Conditions: Hepatocellular Carcinoma
Keywords: Programmed Cell Death-1 (PD1, PD-1) Programmed Cell Death 1 Ligand 1 (PDL1, PD-L1) Programmed Cell Death 1 Ligand 2 (PDL2, PD-L2)
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 413
Healthy volunteers: no

Brief summary:
This is a study of pembrolizumab (MK-3475) in participants with previously systemically treated advanced hepatocellular carcinoma (HCC).

The primary objectives of this study are to determine 1) Progression-Free Survival (PFS) and 2) Overall Survival (OS) of pembrolizumab plus best supportive care (BSC) compared with placebo plus BSC. The primary hypotheses of this study are: 1) pembrolizumab plus BSC prolongs PFS per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, assessed by Blinded Independent Central Review compared to placebo plus BSC, and 2) pembrolizumab plus BSC improves OS compared with placebo plus BSC.

Effective with Amendment 4: Upon study completion, participants are discontinued and may be enrolled in a pembrolizumab extension study, if available.

Detailed description:

Arms:
arm 1: Participants receive a pembrolizumab 200 mg intravenous (IV) infusion on Day 1 of each 3-week cycle for up to 35 cycles of treatment PLUS BSC. Participants who complete 35 administrations or achieve a complete response (CR) but progress after discontinuation can initiate a second course of pembrolizumab for up to 17 cycles (approximately 1 additional year). arm 2: Participants receive a placebo 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
Intervention descriptions: intervention 1: IV infusion intervention 2: 0.90% w/v sodium chloride IV infusion intervention 3: Best supportive care will include pain management and management of other potential complications including ascites per local standards of care.

Protocol document:
Prot_SAP_001.pdf: 
Official Protocol Title: 
NCT number: 
Document Date: 
A Phase III Study of Pembrolizumab (MK-3475) vs. Best 
Supportive Care as Second-Line Therapy in Subjects with 
Previously Systemically Treated Advanced Hepatocellular 
Carcinoma (KEYNOTE-240)
03-Feb-2021
NCT02702401


Product:  MK-3475 
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Confidential
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., 
WHITEHOUSE STATION, NJ, U.S.A.
SPONSOR:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. 
(hereafter referred to as the Sponsor or Merck)
One Merck Drive
P.O. Box 100
Whitehouse Station, New Jersey, 08889-0100, U.S.A.
Protocol-specific Sponsor Contact information can be found in the Investigator Trial File 
Binder (or equivalent).
TITLE:
A Phase III Study of Pembrolizumab (MK-3475) vs. Best Supportive Care as Second-Line 
Therapy in Subjects with Previously Systemically Treated Advanced Hepatocellular 
Carcinoma (KEYNOTE-240)
IND NUMBER:  123,482 
EudraCT NUMBER:  2015-004567-36 
 
 
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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).................................................................. 16
Primary Objective(s) & Hypothesis(es).............................................................. 16
Secondary Objective(s) & Hypothesis(es)........................................................... 17
Exploratory Objectives......................................................................................... 17
4.0
BACKGROUND & RATIONALE.......................................................................... 18
Background ........................................................................................................... 18
Pharmaceutical and Therapeutic Background .................................................... 18
Pre-clinical and Clinical Trials ........................................................................... 20
Ongoing Clinical Trials....................................................................................... 20
Information on Other Trial-related Therapy....................................................... 20
Rationale................................................................................................................ 21
Rationale for the Trial and Selected Subject Population .................................... 21
Rationale for Dose Selection/Regimen............................................................... 21
Rationale for the Use of Comparator/Placebo .................................................... 22
Rationale for Endpoints ...................................................................................... 23
4.2.4.1
Efficacy Endpoints....................................................................................... 23
4.2.4.1.1
Primary Efficacy Endpoint ................................................................... 23
4.2.4.1.2
Secondary Efficacy Endpoint ............................................................... 23
4.2.4.1.3
Exploratory Efficacy Endpoint ............................................................. 23
4.2.4.2
Immune-Related RECIST............................................................................ 23
4.2.4.3
Patient Reported Outcomes.......................................................................... 24
4.2.4.4
Safety Endpoints.......................................................................................... 25
 
 
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4.2.4.5
Biomarker Research..................................................................................... 26
4.2.4.6
Future Biomedical Research........................................................................ 27
Benefit/Risk ........................................................................................................... 28
5.0
METHODOLOGY ................................................................................................... 28
Entry Criteria........................................................................................................ 28
Diagnosis/Condition for Entry into the Trial...................................................... 28
Subject Inclusion Criteria.................................................................................... 28
Subject Exclusion Criteria .................................................................................. 31
Trial Treatment(s) ................................................................................................ 33
Dose Selection/Modification .............................................................................. 34
5.2.1.1
Dose Selection (Preparation) ....................................................................... 34
5.2.1.2
Dose Interval Modification for Non-Hepatic Drug-Related Adverse 
Events........................................................................................................... 34
5.2.1.3
Guidance for Diagnosis and Management of Hepatic Events of Clinical 
Interest (ECIs).............................................................................................. 38
Timing of Dose Administration.......................................................................... 43
Trial Blinding...................................................................................................... 43
Randomization ...................................................................................................... 43
Stratification.......................................................................................................... 44
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 44
Acceptable Concomitant Medications ................................................................ 44
Prohibited Concomitant Medications.................................................................. 45
Rescue Medications & Supportive Care............................................................. 46
Rescue Medications ............................................................................................ 46
Supportive Care Guidelines ................................................................................ 46
Diet/Activity/Other Considerations..................................................................... 49
Diet...................................................................................................................... 49
Contraception...................................................................................................... 49
Use in Pregnancy ................................................................................................ 52
Use in Nursing Women....................................................................................... 52
Subject Withdrawal/Discontinuation Criteria................................................... 52
Discontinuation of Treatment ............................................................................. 52
5.8.1.1
Discontinuation from Study Therapy after Complete Response ................. 53
 
 
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Withdrawal from the Trial .................................................................................. 53
Lost to Follow Up ............................................................................................... 54
Beginning and End of the Trial ........................................................................... 54
Clinical Criteria for Early Trial Termination ................................................... 54
6.0
TRIAL FLOW CHART ........................................................................................... 55
Initial Treatment with Study Drug ..................................................................... 55
Second Course Treatment.................................................................................... 61
7.0
TRIAL PROCEDURES ........................................................................................... 64
Trial Procedures ................................................................................................... 64
Administrative Procedures.................................................................................. 64
7.1.1.1
Informed Consent......................................................................................... 64
7.1.1.1.1
General Informed Consent.................................................................... 64
7.1.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research................................................................................................ 65
7.1.1.2
Inclusion/Exclusion Criteria ........................................................................ 65
7.1.1.3
Subject Identification Card .......................................................................... 65
7.1.1.4
Medical History ........................................................................................... 65
7.1.1.5
Disease Details............................................................................................. 65
7.1.1.6
Prior and Concomitant Medications Review............................................... 65
7.1.1.6.1
Prior Medications.................................................................................. 65
Prior Treatment Details for HCC ................................................... 66
7.1.1.6.2
Concomitant Medications..................................................................... 66
7.1.1.7
Subsequent Anti-Cancer Status.................................................................... 66
7.1.1.8
Assignment of Screening Number............................................................... 66
7.1.1.9
Assignment of Treatment/Randomization Number..................................... 66
7.1.1.10 Trial Compliance (Medication/Diet/Activity/Other)................................... 67
Clinical Procedures/Assessments........................................................................ 67
7.1.2.1
Adverse Event Monitoring........................................................................... 67
7.1.2.2
Physical Exam.............................................................................................. 67
7.1.2.2.1
Full Physical Exam ............................................................................... 67
7.1.2.2.2
Directed Physical Exam........................................................................ 67
7.1.2.3
Height, Weight, and Vital Signs .................................................................. 68
 
 
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7.1.2.4
12-Lead Electrocardiogram ......................................................................... 68
7.1.2.5
Eastern Cooperative Oncology Group Performance Status......................... 68
7.1.2.6
Child-Pugh Score......................................................................................... 68
7.1.2.7
Patient Reported Outcomes (PROs)............................................................. 68
Laboratory Procedures/Assessments .................................................................. 69
7.1.3.1
Laboratory 
Safety 
Evaluations 
(Hematology, 
Chemistry, 
and 
Urinalysis).................................................................................................... 69
7.1.3.2
Pregnancy Tests ........................................................................................... 70
7.1.3.3
Central Laboratory Assessments.................................................................. 70
7.1.3.4
Pharmacokinetic (PK) /Pharmacodynamic Evaluations.............................. 70
7.1.3.4.1
Blood Collection for PK ....................................................................... 70
7.1.3.4.2
Blood Collection for Anti-pembrolizumab Antibodies ........................ 70
7.1.3.5
Blood Samples for RNA Analysis, and Biomarker Studies ........................ 71
7.1.3.6
Tumor Tissue ............................................................................................... 71
7.1.3.7
Planned Genetic Analysis Sample Collection.............................................. 71
7.1.3.8
Future Biomedical Research Sample Collection ......................................... 71
Efficacy Measurements....................................................................................... 72
7.1.4.1
Tumor Imaging and Assessment of Disease................................................ 72
7.1.4.1.1
Initial Tumor Imaging........................................................................... 72
7.1.4.1.2
Tumor Imaging During the Trial .......................................................... 72
7.1.4.1.3
End of Treatment and Follow-up Tumor Imaging................................ 73
7.1.4.1.4
Second Course (Retreatment) Tumor Imaging..................................... 73
7.1.4.1.5
RECIST 1.1 Assessment of Disease..................................................... 74
7.1.4.1.6
Modified RECIST (mRECIST) Assessment of Disease....................... 74
7.1.4.1.7
irRECIST Assessment of Disease......................................................... 75
Other Procedures................................................................................................. 78
7.1.5.1
Withdrawal/Discontinuation........................................................................ 78
7.1.5.1.1
Withdrawal From Future Biomedical Research ................................... 79
7.1.5.2
Blinding/Unblinding .................................................................................... 79
7.1.5.3
Calibration of Equipment............................................................................. 80
Visit Requirements.............................................................................................. 80
7.1.6.1
Screening...................................................................................................... 80
7.1.6.2
Treatment Period.......................................................................................... 81
 
 
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7.1.6.3
Post-Treatment Visits................................................................................... 82
7.1.6.3.1
Safety Follow-up Visits ........................................................................ 82
7.1.6.3.2
Follow-up Visits ................................................................................... 82
7.1.6.3.3
Survival Follow-up ............................................................................... 83
7.1.6.4
Survival Status ............................................................................................. 83
Assessing and Recording Adverse Events .......................................................... 83
Definition of an Overdose for This Protocol and Reporting of Overdose to 
the Sponsor.......................................................................................................... 84
Reporting of Pregnancy and Lactation to the Sponsor ....................................... 84
Immediate Reporting of Adverse Events to the Sponsor.................................... 85
7.2.3.1
Serious Adverse Events ............................................................................... 85
7.2.3.2
Events of Clinical Interest............................................................................ 86
7.2.3.3
Protocol-Specific Exceptions to Serious Adverse Event Reporting............ 87
Evaluating Adverse Events................................................................................. 87
Sponsor Responsibility for Reporting Adverse Events ...................................... 90
Trial Governance and Oversight......................................................................... 90
Scientific Advisory Committee........................................................................... 90
Executive Oversight Committee......................................................................... 90
Data Monitoring Committee............................................................................... 90
8.0
STATISTICAL ANALYSIS PLAN ........................................................................ 90
Statistical Analysis Plan Summary ..................................................................... 91
Responsibility for Analyses/In-House Blinding ................................................. 93
Hypotheses/Estimation......................................................................................... 93
Analysis Endpoints ............................................................................................... 94
Efficacy Endpoints.............................................................................................. 94
8.4.1.1
Primary......................................................................................................... 94
8.4.1.2
Secondary..................................................................................................... 94
Safety Endpoints ................................................................................................. 94
Analysis Populations............................................................................................. 94
Efficacy Analysis Populations ............................................................................ 94
Safety Analysis Populations ............................................................................... 95
Statistical Methods................................................................................................ 95
 
 
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Statistical Methods for Efficacy Analyses.......................................................... 95
8.6.1.1
Progression-free Survival............................................................................. 95
8.6.1.2
Overall Survival........................................................................................... 97
8.6.1.3
Objective Response Rate ............................................................................. 98
8.6.1.4
Disease Control Rate.................................................................................... 98
8.6.1.5
Time to Progression..................................................................................... 98
8.6.1.6
Duration of Response................................................................................... 99
Statistical Methods for Safety Analyses ........................................................... 100
Summaries of Demographic and Baseline Characteristics ............................... 102
Interim Analyses ................................................................................................. 102
Efficacy Interim Analyses................................................................................. 102
Safety Interim Analyses.................................................................................... 102
Multiplicity .......................................................................................................... 102
Sample Size and Power Calculations ................................................................ 106
Subgroup Analyses and Effect of Baseline Factors.......................................... 106
Compliance (Medication Adherence)................................................................ 107
Extent of Exposure.............................................................................................. 107
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ............................................................................................................... 107
Investigational Product ...................................................................................... 107
Packaging and Labeling Information ............................................................... 107
Clinical Supplies Disclosure............................................................................... 108
Storage and Handling Requirements................................................................ 108
Discard/Destruction/Returns and Reconciliation ............................................ 108
Standard Policies................................................................................................. 109
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
 
 
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Compliance with Law, Audit and Debarment ................................................. 110
Compliance with Trial Registration and Results Posting Requirements...... 112
Quality Management System............................................................................. 112
Data Management............................................................................................... 113
Publications ......................................................................................................... 113
11.0
LIST OF REFERENCES....................................................................................... 115
12.0
APPENDICES......................................................................................................... 120
Merck Code of Conduct for Clinical Trials...................................................... 120
Collection and Management of Specimens for Future Biomedical 
Research............................................................................................................... 122
Understanding the Intent, Scope and Public Health Benefits of 
Exploratory Biomarker Research: A Guide for IRBs/IECs and 
Investigational Site Staff .................................................................................... 126
Hepatitis B Definitions and Treatment Considerations .................................. 137
ECOG Performance Status................................................................................ 138
Common Terminology Criteria for Adverse Events ....................................... 139
Child-Pugh Score................................................................................................ 140
Barcelona Clinic Liver Cancer Staging System............................................... 142
List of Abbreviations .......................................................................................... 143
13.0
SIGNATURES......................................................................................................... 146
Sponsor's Representative ................................................................................... 146
Investigator.......................................................................................................... 146
 
 
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LIST OF TABLES
    
Table 1
Adequate Organ Function Laboratory Values ..................................................31
Table 2
Trial Treatment..................................................................................................33
Table 3
Dose Modification and Toxicity Management Guidelines for Non-hepatic 
Immune-related AEs Associated with Pembrolizumab..................................35
Table 4
Infusion Reaction Treatment Guidelines ..........................................................48
Table 5
Laboratory Tests................................................................................................69
Table 6
Imaging and Treatment after First Radiologic Evidence of PD........................77
Table 7
Evaluating Adverse Events ...............................................................................88
Table 8
Censoring Rules for Primary and Sensitivity Analyses of PFS........................97
Table 9
Censoring Rules for TTP ..................................................................................99
Table 10 Censoring Rules for DOR.................................................................................99
Table 11 Analysis Strategy for Key Efficacy Endpoints ...............................................100
Table 12 Analysis Strategy for Safety Parameters.........................................................101
Table 13 Efficacy Boundaries for Testing the PFS Hypothesis.....................................103
Table 14 Efficacy Boundaries for Testing the OS Hypothesis ......................................105
Table 15 Efficacy Boundaries for Testing the ORR Hypothesis ...................................105
Table 16 Product Descriptions.......................................................................................107
Table 17 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........................................78
Figure 3
Multiplicity Strategy .......................................................................................103
Figure 4
Barcelona Clinic Liver Cancer staging system...............................................142
 
 
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
3475-240-04
03-FEB-2021
Language was added to include the requirement of roll over 
of trial participants into an extension trial (if available) when 
this trial is completed
3475-240-03
21-DEC-2017
A second interim analysis was added
3475-240-02
20-JUL-2016
Subject eligibility by radiographic diagnosis for HCC was 
added to address investigator feedback; caps on Asian and 
HBV population was widened following consultation with 
Regulatory and SAC members to help facilitate accrual rate.
3475-240-01
23-FEB-2016
Program wide decision for pembrolizumab to remove health 
economic assessment from patient reported outcomes
Original Protocol
15-JAN-2016
Not applicable
 
 
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SUMMARY OF CHANGES
PRIMARY REASON(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title(s)
Description of Change (s)
Rationale
1.0; 2.1;
Trial Summary
Sentence added: Upon study completion, 
participants are discontinued and may be 
enrolled in a pembrolizumab extension study, if 
available
Language was added to include 
the requirement of roll over of 
trial 
participants 
into 
an 
extension trial (if available) 
when this trial is completed
2.1; 6.1 and 6.2; 
7.1.4.1.3; 7.1.4.1.4; 
Trial Design; Trail Flow 
Chart; End of Treatment 
and Follow-up
Tumor 
Imaging; Second Course 
(Retreatment)
Tumor 
Imaging; 
The frequency of follow up visits and imaging 
were changed from every 6 weeks (42±7 days) 
to 12 weeks (84±7 days)
To align with current follow-up 
schedule 
for 
pembrolizumab 
studies
7.1.6.3.2
Follow-Up Visits
Sentence ‘Follow-up Phase and should be 
assessed Q6W by radiologic imaging’ changed 
to ‘Follow-up Phase and should be assessed 
Q12W by radiologic imaging’
The duration of follow up phase 
was revised.
12.9
List of Abbreviations;
Q12W was added
Additional abbreviation for 12 
weeks duration was added.
ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
No additional changes.
 
 
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1.0 TRIAL SUMMARY
Abbreviated Title
A Phase III Study of Pembrolizumab (MK-3475) vs. Best Supportive 
Care as Second-Line Therapy in Subjects with Previously 
Systemically Treated Advanced Hepatocellular Carcinoma
Sponsor Product Identifiers
MK-3475
Pembrolizumab
Trial Phase
Phase III
Clinical Indication
Hepatocellular carcinoma
Trial Type
Interventional
Type of control
Placebo plus best supportive care (BSC)
Route of administration
Intravenous (IV)
Trial Blinding
Double-blind
Treatment Groups
Pembrolizumab plus BSC or placebo plus BSC
Number of trial subjects
Approximately 408 subjects will be enrolled.
Estimated duration of trial
The Sponsor estimates that the trial will require approximately 
44 months from the time the first subject signs the informed consent 
until the last subject’s last 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 through the final contact.  After a screening 
phase of up to 28 days, each subject will receive pembrolizumab 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 receives 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 a 
centrally confirmed complete response 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 
cancer treatment, withdrawing consent from study participation, or 
becoming lost to follow-up.  All subjects will be followed (e.g., by 
telephone or visit) for overall survival until death, withdrawal of 
consent from study participation, or the end of the study, whichever 
comes first.  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.
Upon study completion, participants are discontinued and may be 
enrolled in a pembrolizumab extension study, if available.
A list of abbreviations used in this document can be found in Section 12.9.  
Randomization Ratio
Pembrolizumab plus BSC or placebo plus BSC at a 2:1 ratio
 
 
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2.0 TRIAL DESIGN
Trial Design
This is a double-blind randomized Phase III trial of pembrolizumab (MK-3475) plus best 
supportive care (BSC) versus placebo plus BSC in previously systemically treated subjects 
with a hepatocellular carcinoma (HCC) diagnosis confirmed by radiology, histology, or 
cytology (fibrolamellar and mixed hepatocellular/cholangiocarcinoma subtypes are not 
eligible).  To be eligible, subjects must have documented objective radiographic progression 
of disease (PD) during or after treatment with sorafenib, or else be intolerant of sorafenib 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). Subjects must have at least one measurable 
lesion that is confirmed by the blinded central imaging vendor per Response Evaluation
Criteria in Solid Tumors (RECIST) 1.1, Child-Pugh liver class A, an Eastern Cooperative 
Oncology Group (ECOG) performance score of 0 or 1, and predicted life expectancy of > 3 
months. 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. Approximately 408
subjects will be randomized at a 2:1 ratio to receive pembrolizumab 200 mg IV plus BSC 
every 3 weeks (Q3W) or placebo IV plus BSC (Q3W).
Enrollment of subjects in the Asian population will be capped to approximately 30% of the 
study population (approximately 122 subjects total); hepatitis B subjects will be capped also 
to approximately 30% of the study population (approximately: 122 subjects total; 61 from 
Asia without Japan population [i.e., 15% of 408]; and 61 subjects from non-Asian with Japan
population [i.e., 15% of 408]).  Additionally, the sorafenib-intolerant population will be 
capped at approximately 20% within each region (approximately: 82 subjects total; 25 from 
Asia without Japan population [i.e., 20% of 122]; and 57 from non-Asia with Japan
population [i.e., 20% of 286]), to ensure that the study population is representative of the 
U.S. population.
The primary objectives of this trial are to determine progression-free survival (PFS) and 
overall survival (OS) of pembrolizumab plus BSC compared with placebo plus BSC.  On-
study imaging assessments will be performed every 6 weeks (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).  PD 
will also be confirmed by the blinded central imaging vendor.  
Following the first radiologic evidence of PD by RECIST 1.1, treatment decisions may be 
made by the adaptation of RECIST 1.1 as described in Section 4.2.4.2 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, the subject should be 
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achieving a clinically meaningful benefit; an exception for continued treatment may be 
considered following consultation with the Sponsor.  
Subjects may continue on study treatment until PD is confirmed by RECIST 1.1, 
unacceptable adverse events (AEs), intercurrent illness that prevents further administration of 
treatment, investigator decides to withdraw the subject, subject withdraws consent, 
pregnancy of the subject, noncompliance with trial treatment or procedure requirements, 
administrative reasons, or the subject has 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 every 12 weeks (84±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 approximately every 12 weeks
for OS until death, withdrawal of consent from participation in the study, or the end of the 
study, whichever occurs first.  In addition to that, survival status will be monitored as needed 
for analysis during the course of the trial.
Subjects who attain a complete response (CR) by 2 tumor imaging assessments at least 
4 weeks apart, and who have received at least 8 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 (see Section 5.8.1).  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.  Treatment switching between
the two arms is not allowed.  
Upon study completion, participants are discontinued and may be enrolled in a 
pembrolizumab extension study, if available.
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.
This trial will use a group sequential design, using an independent, external Data Monitoring 
Committee (eDMC). Details regarding the role of the eDMC are provided in the eDMC 
Charter. There will be 2 planned efficacy interim analyses (see Section 8.7).  The results of 
the interim analyses will be reviewed by the eDMC, which will make recommendations to 
 
 
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the Sponsor to continue, modify, or end the trial according to the plan described in detail in 
Section 8.0 - Statistical Analysis Plan (SAP).  
Trial Diagram
*Participants may roll over if extension study is available 
Abbreviations: ECOG = Eastern Cooperative Oncology Group; IV = intravenous; Q3W = every 3 weeks 
RECIST = Response Evaluation Criteria in Solid Tumors; 
Figure 1
Trial Diagram
3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
Intravenous administration of pembrolizumab or placebo as second-line treatment after 
sorafenib systemic monotherapy in subjects with advanced HCC:
Primary Objective(s) & Hypothesis(es)
In subjects with HCC receiving pembrolizumab plus BSC vs. placebo plus BSC:
1) Objective:  To compare PFS per RECIST 1.1 assessed by a blinded central imaging 
vendor.
Hypothesis:  Pembrolizumab prolongs PFS per RECIST 1.1, assessed by a blinded 
central imaging vendor.
2) Objective:  To compare OS between pembrolizumab plus BSC versus placebo plus 
BSC.
Hypothesis:  Pembrolizumab improves OS compared with placebo.
The trial will be deemed positive if either OS or PFS null hypotheses are rejected.
 
 
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Secondary Objective(s) & Hypothesis(es)
In subjects with HCC receiving pembrolizumab plus BSC vs. placebo plus BSC:
1) Objective:  To compare objective response rate (ORR) per RECIST 1.1 assessed by a 
blinded central imaging vendor.
Hypothesis:  Pembrolizumab increases ORR per RECIST 1.1, assessed by a blinded 
central imaging vendor.
2) Objective:  To evaluate the duration of response (DOR), disease control rate (DCR) 
and time to progression (TTP), per RECIST 1.1 assessed by a blinded central imaging 
vendor.
3) Objective:  Evaluate the safety and tolerability profile of pembrolizumab.
Exploratory Objectives 
In subjects with HCC receiving pembrolizumab plus BSC vs. placebo plus BSC:
1) Objective:  To evaluate PFS, ORR, DOR, DCR, and TTP, assessed by the 
investigator using RECIST 1.1.
2) Objective:  To evaluate PFS, ORR, DOR, DCR, and TTP per modified RECIST for 
HCC (mRECIST) assessed by blinded central imaging vendor review.
3) Objective:  To evaluate PFS, ORR, DOR, DCR, and TTP per irRECIST assessed by 
blinded central imaging vendor review.  
4) Objective:
To
identify molecular (genomic, metabolic and/or proteomic) 
determinants of response or resistance (e.g., PD-L1 IHC, gene expression profiling, 
and/or genomic variation) to pembrolizumab and other treatments in this study, using 
blood and/or tumor tissue to define novel predictive and pharmacodynamic 
biomarkers, to better understand the mechanism of action of pembrolizumab.
5) Objective:  To evaluate score change from baseline of health related quality of life 
using the European Organisation for Research and Treatment of Cancer (EORTC)
Quality of Life Questionnaire—Core 30 (QLQ-C30) and the EORTC Quality of Life 
Questionnaire—HCC 18 (QLQ-HCC18).
6) Objective:  To characterize health utilities using EuroQol-5 Dimension (EuroQol 
EQ-5D™).
7) Objective: To explore the relationship between cause of sorafenib discontinuation 
(intolerant vs. radiographic progression of disease) and response to pembrolizumab.
8) Objective: To explore the response of underlying hepatitis B virus (HBV) or hepatitis 
C virus (HCV) (if present) to pembrolizumab as assessed by viral loads and viral 
serologies.
 
 
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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 second leading cause of cancer deaths worldwide and has one of the most 
rapidly rising mortality rates of any cancer in the United States. Most HCC arises in the 
setting of liver cirrhosis from varied causes, including viral hepatitis, excessive alcohol 
consumption, hemochromatosis, and metabolic syndrome [2].
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 with no curative option.  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. The hazard ratio for OS was 0.69, [95% CI 0.55-0.87], p<0.001
[3]. 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 OS was shorter in this trial 
[4]. 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 [5].
In this trial, there was a nonsignificant trend toward improved OS in the FOLFOX arm, with
some imbalances in the populations favoring the FOLFOX arm.
Despite these advances, 
continued investigation of additional agents for advanced HCC patients remains crucial.
In the second-line setting, there is no clear worldwide standard of care for treatment of 
advanced HCC.  Several large randomized trials had failed to show a significant survival 
advantage of various agents against placebo in the second line, including brivanib [6],
everolimus [7] and ramucirumab [8].
Smaller studies suggested the possible efficacy for 
MET inhibitors and regorafenib in advanced HCC, and larger randomized trials were 
underway to investigate these drugs in more detail [9], [10].  Chemotherapy drugs including 
capecitabine and the gemcitabine/oxaliplatin (GEMOX) combination also used in the second 
line in small trials [11], [12].
Pharmaceutical and Therapeutic Background
Pembrolizumab (MK-3475) is a potent and highly-selective humanized monoclonal antibody 
(mAb) of the IgG4/kappa isotype designed to directly block the interaction between 
programmed cell death 1 (PD-1) and its ligands, PD-L1 and programmed death ligand 2 
(PD-L2).  KEYTRUDA (pembrolizumab) has  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 approved for the treatment of patients with metastatic non-small 
cell lung cancer (NSCLC) whose tumors express PD-L1 as determined by a Food and Drug 
 
 
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Administration (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 [13].  Accumulating evidence shows a correlation between tumor-
infiltrating lymphocytes (TILs) in cancer tissue and a favorable prognosis in various 
malignancies [14], [15], [16], [17], [18].  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) 
[19], [20].  
The structure of murine PD-1 has been identified [21].  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 [19], [22], [23], [24].  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 [25], [26].  PD-1 was shown to be expressed on 
activated lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, T-regulatory 
cells, and natural killer cells [27], [28].  Expression has also been shown during thymic 
development on CD4–/CD8– (double negative) T-cells as well as subsets of macrophages 
and dendritic cells [29].  
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 [30],
[31], [32], [25].  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 PD-1 inhibits 
T-cell activation triggered through the T-cell receptor.    PD-L1 is expressed at low levels on 
various non-hematopoietic tissues, most notably on vascular endothelium, whereas PD-L2 
protein is only detectably expressed on antigen-presenting cells found in lymphoid tissue or 
chronic inflammatory environments.  PD-L2 is thought to control immune T-cell activation 
in lymphoid organs, whereas PD-L1 serves to dampen unwarranted T-cell function in 
peripheral tissues [25].  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 [33].  
 
 
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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 and anti-mouse PD-L1 antibodies have demonstrated 
anti-tumor responses as monotherapy in models of squamous cell carcinoma, pancreatic 
carcinoma, melanoma, and colorectal carcinoma.  Blockade of the PD-1 pathway effectively 
promotes CD8+ T-cell infiltration into the tumor and the presence of interferon-γ, granzyme 
B and perforin, indicating that the mechanism of action involves local infiltration and 
activation of effector T-cell function in vivo [34], [35], [36], [37], [38], [39]. 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, non-small cell lung cancer (NSCLC), head and neck cancer, bladder cancer, 
Hodgkin’s lymphoma, triple-negative breast cancer, and gastric adenocarcinoma. 
In 
addition, recent data demonstrate emerging evidence of single-agent activity in additional 
tumor types such as mesothelioma, urothelial cancer, ovarian cancer, neuroendocrine 
carcinoma, and small cell lung cancer.
In a mouse model of HCC, blockade of PD-1 with immunostimulatory monoclonal 
antibodies extended survival [40]. 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 [41]. High expression levels of PD-1 on tumor-infiltrating 
lymphocytes [TILs] and peripheral blood mononuclear cells [PBMCs] have also been 
correlated with a poor prognosis in HCC patients after surgical resection [42]. An interim 
analysis of a Phase I/II trial of nivolumab in previously treated patients with HCC 
demonstrated that the estimated survival rate in evaluable patients (n=42) was 62% at 12 
months. Results also show the safety profile of nivolumab to be generally consistent with 
that previously reported in other tumor types [43].
Ongoing Clinical Trials
Ongoing clinical trials of pembrolizumab are being conducted in advanced melanoma, 
NSCLC, 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 worsened OS [44]. As discussed above, HCC 
patients with higher tumor expression of PD-L1 have a significantly poorer prognosis than 
patients with lower expression [41].  In addition, high expression levels of PD-1 on T-cells
(both tumor infiltrating lymphocytes and peripheral blood mononuclear cells) also correlate 
with higher recurrence rates in HCC patients after surgical resection [42].  
Recently, immunotherapy has been shown to produce antitumor effects in HCC, a tumor 
which has shown resistance to traditional forms of chemotherapy.  Cytotoxic T-lymphocyte-
associated protein (CTLA)-4 inhibition with tremelimumab was evaluated in a small study of 
HCV-associated HCC patients [45].  Seventeen patients were evaluable for response, and 3 
partial responses (PRs) were seen lasting for 3.6, 9.2 and 15.8 months. Stable disease was 
the best response seen in 59%, and of these, 45% were stable for over 6 months. Toxicity was 
manageable, despite early elevations in transaminases.  
As discussed above, an 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 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 
showed the safety profile of nivolumab in HCC to be generally consistent with that 
previously reported in other tumor types, and no maximum tolerated dose (MTD) has been 
identified [43].  
Rationale for Dose Selection/Regimen
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 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) has 
been 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 a lack of important differences 
in efficacy or safety profile across doses.
 
 
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An integrated body of evidence suggests that 200 mg Q3W is expected to provide a 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 the 
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 mAb, 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
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
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 worldwide standard of care for advanced HCC 
therapy. Several large randomized trials failed to show a significant survival advantage 
against placebo in the second line setting, including brivanib [6], everolimus [7], and 
ramucirumab [8]. 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 [9], [10]. However, at the time of the study start, there were no agents or 
combinations yet approved for second-line HCC, underscoring the high unmet need for
treatment of 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.
 
 
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Rationale for Endpoints
4.2.4.1
Efficacy Endpoints
4.2.4.1.1 Primary Efficacy Endpoint
The primary efficacy objective of this study is to evaluate the anti-tumor activity of 
pembrolizumab in subjects with HCC who were previously treated with sorafenib.  The 
primary endpoints will be PFS per RECIST 1.1 criteria as assessed by the blinded central 
imaging vendor and OS.  The endpoint of OS is the standard for demonstrating superiority of 
antineoplastic therapy in clinical studies in the area of oncology.  PFS is being included as a 
second primary endpoint in case of unplanned treatment switching. 
4.2.4.1.2 Secondary Efficacy Endpoint
The secondary efficacy objectives of this study are to:
(1) Compare ORR per RECIST 1.1 assessed by a blinded central imaging vendor.
(2) Evaluate DOR, DCR and TTP per RECIST 1.1 assessed by a blinded central imaging 
vendor.
Measurable disease will be confirmed centrally 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.
4.2.4.1.3 Exploratory Efficacy Endpoint
Exploratory efficacy objectives of this study are to explore ORR, DOR, DCR, TTP and PFS 
per 1) irRECIST assessed by the central imaging vendor, 2) investigator assessment using 
RECIST 1.1, 3) measurements based on RECIST 1.1 assessed by the central imaging vendor, 
and 4) measurements based on mRECIST assessed by the blinded central imaging vendor, to 
assess these different evaluations in the HCC population. Additional objectives of this study 
are to explore the association between genomic, metabolic and/or proteomic biomarkers and 
antitumor efficacy of pembrolizumab based on RECIST 1.1 as assessed by the central 
imaging vendor. The relationship of biomarkers in tumor compared with blood samples will 
be explored. Quality of life and health utilities will be examined, along with an assessment 
between groups with respect to hepatitis serologies and viral loads. The relationship between 
cause of sorafenib discontinuation (intolerance vs. radiographic progression to disease) and 
response to pembrolizumab in terms of overall survival will also be explored.
4.2.4.2
Immune-Related RECIST
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, 
 
 
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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. 
Immune-related RECIST is RECIST 1.1 adapted to account for the unique tumor response 
seen with immuno-therapeutics as described in Nishino et al. 2013 [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 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 central imaging retrospectively, according to irRECIST definition.
For further information on irRECIST, see Section 7.1.4.1.7.  In addition, Modified RECIST 
(mRECIST) for HCC allows evaluation of treatment effects that are not reflected in simple 
total size changes of lesions.  Details are fully described in [46], and key differences from 
RECIST 1.1 listed in Section 7.1.4.1.6.
4.2.4.3
Patient Reported Outcomes
As part of an exploratory analysis, subjects will provide information regarding their health-
related quality of life (HRQoL) via the following European Organisation for Research and 
Treatment of Cancer (EORTC) assessment tools: EORTC QLQ-C30, QLQ-HCC18, and 
EuroQol-5D-3L (EQ-5D-) questionnaires. 
These measures are not pure efficacy or safety 
endpoints because they are affected by both disease progression and treatment tolerability. 
EORTC QLQ-C30 and EORTC QLQ-HCC18
The EORTC QLQ-C30 is the most widely used cancer-specific HRQoL instrument, which 
contains 30 items and measures 5 functioning dimensions (physical, role, cognitive, 
emotional, and social), 3 symptom items (fatigue, nausea/vomiting, pain), 6 single items 
(dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, and financial impact), and a 
global health and quality of life scale [47]. This instrument has been translated and validated 
into 81 languages and used in more than 3000 studies worldwide.
The EORTC QLQ-HCC18 is a disease-specific questionnaire developed and validated to 
address measurements specific to HCC [48].  It is one of multiple disease-specific modules 
developed by the EORTC QLG (Quality of Life Group) designed for use in clinical trials, to 
be administered in addition to the QLQ-C30 to assess disease-specific treatment 
measurements.  It consists of 18 items containing 6 scales and 2 single items.
 
 
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EuroQoL-5D
The EQ-5D is a standardized instrument for use as a measure of health outcome.  The EQ-5D
will provide data for use in economic models and analyses including developing health 
utilities or quality adjusted life years (QALYs).  The 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 EQ-5D also includes a graded (0 to 100) vertical visual analog scale 
on which the subject rates his or her general state of health at the time of the assessment.  The 
EQ-5Dwill always be completed by subjects first before completing the EORTC QLQ-C30 
and QLQ-HCC18 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).
4.2.4.4
Safety Endpoints
The safety objective of this trial is to characterize the safety and tolerability of 
pembrolizumab in subjects with previously systemically treated HCC.  The primary safety 
analysis will be based on subjects who have toxicities as defined by NCI-CTCAE, version 
4.0 (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.  AEs will be analyzed including, but 
not limited to, all 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 7.2.3.2.  
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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4.2.4.5
Biomarker Research
Introduction:  Cancer immunotherapies are an important novel class of anti-tumor agents.  
However, much remains to be learned about how cancer immunotherapies work and how 
best to leverage these new drugs in treating patients.  Thus, to aid future patients, it is 
important to investigate the determinants of response or resistance to cancer 
immunotherapies, as well as determinants of AEs in the course of our clinical trials.  To that 
end we seek to define novel predictive/pharmacodynamic biomarkers and the best strategies 
of combination therapy with immuno-oncology drugs. To fully leverage the clinical data 
collected in this trial, we will also collect biospecimens (blood components, tumor material, 
etc.) to support biomarker analyses of cellular components (e.g., protein, DNA, RNA, 
metabolites) and other circulating molecules.  Investigations may include but are not limited 
to:
Germline (blood) DNA analyses (e.g., single nucleotide polymorphism analyses, whole 
exome sequencing, whole genome sequencing):  
This research will evaluate whether genetic variation within a clinical trial population 
correlates with response to the treatment(s) under evaluation. If genetic variation is found to 
predict efficacy or adverse events, the data might inform optimal use of therapies in the 
patient population. Furthermore, it is important to evaluate germline DNA variation across 
the genome in order to interpret tumor-specific DNA mutations.  
Tumor DNA analyses:  
The application of new technologies, such as next generation sequencing, has provided 
scientists the opportunity to identify tumor-specific DNA changes (i.e., mutations, 
methylation status, and microsatellite instability).  Key molecular changes of interest to 
immuno-oncology drug development are the mutational burden of tumors and the clonality of 
T-cells in the tumor microenvironment.  Increased mutational burden (sometimes referred to 
as a ‘hyper-mutated’ state) is one of the major mechanisms of neo-antigen presentation in the 
context of a tumor.  The increased presence of foreign-like peptides on the cell surface due to 
somatic mutations in the DNA of the tumor increases the chances that the tumor will be 
‘visible’ to the adaptive immune system through the MHC-I antigen presentation mechanism. 
There are a number of mechanisms by which a tumor can have increased mutational burden, 
such as defects in key genes related to DNA mismatch repair mechanisms or environmental 
induced factors such as smoking or UV light exposure.  Additionally, a DNA tetrapeptide 
neo-antigen mutational signature can also be obtained by use of bioinformatic prediction 
tools of HLA-restricted mutated peptide binding to MHC class I and to the T-cell. There is a 
potential that in the hyper-mutated state, the presence of neo-antigen mutational patterns and 
the detection of increased T-cell clonality, both of which can be determined by use of next-
generation sequencing methods, may correlate with response to pembrolizumab therapy 
and/or that the converse, the ‘hypomutated’ state (the absence of neo-antigens) may correlate 
with non-response.  To conduct this type of research, it is important to identify tumor-
specific mutations that occur across all genes in the tumor genome.  Thus, genome wide 
approaches may be used for this effort. Note that in order to understand tumor-specific 
mutations, it is necessary to compare the tumor genome with the germline genome (e.g., from 
germline blood DNA).  
 
 
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Tumor and blood RNA analyses: 
Both genome-wide and targeted messenger RNA (mRNA) expression profiling and 
sequencing in tumor tissue and in blood may be performed to define gene signatures that 
correlate to clinical response to treatment with pembrolizumab or other immunotherapies.  
Pembrolizumab induces a response in tumors that likely reflects an inflamed/ immune 
phenotype.  Specific immune-related gene sets (such as those capturing interferon-gamma 
transcriptional pathways) may be evaluated and new signatures may be identified.   
Individual genes related to the immune system may also be evaluated (e.g., interleukin-10).  
MicroRNA profiling may also be pursued.
Proteomics and Immunohistochemistry (IHC) using Blood or Tumor:  
Tumor and blood samples from this study may undergo proteomic analyses (e.g., PD-L1 
IHC).  PD-L1 protein level, as assessed by IHC in tumor sections, has been shown to 
correlate with response to pembrolizumab in patients with NSCLC, and a PD-L1 IHC 
diagnostic is marketed for use with pembrolizumab in NSCLC.  Preliminary data indicate 
that this association may also be true in additional cancer types (i.e., triple-negative breast 
cancer, head and neck, and gastric).  Additional tumor- or blood-derived proteins may also 
correlate with response to pembrolizumab.  Therefore, tumor tissue may be subjected to 
proteomic profiling using a variety of platforms that could include but are not limited to 
immunoassay, and/or liquid chromatography/mass spectrometry.  This approach could 
identify novel protein biomarkers that could aid in patient selection for pembrolizumab (MK-
3475) therapy.
Other Blood Derived Biomarkers
In addition to expression within the tumor tissue, tumor-derived proteins (e.g., PD-L1) or 
tumor-derived DNA can be shed from tumor and released into the blood.  In the case of 
proteins, enzyme-linked immunosorbent assay can measure such proteins in serum and 
plasma and correlate this expression with response to pembrolizumab therapy, as well as 
levels of protein in the tumor.  DNA can be analyzed using next generation sequencing or 
polymerase chain reaction-based technologies. Advantages to this method are that blood is a 
less invasive compartment from which tumor derived protein or nucleic acid biomarkers may 
be measured.  
4.2.4.6
Future Biomedical Research
The Sponsor will conduct Future Biomedical Research on specimens collected for future 
biomedical research during this clinical trial.  This research may include genetic analyses 
(DNA), gene expression profiling (RNA), proteomics, metabolomics (serum, plasma) and/or 
the measurement of other analytes.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main trial) and will only be conducted on specimens from 
appropriately consented subjects. The objective of collecting specimens for Future 
Biomedical Research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. The overarching goal is to use 
such information to develop safer, more effective drugs/vaccines, and/or to ensure that 
subjects receive the correct dose of the correct drug/vaccine at the correct time.  The details 
 
 
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of this Future Biomedical Research sub-trial are presented in Section 12.2 - Collection and 
Management of Specimens for Future Biomedical Research.  Additional informational 
material for institutional review boards/ethics committees (IRBs/ERCs) and investigational 
site staff is provided in Section 12.3.
Benefit/Risk
Subjects in clinical trials generally cannot expect to receive direct benefit from treatment 
during participation, as clinical trials are designed to provide information about the safety 
and effectiveness of an investigational medicine.
However, experience with this drug 
approved in other indications, as well as with similar drugs in HCC 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 were not previously studied.  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 myeloma, and other 
advanced solid tumors.  Based on pembrolizumab data from other indications and from data 
in HCC patients 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 and female subjects with advanced HCC after progression on sorafenib or intolerance 
of sorafenib 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.
 
 
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3. Have a HCC diagnosis confirmed by radiology, histology, or cytology (fibrolamellar and 
mixed hepatocellular/cholangiocarcinoma subtypes are not eligible).  
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 disease, or BCLC Stage B disease 
not amenable to locoregional therapy or refractory to locoregional therapy, and not 
amenable to a curative treatment approach (see Section 12.8). 
5. Have a Child-Pugh class A liver score within 7 days of first dose of study drug (see
Section 12.7).
6. Have a predicted life expectancy of >3 months.
7. Have at least one measurable lesion based on RECIST 1.1 as confirmed by the blinded 
central imaging vendor.  
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 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 intolerance to sorafenib.  
Sorafenib intolerance definition:
Any Grade ≥2 drug-related AE which 
1)
despite supportive therapy, recurred after sorafenib treatment 
interruption of at least 7 days and dose reduction, resulting in the 
subject requesting, or the physician recommending, discontinuation 
due to toxicity.  
OR
2)   required discontinuation of sorafenib due to toxicity, recommended by 
the physician with no rechallenge.  
10. Subjects with chronic infection by HCV who are treated (successfully or treatment 
failure) or untreated are allowed on study.  In addition, subjects with successful HCV 
treatment are allowed as long as there are ≥4 weeks between achieving sustained viral 
response (SVR12) and start of study drug.
Successful HCV treatment definition: SVR12.
 
 
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11. Has been treated with anti-Hepatitis B therapy.  
Controlled (treated) hepatitis B subjects will be allowed if they meet the 
following criteria:
Antiviral therapy for HBV must be given for at least 12 weeks and HBV viral 
load must be less than 100 IU/mL prior to first dose of study drug.  Subjects 
on active HBV therapy with viral loads under 100 IU/mL should stay on the 
same therapy throughout study treatment.  
Subjects who are anti-HBc (+), negative for HBsAg, and negative or positive
for anti-HBs, and who have an HBV viral load under 100 IU/mL, do not 
require HBV anti-viral prophylaxis.  
12. 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.  
13. 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.
14. 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.
15. Demonstrate adequate organ function as defined in Table 1.
 
 
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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 >2 mg/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
International normalized ratio (INR) or 
PT
aPTT
≤1.5×ULN unless subject is receiving anticoagulant 
therapy
as long as PT or aPTT is within therapeutic range of 
intended use of anticoagulants
Subject Exclusion Criteria
The subject must be excluded from participating in the trial if the subject:
1. Is currently participating, or has participated, in a study of an investigational agent
and received study therapy, herbal/complementary oral or IV medicine, or used an 
investigation device within 4 weeks of the first dose of treatment. Subjects must also 
have recovered from associated therapy (i.e., to Grade ≤1 or baseline) and from AEs
due to any prior therapy. 
2. Has received sorafenib within 14 days of first dose of study medication.
3. Has had esophageal or gastric variceal bleeding within the last 6 months. All subjects 
will be screened for esophageal varices, unless such screening has been performed in 
the past 12 months before first dose of treatment.  If varices are present, they should 
be treated according to institutional standards before starting study treatment. 
4. Has clinically apparent ascites on physical examination.
Note: ascites detectable on imaging studies only are allowed.
5. Portal vein invasion at the main portal (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 hepatic encephalopathy are not allowed.
7. Had a solid organ or hematologic transplant.
8. Had prior systemic therapy for HCC in the advanced (incurable) setting other than 
sorafenib, 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 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 (i.e., 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 a known psychiatric or substance abuse disorder 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 immunotherapy including anti–PD-1, anti–PD-L1, or anti–PD-L2 
agents, 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).
25. Has dual active HBV infection (HBsAg (+) and /or detectable HBV DNA) and HCV 
infection (anti-HCV Ab (+) and detectable HCV RNA) at study entry.
26. 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.  
Trial Treatment(s)
Study medication to be used in this trial is outlined below in Table 2.  Best supportive care 
(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
Day 1 of each 
21-day cycle
Experimental
Placebo
0.90% w/v 
NaCl
Q3W
IV infusion
Day 1 of each 
21-day cycle
Note:  Both treatment arms will also receive best supportive care. 
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 
 
 
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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
5.2.1.1
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.
5.2.1.2
Dose Interval Modification for Non-Hepatic Drug-Related Adverse Events
Adverse events associated with pembrolizumab exposure may represent an immunologic 
etiology. These immune-related AEs (irAEs) may occur shortly after the first dose or several 
months after the last dose of pembrolizumab treatment, and may affect more than 1 body 
system simultaneously. Therefore, early recognition and initiation of treatment is critical to 
reduce complications.  Based on existing clinical trial data, most irAEs were reversible and 
could be managed with interruptions of pembrolizumab, administration of corticosteroids, 
and/or other supportive care. For suspected irAEs, ensure adequate evaluation to confirm 
etiology or exclude other causes. Additional procedures or tests such as bronchoscopy, 
endoscopy, or skin biopsy may be included as part of the evaluation. Based on the severity 
of irAEs, withhold or permanently discontinue pembrolizumab and administer 
corticosteroids. Dose modification and toxicity management guidelines for non-hepatic 
irAEs associated with pembrolizumab are provided in Table 3. 
 
 
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Table 3
Dose Modification and Toxicity Management Guidelines for Non-hepatic Immune-related AEs Associated with 
Pembrolizumab
Dose modification, diagnosis, and management guidance for hepatic events of clinical interest is provided in Section 5.2.1.3.
General instructions:
1.
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks.
2.
For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and 
corticosteroid has been tapered. Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last dose or 
corticosteroids cannot be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks. 
3.
For severe and life-threatening irAEs, IV corticosteroid should be initiated first, followed by oral steroid. Other immunosuppressive treatment 
should be initiated if irAEs cannot be controlled by corticosteroids.
Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE 
management 
with 
corticosteroid 
and/or 
other 
therapies 
Monitor and follow-up 
Pneumonitis 
Grade 2
Withhold 

Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent), followed by taper

Monitor subjects for signs and symptoms of 
pneumonitis

Evaluate 
subjects
with 
suspected 
pneumonitis with radiographic imaging and 
initiate corticosteroid treatment

Add 
prophylactic 
antibiotics 
for 
opportunistic infections
Grade 3 or 4, or 
recurrent Grade 2
Permanently 
discontinue
Diarrhea / Colitis 
Grade 2 or 3
Withhold

Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent), followed by taper

Monitor subjects for signs and symptoms of 
enterocolitis (i.e., diarrhea, abdominal pain, 
blood or mucus in stool with or without 
fever) 
and 
of 
bowel 
perforation 
(i.e., peritoneal signs and ileus).

Subjects with ≥ Grade 2 diarrhea suspecting 
colitis should consider GI consultation and 
performing endoscopy to rule out colitis. 

Subjects with diarrhea/colitis should be 
advised to drink liberal quantities of clear 
fluids. If sufficient oral fluid intake is not 
feasible, fluid and electrolytes should be 
substituted via IV infusion.
Grade 4
Permanently 
discontinue
 
 
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Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE 
management 
with 
corticosteroid 
and/or 
other 
therapies 
Monitor and follow-up 
Type 1 diabetes 
mellitus (T1DM) 
or 
Hyperglycemia
Newly 
onset 
T1DM or 
Grade 
3 
or 
4 
hyperglycemia 
associated 
with 
evidence of -cell 
failure
Withhold

Initiate 
insulin 
replacement 
therapy for subjects with T1DM 

Administer anti-hyperglycemic in 
subjects with hyperglycemia 

Monitor subjects for hyperglycemia or other 
signs and symptoms of diabetes.
Hypophysitis
Grade 2
Withhold

Administer 
corticosteroids 
and 
initiate hormonal replacements as 
clinically indicated.  

Monitor for signs and symptoms of 
hypophysitis (including hypopituitarism and 
adrenal insufficiency)
Grade 3 or 4 
Withhold 
or 
permanently 
discontinue1
Hyperthyroidism 
Grade 2
Continue 

Treat with non-selective beta-
blockers (e.g., propranolol) or 
thionamides, as appropriate 

Monitor for signs and symptoms of thyroid 
disorders. 
Grade 3 or 4 
Withhold or 
permanently 
discontinue1
Hypothyroidism
Grade 2-4
Continue 

Initiate 
thyroid 
replacement 
hormones (e.g., levothyroxine or 
liothyronine) per standard of care

Monitor for signs and symptoms of thyroid 
disorders. 
Nephritis 
and 
Renal 
dysfunction
Grade 2
Withhold 

Administer 
corticosteroids 
(prednisone 
1-2 
mg/kg 
or 
equivalent), followed by taper.

Monitor changes of renal function
Grade 3 or 4 
Permanently 
discontinue
Myocarditis
Grade 1 or 2
Withhold

Based 
on 
severity 
of 
AE 
administer corticosteroids

Ensure adequate evaluation to confirm 
etiology and/or exclude other causes
Grade 3 or 4
Permanently 
discontinue
All 
other 
immune-related 
Intolerable/ 
persistent Grade 2
Withhold

Based on type and severity of AE 
administer corticosteroids 

Ensure adequate evaluation to confirm 
etiology and/or exclude other causes
 
 
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Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE 
management 
with 
corticosteroid 
and/or 
other 
therapies 
Monitor and follow-up 
AEs
Grade 3
Withhold 
or 
discontinue based 
on the type of 
event. Events that 
require 
discontinuation 
include and are not 
limited 
to:  
Guillain-Barre 
Syndrome, 
encephalitis
Grade 
4 
or 
recurrent Grade 3 
Permanently 
discontinue
1.
Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.  
NOTE: 
For subjects with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may be resumed when 
AE resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM).  
 
 
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Dosing interruptions are permitted in the case of medical/surgical events or for logistical 
reasons not related to study therapy (e.g., elective surgery, unrelated medical events, patient 
vacation, and/or holidays). Subjects should be placed back on study therapy within 3 weeks
of the scheduled interruption, unless otherwise discussed with the Sponsor. The reason for 
interruption should be documented in the subject's study record.
5.2.1.3
Guidance for Diagnosis and Management of Hepatic Events of Clinical Interest
(ECIs)
In addition to overdose, hepatic ECIs will include any of the following events. All of these 
events will require holding study treatment and notification of the Sponsor within 24 hours.
A hepatology consultation may also be considered. Refer to Section 7.2.3.2 for reporting 
guidelines and the definition of hepatic ECIs.
All cases of retreatment and permanent discontinuation must be reported to the Sponsor and 
recorded in the database.
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
c.
Total Bilirubin:
i. Among subjects with baseline  levels <1.5 mg/dL: a value of >2
mg/dL
ii. Among subjects with baseline  levels that are ≥1.5mg/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
 
 
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Immediate assessment
All subjects

All subjects should be considered for evaluation according to the directions 
below within 72 hours of the alert for a non-overdose ECI.

Procedures:
o
Consider obtaining a consultation with a hepatologist
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, total bilirubin (Tbil), direct bilirubin (Dbil), alkaline 
phosphatase (ALP), -glutamyl transpeptidase (GGT), 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
Hepatitis C-Infected Subjects (including subjects who previously achieved SVR 12)

In addition to the above, measure HCV RNA viral load
Hepatitis B-infected Subjects

HBV DNA, HBsAg, HBeAg, anti-HBc (total and IgM), anti-HBe, and anti-
HBs

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 any of the following: 

ALT >20×ULN

CP score of ≥9 points

Gastrointestinal bleeding suggestive of portal hypertension (e.g., esophageal 
or gastric varices)

New onset of clinically detectable ascites

Hepatic encephalopathy 

Recurrence of a severe or life-threatening event, or of any of the laboratory 
abnormalities listed above, that are presumed to be immune-related
 
 
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Diagnosis and Management of Non-Overdose Hepatic ECIs
HCC patients are at risk for a range of complications that can cause hepatic laboratory 
abnormalities with or without clinical decompensation. Those with a history of 
chronic HCV or HBV infection also have the potential to experience virologic flares. 
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 in this 
study. 
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.  
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.

For subjects who have detectable HBV DNA, re-institute anti-viral therapy.

If the subject is clinically stable, study treatment dosing may be interrupted 
for up to 12 weeks. Subjects should undergo weekly laboratory tests 
including: AST, ALT, ALP, Tbil, Dbil, INR, HBsAg, HBV DNA (if detected 
at the onset of the flare). Obtain anti-HBe, anti-HBs, 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 study treatment. If these conditions are not met, 
then study treatment should be permanently discontinued.
b. Hepatitis C Recurrence or Flare
Subjects who achieved SVR12 and subjects with ongoing HCV infection are 
eligible for enrollment. In rare circumstances, HCV subjects who achieve SVR 12
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).
 
 
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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, Tbil, Dbil, and INR weekly

Measure HCV RNA levels every 2 weeks

Therapy with HCV anti-viral treatments should be strongly considered.
ii. HCV Flare:

At the time of first detection of HCV RNA, send a specimen for HCV 
genotyping

Measure AST, ALT, ALP, Tbil, Dbil, INR weekly

Measure HCV RNA levels every 2 weeks

Therapy with HCV anti-viral treatments should be strongly considered.
iii. 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 
study treatment. If these conditions are not met, then study treatment should 
be permanently discontinued.
c.
Immune-related hepatitis 
i. Description: Immune-related hepatitis due to study treatment should be 
suspected if any of the following is seen:

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
 
 
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
AST/ALT >500 U/L regardless of baseline level

Among subjects with baseline Tbil levels <1.5 mg/dL: a value of 
>2.0 mg/dL

Among subjects with baseline Tbil levels that are ≥1.5 mg/dL: a value of 
≥2× the baseline level

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 study treatment and alert the Sponsor as per ECI criteria above 
for ALT, AST, bilirubin, and hepatic decompensation. 

Start IV corticosteroid (methylprednisolone 125 mg or equivalent) 
followed by oral corticosteroid.

Monitor with biweekly laboratory tests including AST, ALT, Tbil, Dbil, 
ALP, and INR.

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 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 Tbil is elevated above baseline, imaging 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. 
 
 
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
For all of these cases, subjects may resume study 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 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.
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.
All trial treatments will be administered on an outpatient basis.
Trial Blinding 
A double-blinding technique with in-house blinding will be used.  Pembrolizumab and 
placebo will be packaged identically by the site pharmacy so that the 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.
 
 
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Stratification
Treatment allocation/randomization will be stratified according to the following factors:
1. Geographic region (Asia without Japan, Non-Asia with Japan)
2. Macrovascular invasion (Yes, No)
3. α-Fetoprotein (ng/mL) (<200, ≥200)
Concomitant Medications/Vaccinations (Allowed & Prohibited)
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for any medication or vaccination 
specifically prohibited during the trial, discontinuation from trial therapy or vaccination may 
be required.  The investigator should discuss any questions regarding this with the Sponsor 
Clinical Director.  The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the subject's primary physician.  However, the decision to continue the 
subject on trial therapy or vaccination schedule requires the mutual agreement of the 
investigator, the Sponsor and the subject.
Acceptable Concomitant Medications
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care. 
All concomitant medication will be recorded on the 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 should be 
included on the CRF.
Palliative and supportive care is permitted during the course of the trial for underlying 
medical conditions and management of symptoms. Surgery for tumor control or symptom 
management is not permitted during the study. Palliative radiotherapy is permitted to a 
single lesion if considered medically necessary by the treating physician as long as the lesion 
is NOT a RECIST 1.1 defined target lesion and is NOT administered for tumor control. Trial 
therapy should be held during the course of palliative radiotherapy and should be resumed no 
earlier than the next scheduled administration of trial therapy. The specifics of the radiation 
treatment, including the location, will be recorded on the CRF.
All medications received within 30 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.
 
 
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Prohibited Concomitant Medications
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-CR relapse) of this trial:

Antineoplastic systemic chemotherapy or biological therapy

Immunotherapy not specified in this protocol

Chemotherapy not specified in this protocol

Investigational agents other than pembrolizumab

Radiation therapy for tumor control.
o
Note: Radiation for pain or palliation is acceptable (see Section 5.5.1).

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, bacille 
Calmette-Guerin (BCG) vaccine, and typhoid (oral) vaccine. The killed virus 
vaccines used as 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 suspected of having an 
immunologic etiology. 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.
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.
 
 
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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
Herbal Supplements/Alternative Medicines

No herbal supplements or alternative medicines are allowed during the Screening and 
Treatment Phase of this trial.
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
Rescue Medications
No rescue 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 in 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 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. Refer to Section 5.2.1 for dose modification. 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event. 
Guidance for the diagnosis and management of hepatic events of clinical interest is in 
Section 5.2.1.3.
 
 
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Signs and symptoms of infusion reactions usually develop during or shortly after drug 
infusion and generally resolve completely within 24 hours of completion of infusion.
Table 4 shows treatment guidelines for subjects who experience an infusion reaction 
associated with study drug administration.
 
 
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Table 4
Infusion Reaction Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at subsequent 
dosing
Grade 1
Mild reaction; infusion 
interruption 
not 
indicated; 
intervention 
not indicated
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator.
None
Grade 2
Requires 
infusion 
interruption but responds 
promptly to symptomatic 
treatment 
(e.g., 
antihistamines, NSAIDS, 
narcotics, 
IV 
fluids); 
prophylactic medications 
indicated for ≤24 hours
Stop Infusion and monitor symptoms.
Additional appropriate medical therapy may 
include but is not limited to:
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator.
If symptoms resolve within one hour of 
stopping drug infusion, the infusion may be 
restarted at 50% of the original infusion 
rate. Otherwise dosing will be held until 
symptoms resolve and the subject should be 
premedicated for the next scheduled dose.
Subjects who develop Grade 2 toxicity 
despite adequate premedication should 
be 
permanently 
discontinued 
from 
further trial treatment administration.
Subject may be premedicated 
1.5 h 
(±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 antipyretic).
Grades 3 or 4
Grade 3:
Prolonged 
(i.e., 
not 
rapidly 
responsive 
to 
symptomatic medication 
and/or brief interruption 
of infusion); recurrence 
of symptoms following 
initial 
improvement; 
hospitalization indicated 
for 
other 
clinical 
sequelae 
(e.g., 
renal 
impairment, pulmonary 
infiltrates)
Grade 4:
Life-threatening; pressor 
or ventilatory support 
indicated
Stop Infusion.
Additional appropriate medical therapy may 
include but is not limited to:
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Epinephrine
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator.
Hospitalization may be indicated.
Subject is permanently discontinued 
from 
further 
trial 
treatment 
administration.
No subsequent dosing
Appropriate resuscitation equipment should be available in the room and a physician readily available 
during the period of drug administration.
 
 
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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 are either: 
(1) postmenopausal (defined as at least 12 months with no menses without an alternative 
medical cause; in women <45 years of age a high follicle-stimulating hormone [FSH]
level in the postmenopausal range may be used to confirm a post-menopausal state in 
women not using hormonal contraception or hormonal replacement therapy. In the 
absence of 12 months of amenorrhea, a single FSH measurement is insufficient); 
OR
(2) have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy, or 
bilateral tubal ligation/occlusion at least 6 weeks prior to screening ; 
OR
(3) 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, 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 drug by complying with one of the following:
(1) practice abstinence† from heterosexual activity; 
OR
(2) use (or have their partner use) acceptable contraception during heterosexual activity.
 
 
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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
†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 ERCs/IRBs. Periodic abstinence 
(e.g., calendar, ovulation, sympto-thermal, post-ovulation methods, etc.) and withdrawal are 
not acceptable methods of contraception. 
‡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) starting with the first dose of study medication (or 14 days prior to the 
initiation of study medication for oral contraception) through at least 120 days or longer 
based on local regulation, after the last dose of trial therapy. 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.
 
 
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For countries or sites that follow the Clinical Trial Facilitation Group guidance, please 
use the following:
Pembrolizumab may have adverse effects on a fetus in utero. Furthermore, it is not known if 
these therapies have transient adverse effects on the composition of sperm. Therefore, non-
pregnant, non-breastfeeding women may only be enrolled if they are willing to follow the 
Clinical Trial Facilitation Group (CTFG) Guidance (Final Version 2014-09-15, Sections 4.1 
and 4.2) for highly effective birth control as outlined below, or are considered to be highly 
unlikely to conceive. Highly unlikely to conceive is defined as 1) surgically sterilized, or 2) 
postmenopausal (defined as at least 12 months with no menses without an alternative medical 
cause; in women <45 years of age a high follicle-stimulating hormone [FSH] level in the 
postmenopausal range may be used to confirm a post-menopausal state in women not using 
hormonal contraception or hormonal replacement therapy. In the absence of 12 months of 
amenorrhea, a single FSH measurement is insufficient), or 3) not heterosexually active for 
the duration of the study. Subjects should use birth control methods that can achieve a
failure rate of less than 1% per year when used consistently and correctly and are considered 
as highly effective birth control methods. Such methods include:

Combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation:
o
Oral
o
Intravaginal
o
Transdermal

Progestogen-only hormonal contraception associated with inhibition of ovulation:
o
Oral
o
Injectable
o
Implantable

IUD

Intrauterine hormone-releasing system (IUS)

Bilateral tubal occlusion

Vasectomized partner

Sexual abstinence
Subjects should be using birth control 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.
Subjects should be informed that taking the study medication may involve unknown risks to
the fetus (unborn baby) if pregnancy were to occur during the study. In order to participate
in the study they must adhere to the contraception requirement (described above) for the
duration of the study and during the follow-up period defined in Section 7.2.2 – Reporting of
Pregnancy and Lactation to the Sponsor.
If there is any question that a subject will not
reliably comply with the requirements for contraception, that subject should not be entered
into the study.
 
 
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Use in Pregnancy
If a subject inadvertently becomes pregnant while on study treatment, the subject will 
immediately be removed from the study 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 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 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
The subject or legal representative (such as a parent or legal guardian) withdraws consent 
for treatment
o
Unacceptable adverse events as described in Section 7.2.
 
 
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o
Intercurrent illness that prevents further administration of treatment
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
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.
o
Confirmed radiographic disease progression outlined in Section 7.1.4 (exception if the 
Sponsor approves treatment continuation).
o
Any progression or recurrence of any malignancy, or any occurrence of another 
malignancy that requires active treatment
o
Recurrent Grade 2 pneumonitis
5.8.1.1
Discontinuation from Study Therapy after Complete Response
Discontinuation of treatment may be considered for subjects who have attained a centrally 
confirmed CR that have received at least 8 study treatments (approximately 6 months) and 
had at least 2 treatments beyond the date when the initial CR was declared. Subjects who 
stop treatment then experience radiographic PD may be eligible for up to 17 additional 
treatments (approximately 1 year) with the initial study treatment in the Second Course 
Phase at the discretion of the investigator if:
o
No cancer treatment was administered since the last dose of study drug
o
The subject meets the parameters listed in the Inclusion/Exclusion criteria
o
The trial is ongoing
Subjects will resume therapy at the same treatment and schedule as at the time of initial 
discontinuation. Additional details are provided in Section 7.1.6.2. Response or progression 
in this Second Course Phase will not count towards the primary endpoint in this trial.
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 trial treatment or be 
followed at scheduled protocol visits.
 
 
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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 trial site is unable to contact the subject, as well as specific 
details regarding withdrawal from Future Biomedical Research are outlined in Section 5.8 –
Subject Withdrawal/Discontinuation.
Lost to Follow Up
If a subject fails to return to the clinic for a required trial 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.

The investigator or designee must make every effort to regain contact with the subject 
at each missed visit (eg, phone calls and/or a certified letter to the subject’s last 
known mailing address or locally equivalent methods). These contact attempts should 
be documented in the subject’s medical record.

Note:  A subject is not considered lost to follow-up until the last scheduled visit for 
the individual subject.  The missing data for the subject will be managed via the pre-
specified statistical data handling and analysis guidelines.
Beginning and End of the Trial
The overall trial begins when the first subject signs the informed consent form.  The overall 
trial ends when the last subject completes the last study-related phone-call or visit,
discontinues from the trial or is lost to follow-up (i.e. the subject is unable to be contacted by 
the investigator).
Clinical Criteria for Early Trial Termination
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 
Treat-
ment
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
12 Weeks Post
Discon
Approx. 
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 (including smoking 
and alcohol use)
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
X
 
 
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Trial Period:
Screening 
Phase
Treatment Cycles (3-Week Cycles)
End of 
Treat-
ment
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
12 Weeks Post
Discon
Approx. 
Every 12 
Weeks
Scheduling Window (Days) b
-28 to -1
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±7
Directed physical examination
X
X
X
X
X
X
X
X
Child-Pugh Score d
X e
Height, weight, and vital signs 
(T, P, RR, BP) f
X
X
X
X
X
X
X
X
X
X
12-Lead electrocardiogram
X
Upper endoscopy
X g
ECOG performance status
X e
X
X
X
X
X
X
X
X
X
EQ-5D, EORTC QLQ-C30, 
EORTC QLQ-HCC18 h
X
X
X
X
X
X
Xg
X
X
Pembrolizumab/placebo 
administration
X b
X
X
X
X
X
X
X
LOCAL Laboratory 
Assessments
Pregnancy test i
X
X j
X
X
X
X
X
X
X
X
X
PT/INR and aPTTy
X e,y
X
X
X
X
X
X
X
X
X
CBC with differential k
X e
X
X
X
X
X
X
X
X
X
Chemistry panel and liver 
panel k
X e
X
X
X
X
X
X
X
X
X
Urinalysis l
X e
X
X
X
X
X
T3, FT4, and TSH l, m
X e
X
X
X
X
X
X
AFP m, n
X
X
X
X
X
X
X
X
X
X
 
 
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Trial Period:
Screening 
Phase
Treatment Cycles (3-Week Cycles)
End of 
Treat-
ment
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
12 Weeks Post
Discon
Approx. 
Every 12 
Weeks
Scheduling Window (Days) b
-28 to -1
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±7
C-Reactive protein m, o
X
X
X
X
CENTRAL Laboratory 
Assessments
Pembrolizumab 
pharmacokinetics r, s
X
X
X
X
X
X
Pembrolizumab anti-drug 
antibodies r
X
X
X
X
X
X
Anti-HCV 
X
If Anti-HCV positive:
HCV genotype p
X
HCV viral load q
X
X
X
X
X
X
X
X
X
X
Anti-HBc (total and IgM), 
anti-HBs, HBV viral load, 
HBsAg
X
If (1) HBsAg+ or (2) anti-
HBc+, 
anti-HBs-, HBsAg- and 
viral load <100 IU/mL:
Anti-HDV p
X
Anti-HBe and HBeAg
X
HBsAg, and HBV viral 
load q
X
X
X
X
X
X
X
X
X
 
 
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Trial Period:
Screening 
Phase
Treatment Cycles (3-Week Cycles)
End of 
Treat-
ment
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
12 Weeks Post
Discon
Approx. 
Every 12 
Weeks
Scheduling Window (Days) b
-28 to -1
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±7
Anti-HBc (total), anti-HBe, 
anti-HBs, and HBeAg q
X
X
X
Blood for genetic analyses t
X
Blood for biomarker studies 
(serum and plasma) o
X
X
X
X
Blood for ctDNA (plasma) o
X
Blood for RNA Analysis o
X
X
X
X
Tumor tissue for biomarker 
analysis u
X
Efficacy Measurements
Tumor imaging
X v
X w
X x
X
a.
In subjects who experience PD or start a new anti-cancer therapy, contact should be made (by telephone or visit) approximately every 12 weeks to assess for survival status.  
Updated survival status may be requested by the Sponsor at any time during the course of the study.  Upon Sponsor notification, all subjects who do not/will not have a 
scheduled study visit or study contact during the Sponsor-defined time period will be contacted for their survival status (excluding subjects who 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.
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.
Height will be measured at Visit 1 only. 
g.
Upper endoscopy to be performed at any time within 12 months before the first dose of study drug.
h.
See Section 4.2.4.3 for details regarding administration of Patient Reported Outcomes (PROs).  All PROs are to be performed at Cycle 1, Cycle 2, Cycle 3, Cycle 4, 
 
 
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Trial Period:
Screening 
Phase
Treatment Cycles (3-Week Cycles)
End of 
Treat-
ment
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
12 Weeks Post
Discon
Approx. 
Every 12 
Weeks
Scheduling Window (Days) b
-28 to -1
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±7
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. 
i.
For women of reproductive potential, a urine or serum pregnancy test should be performed within 72 hours prior to day 1 of each treatment cycle and 30 days post 
treatment.   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. 
j.
Not necessary if screening evaluation performed within 72 hours.  
k.
CBC with differential, chemistry panel, and liver panel to be performed every cycle.  Liver panel to include albumin, ALT, AST, total bilirubin, alkaline phosphatase, 
direct bilirubin, GGT, and total protein. 
l.
While on treatment, UA and thyroid function tests will be performed every other cycle. 
m.
At Cycle 1, subjects may be dosed even if CRP evaluation is not available prior to dosing. After Cycle 1, subject will be dosed even if AFP, thyroid, and CRP evaluations 
are not available prior to dosing; however, the results must be available and reviewed before the next scheduled visit.
n.
AFP will be measured every 3 weeks (21±7 days) calculated from the date of randomization, or earlier if clinically indicated.
o.
Whole blood samples for serum, plasma, and RNA should be collected pre-dose at Cycle 1, Cycle 2, Cycle 5, and again at discontinuation or progression of disease. 
Plasma for ctDNA should be collected pre-dose at Cycle 1.  These samples can be taken up to 72 hours prior to dosing. 
p.
Subject may be randomized if results are pending and the subject meets all other eligibility criteria. 
q.
At screening, subjects must have results within 28 days of first dose; at each subsequent visit, the values must be evaluated before the next visit (3 weeks later).  HBsAg, 
HBV viral load, and HCV viral load are to be performed every 3 weeks during treatment, or earlier if clinically indicated. Anti-HBc (total), anti-HBe, anti-HBs, and 
HBeAg are to be performed every 12 weeks during treatment, or earlier if clinically indicated. Additional tests to be performed for ECIs are described in Section 5.2.1.3.  If 
the viral load results are not reported in IU/mL, the site should provide the conversion factor specific for the assay method used to convert the assay units of measure to 
IU/mL.  For HBsAg, quantitative and/or qualitative results are submitted.
r.
Both PK and anti-pembrolizumab antibody samples:  pre-dose (trough) PK and anti-pembrolizumab antibody samples will be collected within 24 hours before infusion at 
Cycles 1, 2, 4, 6, 8 and every 4 cycles thereafter, 30 days after discontinuation of study drug (or until the subject starts new anti-cancer therapy).
s.
PK Samples:  additional post-dose (peak) PK samples will be drawn within 30 minutes after end of study treatment infusion at Cycles 1 and 8.  Additional PK samples 
should be drawn at 24 hours (Day 2), between 72 and 168 hours (Days 4–8), and 336 hours (Day 15) after Cycle 1 dosing. 
t.
Details for collection of blood for genetic testing can be found in Section 7.1.3.6 Planned Genetic Analysis Sample Collection.
u.
Tissue is not required for enrollment, but is strongly encouraged to be submitted if available.  Newly obtained tissue is preferred (after sorafenib treatment); formalin-fixed, 
paraffin-embedded block specimens are preferred to slides.  Leftover tumor tissue will be stored for future biomedical research if the subject signs the FBR consent.
v.
Screening tumor imaging will be performed within 21 days prior to randomization.  Confirmation of baseline measurable disease per RECIST 1.1 by the central imaging 
vendor is required prior to subject randomization. Imaging at screening should include the chest, abdomen, and pelvis, as detailed in the Site Imaging Manual.  
w.
The first on-study imaging time point will be performed at 6 weeks calculated from the date of randomization and will continue to be performed Q6W (42±7 days), or 
 
 
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Trial Period:
Screening 
Phase
Treatment Cycles (3-Week Cycles)
End of 
Treat-
ment
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
12 Weeks Post
Discon
Approx. 
Every 12 
Weeks
Scheduling Window (Days) b
-28 to -1
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±7
earlier if clinically indicated.  Imaging details can be found in the Site Imaging Manual.
x.
In subjects who discontinue study therapy without confirmed PD by the site per irRECIST, tumor imaging should be performed at the time of treatment discontinuation.  If 
previous tumor imaging was obtained within 4 weeks prior to the date of discontinuation, then additional tumor imaging at treatment discontinuation is not required.
y.
Activated partial prothrombin time is to be assessed at screening 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-
up a
At Time of 
Discon
30 Days 
Post-Discon
Every 12 
Weeks Post-
Discon
Approx. 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 c
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
Child-Pugh Score d
X e
Weight, and vital signs (T, P,
RR, BP)
X
X
X
X
X
X
X
X
X
ECOG performance status e
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 test f
X
X
X
X
X
X
X
X
X
X
PT/INR and aPTTm
X e,m
X
X
X
X
X
X
X
X
X
CBC with differential g
X e
X
X
X
X
X
X
X
X
X
Chemistry and liver panels g
X e
X
X
X
X
X
X
X
X
X
Urinalysis g
X e
X
X
X
X
X
T3, FT4, and TSH g, h
X e
X
X
X
X
X
X
AFP h
X e
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-
up a
At Time of 
Discon
30 Days 
Post-Discon
Every 12 
Weeks Post-
Discon
Approx. Every 
12 Weeks
CENTRAL Laboratory 
Assessments
Anti-HCV i
X
If Anti-HCV positive:
HCV viral load j
X
X
X
X
X
X
X
X
X
HCV genotype
X
If (1) HBsAg+ or (2) anti-
HBc+, anti-HBs-, HBsAg-
and 
viral load <100 IU/mL:
HBsAg and HBV viral load j
X
X
X
X
X
X
X
X
X
Anti-HBc (total), anti-HBe, 
anti-HBs, and HBeAg j
X
X
X
Efficacy Measurements
Tumor imaging
X k
X k
X l
X
a.
In subjects that experience site assessed PD or starts a new anti-cancer therapy contact should be made (by telephone or visit) approximately every 12 weeks to assess for 
survival status.  Updated survival status may be requested by the Sponsor at any time during the course of the study.  Upon Sponsor notification, all subjects who do 
not/will not have a scheduled study visit or study contact during the Sponsor-defined time period will be contacted for their survival status (excluding subjects who 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.
If any of the hepatic ECI criteria are met, collect the Child Pugh score until the hepatic ECIs resolve. 
e.
Laboratory and ECOG tests for determining eligibility are to be performed within 7 days prior to the first retreatment dose of study drug.
f.
For women of reproductive potential, a urine or serum pregnancy test should be performed within 72 hours prior to day 1 of each treatment cycle and 30 days post 
treatment  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. 
g.
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, GGT, direct bilirubin, and total protein.
h.
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.
i.
If anti-HCV was negative prior to retreatment in the Second Course Phase, anti-HCV must be performed.
j.
At each visit, the values must be evaluated before the next visit (3 weeks later).  HBsAg, HBV viral load, and HCV viral load are to be performed every 3 weeks during 
 
 
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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-
up a
At Time of 
Discon
30 Days 
Post-Discon
Every 12 
Weeks Post-
Discon
Approx. Every 
12 Weeks
treatment, or earlier if clinically indicated.  Anti-HBc (total), anti-HBe, and anti-HBs, and HBeAg are to be performed every 12 weeks during treatment, or earlier if 
clinically indicated.  Additional tests to be performed for ECIs are described in Section 5.2.1.3.  If the viral load results are not reported in IU/mL, the site should provide 
the conversion factor specific for the assay method used to convert the assay units of measure to IU/mL.  For HBsAg, quantitative and/or qualitative results can be 
submitted.
k.
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.  
l.
Tumor imaging should be performed at the time of treatment discontinuation.  If previous tumor imaging was obtained within 4 weeks prior to the date of discontinuation, 
then additional tumor imaging at treatment discontinuation is not mandatory. 
m.
Activated partial prothrombin time is to be assessed at screening only.
 
 
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7.0 TRIAL PROCEDURES
Trial Procedures
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to 
perform these procedures at unscheduled time points if deemed clinically necessary by the 
investigator.
Furthermore, additional evaluations/testing may be deemed necessary by the investigator and 
or the Sponsor for reasons related to subject safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations 
may require that additional informed consent be obtained from the subject.  In these cases, 
such evaluations/testing will be performed in accordance with those regulations.
Administrative Procedures
7.1.1.1
Informed Consent
The investigator or qualified designee must obtain documented consent from each potential 
subject or each subject’s legally acceptable representative prior to participating in a clinical 
trial or Future Biomedical Research. 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.
7.1.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.
7.1.1.3
Subject Identification Card
All subjects will be given a Subject Identification Card identifying them as participants in a 
research trial. The card will contain trial site contact information (including direct telephone 
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.
7.1.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee.  Medical history 
will include smoking and alcohol use, all active conditions, and any condition diagnosed 
within the prior 10 years that is considered to be clinically 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 15 lbs. (6.8 kg) over the 3 months prior to screening, “weight 
loss” should be entered as an active condition on the medical history.  Any autoimmune 
disorders, regardless of onset date, should be recorded.  
7.1.1.5
Disease Details
The investigator or qualified designee will obtain prior and current details regarding the 
subject’s HCC.  
7.1.1.6
Prior and Concomitant Medications Review
7.1.1.6.1 Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject 
within 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 
 
 
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as a prior medication.  In addition, for all subjects with a history of hepatitis B or hepatitis C, 
information on past and /or present anti-viral treatment will be collected.
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.
7.1.1.6.2 Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial from the time of signing the informed consent 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.  
7.1.1.7
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.  
7.1.1.8
Assignment of Screening Number
All consented subjects will be given a unique screening number that will be used to identify 
the subject for all procedures that occur prior to randomization or treatment allocation.  Each 
subject will be assigned only one screening number.  Screening numbers must not be re-used 
for different subjects.
Any subject who is screened multiple times will retain the original screening number 
assigned at the initial screening visit.
Specific details on the screening visit requirements (screening/rescreening) are provided in 
Section 7.1.6.1.  
7.1.1.9
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.
 
 
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7.1.1.10 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.  
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 treatment will be witnessed by the investigator and/or trial staff or 
qualified designee per institutional guidelines and procedures.  
Clinical Procedures/Assessments
7.1.2.1
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 5.6.2.
Please refer to Section 7.2 for detailed information regarding the assessment and recording of 
AEs.
7.1.2.2
Physical Exam
7.1.2.2.1 Full Physical Exam
The investigator or 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.  
 
 
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7.1.2.3
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.  
Vital signs should include temperature, pulse, respiratory rate, blood pressure, height, and 
weight.  
7.1.2.4
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.
7.1.2.5
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.  
7.1.2.6
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., Tbil 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).
7.1.2.7
Patient Reported Outcomes (PROs)
It is strongly recommended that PROs are administered prior to drug administration, adverse 
event evaluation, and disease status notification starting with the EQ-5D, followed by 
EORTC QLQ-C30 and EORTC QLQ-HCC18; 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.  
If, at the time of first dose of study treatment, the translated version of the HCC18—one of 
the PRO measures—is not available for that language/country, and it cannot be completed by 
the subject at Cycle 1, Day 1, then the HCC18 will not be required for this subject at any 
point of the study. The other study PRO measures must be completed as scheduled. Note: 
for some sites, the translated HCC18 might become available after study startup and should 
be administered to subjects at their time of first dose of study treatment; for some sites the 
HCC18 translation might not be available for the entire duration of the study.
 
 
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Laboratory Procedures/Assessments
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below. The total amount of blood/tissue to be drawn/collected over the course of 
the trial (from pre-trial to post-trial visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per subject can be found in the Laboratory
Procedures Manual.  Refer to the Trial Flow Chart - Section 6 for the schedule of laboratory 
assessments.
7.1.3.1
Laboratory Safety Evaluations (Hematology, Chemistry, and Urinalysis)
Laboratory tests for hematology, chemistry and urinalysis are specified in Table 5.
Table 5
Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Hematocrit
Albumin
Blood
Pregnancy test (serum or 
urine)a
Hemoglobin
Alkaline phosphatase
Glucose
PT/INR
Platelet count
Alanine aminotransferase
Protein
aPTTb
WBC (total and 
differential)c
Aspartate aminotransferase
Specific gravity 
Total T3 or free T3, FT4, 
and TSHd,e
RBC
Bicarbonatef
Microscopic 
exam, 
if 
abnormal 
results 
are 
noted
Anti-HCVg
Absolute 
lymphocyte countc
Calcium
HCV viral loadg
Chloride
HCV genotypeg
Absolute 
neutrophil countc
Creatinine
anti-HBsg
Glucose
Phosphorus
HBsAgg
Potassium
Anti-HBc (total and IgM)g
Sodium
HBeAgg
Total bilirubin  
anti-HBeg
Direct bilirubin
HBV viral loadg
Total protein
Anti-HDVg
AFP e
CRP e
Blood urea nitrogen
GGT
a
Perform on women of childbearing potential 72 hours prior to Day 1 of Cycle 1.  Pregnancy tests must be repeated 
prior to every cycle if required or as specified per local regulatory guidance.
b.
Activated partial thromboplastin time is to be assessed at screening only.
c.
Report % or absolute results per standard of practice. Report the results in the same manner throughout the study.
d.
T3 is preferred; if not available free T3 may be tested.
e.
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 Laboratory Procedure Manual.
f.   If this test is not done as part of local standard of care, this test does not need to be performed. 
g.  All hepatitis tests (including HBsAg) will be done centrally. 
 
 
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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 test, which may be performed 
within 28 days prior to first dose.
Subjects eligible for study retreatment should have 
imaging performed within 21 days and 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.  
7.1.3.2
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 of each cycle of 
trial treatment and 30 days post treatment.  If a urine test is positive or not evaluable a serum 
test will be required.  Subjects must be excluded/discontinued from the study in the event of 
a positive or borderline-positive test result.  
7.1.3.3
Central Laboratory Assessments
Sample collection timing, storage and shipment instructions for the central laboratory 
assessments will be provided in the Laboratory Manual.  
7.1.3.4
Pharmacokinetic (PK) /Pharmacodynamic Evaluations
To evaluate the immunogenicity of and exposure to pembrolizumab in this indication, 
sample collections for analysis of anti-pembrolizumab antibodies (ADA) and PK are 
currently planned as shown in Section 6.1 . Blood samples collected for PK and ADA may be 
stored. Analysis will be performed only if required. If ongoing PK and/or ADA sampling is 
deemed unnecessary by the Sponsor, it may be reduced or discontinued. 
7.1.3.4.1 Blood Collection for PK
Sample collection, storage and shipment instructions for serum samples will be provided in 
the procedure manual.  PK samples should be drawn according to the PK collection schedule 
for all subjects.  Every effort should be taken to collect samples at 30 days after end of study
treatment.  
7.1.3.4.2 Blood Collection for Anti-pembrolizumab Antibodies 
Sample collection, storage and shipment instructions for serum samples will be provided in 
the procedure manual. Anti- pembrolizumab antibody samples should be drawn according to 
the ADA collection schedule for all subjects (Section 6.1).  Every effort should be taken to 
collect samples at 30 days after end of study treatment for ADA.  Simultaneous PK sampling 
is required for interpretation of ADA analysis. 
 
 
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7.1.3.5
Blood Samples for RNA Analysis, and Biomarker Studies  
Information about sample collection, storage and shipment for blood, plasma, and serum is 
provided in the Laboratory Procedure Manual.  Any leftover samples from the RNA analysis 
and biomarker studies will be stored for future biomedical research if the subject signs the 
FBR consent.  
7.1.3.6
Tumor Tissue
Supplying tumor tissue for biomarker analysis is strongly encouraged but is not required for 
study enrollment.  Biopsies should not be performed for the sole purpose of biomarker 
analysis for this protocol.  Newly obtained tissue is preferred (after sorafenib treatment) to an 
older archival sample if available.  Formalin-fixed, paraffin-embedded (FFPE) block
specimens are preferred to slides. If only slides can be sent, they should be sent within 
7 days of cutting from the block. If the subject signs the FBR consent, any leftover tissue 
that would ordinarily be discarded at the end of the main study will be retained for FBR.  
Detailed instructions for tissue collection, processing and shipment are provided in the 
Procedures Manual.  
7.1.3.7
Planned Genetic Analysis Sample Collection
Sample collection, storage and shipment instructions for Planned Genetic Analysis samples 
will be provided in the Laboratory Procedures Manual. This sample should be drawn for 
planned analysis of the association between genetic variants in DNA and drug response. If 
there is either a documented law or regulation prohibiting collection, or if the IRB/IEC does 
not approve the collection of the sample for these purposes, then this sample will not be 
collected at that site. If the sample is collected, leftover extracted DNA will be stored for 
future biomedical research if the subject signs the FBR consent. If the planned genetic 
analysis is not approved, but FBR is approved and consent is given, this sample will be 
collected for the purpose of FBR.
7.1.3.8
Future Biomedical Research Sample Collection
The following specimens are to be obtained as part of Future Biomedical Research:
• DNA for future research.
•  Leftover tumor for future research
•  Leftover RNA 
•  Leftover plasma and serum from biomarker studies
 
 
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Efficacy Measurements
7.1.4.1
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, strongly preferred).  Magnetic resonance imaging (MRI) should 
be used when CT is contraindicated or for imaging in the brain.  However, when MRI is the 
standard of care at a site, MRI may be used whether or not CT is contraindicated. 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.
Expedited confirmation of measurable disease based on RECIST 1.1 by the blinded central 
imaging vendor at screening will be used to determine subject eligibility. Confirmation of 
measurable disease by the central imaging vendor 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.
7.1.4.1.1 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.  Prior to randomization, the screening images must be 
submitted to the blinded central imaging vendor for review of 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 central imaging vendor.
7.1.4.1.2 Tumor Imaging During the Trial
The first on-study imaging assessment should be performed at 6 weeks (42±7 days) from the 
date of randomization.  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 the blinded central imaging vendor (unless site 
principal investigator [PI] elects to continue treatment and follow irRECIST), the start of new 
anti-cancer treatment, withdrawal of consent, death, or notification by the Sponsor, 
 
 
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whichever occurs first.  All supplemental imaging must be submitted to the central imaging 
vendor.  
Per RECIST 1.1 partial response (PR) and 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 7.1.4.1.7), disease progression on subjects treated with trial treatment
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 7.1.4.1.7. Subjects who obtain a confirmation scan do not need to undergo the next 
scheduled tumor imaging if it is <4 weeks later; tumor imaging may resume at the 
subsequent scheduled imaging time point if clinically stable. Subjects who have confirmed 
disease progression as assessed by the site will discontinue the treatment. Exceptions are 
detailed in Section 7.1.4.1.7. 
7.1.4.1.3 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. 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 12 weeks (84±7 days) to monitor 
disease status until (1) the start of new anti-cancer treatment, (2) disease progression, (3) 
death, or (4) the end of the study, whichever occurs first.
7.1.4.1.4 Second Course (Retreatment) Tumor Imaging
A scan must be performed within 21 days prior to restarting study treatment.  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.
The first on-study imaging assessment should be performed 6 weeks (42±7 days) after the 
restart of treatment. 
Subsequent tumor imaging should be performed every 6 weeks 
(42±7 days) or more frequently if clinically indicated.  
Per irRECIST 1.1 (Section 7.1.4.1.7), if tumor imaging shows initial PD, 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 
 
 
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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 if clinically stable.
Imaging should continue to be performed until disease progression, the start of new 
anti-cancer 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 progressive disease in clinically stable subjects.
In subjects who discontinue trial treatment, tumor imaging should be performed at the time
of treatment discontinuation. 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  
12 weeks (84±7 days) until the start of new anti-cancer treatment, disease progression, death, 
or the end of the study, whichever occurs first.  
7.1.4.1.5 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.
7.1.4.1.6 Modified RECIST (mRECIST) Assessment of Disease
Modified RECIST for HCC allows evaluation of treatment effects that are not reflected in 
simple total size changes of lesions.  RECIST 1.1 by the blinded central imaging vendor will 
still be the primary measure of the tumor response.
Details are fully described in [46]. 
Extrahepatic lesion assessment, as well as response categories and definitions, are identical to 
RECIST 1.1. Key differences from RECIST 1.1 include:

Lesions within the liver parenchyma are measured so as to include only the portion 
showing increased contrast enhancement in the arterial phase.

New lesions in the liver must meet one of the following conditions to be considered 
indicators of progression:
o
At least 10 mm in longest diameter, and showing typical HCC enhancement 
(enhancement during the arterial phase and washout during the portal venous 
phase)
o
At least 10 mm in longest diameter with atypical enhancement, but showing at 
least 10 mm of growth on a subsequent scan
 
 
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o
Porta hepatis lymph nodes should never be selected as target lesions, and 
should only be followed as non-target lesions if their short axis measurement at 
screening is ≥20 mm.
7.1.4.1.7 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 the blinded central imaging vendor review 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 PD takes into account the observation that some subjects can have a 
transient tumor flare in the first few months after the start of immunotherapy, and then 
experience subsequent disease response. Subjects that are deemed clinically unstable are not 
required to have repeat tumor imaging for confirmation of PD. Tumor flare includes any of 
the following scenarios:

Worsening of existing target lesion(s)

Worsening of existing 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.
 
 
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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.
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.
If repeat imaging confirms PD due to any of the scenarios listed above, subjects will be 
discontinued from study therapy.
NOTE: If a subject has confirmed radiographic progression (i.e., 2 scans at least 4 weeks 
apart demonstrating progressive disease [first PD also verified by the central imaging 
vendor]) 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 Sections 6.1 and 6.2; consultation with the Sponsor is also necessary 
after each subsequent site assessment of irPD for treatment to be continued.  All images must 
be submitted to the blinded central imaging vendor.
Additional details about irRECIST are referenced in the 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
blinded
central 
imaging vendor
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
 
 
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Figure 2
Imaging and Treatment for Clinically Stable Subjects after First Radiologic 
Evidence of Progressive Disease Assessed by Site
Other Procedures
7.1.5.1
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 
 
 
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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.
7.1.5.2
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 participant’s treatment assignment, the 
investigator or delegate should make reasonable attempts to enter the intensity/toxicity grade 
of the AEs observed, the relation to study drug, the reason thereof, etc., in the medical chart. 
If it is not possible to record this assessment in the chart prior to the unblinding, the 
unblinding should not be delayed.
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 
 
 
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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.
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 subject.
Adverse event information should be entered in the participant’s chart, if possible, before the 
investigator or delegate contacts the emergency unblinding call center to request unblinding 
of a participant’s treatment assignment.  Unblinding should not be delayed if this information 
cannot be recorded in the chart before unblinding takes place.
At the end of the trial, unblinding logs are to be returned to the Sponsor or designee.
7.1.5.3
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical trial that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained is reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
trial site.
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.
7.1.6.1
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.
Results from assessments performed during the initial screening period are acceptable in lieu 
of repeat screening test if performed within the specified time frame and the 
inclusion/exclusion criteria is met. Subjects who are rescreened will retain their original 
screening number. 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.
 
 
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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 performance status (PS) are to be performed within 7 days 
prior to the first dose of trial treatment. An exception is hepatitis testing which may be 
done up to 28 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.
7.1.6.2
Treatment Period
Visit requirements are outlined in the Trial Flow Chart (Section 6.0). Specific procedure-
related details are provided above in 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

Was treated with at least 8 trial treatments (approximately 6 months) 
before discontinuing therapy

Received at least two study treatments beyond the date when the initial 
CR was declared
OR
o
Had stable disease (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).
 
 
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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 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.
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).
7.1.6.3
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 treatment or before initiation of a new anti-cancer treatment 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 Q12W by radiologic imaging to monitor 
disease status. Every effort should be made to collect information regarding disease status 
until the start of a new anti-cancer therapy, disease progression, death, or the end of the 
study. 
 
 
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Information regarding post-study anti-cancer treatment will be collected if new treatment is 
initiated.
Subjects who are eligible to receive retreatment according to the criteria in Section 7.1.4.1.4
will move from the Follow-up Phase to the Second Course Phase when they experience 
disease progression.
7.1.6.3.3 Survival Follow-up
Subjects, who experience disease progression (by site assessment) or start a new anti-cancer 
therapy, will move into the Survival Follow-Up Phase. Subjects should be contacted (by 
telephone or visit) approximately every 12 weeks to assess for survival status until death, 
withdrawal of consent, or the end of the study, whichever occurs first. Post-study anti-cancer 
therapy will be collected during survival follow-up.
7.1.6.4
Survival Status
To ensure current and complete survival data are available at the time of database locks, 
updated survival data may be requested during the course of the trial by the Sponsor. For 
example, updated survival status may be requested prior to but not limited to an external Data 
Monitoring Committee eDMC review, interim, and/or final analysis. Upon Sponsor 
notification, all subjects who do not/will not have a scheduled study visit or study contact 
during the Sponsor-defined time period will be contacted for their survival status (excluding 
subjects who 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.
 
 
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All adverse events that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure. From the time of treatment allocation/randomization through 30 days following 
cessation of treatment, all adverse events must be reported by the investigator. Such events 
will be recorded at each examination on the Adverse Event case report forms/worksheets.  
The reporting timeframe for adverse events meeting any serious criteria is described in 
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, 
 
 
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whichever is earlier, must be reported by the investigator.  All reported pregnancies must be 
followed to the completion/termination of the pregnancy. Pregnancy outcomes of 
spontaneous abortion, missed abortion, benign hydatidiform mole, blighted ovum, fetal 
death, intrauterine death, miscarriage and stillbirth must be reported as serious events 
(Important Medical Events). If the pregnancy continues to term, the outcome (health of 
infant) must also be reported.
Such events must be reported within 24 hours to the Sponsor either by electronic media or 
paper. Electronic reporting procedures can be found in the EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
Immediate Reporting of Adverse Events to the Sponsor
7.2.3.1
Serious Adverse Events
A serious adverse event is any adverse event occurring at any dose or during any use of 
Sponsor's product that:
●
Results in death;
●
Is life threatening;
●
Results in persistent or significant disability/incapacity;
●
Results in or prolongs an existing inpatient hospitalization;
●
Is a congenital anomaly/birth defect;
●
Is an other important medical event.
Note: In addition to the above criteria, adverse events meeting either of the below criteria, 
although not serious per ICH definition, are reportable to the Sponsor in the same timeframe 
as SAEs to meet certain local requirements. Therefore, these events are considered serious by 
the Sponsor for collection purposes.
●
Is a 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 (reference 
Section 7.2.3.3 for additional details), that occurs to any subject must be reported within 24 
hours to the Sponsor if it causes the subject to be excluded from the trial, or is the result of a 
protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 90 days 
following cessation of treatment, or 30 days following cessation of treatment if the subject 
initiates new anticancer therapy, whichever is earlier, any serious adverse event, or follow up 
to a serious adverse event, including death due to any cause, other than progression of the 
cancer under study (reference Section 7.2.3.3 for additional details) whether or not related to 
the Sponsor's product, must be reported within 24 hours to the Sponsor either by electronic 
media or paper. Electronic reporting procedures can be found in the EDC data entry 
 
 
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guidelines. Paper reporting procedures can be found in the Investigator Trial File Binder (or 
equivalent).
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to the Sponsor's product that is brought to the attention of the 
investigator at any time following consent through the end of the specified safety follow-up 
period specified in the paragraph above, or at any time outside of the time period specified in 
the previous paragraph also must be reported immediately to the Sponsor.  
All subjects with serious adverse events must be followed up for outcome.
7.2.3.2
Events of Clinical Interest
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI)  and must be reported to the Sponsor.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any subject must be 
reported within 24 hours to the Sponsor if it causes the subject to be excluded from the trial, 
or is the result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 30 days 
following cessation of treatment, any ECI, or follow up to an ECI, whether or not related to 
the Sponsor’s product, must be reported within 24 hours to the Sponsor, either by electronic 
media or paper.  Electronic reporting procedures can be found in the EDC data entry 
guidelines.  Paper reporting procedures can be found in the Investigator Trial File Binder (or 
equivalent).
Events of clinical interest for this trial include:
1. an overdose of Sponsor's product, as defined in Section 7.2.1 - Definition of an Overdose 
for This Protocol and Reporting of Overdose to the Sponsor, that is not associated with 
clinical symptoms or abnormal laboratory results.
2. 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. These hepatic ECIs must be reported to the 
Sponsor within 24 hours, even if they are considered due to progression of the cancer under 
study.
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
 
 
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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 mg/dL
ii. Among subjects with Baseline levels that are ≥1.5mg/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
7.2.3.3
Protocol-Specific Exceptions to Serious Adverse Event Reporting
Efficacy endpoints as outlined will not be reported to the Sponsor as described in 
Section 7.2.3 - Immediate Reporting of Adverse Events to the Sponsor. 
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study. 
The Sponsor will monitor 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
Scientific Advisory Committee
This trial was developed in collaboration with a Scientific Advisory Committee (SAC). The
SAC comprises both Sponsor and non-Sponsor scientific experts who provide input with
respect to trial design, interpretation of trial results and subsequent peer-reviewed scientific
publications.
Executive Oversight Committee
The Executive Oversight Committee (EOC) comprises members of Sponsor Senior 
Management.  The EOC will receive and decide upon any recommendations made by the 
external data monitoring committee (eDMC) regarding the trial.  
Data Monitoring Committee
To supplement the routine trial monitoring outlined in this protocol, an eDMC 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 DMC will review interim trial 
results, consider the overall risk and benefit to trial participants (see Section 8.7 - Interim 
Analyses) and recommend to the EOC if the trial should continue in accordance with the 
protocol.
Specific details regarding composition, responsibilities, and governance, including the roles 
and responsibilities of the various members and the Sponsor protocol team; meeting 
facilitation; the trial governance structure; and requirements for and proper documentation of 
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 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 
 
 
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after the protocol has been finalized, but prior to the conduct of any analysis, will be 
documented in a supplemental (sSAP) and referenced in the Clinical Study Report (CSR) for 
the study. There will be a separate PK analysis plan as well as biomarker analysis plan. Post 
hoc exploratory analyses will be clearly identified in the CSR. The PRO analysis plan will 
be included in the sSAP.
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Sections 8.2 through 8.12.
Study Design Overview
A Phase III Study of Pembrolizumab (MK-3475) vs. Best Supportive Care
(BSC) as Second-Line Therapy in Subjects with Previously Systemically 
Treated Advanced Hepatocellular Carcinoma
Treatment Assignment
Subjects will be randomized in a 2:1 ratio to receive pembrolizumab plus 
BSC or placebo plus BSC (control arm). This is a double-blind study. 
Treatment allocation/randomization will be stratified according to the 
following factors:
1.
Geographic region (Asia without Japan, Non-Asia with Japan)
2.
Macrovascular invasion (Yes, No)
3.
α-Fetoprotein (ng/mL) (<200, ≥200)
Analysis Populations
Efficacy: Intention to Treat (ITT)
Safety: All Subjects as Treated (ASaT)
Primary
Endpoints/Hypotheses
1. Pembrolizumab + BSC improves progression-free survival (PFS) per
RECIST 1.1 assessed by blinded central imaging vendor compared to 
placebo + BSC.
2. Pembrolizumab+ BSC improves overall survival (OS) compared to 
placebo + BSC.
Statistical Methods for
Key Efficacy Analyses
The primary hypotheses will be evaluated by comparing pembrolizumab to
the control on PFS and OS using a stratified log-rank test. Estimation of
the hazard ratio will be done using a stratified Cox regression model. Event
rates over time will be estimated within each treatment group using the
Kaplan-Meier method. Stratified Miettinen and Nurminen’s method [49]
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, an unconditional, asymptotic method [49].
 
 
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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.

Interim Analysis (IA)
o
Timing: To be performed when
approximately 183 OS 
events (67% of expected total OS events) are observed. With 
16 months enrollment, the IA is expected approximately at 
Month 22, at which time approximately 183 OS events (67% 
of expected total OS events) and 331 PFS events are 
expected to have been accumulated.
o
Purpose: Primary efficacy hypothesis testing for PFS (a 
single analysis) and interim efficacy analysis for OS . Only if 
PFS or OS are significant, the analysis of the secondary 
endpoint of ORR (a single analysis) will also be performed.

Second Interim Analysis 
o
Timing: To be performed when approximately 232 OS events 
(85% of expected total OS events) have been observed, 
projected to occur at approximately Month 28.
o
Purpose:  Second efficacy IA for OS (assuming not declared 
successful at the first IA).    

Final analysis (event-driven trial)
o
Timing: when approximately 273 OS events have been 
observed, estimated to be 35 months after study start.
o
Purpose:
Final efficacy analysis for OS (assuming not 
declared successful at either of the 2 interim analyses).
Multiplicity
The multiplicity strategy in this study will be applied to the 2 primary 
hypotheses (superiority of pembrolizumab in PFS and superiority of 
pembrolizumab in OS) and the secondary hypothesis of superiority of 
pembrolizumab in ORR. The overall Type I error across the 3 hypotheses 
above is strongly controlled at 2.5% (one-sided). The multiplicity strategy 
will follow the graphical approach of Maurer and Bretz [50] as described in 
Section 8.8, with initially 0.2% allocated to PFS hypotheses and 2.3% 
allocated to OS hypotheses. Within the OS hypothesis that is analyzed 
following a group sequential approach, the Type I error rates for the interim 
and final analyses will be controlled through the alpha-spending functions 
specified for this endpoint as described in Section 8.8. The PFS analysis and 
the ORR analysis do not use the group sequential approach. The PFS 
hypothesis is tested using only the PFS data collected at the time of the first 
interim OS analysis. Similarly, the secondary ORR hypothesis is tested using 
only the ORR data collected at the time of the first interim OS analysis,
whenever the Type I error becomes available for the ORR analysis.
 
 
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Sample Size and Power
The sample size is approximately 408.
The analysis of the OS endpoint is event driven. 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 273
OS events (unless superiority in OS is proven at an interim analysis).
For the primary endpoint PFS, the trial is anticipated to have approximately 
94% power at the time of the testing of the primary PFS hypothesis to 
demonstrate that pembrolizumab is superior to the control at a one-sided 
0.2% alpha-level, if the underlying hazard ratio of PFS is 0.60.
For the primary endpoint OS, the trial has approximately 92% 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 0.65.  
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. 
This study will be conducted as a double-blind study under in-house blinding procedures.  
The official, final database will not be unblinded until medical/scientific review has been 
performed, protocol deviations have been identified, and data have been declared final and 
complete.
Since the trial is double-blinded, analyses or summaries generated by randomized treatment 
assignment, and actual treatment received will be limited and documented. 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, 
revisions to the above plan and data monitoring guidance will be provided in the eDMC 
Charter. 
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.0.
 
 
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Analysis Endpoints
Efficacy Endpoints
8.4.1.1
Primary
Progression-Free Survival (PFS) – RECIST 1.1 by Blinded Central Imaging Vendor
Review
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 definition of censoring.
Overall Survival (OS)
OS is defined as the time from randomization to death due to any cause. Subjects without 
documented death at the time of the final analysis will be censored at the date of the last 
follow-up.
8.4.1.2
Secondary
Objective Response Rate (ORR) – RECIST 1.1 by blinded central imaging vendor
review
ORR is defined as the proportion of the subjects in the analysis population who have a CR or 
PR per RECIST 1.1.
Disease Control Rate (DCR) - RECIST 1.1 by blinded central imaging vendor review
DCR is defined as the proportion of subjects who have achieved CR, PR, or stable disease 
(SD) after ≥5 weeks (the start of the window for the first scheduled scan) based on 
assessments by the blinded central imaging vendor per RECIST 1.1.
Time to Progression (TTP) - RECIST 1.1 by blinded central imaging vendor review
TTP is defined as the time from randomization to the first documented disease progression 
per RECIST 1.1. See Section 8.6.1 for definition of censoring.
Duration of Response (DOR) - RECIST 1.1 by blinded central imaging vendor review
For subjects who demonstrate CR or PR, DOR 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. See Section 8.6.1 for definition of censoring.
Safety Endpoints
Safety endpoints are described in Sections 4.2.4.4 and 7.2.
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.
 
 
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Details on the approach to handling missing data are provided in Section 8.6 Statistical 
Methods.
Safety Analysis Populations
The All Subjects as Treated (ASaT) population will be used for the analysis of safety data in 
this study. The ASaT population consists of all randomized subjects who received at least 
one dose of study treatment. Subjects will be included in the treatment group corresponding 
to the study treatment they actually received for the analysis of safety data using the ASaT 
population. For most subjects this will be the treatment group to which they are randomized. 
Subjects who take incorrect study treatment for the entire treatment period will be included in 
the treatment group corresponding to the study treatment actually received. Any subject who 
receives the incorrect study medication for one cycle but receives the correct treatment for all 
other cycles will be analyzed according to the correct treatment group and a narrative will be 
provided for any events that occur during the cycle for which the subject is incorrectly dosed.  
At least one laboratory or vital sign measurement obtained subsequent to at least one dose of 
study treatment is required for inclusion in the analysis of each specific parameter. To assess 
change from baseline, a baseline measurement is also required.
Details on the approach to handling missing data for safety analyses are provided in 
Section 8.6 Statistical Methods.
Statistical Methods
Statistical Methods for Efficacy Analyses
This section describes the statistical methods that address the primary and secondary 
objectives. Methods related to exploratory objectives will be described in the sSAP.
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.
8.6.1.1
Progression-free Survival
The non-parametric Kaplan-Meier method will be used to estimate the PFS curve in each 
treatment group. The hypotheses of treatment difference in PFS will be tested by the 
stratified log -rank test. A stratified Cox proportional hazard model with Efron's method of 
tie handling will be used to estimate the magnitude of the treatment difference (i.e., hazard 
ratio) between the treatment arms. The hazard ratio and its 95% confidence interval from the 
stratified Cox model with Efron's method of tie handling and with a single treatment 
covariate will be reported. The stratification factors used for randomization (see Section 5.4) 
will be applied to both the stratified log-rank test and the stratified Cox model. Due to the 
small number in the stratum of presence of macrovascular invasion, subjects from any 
geographic 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) + Geographic region (Asia without Japan) + α-
fetoprotein (ng/mL) (<200)
 
 
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
Macrovascular invasion (No) + Geographic region (Non-Asia with Japan) + α-
fetoprotein (ng/mL) (<200)

Macrovascular invasion (No) + Geographic region (Asia without Japan) + α-
fetoprotein (ng/mL) (≥200)

Macrovascular invasion (No) + Geographic region (Non-Asia with Japan) + α-
fetoprotein (ng/mL) (≥200)

Macrovascular invasion (Yes) + Geographic region (Asia without Japan or Non-Asia 
with Japan) + α-fetoprotein (ng/mL) (<200 or ≥200)
Since disease progression is assessed periodically, PD can occur any time in the time interval 
between the last assessment where PD was not documented and the assessment when PD is 
documented. For the primary analysis, for the subjects who have PD, the true date of disease 
progression will be approximated by the date of the first assessment at which PD is 
objectively documented per RECIST 1.1 by blinded central imaging vendor review, 
regardless of discontinuation of study drug. Sensitivity analyses will be performed for 
comparison of PFS based on investigator's assessment and PFS analysis for PD per 
irRECIST by the blinded central imaging vendor review.
In order to evaluate the robustness of the PFS endpoint per RECIST 1.1 by the blinded 
central imaging vendor review, 2 sensitivity analyses will be performed with a different set 
of censoring rules. The first sensitivity analysis is the same as the primary analysis except 
that (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 8.
 
 
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Table 8
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 anti-cancer 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 
anti-cancer therapy
Censored at last disease 
assessment 
prior 
to 
the earlier date of  ≥ 2 
consecutive missed disease 
assessment and new anti-
cancer 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 anti-cancer therapy 
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 
or 
completed study therapy 
No PD and no death; new 
anti-cancer 
therapy 
is 
initiated
Censored at last disease 
assessment 
before 
new 
anti-cancer therapy
Censored 
at 
last 
disease assessment 
Progressed at date of 
new anti-cancer therapy
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 Restricted Mean Survival Time method [51], 
parametric method [52], etc.
Further details of sensitivity analyses will be described in 
supplemental SAP.  
The main PFS analysis will be conducted according to the hypotheses testing plan as 
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. 
8.6.1.2
Overall Survival
The non-parametric Kaplan-Meier method will be used to estimate the survival curves. The 
hypotheses of treatment difference in survival will be tested by the stratified log -rank test. A 
stratified Cox proportional hazard model with Efron's method of tie handling will be used to 
estimate the magnitude of the treatment difference (i.e., the hazard ratio). The hazard ratio 
and its 95% confidence interval from the stratified Cox model with a single treatment 
covariate will be reported. The stratification factors used for randomization will be applied 
to both the stratified log-rank test and the stratified Cox model. The same 5 strata defined for 
the PFS analysis (see Section 8.6.1.1) will be used for the OS analysis.
 
 
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Subjects in the control arm are expected to discontinue treatment earlier compared to subjects 
in the pembrolizumab arm, and may switch to another anti PD-1 treatment following the 
verification of progressive disease by blinded central imaging vendor review. Exploratory 
analyses to adjust for the effect of treatment switching to other PD-1 therapies on OS may be 
performed based on recognized methods, e.g. the Rank Preserving Structural Failure Time
model proposed by Robins and Tsiatis [53], two-stage model, etc., based on an examination 
of the appropriateness of the data to the assumptions required by the methods.
8.6.1.3
Objective Response Rate
Stratified Miettinen and Nurminen’s method [49] with weights proportional to the stratum 
size will be used for comparison of the objective response rates between the treatment arms.  
A 95% confidence interval for the difference in response rates between the pembrolizumab 
arm and the control arm will be provided.  The stratification factors used for randomization 
will be applied to the analysis. The same 5 strata defined for the PFS analysis (see 
Section 8.6.1.1) will be used for the ORR analysis.
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.
8.6.1.4
Disease Control Rate
Stratified Miettinen and Nurminen’s method [49] with weights proportional to the stratum 
size will be used for 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 used for randomization will be applied to the 
analysis. The same 5 strata defined for the PFS analysis (see Section 8.6.1.1) will be used for 
the DCR analysis.
8.6.1.5
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. The stratification factors used for randomization (see Section 5.4) 
will be applied to both the stratified log-rank test and the stratified Cox model. The same 
5 strata defined for the PFS analysis (see Section 8.6.1.1) will be used for the TTP analysis.
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 central imaging vendor review, 
regardless of discontinuation of study drug. Unlike in PFS analysis, death is not considered 
as an event.  Censoring rules for TTP are summarized in Table 9.  
 
 
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Table 9
Censoring Rules for TTP
Situation
Primary Analysis
Death only
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
PD documented after ≤1 missed disease 
assessment
Progressed at date of documented PD
PD documented after ≥2 missed disease 
assessments
Censored at last disease assessment prior to 
the
≥2 
consecutive 
missed 
disease 
assessments
8.6.1.6
Duration of Response
Subjects who achieved CR or PR and are alive, have not progressed, have not initiated new 
anti-cancer treatment, have not missed ≥2 consecutive missed 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 10.
Table 10
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 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.
 
 
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Table 11 summarizes the primary analysis approach for primary and secondary 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 analysis 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.
Table 11
Analysis Strategy for Key Efficacy Endpoints
Endpoint/Variable
(Description, Time Point)
Statistical Method†
Analysis Population
Missing Data
Approach
Primary Hypothesis #1
PFS per RECIST 1.1 by 
blinded 
central 
imaging 
vendor  review
Test: Stratified Log-
rank test Estimation: 
Stratified Cox model 
with 
Efron’s 
tie 
handling method
ITT 

Primary 
censoring rule

Sensitivity analysis 
1

Sensitivity analysis 
2 (More details are 
in Table 8)
Primary Hypothesis #2
OS
Test: Stratified Log-
rank test Estimation: 
Stratified Cox model 
with 
Efron’s 
tie 
handling method
ITT
Censored 
at 
last 
known alive date
Secondary Hypothesis #1
ORR per
RECIST 1.1
by 
blinded central imaging vendor
review
Stratified 
M 
& 
N 
method‡
ITT
Subjects 
with 
missing 
data 
are 
considered 
non-
responders
† Statistical models are described in further detail in the text. For stratified analyses, the stratification factors used for
randomization (see Section 5.4) will be applied to the analysis model.
‡  Miettinen and Nurminen method [49]
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, laboratory tests, vital signs, etc.
Tiered Approach
The analysis of safety results will follow a tiered approach (Table 12).  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, 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 [49], an unconditional, asymptotic method.
Table 12
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), AEOSI 
X
Change from Baseline Results (Labs, ECGs, Vital 
Signs)
X
AE = adverse event; AEOSI = adverse events of special interest; ECG = electrocardiogram; PDLC = pre-defined 
limit of change; SOC = system organ class. 
 
 
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Summaries of Demographic and Baseline Characteristics
The comparability of the treatment groups for each relevant characteristic will be assessed by 
the use of tables and/or graphs. No statistical hypothesis tests will be performed on these 
characteristics. The number and percentage of subjects screened, randomized, the primary 
reasons for screening failure, and the primary reason for discontinuation will be displayed. 
Demographic variables (e.g., age), baseline characteristics, primary and secondary diagnoses, 
and prior and concomitant therapies will be summarized by treatment either by descriptive 
statistics or categorical tables.
Interim Analyses
There are 2 planned interim analyses in this trial in addition to the final analysis. Results will 
be reviewed by an eDMC.
Efficacy Interim Analyses
The purpose of the first interim analysis is to conduct the main testing for efficacy on the 
PFS and ORR endpoints and to conduct an interim testing for efficacy on the OS endpoint. It 
will be performed when approximately 183 OS events (67% of expected total OS events) are 
observed. With approximately 16 months enrollment, the IA1 is expected approximately at 
Month 22, at which time approximately 331 PFS events are expected to have been 
accumulated.
The purpose of the second interim analysis is to conduct the efficacy testing on the OS 
endpoint if the result of OS endpoint is not successful at the first IA. The second IA will be 
performed when approximately 232 OS events (85% of expected total OS events) are 
observed, which is expected at approximately Month 28.
The final analysis (FA) will be performed when approximately 273 OS events are observed 
which is expected at Study Month 35.
The operating characteristics of conducting the IA for testing the OS hypothesis at 67% and 
85% expected total OS information are shown in Table 14. A detailed description of the 
multiplicity adjustment and hypotheses testing plan is provided in Section 8.8 Multiplicity.
Safety Interim Analyses
As noted in Section 7.3.3 – Data Monitoring Committee, the DMC 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 two primary 
hypotheses (superiority of pembrolizumab on PFS or OS) and the secondary hypothesis of 
superiority of pembrolizumab in 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 Maurer and Bretz [50]. 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 is re-distributed to the other two hypotheses. The arrows on the diagram show how 
the Type I error allocated to a hypothesis that was successfully tested will be re-distributed 
for the testing of the other two hypotheses.
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.
The testing of the PFS, OS, and ORR will proceed as follows.
PFS Hypothesis: The testing of the primary PFS hypothesis will be conducted at the time of 
the first OS IA.
The testing of the PFS hypothesis will be based on a PFS test statistic 
calculated only from study data available at the time of the main PFS analysis at the first OS 
IA. The PFS hypothesis will initially be tested at Type I error =0.2%. Depending on the 
result of the initial testing of the PFS hypothesis and the results of testing of the OS and ORR 
hypotheses, the PFS hypothesis can be tested at Type I error levels of =0.2%, =1.35%, or 
=2.5%. Table 13 shows the boundary thresholds corresponding to a successful testing of the 
PFS hypothesis at each of these Type I error levels. From Table 13, to declare success on the 
PFS hypothesis at Type I error =0.2%, the nominal calculated p-value should be 0.002, 
and the PFS hazard ratio should be 0.71. At the time of the main PFS analysis at
approximately Month 22, it is expected that 331 PFS events would have been accumulated 
under assumptions specified in Section 8.9 - Sample Size and Power Calculations.
Table 13
Efficacy Boundaries for Testing the PFS Hypothesis
Analysis
Study 
Calendar 
Time
Nb
Events
Information 
Fraction
Efficacy Boundary Crossing
Type I 
Error ()
Hazard 
Ratio
Powerc
Primary
Month 22a
408
331
1.0
0.20%
0.71
99.00%
1.35%
0.77
>99%
2.50%
0.80
>99%
a The main analysis of PFS will occur based on PFS data at this time. Per the multiplicity adjustment scheme, it 
is possible for the main analysis PFS test statistic (based on PFS data at this time) to be used again at the time of 
the second  interim OS analysis (Month 28) and end-of-study time point (Month 35) for a re-testing of the PFS 
hypothesis.
b Expected number of subjects randomized into the study at the time of analysis.
cThe power calculation is based on the assumptions in Section 8.9.
 
 
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OS Hypothesis: The OS hypothesis will be tested following a group sequential approach. 
The testing of the OS hypotheses will be first conducted at approximately Month 22 of the 
study (i.e., the first IA time point when approximately 183 OS events would have been 
accumulated). If unsuccessful at the first IA, the OS hypotheses will be tested at the second 
IA time point when approximately 232 OS events would have been accumulated at
approximately Month 28 of the study, and if unsuccessful at the second IA, the OS 
hypotheses will be tested at the final analysis time point when 273 events will be 
accumulated at Month 35, approximately. The nominal Type I error rates for the 2 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 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 a Type I error level of =2.5%. 
Table 14 shows the boundary thresholds corresponding to a successful group sequential 
testing of the OS hypothesis at each of these Type I error levels. From Table 14, with an 
overall Type I error α=2.3%, the first interim OS hypothesis testing with 183 events at Type I 
error =0.55% has an associated power of 60% following a group sequential approach under 
assumptions specified in Section 8.9. For example at overall Type I error α=2.3%, to declare 
success on the OS hypothesis at Type I error =0.55% at the first IA, the OS hazard ratio 
should be 0.67; to declare success on the OS hypothesis at Type I error α=1.20% at the
second IA, the OS hazard ratio should be ≤ 0.73; and to declare success on the OS hypothesis 
at Type I error α=1.87% at the final analysis, the OS hazard ratio should be ≤0.77. 
Conducting the OS hypothesis testing with 273 events at the final analysis at overall Type I 
error =2.3% has an associated power of 91%. The projected interim analyses information
fraction of 0.67 and 0.85 will be adjusted according to the proportion of the 273 final planned 
OS events actually available at the time of the interim analyses. Table 14 shows the example 
of the hazard ratio boundaries that will be applied if 0.67 and 0.85 of required OS events are 
observed by the time of the first and second IA, respectively. If the final OS events vary
from 273, a minor adjustment in the final bound may be required as well.
The spending function planned to be used for the testing of the OS hypothesis satisfies the 
requirements laid out in Maurer and Bretz [50].
 
 
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Table 14
Efficacy Boundaries for Testing the OS Hypothesis
Type I 
Error 
(Overall )
Analysis
Study 
Calendar 
Time
N§
Events
Information 
Fraction
Efficacy Boundary Crossing†
Nominal 
Hazard 
Ratio
Power
2.3%
Interim1
Month 22
408
183
0.67
0.55%
0.67
0.73
0.77
60%
Interim2
Month 28
408
232
0.85
1.20%
82%
Final
Month 35
408
273
1.00
1.87%
91%
2.5%
Interim1
Month 22
408
183
0.67
0.62%
0.68
0.73
0.77
62%
Interim2
Month 28
408
232
0.85
1.32%
83%
Final
Month 35
408
273
1.00
2.02%
92%
† Based on O’Brien-Fleming spending function. The power calculation is based on the assumptions in 
Section 8.9.
§ Expected number of subjects randomized into the study at the time of analysis.
ORR Hypothesis: The testing of the secondary ORR hypothesis will be conducted at the 
time of the first OS IA.  The testing of the ORR hypothesis will be based on an ORR test 
statistic calculated only from study data available at the time of the main ORR analysis at the 
first OS IA from all randomized subjects. 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 15 shows the boundary thresholds corresponding to each of three possible Type I error 
levels. To declare success on the ORR hypothesis at overall Type I error =0.2%, the 
nominal calculated p-value should be 0.2% (i.e. the Type I error level), and the ORR 
percentage point difference (pembrolizumab–control) should be 8.5%. 
Table 15
Efficacy Boundaries for Testing the ORR Hypothesis
Analysis
Study Calendar 
Time
N‡
Efficacy Boundary Crossing
Type I Error ()
ORR §
Power
Primary 
Month 22†
408
0.20%
8.5%
84%
1.15%
5.8%
97%
2.50%
5.0%
98%
‡ Expected number of subjects randomized into the study at the time of analysis. 
§ = ORR in pembrolizumab group – ORR in control group. The assumed expected ORR in 
pembrolizumab and control groups are 15% and 3%, respectively.
† Per the multiplicity adjustment scheme, it is possible for the main analysis ORR test statistic (based on
ORR data at this time) to be used again at the second IA (i.e., Month 28) and end-of-study time point 
(i.e., Month 35) for a re-testing of the ORR hypothesis.
 
 
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Sample Size and Power Calculations
The study will randomize subjects in a 2:1 ratio into pembrolizumab arm and the control arm.
Approximately 408 subjects are required to be enrolled in order to test the OS hypothesis at 
the desired study requirements.
The analysis of the OS endpoint is event driven.
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 273 OS events.
PFS Analysis: As described in Section 8.7 Interim Analysis, the main PFS analysis will be 
conducted at the same time as the first OS IA at approximately Month 22 of the study. It is 
projected that approximately 331 PFS events will be accumulated at this time. With 331 PFS 
events, the testing of the PFS hypothesis at Type I error =0.2% has 94% power to 
demonstrate that pembrolizumab is superior to the control with respect to PFS if the 
underlying PFS hazard ratio (pembrolizumab/control) is 0.60.
The power calculation is based on the following assumptions: 1) PFS follows an exponential 
distribution with a median of 2.5 months in the control arm; 2) An enrollment period of 
16 months; 3) a minimum follow-up of approximately 6 months; and 4) A yearly drop-out 
rate of ~10%.   
OS Analysis: A total of 273 OS events are required to test the OS hypothesis at Type I error 
=2.3% with ~92% power (see Table 14)
if the underlying OS hazard ratio 
(pembrolizumab/control) is 0.65. A total of 408 subjects are needed to be enrolled into the 
study in order to accumulate 273 OS events at approximately Month 35 of the study.
The sample size and power calculation is based on the following assumptions: 1) OS follows 
a piece-wise exponential distribution with zero hazard during the first month and a median of 
10 months in the control arm; 2) An enrollment period of 16 months; 3) a minimum follow-
up of 19 months; and 4) A yearly dropout rate of ~2%.  
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% confidence interval 
[CI]) for the dual primary endpoints will be estimated and plotted within each category of the 
following classification variables:

Geographic region (Asia without Japan, Non-Asia with Japan)

Macrovascular invasion (Yes, No)

α-Fetoprotein (ng/mL) (<200, ≥200)

Etiology (HCV, HBV, and uninfected)

Reason for discontinuation of sorafenib (progressive disease, intolerance)

ECOG performance status (0, 1)

Age (<65 years, ≥65 years)

Extrahepatic spread (Yes, No)
 
 
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
Gender (Male, Female)

Current disease overall BCLC stage (B, C)
Country-specific populations may also be analyzed per local regulatory requirements.  
Compliance (Medication Adherence)
Drug accountability data for trial treatment will be collected during the study. Any deviation 
from protocol-directed administration will be reported.
Extent of Exposure
The extent of exposure will be summarized as duration of treatment in cycles.
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES
Investigational Product
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations.
Clinical Supplies will be provided by the Sponsor as summarized in Table 16.  
Clinical supplies will be packaged to support enrollment and replacement subjects as 
required.  When a replacement subject is required, the Sponsor or designee needs to be 
contacted prior to dosing the replacement supplies.
Table 16
Product Descriptions
Product Name & 
Potency
Dosage Form
Source/Additional Information
Pembrolizumab 
100 mg/4 mL
Solution for infusion
Provided centrally by the Sponsor
All supplies indicated in Table 16 will be provided per the “Source/Additional Information” 
column depending on local country operational requirements.
Any commercially available product not included in Table 16 will be provided by the trial 
site, subsidiary or designee. Every attempt should be made to source these supplies from a 
single lot/batch number. The trial site is responsible 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 vials of study drug. No kitting is required.
 
 
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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.
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 
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.  Only the principal investigator or 
delegate and the respective subject’s code should be unblinded.  Trial site personnel and 
Sponsor personnel directly associated with the conduct of the trial should not be unblinded to 
treatment assignment.
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.
 
 
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Standard Policies
Trial 
site 
personnel 
will 
have 
access 
to 
a 
central 
electronic 
treatment 
allocation/randomization system (IVRS/IWRS system) to allocate subjects, to assign 
treatment to subjects and to manage the distribution of clinical supplies. Each person 
accessing the IVRS system must be assigned an individual unique PIN.  They must use only 
their assigned PIN to access the system, and they must not share their assigned PIN with 
anyone.
10.0 ADMINISTRATIVE AND REGULATORY DETAILS
Confidentiality
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the institutional review board, ethics review committee (IRB/ERC) or similar 
or expert committee; affiliated institution and employees, only under an appropriate 
understanding of confidentiality with such board or committee, affiliated institution and 
employees.  Data generated by this trial will be considered confidential by the investigator, 
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.
 
 
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Consistent with the purposes described above, this information may be transmitted to the 
Sponsor, and subsidiaries, affiliates and agents of the Sponsor, in your country and other 
countries, including countries that do not have laws protecting such information.  
Additionally, the investigator’s name and business contact information may be included 
when reporting certain serious adverse events to regulatory authorities or to other 
investigators.  By signing this protocol, the investigator expressly consents to these uses and 
disclosures.
If this is a multicenter trial, in order to facilitate contact between investigators, the Sponsor 
may share an investigator’s name and contact information with other participating 
investigators upon request.
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this trial.  The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
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.
 
 
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The investigator also agrees to allow monitoring, audits, IRB/ERC review and regulatory 
authority inspection of trial-related documents and procedures and provide for direct access 
to all trial-related source data and documents.
The investigator agrees not to seek reimbursement from subjects, their insurance providers or 
from government programs for procedures included as part of the trial reimbursed to the 
investigator by the Sponsor.
The investigator shall prepare and maintain complete and accurate trial documentation in 
compliance with Good Clinical Practice standards and applicable federal, state and local 
laws, rules and regulations; and, for each subject participating in the trial, provide all data, 
and, upon completion or termination of the clinical trial, submit any other reports to the 
Sponsor as required by this protocol or as otherwise required pursuant to any agreement with 
the Sponsor.
Trial documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the trial site upon request for inspection, 
copying, review and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities.  The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor as a result of an audit to cure deficiencies in the trial documentation 
and worksheets/case report forms.
The investigator must maintain copies of all documentation and records relating to the 
conduct of the trial in compliance with all applicable legal and regulatory requirements.  This 
documentation includes, but is not limited to, the protocol, worksheets/case report forms, 
advertising for subject participation, adverse event reports, subject source data, 
correspondence with regulatory authorities and IRBs/ERCs, consent forms, investigator’s 
curricula vitae, monitor visit logs, laboratory reference ranges, laboratory certification or 
quality control procedures and laboratory director curriculum vitae.  By signing this protocol, 
the investigator agrees that documentation shall be retained until at least 2 years after the last 
approval of a marketing application in an ICH region or until there are no pending or 
contemplated marketing applications in an ICH region or until at least 2 years have elapsed 
since the formal discontinuation of clinical development of the investigational product.  
Because the clinical development and marketing application process is variable, it is 
anticipated that the retention period can be up to 15 years or longer after protocol database 
lock. The Sponsor will determine the minimum retention period and notify the investigator 
when documents may be destroyed.  The Sponsor will determine the minimum retention 
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.
 
 
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Persons debarred from conducting or working on clinical trials by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s trials.  The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the trial is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will 
promptly notify that trial site’s IRB/IEC.
According to European legislation, a Sponsor must designate an overall coordinating 
investigator for a multi-center trial (including multinational).  When more than one trial site 
is open in an EU country, Merck, as the Sponsor, will designate, per country, a national 
principal coordinator (Protocol CI), responsible for coordinating the work of the principal 
investigators at the different trial sites in that Member State, according to national 
regulations.  For a single-center trial, the Protocol CI is the principal investigator.  In 
addition, the Sponsor must designate a principal or coordinating investigator to review the 
trial report that summarizes the trial results and confirm that, to the best of his/her 
knowledge, the report accurately describes the conduct and results of the trial [Clinical Study 
Report (CSR) CI].  The Sponsor may consider one or more factors in the selection of the 
individual to serve as the Protocol CI and or CSR CI (e.g., availability of the CI during the 
anticipated review process, thorough understanding of clinical trial methods, appropriate 
enrollment of subject cohort, timely achievement of trial milestones).  The Protocol CI must 
be a participating trial investigator.
Compliance with Trial Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Amendments Act (FDAAA) of 2007, 
and the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, the Sponsor 
of the trial is solely responsible for determining whether the trial and its results are subject to 
the requirements for submission to http://www.clinicaltrials.gov, www.clinicaltrialregister.eu
or other local registries. Merck, as Sponsor of this trial, will review this protocol and submit 
the information necessary to fulfill these requirements. Merck entries are not limited to 
FDAAA or the EMA clinical trials directive mandated trials. Information posted will allow 
subjects to identify potentially appropriate trials for their disease conditions and pursue 
participation by calling a central contact number for further information on appropriate trial 
locations and trial site contact information.   
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this trial or its results to those 
registries.
Quality Management System
By signing this protocol, the Sponsor agrees to be responsible for implementing and 
maintaining a quality management system with written development procedures and 
functional area standard operating procedures (SOPs) to ensure that trials are conducted and
data are generated, documented, and reported in compliance with the protocol, accepted 
 
 
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standards of Good Clinical Practice, and all applicable federal, state, and local laws, rules and 
regulations relating to the conduct of the clinical trial.
Data Management
The investigator or qualified designee is responsible for recording and verifying the accuracy 
of subject data.  By signing this protocol, the investigator acknowledges that his/her 
electronic signature is the legally binding equivalent of a written signature.  By entering 
his/her electronic signature, the investigator confirms that all recorded data have been 
verified as accurate.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
Publications
This trial is intended for publication, even if terminated prematurely. Publication may include 
any or all of the following: posting of a synopsis online, abstract and/or presentation at a 
scientific conference, or publication of a full manuscript.  The Sponsor will work with the 
authors to submit a manuscript describing trial results within 12 months after the last data 
become available, which may take up to several months after the last subject visit in some 
cases such as vaccine trials.  However, manuscript submission timelines may be extended on 
OTC trials.  For trials intended for pediatric-related regulatory filings, the investigator agrees 
to delay publication of the trial results until the Sponsor notifies the investigator that all 
relevant regulatory authority decisions on the trial drug have been made with regard to 
pediatric-related regulatory filings. Merck will post a synopsis of trial results for approved 
products on www.clinicaltrials.gov by 12 months after the last subject's last visit for the 
primary outcome, 12 months after the decision to discontinue development, or product 
marketing (dispensed, administered, delivered or promoted), whichever is later.
These timelines may be extended for products that are not yet marketed, if additional time is 
needed for analysis, to protect intellectual property, or to comply with confidentiality 
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 
 
 
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paper may be of value.  Limitations of single trial site observations in a multicenter trial 
should always be described in such a manuscript.
Authorship credit should be based on 1) substantial contributions to conception and design, 
or acquisition of data, or analysis and interpretation of data; 2) drafting the article or revising 
it critically for important intellectual content; and 3) final approval of the version to be 
published. Authors must meet conditions 1, 2 and 3.  Significant contributions to trial 
execution may also be taken into account to determine authorship, provided that 
contributions have also been made to all three of the preceding authorship criteria.  Although 
publication planning may begin before conducting the trial, final decisions on authorship and 
the order of authors’ names will be made based on participation and actual contributions to 
the trial and writing, as discussed above. The first author is responsible for defending the 
integrity of the data, method(s) of data analysis and the scientific content of the manuscript.
The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or 
presentations regarding this trial 45 days prior to submission for publication/presentation. 
Any information identified by the Sponsor as confidential must be deleted prior to 
submission; this confidentiality does not include efficacy and safety results. Sponsor review 
can be expedited to meet publication timelines.
 
 
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Blazeby JM, Currie E, Zee BC, Chie WC, Poon RT, Garden OJ, et al. 
Development of a questionnaire module to supplement the EORTC QLQ-C30 to 
assess quality of life in patients with hepatocellular carcinoma, the EORTC QLQ-
HCC18. Eur J Cancer. 2004 Nov;40(16):2439-44.
 
 
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[49]
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Maurer W, Bretz F. Multiple testing in group sequential trials using graphical 
approaches. Stat Biopharm Res 2013;5(4):311-20.
[51]
Uno H, Claggett B, Tian L, Inoue E, Gallo P, Miyata T, et al. Moving beyond the 
hazard ratio in quantifying the between-group difference in survival analysis. J 
Clin Oncol. 2014 Aug 1;32(22):2380-5.
[52]
Odell PM, Anderson KM, Kannel WB. New models for predicting cardiovascular 
events. J Clin Epidemiol. 1994 Jun;47(6):583-92.
[53]
Robins JM, Tsiatis AA. Correcting for non-compliance in randomized trials using 
rank preserving structural failure time models. Commun Stat-Theor M 
1991;20(8):2609-31.
[54]
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.
3. Summary of Procedures for Future Biomedical Research
a.
Subjects for Enrollment
All subjects enrolled in the clinical trial will be considered for enrollment in the 
Future Biomedical Research sub-trial.
b. Informed Consent
Informed consent for specimens (i.e., DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all subjects or legal guardians, at a trial 
visit by the investigator or his or her designate.  Informed consent for Future 
Biomedical Research should be presented to the subjects on Visit 1.  If delayed, 
present consent at next possible Subject Visit. Informed consent must be obtained 
prior to collection of all Future Biomedical Research specimens.  Consent forms 
signed by the subject will be kept at the clinical trial site under secure storage for 
regulatory reasons.  
 
 
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A template of each trial site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository. Each consent will be assessed for appropriate 
specimen permissions.  
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of subject consent for Future Biomedical Research will be captured in 
the electronic Case Report Forms (eCRFs). Any specimens for which such an 
informed consent cannot be verified will be destroyed.
d. Future Biomedical Research Specimen Collections
Collection of specimens for Future Biomedical Research will be performed as 
outlined in the trial flow chart. In general, if additional blood specimens are being 
collected for Future Biomedical Research, these will usually be obtained at a time 
when the subject is having blood drawn for other trial purposes.
4. Confidential Subject Information for Future Biomedical Research 
In order to optimize the research that can be conducted with Future Biomedical Research 
specimens, it is critical to link subject' clinical information with future test results. In fact 
little or no research can be conducted without connecting the clinical trial data to the 
specimen. The clinical data allow specific analyses to be conducted. Knowing subject 
characteristics like gender, age, medical history and treatment outcomes are critical to 
understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for Future 
Biomedical Research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below. 
At the clinical trial site, unique codes will be placed on the Future Biomedical Research 
specimens for transfer to the storage facility.  This first code is a random number which 
does not contain any personally identifying information embedded within it. The link (or 
key) between subject identifiers and this first unique code will be held at the trial site.  No 
personal identifiers will appear on the specimen tube.  
5. Biorepository Specimen Usage
Specimens obtained for the Merck Biorepository will be used for analyses using good 
scientific practices.  Analyses utilizing the Future Biomedical Research specimens may 
be performed by the Sponsor, or an additional third party (e.g., a university investigator) 
designated by the Sponsor. The investigator conducting the analysis will follow the 
Sponsor’s privacy and confidentiality requirements. Any contracted third party analyses 
will conform to the specific scope of analysis outlined in this sub-trial. Future Biomedical 
Research specimens remaining with the third party after specific analysis is performed 
will be reported to the Sponsor.
6. Withdrawal From Future Biomedical Research 
Subjects may withdraw their consent for Future Biomedical Research and 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 
FBR (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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Hepatitis B Definitions and Treatment Considerations
Table 17 describes the various definitions of treatment considerations and eligibility for study 
participation, along with the definitions of hepatitis B.
Table 17
Hepatitis B Definitions and Treatment Considerations
Test
Patient Status
Eligible for KN-240?
Any HBV Treatment 
Needed?
HBsAg (–)
Total anti-HBc (+)
HBsAb (+)
Immune after natural 
infection
Yes
No
HBsAg (–)
Total anti-HBc (–)
HBsAb (+)
Immune after vaccination
Yes
No
HBsAg (+)
Total anti-HBc (+)
IgM anti-HBc (+)
HBsAb (–)
Acute infection
No 
—
HBsAg (+)
Total anti-HBc (+)
IgM anti-HBc (–)
HBsAb (–)
Chronic infection
Yes
Yes, need to be on a 
HBV treatment for at 
least 12 weeks prior to 
start of study treatment
without evidence of a 
flare during that period 
Exclude 
if:
(a) <12 weeks 
of 
therapy; (b) HBV viral 
load not under control 
during this time frame; 
(c) Documented HBV
flare 
in 
the 
past 
12 weeks
HBsAg (–)
Total anti-HBc (+)
IgM anti-HBc (–)
HBsAb (–)
HBV viral load 
(negative)
Unclear.  Could be:
(1) Resolved 
infection
(2) False positive 
anti-HBc 
(3) Low level 
infection
(4) Resolving acute 
infection 
Yes
No
HBsAg (–)
Total anti-HBc (+)
IgM anti-HBc (–)
HBsAb (–)
HBV viral load (+)
(1) Low level 
infection
(2) Resolving acute 
infection 
Yes
Yes (as above)
 
 
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ECOG Performance Status
Developed by the Eastern Cooperative Oncology Group, Robert L. Comis, MD, Group Chair.*
GRADE
ECOG PERFORMANCE STATUS
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light or sedentary nature, e.g., light house work, office work
2
Ambulatory and capable of all selfcare but unable to carry out any work 
activities; up and about more than 50% of waking hours
3
Capable of only limited selfcare; confined to bed or chair more than 50% of 
waking hours
4
Completely disabled; cannot carry on any selfcare; totally confined to bed or 
chair
5
Dead
*Oken M, Creech R, Tormey D, et al. Toxicity and response criteria of the Eastern Cooperative 
Oncology Group. Am J Clin Oncol. 1982;5:649-655
http://ecog-acrin.org/resources/ecog-performance-status
 
 
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Common Terminology Criteria for Adverse Events
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 encephalopathy 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. 

Grade I:
Trivial lack of awareness; euphoria or anxiety; shortened attention span; 
impaired performance of addition or subtraction

Grade II:
Lethargy or apathy; minimal disorientation for time or place; subtle 
personality change; inappropriate behavior

Grade III: Somnolence to semi-stupor, but responsive to verbal stimuli
Confusion; Gross disorientation

Grade IV: Coma (unresponsive to verbal or noxious stimuli)
 
 
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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 [54].  
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
ALC1
Antibodies to liver cytosol antigen
ALKM-1
Antibodies to liver/kidney microsomes
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
ANA
Antibodies to nuclei
aPTT
Activated partial thromboplastin time
ASaT
All subjects as treated
ASMA
Antibodies to smooth muscle
AST
Aspartate aminotransferase
BCAA
Branched chain amino acids
BCG
Bacille Calmette-Guerin (tuberculosis)
BCLC
Barcelona Clinic Liver Cancer scale
BID
Twice daily
BSC
Best supportive care
CI
Confidence interval
CL
Clearance
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
CTFG
Clinical Trial Facilitation Group
Ctrough
Serum minimum concentration
Dbil
Direct bilirubin
DCR
Disease control rate
DNA
Deoxyribonucleic acid
DOR
Duration of response
ECG
Electrocardiogram
ECI
Events of clinical interest
ECOG
Eastern Cooperative Oncology Group
EDC
Electronic data capture
eDMC
External data monitoring committee
ELISA
Enzyme-linked immunosorbent assay
EOC
Executive Oversight Committee
EORTC QLQ-C30
European Organisation for Research and Treatment of 
Cancer Quality of Life Questionnaire—Core 30
EORTC QLQ-HCC18
European Organisation for Research and Treatment of 
Cancer Quality of Life Questionnaire—HCC 18
EQ-5D
EuroQol EQ-5D (EuroQol EQ-5 Dimension 3 Level)
ER
Emergency room
ERC
Ethics review committee
FBR
Future biomedical research
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
 
 
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Abbreviation/Term
Definition
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
GEP
Gene expression profile
Anti-HBc
Hepatitis B core antibody, Total
Anti-HBc, IgM
Hepatitis B core antibody, IgM
HBeAg
Hepatitis B early antigen
Anti-HBe
Hepatitis B early antibody
Anti-HBs
Hepatitis B surface antibody
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCC
Hepatocellular carcinoma
HCV
Hepatitis C virus
Anti-HCV
Hepatitis C antibody
HDV
Hepatitis D virus
Anti-HDV
Hepatitis D antibody
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
irPD
radiographic progression of disease
irRECIST
Immune related RECIST (modification of RECIST 1.1)
IRB
Institutional Review Board
ITT
Intent-to-treat
ITIM
Immunoreceptor tyrosine-based inhibition motif 
ITSM
Immunoreceptor tyrosine-based switch motif
IUD
Intrauterine device
IUS
Intrauterine hormone-releasing system (IUS)
IV
Intravenous
IVRS
Interactive voice response system
IWRS
Integrated web response system
mAb
Monoclonal antibody
miRNA
Micro RNA
mRECIST
Modified RECIST for HCC
MRI
Magnetic resonance imaging
MTD
Maximum tolerated dose
NCI
National Cancer Institute
NSCLC
Non-small cell lung cancer
ORR
Objective response rate
OS
Overall survival
OTC
Over-the-counter
PBMC
Peripheral blood mononuclear cell
PD
Progressive disease
PD-1
Programmed cell death 1
PD-L1
Programmed death ligand 1
 
 
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Abbreviation/Term
Definition
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
Q2W
Every 2 weeks
Q3W
Every 3 weeks
Q6W
Every 6 weeks
Q12W
Every 12 weeks
QALY
Quality adjusted life years 
QLG
Quality of Life Group
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 
Tbil
Total bilirubin
TACE
Transcatheter chemoembolization
TAE
Transarterial embolization
TIL
Tumor infiltrating lymphocytes
TTP
Time to progression
ULN
Upper limit of normal
V
Volume of distribution
 
 
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03-Feb-2021
Confidential
13.0 SIGNATURES
Sponsor's Representative
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
Investigator
I agree to conduct this clinical trial in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol (including other manuals and documents 
referenced from this protocol).  I agree to conduct the trial in accordance with generally 
accepted standards of Good Clinical Practice.  I also agree to report all information or data in 
accordance with the protocol and, in particular, I agree to report any serious adverse events 
as defined in Section 7.0 – TRIAL PROCEDURES (Assessing and Recording Adverse 
Events).  I also agree to handle all clinical supplies provided by the Sponsor and collect and 
handle all clinical specimens in accordance with the protocol.  I understand that information 
that identifies me will be used and disclosed as described in the protocol, and that such 
information may be transferred to countries that do not have laws protecting such 
information.  Since the information in this protocol and the referenced Investigator’s 
Brochure is confidential, I understand that its disclosure to any third parties, other than those 
involved in approval, supervision, or conduct of the trial is prohibited.  I will ensure that the 
necessary precautions are taken to protect such information from loss, inadvertent disclosure 
or access by third parties.
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
 
 
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