsor has developed strict security, policies and procedures to address subject data 
privacy concerns.  Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality.  In this highly unlikely situation there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be e-mailed directly to 
clinical.specimen.management@merck.com.
13. References
1. National Cancer Institute: http://www.cancer.gov/dictionary/?searchTxt=biomarker
2. International Conference on Harmonization: DEFINITIONS FOR GENOMIC 
BIOMARKERS, PHARMACOGENOMICS, PHARMACOGENETICS, GENOMIC 
DATA 
AND 
SAMPLE 
CODING 
CATEGORIES 
-
E15; 
http://www.ich.org/LOB/media/MEDIA3383.pdf
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Understanding the Intent, Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff
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Approximate Blood/Tissue Volumes Drawn/Collected by Trial Visit and by 
Sample Types
Trial Visit/Cycle/etc:
Screening
& 
Visits 1-2
Treatment 
Visit 3
Treatment
Visit 4
Treatment 
Visits 5-8
End of 
Treatment
Blood Parameter 
Approximate Blood Volume (mL)
Hematology
Serum/Plasma Chemistry
Serum 
β-Human 
Chorionic Gonadotropin 
(β-hCG)a
HIV/Hepatitis Screen 
(Per site SOPs)b
[insert additional rows as 
necessary for protocol 
specified 
procedures 
requiring blood draw]
Expected Total (mL)
a.
For female subjects of child bearing potential only
b.
If applicable and dependent upon site SOP
c.
central lab selected by sponsor and providing kits
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Hepatitis B Definitions and Treatment Considerations
Table 19 describes the various definitions of treatment considerations and eligibility for study 
participation, along with the definitions of hepatitis B.  
Table 19
Hepatitis B Definitions and Treatment Considerations
Test
Patient Status
Eligible for 
KN-394?
Any HBV 
Treatment 
Needed?
HBsAg (–)
Anti-HBc (+)
HBsAb (+)
Immune after natural 
infection
Yes
No
HBsAg (–)
Anti-HBc (–)
HBsAb (+)
Immune after 
vaccination
Yes
No
HBsAg (+)
Anti-HBc (+)
HBsAb (–)
HBV DNA>=2000IU/ml(104copies/ml)
Acute infection
No 
—
HBsAg (+)
Anti-HBc (+)
HBsAb (–)
HBV DNA<2000IU/ml(104copies/ml)
Chronic infection
Yes
Yes, need to be on 
a HBV treatment 
for at least 4 weeks 
prior to start of 
study 
treatment
without evidence of 
a flare during that 
period 
Exclude if:
(a) <
4 weeks of therapy; 
(b) HBV DNA not 
under 
control 
during 
this 
time 
frame; 
HBsAg (–)
Anti-HBc (+)
HBsAb (–)
HBV DNA (negative)
Unclear.  Could be:
(1) Resolved 
infection
(2) False positive 
anti-HBc (
(3) Low level 
infection
(4) Resolving 
Acute 
infection 
Yes
No
HBsAg (–)
Anti-HBc (+)
HBsAb (–)
HBV DNA (+),and <2000IU/ml(104copies/ml)
(5) Low level 
infection
(6) Resolving 
acute 
infection 
Yes
Yes (as above)
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Common Terminology Criteria for Adverse Events
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.html).
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Child-Pugh Score
The Child-Pugh score is used to assess the prognosis of chronic liver disease, mainly 
cirrhosis. Although it was originally used to predict mortality during surgery, it is now used 
to determine the prognosis, as well as the required strength of treatment and the necessity of 
liver transplantation.
Scoring
The score employs five clinical measures of liver disease. Each measure is scored from 1 to 
3, with 3 indicating most severe derangement.
Measure
1 point
2 points
3 points
Total bilirubin1 (mg/dL)
<2.0
2.0 to 3.0
>3.0
Serum albumin (g/dL)
>3.5
2.8 to 3.5
<2.8
INR2
Or
Prothrombin time,
prolongation (seconds)
<1.7
<4.0
1.7 to 2.3
4.0-6.0
> 2.3
>6.0
Ascites
None
Mild (easily 
controlled by 
medication)
Moderate to Severe
(poorly controlled)
Hepatic encephalopathy3
None
Grade I-II (mild or 
moderate)
Grade III-IV (severe 
or coma)
1In primary sclerosing cholangitis and primary biliary cirrhosis, the bilirubin references are changed to reflect the fact 
that these diseases feature high conjugated bilirubin levels.  The upper limit for 1 point is 68 μmol/L (4 mg/dL) and 
the upper limit for 2 points is 170 μmol/L (10 mg/dL).
2 Different textbooks and publications use different measures. Some older reference works substitute PT prolongation 
for INR
3 Hepatic encephelopathy graded according to West Haven Criteria for Semi-quantitative Grading of Mental Status: 
Adapted from: Conn H, Lieberthal M. The hepatic coma syndromes and lactulose. Baltimore: Williams & Wilkins; 
1979.
In primary sclerosing cholangitis and primary biliary cirrhosis, the bilirubin references are 
changed to reflect the fact that these diseases feature high conjugated bilirubin levels. The 
upper limit for 1 point is 68 μmol/L (4 mg/dL) and the upper limit for 2 points is 170 μmol/L 
(10 mg/dL).
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Interpretation
Chronic liver disease is classified into Child-Pugh class A to C, employing the added score 
from above.
Points Class One-year survival Two-year survival
5–6
A
100%
85%
7–9
B
81%
57%
10–15
C
45%
35%
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Barcelona Clinic Liver Cancer Staging System
The Barcelona Clinic Liver Cancer staging system is shown in Figure 4 below [63].  
CLT = cadaveric liver transplantation; LDLT = living donor liver transplantation; PEI = percutaneous ethanol 
injection; RF = radio frequency (ablation); TACE = transarterial chemoembolization. 
Figure 4
Barcelona Clinic Liver Cancer staging system
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List of Abbreviations
Abbreviation/Term
Definition
ADA
Anti-drug antibodies
AE
Adverse event
AFP
Alpha fetoprotein
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
ASaT
All subjects as treated
AST
Aspartate aminotransferase
BCLC
Barcelona Clinic Liver Cancer scale
BICR
Blinded independent central review
BID
Twice daily
BSC
Best supportive care
CBC
Complete blood count
CI
Confidence interval
Cmax
Serum maximum concentration
CNS
Central nervous system
CR
Complete response
CRF
Case Report Form
CRP
C-Reactive protein
CSR
Clinical Study Report
CT
Computed tomography
CTCAE
Common Toxicity Criteria for Adverse Events
CTLA-4
Cytotoxic T-Lymphocyte-Associated Antigen-4
Ctrough
Serum minimum concentration
D-bil
Direct bilirubin
DCR
Disease control rate
DNA
Deoxyribonucleic acid
DOR
Duration of response
ECG
Eletrocardiogram
ECI
Events of clinical interest
ECOG
Eastern Cooperative Oncology Group
EORTC
European Organisation for Research and Treatment of Cancer
ERC
Ethics Review Committee
eDMC
External data monitoring committee
ELISA
Enzyme-linked immunosorbent assay
EOC
Executive Oversight Committee
FBR
Future biomedical research
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FDAMA
Food and Drug Administration Modernization Act
FFPE
Formalin-fixed, paraffin-embedded
FOLFOX
Chemotherapy regimen containing:  folinic acid, 5-fluorouracil, 
and oxaliplatin
FSH
Follicle-stimulating hormone
GCP
Good Clinical Practice
HBc
Hepatitis B core antigen
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCC
Hepatocellular carcinoma
HCV
Hepatitis C virus
HDV
Hepatitis D virus
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Abbreviation/Term
Definition
HEA
Health Economic Assessment
HIV
Human immunodeficiency virus
HRQoL
Health-related quality of life
IB
Investigator’s Brochure
ICF
Informed consent form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IHC
Immunohistochemistry
INR
International normalized ratio
irRECIST
Immune related RECIST (modification of RECIST 1.1)
IRB
Institutional Review Board
ITT
Intent-to-treat
IUD
Intrauterine device
IV
Intravenous
IVRS
Interactive voice response system
IWRS
Integrated web response system
MRI
Magnetic resonance imaging
MSI
Microsatellite instability
MTD
Maximum tolerated dose
NCI
National Cancer Institute
NSAID
Non-steroidal anti-inflammatory drug
NSCLC
Non-small cell lung cancer
ORR
Objective response rate
OS
Overall survival
OTC
Over-the-counter
PD
Progressive disease
PD-1
Programmed cell death 1
PD-L1
Programmed death ligand 1
PD-L2
Programmed death ligand 2
PFS
Progression-free survival
PI
Principal investigator
PK
Pharmacokinetic
PR
Partial response
PRO
Patient Reported Outcome
PS
Performance status
QD
Once daily
RECIST
Response Evaluation Criteria in Solid Tumors
Q3W
Every 3 weeks
Q6W
Every 6 weeks
QALY
Quality adjusted life years 
QLQ
Quality of Life Questionnaire
QoL
Quality of life
RNA 
Ribonucleic acid
SAE
Serious adverse events
SAP
Statistical analysis plan
SD
Stable disease
SIM
Site Imaging Manual
SOP
Standard operating procedures
sSAP
Supplemental SAP
SVR 12
Sustained virologic response for 12 weeks
SVR 24
Sustained virologic response for 24 weeks
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Abbreviation/Term
Definition
T-bil
Total bilirubin
TACE
Transcatheter chemoembolization
TAE
Transarterial embolization
TIL
Tumor infiltrating lymphocytes
TTP
Time to progression
ULN
Upper limit of normal
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13.0 SIGNATURES
Sponsor's Representative
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
Investigator
I agree to conduct this clinical trial in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol (including other manuals and documents 
referenced from this protocol).  I agree to conduct the trial in accordance with generally 
accepted standards of Good Clinical Practice.  I also agree to report all information or data in 
accordance with the protocol and, in particular, I agree to report any serious adverse events as 
defined in Section 7.0 – TRIAL PROCEDURES (Assessing and Recording Adverse Events).  
I also agree to handle all clinical supplies provided by the Sponsor and collect and handle all 
clinical specimens in accordance with the protocol.  I understand that information that 
identifies me will be used and disclosed as described in the protocol, and that such 
information may be transferred to countries that do not have laws protecting such 
information.  Since the information in this protocol and the referenced Investigator’s 
Brochure is confidential, I understand that its disclosure to any third parties, other than those 
involved in approval, supervision, or conduct of the trial is prohibited.  I will ensure that the 
necessary precautions are taken to protect such information from loss, inadvertent disclosure 
or access by third parties.
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
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SAP_001.pdf: 
Official Protocol Title: 
NCT number: 
Document Date: 
A Phase III Randomized Double-blind Study of Pembrolizumab 
plus Best Supportive Care vs. Placebo plus Best Supportive Care 
as Second-Line Therapy in Asian Subjects with
Previously Systemically Treated Advanced Hepatocellular 
Carcinoma (KEYNOTE-394)
22-Jun-2021
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Supplemental Statistical Analysis Plan (sSAP)
TABLE OF CONTENTS
TABLE OF CONTENTS ........................................................................................................1
LIST OF TABLES...................................................................................................................3
LIST OF FIGURES.................................................................................................................4
1
INTRODUCTION............................................................................................................5
2
SUMMARY OF CHANGES...........................................................................................5
3
ANALYTICAL AND METHODOLOGICAL DETAILS ...........................................5
3.1
Statistical Analysis Plan Summary.......................................................................5
3.2
Responsibility for Analyses/In-House Blinding ..................................................7
3.3
Hypotheses/Estimation ..........................................................................................7
3.4
Analysis Endpoints.................................................................................................8
3.4.1
Efficacy Endpoints.........................................................................................8
3.4.1.1
Primary.................................................................................................8
3.4.1.2
Secondary.............................................................................................8
3.4.1.3
Exploratory Endpoints .........................................................................8
3.4.2
Safety Endpoints............................................................................................9
3.4.3
Efficacy Analysis Populations.......................................................................9
3.4.4
Safety Analysis Populations ........................................................................10
3.5
Statistical Methods...............................................................................................10
3.5.1
Statistical Methods for Efficacy Analyses...................................................10
3.5.1.1
Overall Survival (OS) ........................................................................11
3.5.1.2
Progression-Free Survival (PFS) .......................................................11
3.5.1.3
Objective Response Rate ...................................................................13
3.5.1.4
Disease Control Rate..........................................................................13
3.5.1.5
Time to Progression...........................................................................13
3.5.1.6
Duration of Response.........................................................................14
3.5.2
Statistical Methods for Safety Analyses ......................................................16
3.5.3
Summaries of Demographic and Baseline Characteristics..........................18
3.6
Interim Analyses ..................................................................................................18
3.6.1
Efficacy Interim Analyses............................................................................19
3.6.2
Safety Interim Analyses...............................................................................20
3.7
Multiplicity ...........................................................................................................20
3.8
Sample Size and Power Calculations .................................................................24
3.9
Subgroup Analyses and Effect of Baseline Factors ..........................................24
3.10
Compliance (Medication Adherence).................................................................25
3.11
Extent of Exposure...............................................................................................25
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3.12
Statistical considerations for Patient-Reported Outcomes (PRO):.................25
3.12.1
PRO Endpoints.............................................................................................26
3.12.2
Scoring Algorithm .......................................................................................26
3.12.3
The Schedule for PRO Data Collection.......................................................27
3.12.4
Analysis Populations....................................................................................28
3.12.5
Statistical Methods.......................................................................................28
3.12.5.1
PRO Compliance Summary...............................................................28
3.12.5.2
Mean Change from Baseline..............................................................29
3.12.5.3
Time to Deterioration.........................................................................30
3.12.5.4
Proportions of Deterioration/Stable/Improvement ............................31
4
REFERENCES...............................................................................................................32
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LIST OF TABLES
Table 1 Censoring rules for Primary and Sensitivity Analyses of PFS .............................12
Table 2  Censoring rules for TTP ......................................................................................14
Table 3 Censoring Rules for DOR.....................................................................................15
Table 4 Analysis Strategy for Key Efficacy Hypotheses...................................................16
Table 5  Analysis Strategy for Safety Parameters..............................................................18
Table 6 Summary of Interim and Final Analyses Strategy................................................19
Table 7 Summary of Timing, Sample Size and Decision Guidance for the Interim 
Analyses and Final Analysis of Overall Survival........................................................21
Table 8 Summary of Timing, Sample Size and Decision Guidance for the Interim 
Analysis and Final Analysis of Progression Free Survival..........................................22
Table 9 Efficacy Boundaries for Testing the ORR Hypothesis.........................................23
Table 10 PRO Data Collection Schedule...........................................................................27
Table 11 Mapping Relative Day to Analysis Visit............................................................28
Table 12 Censoring Rules for Time-to-Deterioration........................................................31
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LIST OF FIGURES
Figure 1  Multiplicity Strategy...........................................................................................20
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1
INTRODUCTION
This supplemental SAP (sSAP) is a companion document to the protocol. In addition to the 
information presented in the protocol SAP which provides the principal features of 
confirmatory analyses for this trial, this supplemental SAP provides additional statistical 
analysis details/data derivations and documents modifications or additions to the analysis plan 
that are not “principal” in nature and result from information that was not available at the time 
of protocol finalization.
2
SUMMARY OF CHANGES
This sSAP is currently based on MK-3475-394-05. Protocol specific detail that is stated as 
deferred to the sSAP includes the following (note, not all will be addressed in the sSAP unless 
deemed necessary; reference page number is provided if addressed):
•
IA2 will be the final analysis of ORR as all subjects in the ITT population had at least 24 
weeks from randomization to data cutoff. 
•
The analysis methods for OS sensitivity analysis were updated at Section 3.5.1.1.
•
Variable list in subgroup analysis were updated and the baseline factors of gender and 
Barcelona Clinic Liver Cancer (BCLC) were added to the subgroup analyses at Section 
3.9.
•
Description of Patient Reported Outcomes (PRO) analysis was added at Section 3.12.
•
Stable disease (SD) after ≥6 weeks was changed to ≥ 5 weeks based on assessments by the 
blinded central imaging vendor per RECIST 1.1 at Section 3.4.1.2, according to program 
standard.
•
Description of strata used in the analysis was simplified in Section 3.5.1.
•
Adverse events of special interest (AEOSI) and events of immune-mediated hepatitis were 
added to Tier 3 events and determined a short list of Tier 2 events (Table 5) at 
Section 3.5.2.
•
Description of ongoing responders was clarified for the analysis of duration of response 
(DOR) in Section 3.5.1.6.
3
ANALYTICAL AND METHODOLOGICAL DETAILS
3.1
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan is 
provided in Sections 3.2 through 3.12.
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Study Design Overview
A Randomized Double-Blind Phase III Study of Single Agent Pembrolizumab 
plus BSC vs. placebo plus BSC as Second-Line Therapy in Asian Subjects 
with Previously Systemically Treated Advanced Hepatocellular Carcinoma 
after Progression on Sorafenib or Oxaliplatin-based Chemotherapy
Treatment Assignment
Subjects will be randomized in a 2:1 ratio to receive blinded treatment with
pembrolizumab plus BSC or placebo plus BSC (Control Arm). Stratification 
factors are in protocol Section 5.4. This is a double-blinded study.
Analysis Populations
Efficacy: Intention to Treat (ITT)
Safety: All Subjects as Treated (ASaT)
Primary 
Endpoints/Hypotheses
Pembrolizumab improves overall survival (OS) compared to placebo.
Statistical Methods for 
Key Efficacy Analyses
The primary hypothesis will be evaluated by comparing pembrolizumab to the 
control on OS using a stratified log-rank test. Estimation of the hazard ratio 
will be done using a stratified Cox regression model. Event rates over time 
will be estimated within each treatment group using the Kaplan-Meier method. 
PFS will be analyzed using the same method for OS. Stratified Miettinen and 
Nurminen’s method [1] with weights proportional to the stratum size will be
used for comparison of the objective response rates (ORR) between the 
treatment arms.
Statistical Methods for 
Key Safety Analyses
The analysis of safety results will follow a tiered approach. The tiers differ 
with respect to the analyses that will be performed. There are no Tier 1 events 
in this trial. Tier 2 parameters will be assessed via point estimates with 95% 
confidence intervals provided for between-group comparisons; only point 
estimates by treatment group are provided for Tier 3 safety parameters. The 
95% confidence intervals for the between-treatment differences in 
percentages will be provided using the Miettinen and Nurminen method [1].
Interim Analyses
Two interim analyses will be performed in this study. Results will be 
reviewed by an external data monitoring committee. Details are provided in 
Section 3.6.
IA1(ORR-driven):

Timing: to be performed when 163 randomized subjects have at least 
24 weeks follow-up (which is estimated to happen at approximately 17 
months after study start). Approximately 174 PFS events and 100 OS 
events are expected to be accumulated.

Purpose: estimate treatment effect and evaluate consistency with global 
data, interim analysis for ORR, PFS and OS.
IA2 (event-driven):

Timing: to be performed when approximately 276 OS events have been 
observed and enrollment is complete, estimated to be approximately 31 
months after study start. Approximately 395 PFS events are expected 
to be accumulated at IA2.

Purpose: interim efficacy analysis for OS, final analysis for PFS and 
ORR.
Final analysis (event-driven)

Timing: to be performed when approximately 345 OS events have been 
observed, estimated to be approximately 37 months after study start

Purpose: final analysis for OS.
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Multiplicity
The multiplicity strategy in this study will be applied to the primary hypothesis 
(superiority of pembrolizumab in OS to placebo) and the secondary 
hypotheses of superiority of pembrolizumab to placebo in PFS and ORR. The 
overall Type I error across the three hypotheses above is strongly controlled 
at 2.5% (one- sided) by the graphical approach of Maurer and Bretz [2] as 
described in Section 3.7. Initially, α=2.3% will be allocated to the OS 
hypothesis and α=0.2% will be allocated to the PFS hypothesis. Following a 
group sequential approach, the Type I error rates for the two interim and
final analyses will be controlled through the alpha-spending function as 
described in Section 3.7.
Sample Size and Power
The sample size is approximately 450.
The analyses of OS endpoint are event driven (i.e., the testing of the OS 
hypothesis is conducted upon accumulating a preset number of events). The 
study is designed and will be conducted to accumulate approximately 345 OS 
events (unless superiority in OS is proven at the interim analysis).
For primary endpoint OS, the trial has ~87% power to demonstrate that 
pembrolizumab is superior to the control at a one-sided 2.3% alpha-level, if 
the underlying hazard ratio of OS is 0.7.
3.2
Responsibility for Analyses/In-House Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the SPONSOR. The SPONSOR will generate the 
randomized allocation schedule(s) for study treatment assignment for this protocol, and the 
randomization will be implemented in IVRS.
Since the trial is double-blinded with in-house blinding, the Sponsor, the investigators, site 
staffs, and subjects will be blinded to the treatment assignment. In addition, the blinded central 
imaging vendor will perform the central imaging review without knowledge of treatment group 
assignment.
The eDMC will serve as the primary reviewer of the unblinded results of the interim analyses 
and will make recommendations for discontinuation of the study or modification to an 
executive oversight committee of the SPONSOR. An external unblinded statistician and 
statistical programmer will be responsible for generating unblinded data summaries and 
presenting them to the eDMC. Depending on the recommendation of the eDMC, the Sponsor 
may prepare a regulatory submission. If the eDMC recommends modifications to the design 
of the protocol or discontinuation of the study, this executive oversight committee and limited 
additional SPONSOR personnel may be unblinded to results at the treatment level in order to 
act on these recommendations. The extent to which individuals are unblinded with respect to 
results of interim analyses will be documented. Additional logistical details will be provided 
in the eDMC Charter.
3.3
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in protocol Section 3.0.
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3.4
Analysis Endpoints
3.4.1
Efficacy Endpoints
3.4.1.1
Primary
Overall Survival
OS is defined as the time from randomization to death due to any cause. Subjects without 
documented death at the time of the final analysis will be censored at the date of the last follow-
up.
3.4.1.2
Secondary
Progression-Free Survival (PFS) – RECIST 1.1 by BICR
PFS is defined as the time from randomization to the first documented disease progression per 
RECIST 1.1 based on blinded central imaging vendor review or death due to any cause, 
whichever occurs first. See Section 3.5.1 for the censoring rules.
Objective Response Rate (ORR) – RECIST 1.1 by BICR
Objective response rate is defined as the proportion of the subjects in the analysis population 
who have a complete response (CR) or partial response (PR) per RECIST 1.1. Disease Control 
Rate (DCR) - RECIST 1.1 by BICR
DCR is defined as the percentage of subjects who have achieved CR, PR, or have demonstrated 
SD for at least 5 weeks prior to any evidence of progression based on assessments by the central 
imaging vendor per RECIST 1.1.
Time to Progression (TTP) – RECIST 1.1 by BICR
TTP is defined as the time from randomization to the first documented disease progression per 
RECIST 1.1. See Section 3.5.1 for the censoring rules.
Duration of Response (DOR) - RECIST 1.1 by BICR
For subjects who demonstrate CR or PR, duration of response is defined as the time from first 
documented evidence of CR or PR per RECIST 1.1 until disease progression per RECIST 1.1 
or death due to any cause, whichever occurs first.
3.4.1.3
Exploratory Endpoints
Quality of life and health utilities will be examined between groups. EORTC QLQ-C30 will 
be used for evaluating changes from baseline in health related quality of life outcomes; and 
EuroQol EQ-5D-3L will be used to characterize utilities between two treatment arms.
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3.4.2
Safety Endpoints
Safety measurements are described in protocol Section 4.2.3.4 Safety Endpoints and protocol 
Section 7.
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
adverse events (AEs), laboratory tests, and vital signs. Safety parameters to be analyzed 
include, but are not limited to, AEs, SAEs, fatal AEs, and laboratory changes. Furthermore, 
specific events will be collected and designated as events of clinical interest (ECIs) as 
described in protocol Section 7.2.3.
Events of clinical interest for this trial include:
1. An overdose of Sponsor's product, as defined in protocol Section 7.2.1 - Definition of an 
Overdose for This Protocol and Reporting of Overdose to the Sponsor, that is not associated 
with clinical symptoms or abnormal laboratory results.
2. Hepatic ECIs as defined in protocol Section 7.2.3.
There are no “Tier 1” events in this trial. In addition, the broad clinical and laboratory AE 
categories consisting of the percentage of subjects with any AE, any drug related AE, any 
Grade 3-5 AE, any serious AE, any AE which is both drug-related and Grade 3-5, any AE 
which is both serious and drug-related, dose modification due to AE, and who discontinued 
due to an AE, and death will be considered Tier 2 endpoints. AEs (specific terms as well as 
system organ class terms) will be classified as belonging to "Tier 2" or "Tier 3", based on the 
number of events observed. Membership in Tier 2 requires that at least 4 subjects in any 
treatment group exhibit the event; all other AEs and predefined limits of change will belong to 
Tier 3. Analysis Populations
3.4.3
Efficacy Analysis Populations
The Intention-to-Treat (ITT) population will serve as the population for primary efficacy 
analysis. All randomized subjects will be included in this population. Subjects will be included 
in the treatment group to which they are randomized.
Details on the approach to handling missing data are provided in Section 3.5 Statistical 
Methods.
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3.4.4
Safety Analysis Populations
The All Subjects as Treated (ASaT) population will be used for the analysis of safety data in 
this study. The ASaT population consists of all randomized subjects who received at least one 
dose of study treatment. Subjects will be included in the treatment group corresponding to the 
study treatment they actually received for the analysis of safety data using the ASaT 
population. For most subjects this will be the treatment group to which they are randomized. 
Subjects who take incorrect study treatment for the entire treatment period will be included in 
the treatment group corresponding to the study treatment actually received. Any subject who 
receives the incorrect study medication for one cycle but receives the correct treatment for all 
other cycles will be analyzed according to the randomized treatment group and a narrative will 
be provided for any events that occur during the cycle for which the subject is incorrectly 
dosed.
At least one laboratory or vital sign measurement obtained subsequent to at least one dose of 
study treatment is required for inclusion in the analysis of each specific parameter. To assess 
change from baseline, a baseline measurement is also required.
Details on the approach to handling missing data for safety analyses are provided in Section
3.5 Statistical Methods
3.5
Statistical Methods
3.5.1
Statistical Methods for Efficacy Analyses
This section describes the statistical methods that address the primary and secondary 
objectives.
Efficacy results that will be deemed to be statistically significant after consideration of the 
Type I error control strategy are described in Section 3.7, Multiplicity. Nominal p-values may 
be computed for other efficacy analyses, but should be interpreted with caution due to potential 
issues of multiplicity.
The stratification factors applied to all stratified analyses of efficacy endpoints will be: 
macrovascular invasion (Yes, No), α-fetoprotein (ng/mL) (<200, ≥200) and region (China, ex-
China). Due to the small number of subjects in the stratum of presence of macrovascular
invasion, subjects from any region or with any level of α-fetoprotein will be combined in this 
stratum. Thus, the following 5 strata will be applied to all stratified analyses:
•
Macrovascular invasion (No) + Region (China) + α-Fetoprotein (ng/mL) (<200)
•
Macrovascular invasion (No) + Region (ex-China) + α-Fetoprotein (ng/mL) (<200)
•
Macrovascular invasion (No) + Region (China) + α-Fetoprotein (ng/mL) (≥200)
•
Macrovascular invasion (No) + Region (ex-China) + α-Fetoprotein (ng/mL) (≥200)
•
Macrovascular invasion (Yes)
These five strata will be used in all stratified analyses of efficacy endpoints and PRO endpoints.
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3.5.1.1
Overall Survival (OS)
The non-parametric Kaplan-Meier method will be used to estimate the survival curves. The 
superiority hypothesis 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 (i.e., the hazard ratio). The hazard 
ratio and its 95% confidence interval from the stratified Cox model with a single treatment 
covariate will be reported.
Prior to verification of PD by blinded independent central review, switching to another 
treatment is discouraged. Following verification of PD, subjects may switch to another anti-
cancer treatment. Sensitivity analyses to adjust for the effect of the next line anti-cancer 
therapies of HCC on OS in both treatment arms would be considered based on the recognized 
methods. Specifically, three methods would be performed: (1) an analysis with survival 
censored at the start of the next line of HCC anticancer therapy; (2) the inverse probability of 
censoring weighting (IPCW) model proposed by Robins and Finkelstein [3]; and (3) the 
simplified two-stage survival model without re-censoring [4].
3.5.1.2
Progression-Free Survival (PFS)
The non-parametric Kaplan-Meier method will be used to estimate the PFS curve in each 
treatment group. The superiority hypothesis 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 difference (i.e., hazard 
ratio) between the treatment arms. The hazard ratio and its 95% confidence interval from the 
stratified Cox model with Efron's method of tie handling and with a single treatment covariate 
will be reported.
Since disease progression is assessed periodically, progressive disease (PD) can occur any time 
in the time interval between the last assessment where PD was not documented and the 
assessment when PD is documented. For the primary analysis, for the subjects who have PD, 
the true date of disease progression will be approximated by the date of the first assessment at 
which PD is objectively documented per RECIST 1.1 by blinded independent central review, 
regardless of discontinuation of study drug. Death is always considered as a confirmed PD 
event. Sensitivity analyses may be performed for comparison of PFS based on investigator's 
assessment per RECIST 1.1 and PFS analysis for PD per irRECIST by blinded independent 
central review.
In order to evaluate the robustness of the PFS endpoint per RECIST 1.1 by blinded independent 
central review, we will perform two sensitivity analyses with a different set of censoring rules. 
The first sensitivity analysis is the same as the primary analysis except that (1) the date of 
documented PD or death will be the progression date, regardless of whether or not new anti-
cancer treatment is initiated and (2) it censors at the last disease assessment, regardless of 
whether or not new anti-cancer treatment is initiated if no PD and no death occur. The second 
sensitivity analysis is the same as the first sensitivity analysis, except that it considers 
discontinuation of treatment due to reasons other than complete response or initiation of an 
anti-cancer treatment subsequent to discontinuation of study specified treatment, whichever 
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occurs later, to be a PD event for subjects without documented PD or death. The censoring 
rules for primary and sensitivity analyses are summarized in Table 1.
Table 1
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
PD or death documented 
immediately after ≥2
consecutive missed 
disease assessments or 
after new anticancer 
therapy, if any
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
The proportional hazards assumption on PFS will be examined using both graphical and 
analytical methods if warranted. The log[ -log] of the survival function vs. time for PFS will 
be plotted for the comparison between pembrolizumab and the control arm. If the curves are 
not parallel, indicating that hazards are not proportional, supportive analyses may be conducted 
to account for the possible non-proportional hazards effect associated with immunotherapies: 
for example, using the Restricted Mean Survival Time (RMST) method [5], parametric method
[6], etc.
The PFS analyses are described in Section 3.6 Interim Analyses and Section 3.7 Multiplicity. 
The supportive analysis of the PFS data available at the time of the final OS analysis will be 
also conducted.
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3.5.1.3
Objective Response Rate
Stratified Miettinen and Nurminen’s method [1] with weights proportional to the stratum size 
will be used for the comparison of the objective response rates between the treatment arms. A 
95% confidence interval for the difference in response rates between the pembrolizumab arm 
and the control arm will be provided.
The ORR analysis will be conducted according to the hypotheses testing plan as described in 
Section 3.6 Interim Analyses and Section 3.7 Multiplicity.
3.5.1.4
Disease Control Rate
Stratified Miettinen and Nurminen’s method [1] with weights proportional to the stratum size 
will be used for the comparison of the DCR between the treatment arms. A 95% confidence 
interval for the difference in response rates between the pembrolizumab arm and the control 
arm will be provided.
3.5.1.5
Time to Progression
The non-parametric Kaplan-Meier method will be used to estimate the TTP curve in each 
treatment group. A stratified Cox proportional hazard model with Efron's method of tie 
handling will be used to estimate the magnitude of the treatment difference (i.e., hazard ratio) 
between the treatment arms. The hazard ratio and its 95% confidence interval from the 
stratified Cox model with Efron's method of tie handling and with a single treatment covariate 
will be reported.
Since disease progression is assessed periodically, progressive disease (PD) can occur any time 
in the time interval between the last assessment where PD was not documented and the 
assessment when PD is documented. For the analysis, for the subjects who have PD, the true 
date of disease progression will be approximated by the date of the first assessment at which 
PD is objectively documented per RECIST 1.1 by blinded independent central review, 
regardless of discontinuation of study drug. Unlike in PFS analysis, death is not considered as 
an event.
The censoring rules for TTP are summarized in Table 2.
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Table 2
Censoring rules for TTP
Situation
Primary Analysis
Death without a preceding disease progression
Censored at date of randomization or date of
last non-PD disease assessment, whichever 
is later
No PD and no death;
new anticancer treatment is not initiated
Censored at last non-PD disease assessment
No PD and no death;
new anticancer treatment is initiated
Censored at last non-PD disease assessment
before new anticancer treatment is initiated
PD documented after ≤ 1 missed disease 
assessment
Progressed at date of documented PD
PD documented immediately after ≥ 2 missed 
disease assessments
Censored at last non-PD disease assessment 
prior to the ≥2 consecutive missed disease 
assessments
3.5.1.6
Duration of Response
Subjects who achieved confirmed CR or PR and are alive, have not progressed, have not 
initiated new anti-cancer treatment, have not been determined to be lost to follow-up, and have 
had a disease assessment within ~5 months of the data cutoff are considered ongoing 
responders at the time of analysis.
The non-parametric Kaplan-Meier method will be used to estimate the DOR curve in each 
treatment group; estimates and 95% CIs at specific duration time points will be provided.
Censoring rules for DOR are summarized in Table 3.
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Table 3
Censoring Rules for DOR
Situation
Date of Progression or Censoring
Outcome
No progression nor death, no new 
anti-cancer therapy initiated
Last adequate disease assessment
Censor 
(non-event)
No progression nor death, new anti-
cancer therapy initiated
Last adequate disease assessment 
before new anti-cancer therapy 
initiated
Censor 
(non-event)
Death or progression immediately 
after ≥2 consecutive missed disease 
assessments or after new anti-
cancer therapy
Earlier date of last adequate 
disease assessment prior to 2 
missed adequate disease 
assessments and new anti-cancer 
therapy, if any
Censor 
(non-event)
Death or progression after ≤1 
missed disease assessments and 
before new anti- cancer therapy, if
any
PD or death
End of 
response 
(Event)
Subjects are considered to have an ongoing response if censored, alive, have not progressed, have not started 
a new anti-cancer therapy, have not been determined to be lost to follow-up, and have had a disease 
assessment within ~5 months of the data cutoff.
A missed disease assessment includes any assessment that is not obtained or is considered inadequate for 
evaluation of response.
Table 4 summarizes the primary analysis approach for key efficacy endpoints. Sensitivity 
analysis methods are described above for each endpoint.
Analyses of the DCR, TTP, and DOR data will be performed at the time of the interim and 
final analyses of OS. Analyses of the imaging endpoints based on the investigator assessment 
per RECISIT 1.1 will also be provided.
The strategy to address multiplicity issues with regard to multiple efficacy endpoints, multiple 
populations, and interim analyses is described in Section 3.6 Interim Analyses and in 
Section 3.7 Multiplicity.
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Table 4
Analysis Strategy for Key Efficacy Hypotheses
Endpoint/Variable 
(Description, Time Point)
Statistical†Method
Analysis 
Population
Missing Data 
Approach
Primary Hypothesis
OS
Test: Stratified Log-
rank test.
Estimation: Stratified Cox 
model with Efron’s tie 
handling method.
ITT
Censored at the last 
date the subject was 
known to be alive
Secondary Endpoints
PFS per RECIST 1.1 by BICR
Test: Stratified Log- rank 
test.
Estimation: Stratified Cox 
model with Efron’s tie 
handling method
ITT
Primary censoring rule
Sensitivity analysis 1
Sensitivity analysis 2 
(More details are in 
Table 9)
ORR per RECIST 1.1 by BICR
Stratified M& N method‡
ITT
Subjects with missing 
data are considered non-
responders
† Statistical models are described in further detail in the text. For stratified analyses, the stratification factors applied to 
the analysis model will be: macrovascular invasion (Yes, No), -fetoprotein (ng/mL) (<200, ≥200) and region (China, 
ex- China), with all cells that correspond to macrovascular invasion=Yes combined.
‡ Miettinen and Nurminen method.
3.5.2
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
adverse events (AEs), laboratory tests, and vital signs.
Tiered Approach
The analysis of safety results will follow a tiered approach (Table 5). The tiers differ with 
respect to the analyses that will be performed. For this protocol, there are no Tier 1 events.
Tier 2 parameters will be assessed via point estimates with 95% confidence intervals provided 
for between-group comparisons; only point estimates by treatment group are provided for Tier 
3 safety parameters.
AEs (specific terms as well as system organ class terms) will be classified as belonging to "Tier 
2" or "Tier 3", based on the number of events observed. Membership in Tier 2 requires that at 
least 4 subjects in any treatment group exhibit the event; all other AEs and predefined limits 
of change will belong to Tier 3.
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The threshold of at least 4 events was chosen because the 95% confidence interval for the 
between-group difference in percent incidence will always include zero when treatment groups 
of equal size each have less than 4 events and thus would add little to the interpretation of 
potentially meaningful differences. Because many 95% confidence intervals may be provided 
without adjustment for multiplicity, the confidence intervals should be regarded as a helpful 
descriptive measure to be used in review, not a formal method for assessing the statistical 
significance of the between-group differences in AEs and predefined limits of change.
Continuous measures such as changes from baseline in laboratory values and vital signs, that 
are not pre-specified as Tier-1 endpoints will be considered Tier 3 safety parameters. Summary 
statistics for baseline, on-treatment, and change from baseline values will be provided by 
treatment group in table format.
In addition, the broad clinical and laboratory AE categories consisting of the percentage of 
subjects with any AE, any drug related AE, any Grade 3-5 AE, any serious AE, any AE which 
is both drug-related and Grade 3-5, any AE which is both serious and drug-related, dose 
modification due to AE, and who discontinued due to an AE, and death will be considered Tier 
2 endpoints.
The 95% confidence intervals will be provided for between-treatment differences in the 
percentage of subjects with Tier 2 events; these analyses will be performed using the Miettinen 
and Nurminen method [1], an unconditional, asymptotic method. Safety analyses will not be 
stratified.
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Table 5
Analysis Strategy for Safety Parameters
Safety 
Tier
Safety Endpoint†
95% CI for 
Treatment
Comparison
Descriptive 
Statistics
Tier 2
AEs (incidence ≥10% of participants in one of the 
treatment groups)
X
X
Grade 3-5 AE (incidence ≥2% of participants in one of 
the treatment groups)
X
X
Serious AE (incidence ≥1% of participants in one of the 
treatment groups)
X
X
Tier 3
Any AE
X
Any Grade 3-5 AE
X
Any Serious AE
X
Any Drug-Related AE
X
Any Serious and Drug-Related AE
X
Any Grade 3-5 and Drug-Related AE
X
Discontinuation due to AE
X
Death
X
Specific AEs, SOCs (incidence <4% of subjects in all 
of the treatment groups), AEOSI, Immune-mediated 
Hepatitis Events
X
Change from baseline results (laboratory test toxicity 
grade, vital signs)
X
AE = adverse event; CI = confidence interval; X = results will be provided.
The rainforest plots including the treatment difference and its 95% CI will be applied for Tier2 AEs.
3.5.3
Summaries of Demographic and Baseline Characteristics
The comparability of the treatment groups for each relevant characteristic will be assessed by 
the use of tables and/or graphs. No statistical hypothesis tests will be performed on these 
characteristics. The number and percentage of subjects screened, randomized, the primary 
reasons for screening failure, and the primary reason for discontinuation will be displayed. 
Demographic variables (e.g., age), baseline characteristics, primary and secondary diagnoses,
and prior and concomitant therapies will be summarized by treatment either by descriptive 
statistics or categorical tables.
3.6
Interim Analyses
An external data monitoring committee (eDMC) will be convened to review the unblinded 
efficacy results and accumulating safety at the planned IAs.
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3.6.1
Efficacy Interim Analyses
Two interim analyses and one final analysis are planned in this trial. The timing and the 
purpose of each analysis are summarized in Table 6. A detailed description of the multiplicity 
adjustment and hypotheses testing plan is provided in Section 3.7 Multiplicity.
The first interim analysis will be performed at approximately Month 17, at which time the first 
163 randomized subjects have at least 24 weeks follow-up. The main purpose of this interim 
analysis is to conduct the analysis for ORR on the first 163 randomized subjects, evaluate the 
consistency of efficacy and safety in this study to the reference global data, and to conduct an 
interim testing for efficacy on the PFS and OS endpoints for all the subjects randomized at that 
time (superiority only). Consistency of efficacy will be evaluated by comparing the treatment 
effect observed in this study to the reference global data (based on point estimates). 
Approximately 225 subjects will be enrolled at the first interim analysis cutoff, with 
approximately 174 PFS events and 100 OS events projected to be accumulated. The main 
purpose of the second interim analysis is to conduct the primary testing for efficacy on the PFS 
hypothesis and to conduct an interim testing for efficacy on the OS hypothesis (superiority 
only). It will be performed when enrollment is complete and approximately 276 OS events 
(~80% of the target 345 total OS events) are observed. It is projected that this event count will 
be accumulated at approximately 31 months after the start of the study. Approximately 395 
PFS events are expected to be accumulated by then. Under assumptions specified in Section 
3.8 sample size and power calculation, at the time of the secondary interim analysis: 1) a total 
of approximately 395 PFS events for testing the PFS hypothesis at Type I error =0.2% 
provides approximately 88% power to successfully demonstrate the PFS hypothesis; and 2) a 
total of approximately 276 OS events for testing the OS hypothesis at Type I error =1.10% 
provides approximately 70% power to successfully demonstrate the OS hypothesis.
If superiority of PFS or OS (pembrolizumab vs. placebo) is demonstrated at one of the interim 
analyses, the ORR hypothesis will be tested according to the group-sequential boundaries for 
ORR analysis (see Table 9 in Section 3.7 Multiplicity).
The final analysis (FA) will be performed when approximately 345 OS events are observed 
which is expected at Month 37.
Table 6
Summary of Interim and Final Analyses Strategy
Analysis
Endpoint(s)
Criteria for Conduct of 
Analysis
Estimated Time after 
First Participant 
Randomized
Primary Purpose of 
Analysis
IA 1
ORR, DOR, 
PFS, OS
First 163 randomized subjects 
have at least 24 weeks follow-
up
~17 months
Descriptive ORR 
analysis, 
consistency 
evaluation
IA 2
ORR, PFS, 
OS
~276 OS events observed
~31 months
PFS FA
ORR FA
OS IA
FA
OS, ORR
~345 OS events observed
~37 months
OS FA
Abbreviations: FA = final analysis; IA = interim analysis; PFS = progression-free survival; ORR = overall response rate; 
OS = overall survival
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The eDMC will serve as the primary reviewer of the unblinded results of the interim analyses 
and will make recommendations. Depending on the recommendation of the eDMC, the 
Sponsor may prepare a regulatory submission. NOTE: no futility test is planned in the interim 
analysis.
3.6.2
Safety Interim Analyses
As noted in protocol Section 7.3.2 – Data Monitoring Committee, the eDMC will be 
responsible for periodic interim safety reviews as specified in the DMC charter.
3.7
Multiplicity
The multiplicity strategy specified in this section will be applied to the primary hypothesis 
(superiority of pembrolizumab to placebo in OS) and the secondary hypotheses of superiority 
of pembrolizumab in PFS or ORR.
The overall Type-I error across the testing of the OS, PFS, and ORR hypotheses is strongly 
controlled at =2.5% (one-sided). The multiplicity strategy will follow the graphical approach 
of Mauer and Bretz [2]. Figure 1 provides the multiplicity strategy diagram of the study.
Figure 1  Multiplicity Strategy
In the diagram shown in Figure 1, when a particular null hypothesis is rejected, the arrows 
leading to it are removed, and the Type I error allocated to the null hypothesis that was rejected 
are re-distributed to other hypotheses. The arrows on the diagram show how the Type I error 
allocated to a hypothesis that was successfully tested will be re-distributed. Initially, =2.3% 
(23/25 of the overall total =2.5% for testing the OS, PFS and ORR) is allocated to the OS 
hypothesis and =0.2% is allocated to the PFS hypothesis.
In detail, if PFS and OS hypotheses are both rejected on the initial alpha, then ORR hypothesis 
will be tested on the 2.5% alpha level. If PFS hypothesis is rejected on the initial alpha level 
0.2% while OS is NOT rejected on the initial alpha 2.3%, then ORR hypothesis will be tested 
on the 0.2% alpha level. If ORR hypothesis can be rejected on the 0.2% alpha level, then OS 
hypothesis will be retested on the 2.5% alpha level. If PFS hypothesis is NOT rejected on the 
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initial alpha level 0.2% but OS hypothesis is rejected on the initial alpha 2.3%, then PFS 
hypothesis can be re-tested on the 1.35% alpha level and ORR hypothesis can be tested on the 
1.15% level. After that, we will follow the same procedure of hypothesis testing and type-I 
error re-distribution as illustrated in Figure 1.
OS hypothesis: The OS hypothesis will be tested following a group sequential approach. The 
testing of the OS hypothesis will be based on an OS test statistic calculated from study data at 
the first interim analysis. If unsuccessful at the first IA, the OS hypothesis will be tested at the 
second interim analysis time and, if unsuccessful at the second IA, the OS hypothesis will be 
tested at the final analysis time. No futility test is planned at the interim analyses. The nominal 
Type I error rates for the two interim analyses and final analysis that will allow tight control 
of the overall Type I error for testing the OS hypothesis will be derived using the alpha-
spending function approach based on the overall Type I error allocated to the OS hypothesis. 
The group sequential testing of the OS hypothesis will be conducted with efficacy boundaries 
(superiority test only). The OS efficacy boundary will be set using the Lan-DeMets spending 
function that approximates an O’Brien-Fleming boundary. The OS hypothesis will initially be 
tested at the overall Type I error =2.3%. If both the PFS and ORR null hypotheses have been 
rejected at the =0.2% level, the OS hypothesis will be tested at Type I error level of =2.5%.
Table 7 summarizes the timing, sample size and decision guidance of the interim analyses and 
final OS analysis. Interim analysis spending for OS analyses will be based on the expectation 
of 345 OS events at the final analysis and the final analysis spending will be updated based on 
spending alpha using the actual number of OS events at times of analysis using spending 
functions as noted above.
Table 7
Summary of Timing, Sample Size and Decision Guidance for the Interim Analyses 
and Final Analysis of Overall Survival
Type I Error 
(Overall )
Analysis
Study 
Calendar 
Time
N§
Events
Information 
Fraction
Efficacy Boundary Crossing†
Nominal

Hazard 
Ratio
Power
2.3%
IA1
IA2
Final
Month 17
Month 31
Month 37
225
450
450
100
276
345
0.30
0.80
1.00
<0.01%
1.10%
1.98%
~0.42
~0.75
~0.79
0.9%
70%
87%
2.5%
IA1
IA2
Final
Month 17
Month 31
Month 37
225
450
450
100
276
345
0.30
0.80
1.00
<0.01%
1.22%
2.14%
~0.43
~0.75
~0.79
1.1%
72%
88%
† Based on Lan-DeMets spending function that approximates an O’Brien-Fleming boundary.
§ Expected number of subjects randomized into the study at the time of analysis.
PFS hypothesis: The group sequential testing of the PFS hypothesis will be conducted with 
efficacy boundaries (superiority test only). The PFS efficacy boundary will be set using the 
Lan-DeMets spending function that approximates an O’Brien-Fleming boundary. The interim 
analysis of PFS will be conducted at the time of the first interim OS analysis; the final PFS 
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analysis will be conducted at the time of the second OS analysis.   The testing of the PFS 
hypothesis will initially be tested at one-sided Type I error =0.2%. Depending on the results 
of testing of the OS and ORR hypothesis, the PFS hypothesis can be tested at a one-sided Type 
I error level of =1.35% or =2.5%. At the second interim analysis, it is expected that 
approximately 395 PFS events would have been accumulated assuming 1) a hazard ratio of 
0.65; 2) Progression-free survival follows an exponential distribution with a median of 1.5 
months in the control arm; 3) an enrollment time of 31 months with a recruitment rate of 16 
subjects per month and a 6-month ramp up time, and 4) a monthly drop-out rate of ~1%. 
Table 8 summarizes the timing, sample size and decision guidance of the interim and final PFS 
analyses. Interim analysis spending for PFS analysis will be based on the expectation of 395 
PFS events at the final analysis and the final analysis spending will be updated on spending 
alpha using the actual number of PFS events at times of analysis when the criteria for triggering 
the final PFS analysis is complete.
Table 8
Summary of Timing, Sample Size and Decision Guidance for the Interim Analysis 
and Final Analysis of Progression Free Survival
Type I Error 
(Overall )
Analysis
Study 
Calendar 
Time
N§
Events
Information 
Fraction
Efficacy Boundary Crossing†
Nominal 

Hazard 
Ratio
Power
0.2%
IA 
FA
Month 17
Month 31
225
450
174
395
0.44
1.00
<0.01%
0.2%
~0.48
~0.74
3.4%
88%
1.35%
IA
FA
Month 17
Month 31
225
450
174
395
0.44
1.00
0.02%
1.34%
~0.57
~0.79
20%
97%
2.5%
IA
FA
Month 17
Month 31
225
450
174
395
0.44
1.00
0.07%
2.5%
~0.60
~0.81
31%
98%
† Based on Lan-DeMets spending function that approximates an O’Brien-Fleming boundary.
§ Expected number of subjects randomized into the study at the time of analysis.
ORR hypothesis: ORR by treatment group will be estimated at each interim analysis and the 
final analysis. The initial alpha allocated to ORR is zero. If PFS or OS null hypothesis is 
rejected, depending on the results of testing of the OS and PFS hypothesis, the ORR hypothesis 
can be tested at a one-sided Type I error level of =0.2%, =1.15%, or =2.5%. The ORR 
hypothesis will be tested following a group sequential approach. The testing of the ORR 
hypotheses will be at the first interim analysis time. If unsuccessful at the first IA, the ORR 
hypotheses will be tested at the second interim analysis time which will be the final analysis 
for ORR. Subjects who will be included in the ORR analysis are those who have “mature ORR 
information”, defined as subjects who were enrolled at least 24 weeks prior to the interim data 
cutoff dates and thus had an opportunity to have at least 4 scheduled scans if not discontinued. 
For the first interim analysis, 163 subjects with at least 24 weeks follow up will be included 
for ORR analysis and information fraction is expected to be about 0.36.  At the time of the 
second interim analysis, all randomized subjects will have at least 24 weeks follow-up and 
thus, 100% of information will be reached. At this time, the final ORR analysis will be 
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conducted. The nominal Type I error rates for the interim analyses and final analysis that will 
allow tight control of the overall Type I error for testing the ORR hypothesis will be derived 
using the alpha-spending function approach. The group sequential testing of the ORR 
hypothesis will be conducted with an efficacy boundary only. The efficacy boundary for the 
ORR will be set using an Exponential spending function
[7] with parameter 
=0.25, which yields a Pocock-like boundary. The ORR hypothesis is initially allocated a Type 
I error =0% and thus, cannot be tested unless one or both of the PFS and OS null hypotheses 
have been rejected. Depending on the results of the OS and PFS hypotheses testing, the ORR 
hypothesis can be tested at Type I error levels of =0.2%, 1.15%, or 2.5%.
Table 9 shows the boundary thresholds corresponding to a group sequential testing of the ORR 
hypothesis at each of these Type I error levels. The p-value at the boundary for the final 
analysis will be adjusted according to the exact number of subjects enrolled in the study.
Table 9
Efficacy Boundaries for Testing the ORR Hypothesis
Type I Error 
(Overall )
Analysis
N‡
Information 
Fraction
Efficacy Boundary Crossing†
Nominal 
ORR §
Power
0.2%
IA1
Final
163
450
0.36
1.00
0.03%
0.17%
~16.77%
~8.61%
17%
88%
1.15%
IA1
Final
163
450
0.36
1.00
0.31%
0.92%
~12.95%
~6.70%
42%
97%
2.50%
IA1
Final
163
450
0.36
1.00
0.86%
1.89%
~11.09%
~5.79%
58%
99%
† Based on Exponential (=0.25) spending function. ORR is tested for superiority only.
‡ Expected number of subjects who were enrolled at least 24 weeks prior to the data cutoff date and thus had an 
opportunity to have at least 4 scheduled scans at the time of ORR analysis.
§= ORR in pembrolizumab group – ORR in control group. The assumed expected ORR in pembrolizumab and control 
groups are 15% and 3%, respectively.
The spending function planned to be used for the testing of the OS and ORR hypotheses satisfy 
the requirements laid out in Maurer and Bretz [2].
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3.8
Sample Size and Power Calculations
The study will randomize subjects in a 2:1 ratio into the pembrolizumab plus BSC arm and the 
control arm (placebo plus BSC).
The final analysis is event driven (i.e., the testing of the OS and PFS hypotheses will be 
conducted upon accumulation of a preset number of events). The study is designed and will be 
conducted to accumulate approximately 345 OS events unless superiority in OS is proven at 
the interim analyses.
OS Analysis: A total of approximately 345 OS events are required to test the OS hypothesis 
at Type I error rate of =2.3% with ~87% power (see Table 7) if the underlying OS hazard 
ratio (pembrolizumab/control) is 0.7. A total of approximately 450 subjects are needed to be 
enrolled into the study in order to accumulate approximately 345 OS events at approximately 
Month 37 after study start. The sample size and power calculation is based on the following 
assumptions: 1) a hazard ratio of 0.7; 2) overall survival follows an exponential distribution 
with a median of 6.0 months in the control arm; 3) an enrollment rate of 16 subjects per month 
with a 6-month ramp up time; and 4) a monthly dropout rate of ~0.2%.
PFS Analysis: As described in Section 3.6 Interim Analysis, the final PFS analysis will be
conducted at the same time as the OS interim analysis 2 at approximately Month 31 after study 
start. It is projected that approximately 395 PFS events will be accumulated at this time. With 
395 PFS events, the testing of the PFS hypothesis at Type I error =0.2% has approximately 
88% power to demonstrate that pembrolizumab is superior to the control with respect to PFS 
if the underlying PFS hazard ratio (pembrolizumab/control) is 0.65.
The sample size and power calculation is based on the following assumptions: 1) a hazard ratio 
of 0.65; 2) progression-free survival follows an exponential distribution with a median of 1.5 
months in the control arm; 3) an enrollment rate of 16 subjects per month with a 6- month ramp 
up time; and 4) a monthly dropout rate of ~1%.
The sample size and power calculation were performed in the software EAST and R (package 
“gsDesign”).
3.9
Subgroup Analyses and Effect of Baseline Factors
To determine whether the treatment effect is consistent across various subgroups, the estimate 
of the between-group treatment effect (with a nominal 95% CI) for the primary endpoint will 
be estimated and plotted within each category of the following classification variables:
•
Prior treatment (Sorafenib, chemotherapy)
•
Macrovascular invasion (Yes, No)
•
HBV (Active Positive, Negative)
•
α-Fetoprotein (ng/mL) (<200, ≥200)
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•
α-Fetoprotein (ng/mL) (<400, ≥400)
•
Prior Locoregional Therapy (Yes, No)
•
Prior Treatment Surgery (Yes, No)
•
ECOG performance status (0, 1)
•
Age (<65 years, ≥65 years)
•
Extrahepatic spread (Yes, No)
•
Region (China, ex-China)
•
Gender (Male, Female)
•
Current disease overall BCLC stage (B, C)
3.10
Compliance (Medication Adherence)
Drug accountability data for trial treatment will be collected during the study. Any deviation 
from protocol-directed administration will be reported.
3.11
Extent of Exposure
The extent of exposure will be summarized as duration of treatment in cycles.
3.12
Statistical considerations for Patient-Reported Outcomes (PRO):
The patient-reported outcomes endpoints are exploratory objectives in KN394.  No formal 
hypotheses were formulated. Since multiplicity adjustments are only applied to primary and 
secondary hypotheses, nominal p-value to compare the pembrolizumab arm to the control arm 
will be provided without multiplicity adjustment 
The PRO instruments included in the study are the EORTC QLQ-C30 and EuroQol-5D-3L 
(EQ-5D3L).
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3.12.1
PRO Endpoints
Exploratory PRO endpoints include mean score changes from baseline to the latest time point, 
where the completion rate and compliance rates are still high enough (e.g. close to 60 and 80%, 
respectively) based on blinded data review, as measured by: 
•
EORTC QLQ-C30 global health status/quality of life scale 
•
All EORTC QLQ-C30 sub-scales/items
•
EQ-5D VAS
The other PRO endpoints are:
•
The time to deterioration (TTD) for the QLQ-C30 global health status/quality of life scale. 
•
The number and proportions of deterioration/stable/improvement from baseline to the 
latest time point, where the completion rate and compliance rates are still high enough (e.g. 
close to 60 and 80%, respectively) for all QLQ-C30 sub-scales/items. 
3.12.2
Scoring Algorithm
The QLQ-C30 includes five functional dimensions (physical, role, emotional, cognitive, and
social), three symptom scales (fatigue, nausea/vomiting, and pain), and six single item 
measures (dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, and financial 
difficulties).
QLQ-C30 Scoring: For each scale or item, a linear transformation will be applied to 
standardize the score as between 0 and 100, according to the corresponding scoring standard. 
For functioning and global health status/quality-of-life scales, a higher value indicates a better 
level of function; for symptom scales and items, a higher value indicates increased severity of 
symptoms. 
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According to the QLQ-C30 Manuals [12], if items I1, I2, ,  are included in a scale, the 
linear transformation procedure is as follows:
1. Compute the raw score:
2. Linear transformation to obtain the score S:
Function scales: 
Symptom scales/items: 
Global health status/QoL: 
Range is the difference between the maximum possible value of RS and the minimum possible 
value. If more than half of the items within one scale are missing, then the scale is considered 
missing, otherwise, the score will be calculated as the average score of those available items.
3.12.3
The Schedule for PRO Data Collection
Table 10 provides the schedule for PRO data collection.
Table 10
PRO Data Collection Schedule
Week
Cycle
MK-3475
Placebo
Week 0
C1


Week 3
C2


Week 6
C3


Week 9
C4


Week 12
C5


Week 18
C7


Week 27
>=C8


Week 36
>=C8


Week 45
>=C8


End of Treatment


30-day Safety follow-up


All PROs are to be performed at Cycle 1, Cycle 2, Cycle 3, Cycle 4, Cycle 5, and Cycle 7 before dosing. After 
Cycle 7 (Week 18), PROs are to be performed every 9 weeks (e.g., Week 27, Week 36, Week 45). PROs are to 
be performed up to a year or End of Treatment, whichever comes first, at treatment discontinuation, and at the 
30-day post-treatment discontinuation follow-up visit. 
n
I
I
I
RS
n /)
...
(
2
1




100
1
1










Range
RS
S
100
1 

Range
RS
S
100
1 

Range
RS
S
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The general rule of mapping relative day to analysis visit is provided in Table 11. The relative 
days are counted from the date the first dose.
Table 11
Mapping Relative Day to Analysis Visit
Week
Day
Day Range
Week 0
1
-7 - 1
Week 3
21
2 - 31
Week 6
42
32 - 52
Week 9
63
53 - 73
Week 12
84
74 - 105
Week 18
126
106 - 157
Week 27
189
158 - 220
Week 36
252
221 - 283
Week 45
315
284 - 346
At each scheduled visit, two instruments, EORTC QLQ-C30 and EQ-5D-3L, will be collected. 
If a patient does not complete the PRO instruments, the site staff will record the reason for 
missingness from pre-defined choices by using a miss-mode form. If there are multiple PRO 
collections within any of the stated time windows, we use the closest collection to the target 
day.
3.12.4
Analysis Populations
The PRO analyses are based on the PRO Full Analysis Set (FAS) population, defined as all 
randomized participants who have at least one PRO assessment available and have received at 
least one dose of the study intervention.  This population consists of all randomized patients 
who have received at least one dose of study medication and have completed at least one PRO 
assessment. 
3.12.5
Statistical Methods
3.12.5.1
PRO Compliance Summary
Completion and compliance of EORTC QLQ-C30 and EQ-5D3L by visit and by treatment will 
be described based on PRO FAS population. Numbers and percentages of complete and 
missing data at each visit will be summarized for each of the treatment groups. An instrument 
is considered complete if at least one valid score is available according to the missing item 
rules outlined in the scoring manual for the instrument. 
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Completion rate in the FAS population is defined as the percentage of number of subjects who 
complete at least one item over the number of subjects in the PRO FAS population at each time 
points.
The completion rate is expected to shrink in the later visits during study period due to the 
subjects who discontinued early. Therefore, another measurement, compliance rate of eligible 
subjects will also be employed as the support for completion rate.  Compliance rate is defined 
as the percentage of number of subjects who complete at least one item over number of eligible 
subjects who are expected to complete the PRO assessment (not including the subjects missing 
by design (such as death, discontinuation, translation not available)).
The reasons for non-completion and non-compliance will be summarized. 
In addition, reasons for non-completion as scheduled of these measures will be collected using 
miss-mode forms filled by site personnel and will be summarized in table format.  The schedule 
(study visits and estimated study times) and mapping of study visit to analysis visit for PRO 
data collection is provided in the Table 10 and Table 11.
3.12.5.2
Mean Change from Baseline
The time point for the mean change from baseline is defined as the latest time point at which 
completion rate ≥ 60% and compliance rate ≥ 80% based on blinded data review prior to the 
database lock for any PRO analysis. The primary time point for the analyses of PRO endpoint 
is Week 12. 
To assess the treatment effects based on the PRO score change from baseline, for each 
continuous endpoint defined, a constrained longitudinal data analysis (cLDA) model proposed 
by Liang and Zeger [8] will be used. This model assumes a common mean across treatment 
groups at baseline and a different mean for each treatment at each of the post-baseline time 
points. In this model, the response vector consists of the baseline value and the values observed 
at each post-baseline time point. Time is treated as a categorical variable so that no restriction 
is imposed on the trajectory of the means over time. The analysis model will include the PRO 
score as the response variable, and treatment by study visit interaction, and stratification factors
used for analyses of the primary endpoints as covariates.  
The cLDA model is specified as follows:
	
  =
   ℎ 	
  
  
       		
 
	
  =
   ℎ 	
  
  
  
!
  ℎ  "	#  	

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Where Yijt is the PRO score for subject i, with treatment assignment j at visit t, is the baseline 
mean for both treatment groups, jt is the mean change from baseline for treatment group j at 
time t, Xi is the stratification factor vector for this patient, and is the coefficient vector for 
stratification factors. An unstructured covariance matrix will be used to model the correlation 
among repeated measurements. The cLDA model implicitly treats missing data as missing at 
random (MAR).
The treatment difference in terms of least square (LS) mean score change from baseline to the 
time point as specified at the beginning of this section will be estimated from this model, 
together with 95% CI and nominal p-value.  In addition, model-based LS mean score with 95% 
CI will be provided by treatment group and study visit.
If the unstructured covariance model fails to converge with the default algorithm, then Fisher 
scoring algorithm or other appropriate methods can be used to provide initial values of the 
covariance parameters. In the rare event that none of the above methods yield convergence, a 
structured covariance such as Toeplitz can be used to model the correlation among repeated 
measurements. In this case, the empirical option for PROC MIXED in SAS 9.4 will be used 
because the sandwich variance estimator is asymptotically unbiased. 
3.12.5.3
Time to Deterioration
Time to deterioration (TTD): For the EORTC QLQ-C30, a 10 points or greater worsening from 
baseline for each scale represents a clinically relevant deterioration based on prior literature 
[9] [10] [11] TTD is defined as the time to first onset of 10 or more (out of 100) deterioration
from baseline in a given scale/sub-scale/item and confirmed by a second adjacent 10 or more 
deterioration from baseline. 
The Kaplan-Meier method will be used to estimate the TTD curve for each treatment group.  
The estimate of median time to deterioration and its 95% confidence interval will be obtained 
from the Kaplan-Meier estimates. The treatment difference in TTD will be assessed by the 
stratified log-rank test.  A stratified Cox proportional hazard model with Efron's method of tie 
handling and with a single treatment covariate will be used to assess the magnitude of the 
treatment difference (i.e., hazard ratio). The hazard ratio and its 95% CI will be reported. The 
stratification factors used for analyses of the primary endpoints will be used as the stratification 
factors in both the stratified log-rank test and the stratified Cox model.  
The approach for the time-to-deterioration analysis will be based on the assumption of non-
informative censoring. The participants who do not have deterioration on the last date of 
evaluation will be censored. Table 12 provides censoring rule for TTD analysis.
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Table 12
Censoring Rules for Time-to-Deterioration
Scenario
Outcome
Deterioration documented
Event observed at time of assessment (first 
deterioration)
Ongoing or discontinued from study 
without deterioration
Right censored at time of last assessment
No baseline assessments
Right censored at treatment start date
3.12.5.4
Proportions of Deterioration/Stable/Improvement
Patients’ post-baseline PRO score will be classified as “improved”, “stable” or “deteriorated” 
according to a 10 points or greater change for each of the instrument/scale, as this magnitude 
of change is perceived by patients as being clinically significant.
Since missing data cannot be ignored at the time point as specified at the beginning of 
Section 3.12.5.2, the number and proportion of patients who “improved”, “stable”, or 
“deteriorated”, from baseline will be summarized by treatment group and at the prior analysis 
visit based on MAR imputation of missing data.
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4
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