A Phase 2 Study of Pembrolizumab (MK-3475) as Monotherapy in Subjects With Advanced Hepatocellular Carcinoma (KEYNOTE-224)
Phase: PHASE2
Conditions: Hepatocellular Carcinoma
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title:
NCT number:
Document Date:
A Phase 2 Study of Pembrolizumab (MK-3475)
as Monotherapy in Subjects with Advanced
Hepatocellular Carcinoma (KEYNOTE-224)
NCT02702414
24-Jun-2022

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THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME LLC, RAHWAY, NJ, USA (MSD).
SPONSOR:
Merck Sharp & Dohme LLC. 
(hereafter referred to as the Sponsor or MSD)
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Protocol-specific Sponsor Contact information can be found in the Investigator Trial File 
Binder (or equivalent).
TITLE:
A Phase 2 Study of Pembrolizumab (MK-3475) as Monotherapy in Subjects with Advanced 
Hepatocellular Carcinoma (KEYNOTE-224)
IND NUMBER:  123,482
EudraCT NUMBER:  2015-004566-28
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TABLE OF CONTENTS
DOCUMENT HISTORY ..................................................................................................... 11
SUMMARY OF CHANGES................................................................................................ 12
1.0
TRIAL SUMMARY.................................................................................................. 13
2.0
TRIAL DESIGN........................................................................................................ 14
Trial Design ........................................................................................................... 14
Trial Diagram........................................................................................................ 16
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 17
Primary Objective(s) & Hypothesis(es).............................................................. 17
Secondary Objective(s) & Hypothesis(es)........................................................... 17
Exploratory Objectives......................................................................................... 17
4.0
BACKGROUND & RATIONALE.......................................................................... 18
Background ........................................................................................................... 18
Pharmaceutical and Therapeutic Background .................................................... 19
Pre-clinical and Clinical Trials ........................................................................... 20
Ongoing Clinical Trials....................................................................................... 21
Rationale................................................................................................................ 21
Rationale for the Trial and Selected Subject Population .................................... 21
Rationale for Dose Selection/Regimen............................................................... 21
Rationale for Endpoints ...................................................................................... 23
4.2.3.1
Efficacy Endpoints....................................................................................... 23
4.2.3.1.1
Primary Efficacy Endpoints.................................................................. 23
4.2.3.1.2
Secondary Efficacy Endpoints.............................................................. 23
4.2.3.1.3
Exploratory Efficacy Endpoints............................................................ 23
4.2.3.2
Immune-related RECIST ............................................................................. 23
4.2.3.3
Safety Endpoints.......................................................................................... 24
4.2.3.4
Biomarker Research..................................................................................... 24
4.2.3.5
Future Biomedical Research........................................................................ 26
Benefit/Risk ........................................................................................................... 27
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5.0
METHODOLOGY ................................................................................................... 27
Entry Criteria........................................................................................................ 27
Diagnosis/Condition for Entry into the Trial...................................................... 27
Subject Inclusion Criteria.................................................................................... 27
Subject Exclusion Criteria .................................................................................. 29
Trial Treatment(s) ................................................................................................ 31
Dose Selection/Modification .............................................................................. 32
5.2.1.1
Dose Selection (Preparation) ....................................................................... 32
5.2.1.2
Dose Interval Modification for Non-hepatic Drug-related Adverse 
Events........................................................................................................... 32
5.2.1.3
Guidance for Diagnosis and Management of Hepatic Events of Clinical 
Interest ......................................................................................................... 36
Timing of Dose Administration.......................................................................... 43
Trial Blinding...................................................................................................... 44
Randomization or Treatment Allocation............................................................ 44
Stratification.......................................................................................................... 44
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 44
Acceptable Concomitant Medications ................................................................ 44
Prohibited Concomitant Medications.................................................................. 45
Rescue Medications & Supportive Care............................................................. 47
Rescue Medications ............................................................................................ 47
Supportive Care Guidelines ................................................................................ 47
Diet/Activity/Other Considerations..................................................................... 50
Diet...................................................................................................................... 50
Contraception...................................................................................................... 50
Use in Pregnancy ................................................................................................ 53
Use in Nursing Women....................................................................................... 53
Subject Withdrawal/Discontinuation Criteria................................................... 53
Discontinuation of Study Therapy after Complete Response............................. 54
Subject Replacement Strategy............................................................................. 55
Beginning and End of the Trial ........................................................................... 55
Clinical Criteria for Early Trial Termination ................................................... 55
6.0
TRIAL FLOW CHART ........................................................................................... 56
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Initial Treatment with Pembrolizumab.............................................................. 56
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........................................................................ 68
7.1.2.3
Height, Weight, and Vital Signs .................................................................. 68
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
Laboratory Procedures/Assessments .................................................................. 68
7.1.3.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) .. 69
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7.1.3.1.1
Pregnancy Tests .................................................................................... 70
7.1.3.2
Central Laboratory Assessments.................................................................. 70
7.1.3.3
Blood Samples for RNA Analysis, and Biomarker Studies ........................ 70
7.1.3.4
Tumor Tissue ............................................................................................... 70
7.1.3.5
Planned Genetic Analysis Sample Collection.............................................. 70
7.1.3.6
Future Biomedical Research Sample Collection ......................................... 71
Efficacy Measurements....................................................................................... 71
7.1.4.1
Tumor Imaging and Assessment of Disease................................................ 71
7.1.4.1.1
Initial Tumor Imaging........................................................................... 71
7.1.4.1.2
Tumor Imaging During the Trial .......................................................... 72
7.1.4.1.3
End of Treatment and Follow-up Tumor Imaging................................ 72
7.1.4.1.4
Second Course (Retreatment) Tumor Imaging..................................... 73
7.1.4.1.5
RECIST 1.1 Assessment of Disease..................................................... 73
7.1.4.1.6
Modified RECIST (mRECIST) Assessment of Disease....................... 73
7.1.4.1.7
irRECIST Assessment of Disease......................................................... 74
Other Procedures................................................................................................. 77
7.1.5.1
Withdrawal/Discontinuation........................................................................ 77
7.1.5.1.1
Withdrawal From Future Biomedical Research ................................... 78
7.1.5.2
Blinding/Unblinding .................................................................................... 78
7.1.5.3
Calibration of Critical Equipment................................................................ 78
Visit Requirements.............................................................................................. 78
7.1.6.1
Screening...................................................................................................... 79
7.1.6.2
Treatment Period.......................................................................................... 79
7.1.6.2.1
Second Course Phase (Retreatment Period) ......................................... 79
7.1.6.3
Post-Treatment Visits................................................................................... 81
7.1.6.3.1
Safety Follow-up Visits ........................................................................ 81
7.1.6.3.2
Follow-up Visits ................................................................................... 81
7.1.6.3.3
Survival Follow Up............................................................................... 81
7.1.6.4
Survival Status ............................................................................................. 81
Assessing and Recording Adverse Events .......................................................... 82
Definition of an Overdose for This Protocol and Reporting of Overdose to 
the Sponsor.......................................................................................................... 82
Reporting of Pregnancy and Lactation to the Sponsor ....................................... 83
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Immediate Reporting of Adverse Events  to the Sponsor................................... 83
7.2.3.1
Serious Adverse Events ............................................................................... 83
7.2.3.2
Events of Clinical Interest............................................................................ 84
7.2.3.3
Protocol-Specific Exceptions to Serious Adverse Event Reporting............ 86
Evaluating Adverse Events................................................................................. 86
Sponsor Responsibility for Reporting Adverse Events ...................................... 89
TRIAL GOVERNANCE AND OVERSIGHT................................................... 89
Scientific Advisory Committee........................................................................... 89
Executive Oversight Committee......................................................................... 89
Data Monitoring Committee............................................................................... 89
8.0
STATISTICAL ANALYSIS PLAN ........................................................................ 89
Statistical Analysis Plan Summary ..................................................................... 90
Responsibility for Analyses.................................................................................. 90
Hypotheses/Estimation......................................................................................... 91
Analysis Endpoints ............................................................................................... 91
Efficacy Endpoints.............................................................................................. 91
8.4.1.1
Primary Efficacy Endpoint .......................................................................... 91
8.4.1.2
Secondary Efficacy Endpoints..................................................................... 91
8.4.1.3
Exploratory Efficacy Endpoints................................................................... 91
Safety Endpoints ................................................................................................. 92
Analysis Populations............................................................................................. 92
Efficacy Analysis Populations ............................................................................ 92
Safety Analysis Populations ............................................................................... 92
Statistical Methods................................................................................................ 92
Statistical Methods for Efficacy Analyses.......................................................... 92
Statistical Methods for Safety Analyses ............................................................. 94
Demographic and Baseline Characteristics ........................................................ 94
Interim Analyses ................................................................................................... 94
Multiplicity ............................................................................................................ 94
Sample Size............................................................................................................ 94
Subgroup Analyses and Effect of Baseline Factors ........................................... 95
Compliance (Medication Adherence).................................................................. 95
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Extent of Exposure................................................................................................ 95
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 95
Investigational Product ........................................................................................ 95
Packaging and Labeling Information ................................................................. 96
Clinical Supplies Disclosure................................................................................. 96
Storage and Handling Requirements.................................................................. 96
Discard/Destruction/Returns and Reconciliation .............................................. 96
Standard Policies................................................................................................... 97
10.0
ADMINISTRATIVE AND REGULATORY DETAILS....................................... 97
Confidentiality....................................................................................................... 97
Confidentiality of Data ....................................................................................... 97
Confidentiality of Subject Records..................................................................... 97
Confidentiality of Investigator Information........................................................ 97
Confidentiality of IRB/IEC Information............................................................. 98
Compliance with Financial Disclosure Requirements....................................... 98
Compliance with Law, Audit and Debarment ................................................... 98
Compliance with Trial Registration and Results Posting Requirements...... 100
Quality Management System............................................................................. 100
Data Management............................................................................................... 101
Publications ......................................................................................................... 101
11.0
LIST OF REFERENCES....................................................................................... 102
12.0
APPENDICES......................................................................................................... 107
Code of Conduct for Clinical Trials.................................................................. 107
Collection and Management of Specimens for Future Biomedical 
Research............................................................................................................... 110
Understanding the Intent, Scope and Public Health Benefits of 
Exploratory Biomarker Research: A Guide for IRBs/IECs and 
Investigational Site Staff .................................................................................... 114
Hepatitis B Definitions and Treatment Considerations .................................. 125
ECOG Performance Status................................................................................ 126
Common Terminology Criteria for Adverse Events ....................................... 127
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Child-Pugh Score................................................................................................ 128
Barcelona Clinic Liver Cancer Staging System............................................... 130
List of Abbreviations .......................................................................................... 131
13.0
SIGNATURES......................................................................................................... 134
Sponsor's Representative ................................................................................... 134
Investigator.......................................................................................................... 134
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LIST OF TABLES
Table 1
Adequate Organ Function Laboratory Values...................................................29
Table 2
Trial Treatment..................................................................................................32
Table 3
Dose Modification and Toxicity Management Guidelines for Immune-
related AEs Associated with Pembrolizumab ...................................................33
Table 4
Guidance for Diagnosis and Management of Hepatic Events of Clinical 
Interest...............................................................................................................41
Table 5
Infusion Reaction Treatment Guidelines...........................................................49
Table 6
Laboratory Tests................................................................................................69
Table 7
Imaging and Treatment after First Radiologic Evidence of Progressive 
Disease...............................................................................................................76
Table 8
Evaluating Adverse Events ...............................................................................87
Table 9
Analysis Strategy for Efficacy Variables ..........................................................93
Table 10 Censoring Rules for DOR .................................................................................94
Table 11 Two-sided 95% Confidence Interval of ORR with 100 Subjects (Cohort 
1)........................................................................................................................95
Table 12 Product Descriptions .........................................................................................96
Table 13 Hepatitis B Definitions and Treatment Considerations...................................125
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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 the Site ..................77
Figure 3 Barcelona Clinic Liver Cancer Staging System..............................................130
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
3475-224-08
24-JUN-2022
Merck Sharp & Dohme Corp. underwent an entity name and address change to Merck 
Sharp & Dohme LLC, Rahway, NJ, USA. This conversion resulted only in an entity name 
change and update to the address.
3475-224-07
05-FEB-2021
To add language to include the requirement of roll over of trial participants into an 
extension trial (if available) when this trial is completed
3475-224-06
23-MAY-2018
To add an additional cohort for first-line treatment
3475-224-05
13-DEC-2017
To modify benefit-risk text modified per request from Agence Nationale de Sécurité du 
Médicament et des Produits de Santé (ANSM) and align with a prior protocol clarification 
letter (PCL).
3475-224-04
12-DEC-2017
To provide current, comprehensive guidelines for management of immune-related adverse 
events, survival follow up procedures and analysis of survival data, mRECIST evaluation of 
exploratory objectives and exploratory efficacy endpoints
3475-224-03
11-OCT-2016
To address German HA request to add language to exclude subjects with a hypersensitivity 
pembrolizumab’s excipients (exclusion criterion 16)
3475-224-02
11-JUL-2016
To address German HA request to add language to exclude subjects with a hypersensitivity 
to study drug
3475-224-01
22-FEB-2016
To clarify and correct inclusion/exclusion criteria, trail flow chart, supportive care 
guidelines, irRECIST text, and statistical analyses
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
Title Page
Section 12.1
Throughout
Title page
Code of Conduct for Clinical 
Trials
Throughout
Sponsor 
entity 
name 
and 
address change.
Merck 
Sharp 
& 
Dohme 
Corp. 
underwent an entity name and address 
change to Merck Sharp & Dohme 
LLC, 
Rahway, 
NJ, 
USA. 
This 
conversion resulted only in an entity 
name change and update to the address.
ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
No additional changes.
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1.0 TRIAL SUMMARY
Abbreviated Title
A Phase 2 Study of Pembrolizumab (MK-3475) as Monotherapy in 
Subjects with Advanced Hepatocellular Carcinoma
Sponsor Product Identifiers
MK-3475
Pembrolizumab
Trial Phase
Phase 2
Clinical Indication
Hepatocellular carcinoma (HCC)
Trial Type
Interventional
Type of control
No treatment control
Route of administration
Intravenous (IV)
Trial Blinding
Unblinded Open-label
Treatment Groups
Pembrolizumab 200 mg IV every 3 weeks
Number of trial subjects
Approximately 150 (100 subjects in Cohort 1 and 50 subjects in Cohort 
2) subjects will be enrolled.
Estimated duration of trial
The Sponsor estimates that the trial will require approximately 
60 months from the time the first subject signs the informed consent until 
the last subject’s last study-related phone call or visit.
Duration of Participation
Each subject will participate in the trial from the time the subject signs 
the informed consent form (ICF) through the final contact.  After a 
screening phase of up to 28
days, each subject will receive 
pembrolizumab 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 pembrolizumab, or administrative reasons requiring 
cessation of treatment. Subjects who stop pembrolizumab as a result of 
obtaining a confirmed complete response (CR) or those subjects who 
stop after receiving 35 trial treatments may be eligible, at the discretion 
of the investigator, for an additional 17 trial treatments (approx. 1 year) 
after progressive disease if they meet the criteria for re-treatment 
(Second Course Phase) and the study is ongoing.
Subjects who 
discontinue for reasons other than progressive disease will have post-
treatment follow-up visits for monitoring disease status 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 trial 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.
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Randomization Ratio
Not applicable
A list of abbreviations used in this document can be found in Section 12.9.
2.0 TRIAL DESIGN
Trial Design
This is a single-arm, open-label, multi-site Phase 2 trial of pembrolizumab (MK-3475) in 
subjects with advanced hepatocellular carcinoma (HCC). For Cohort 1, the trial will include 
previously systemically treated subjects with a histologically or cytologically confirmed 
diagnosis of HCC (fibrolamellar and mixed hepatocellular/cholangiocarcinoma subtypes are 
not eligible) based on pathology report. For Cohort 2, the trial will include subjects with a 
radiologically or histologically or cytologically confirmed diagnosis of HCC who have not 
received prior systemic therapy in the advanced disease setting. To be eligible, subjects must 
have disease not amenable to a curative treatment approach (eg, transplant, surgery, or 
ablation).  In addition, subjects in Cohort 1 will have evidence of disease progression after 
stopping treatment with sorafenib or else intolerance to sorafenib. Subjects must also have at 
least one measurable lesion that is confirmed by the central imaging vendor per Response 
Evaluation Criteria in Solid Tumors (RECIST) 1.1, Child Pugh liver score A, an Eastern 
Cooperative Oncology Group (ECOG) performance score of 0 or 1, and predicted life 
expectancy of greater than 3 months.  Subjects will be enrolled regardless of tissue 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 150 
subjects will be allocated to 1 of the following 2 cohorts:
Cohort 1 (2L): approximately 100 subjects who received prior systemic therapy of sorafenib 
for HCC in the advanced disease setting
Cohort 2 (1L): approximately 50 subjects who did not receive prior systemic therapy for 
HCC in the advanced disease setting.
The primary objective of this trial is to determine the objective response rate (ORR) of 
pembrolizumab given as monotherapy. Beginning with screening, all imaging assessments 
will be submitted for central imaging vendor review and will be evaluated using RECIST 1.1. 
On-study imaging assessments will be performed every 9 weeks (Q9W) calculated from the 
date of allocation and independent of treatment delays. RECIST 1.1 will be used by the site 
for treatment decisions until the first radiologic evidence of progressive disease (PD). 
Following the first radiologic evidence of PD by RECIST 1.1, treatment decisions may be 
made by the adaptation of RECIST 1.1 as described in Section 4.2.3.2 termed immune-
related RECIST (irRECIST) to accommodate the tumor response patterns seen with 
pembrolizumab treatment (e.g., tumor flare). This was first described by Nishino, et al. 2013 
[1] and 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 pembrolizumab until PD is confirmed at least 4 weeks after the date 
of the first tumor imaging suggesting PD per the site investigator. If radiologic PD is 
confirmed by the subsequent tumor imaging, the subject should be discontinued from 
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treatment unless, in the opinion of the investigator, the subject is achieving a clinically 
meaningful benefit; an exception for continued treatment may be considered following 
consultation with the Sponsor.
Subjects may continue to be treated with pembrolizumab until PD is confirmed by 
RECIST 1.1, unacceptable adverse events (AEs), 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, administrative reasons, or the subject has received 35 trial 
treatments (approximately 2 years) with pembrolizumab. 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 whichever of the following occurs 
first:  The start of new anti-cancer treatment, disease progression, death, or the end of the 
study.  All subjects will be followed every 12 weeks for overall survival (OS) until death, 
withdrawal of consent from participation in the study, or the end of the study, whichever 
comes first.  
Subjects who attain a CR by 2 tumor imaging assessments at least 4 weeks apart and who 
have received at least 8 treatments (approximately 6 months of therapy) with pembrolizumab 
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 pembrolizumab after 
receiving 35 trial treatments (approx. 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 re-treat will be at the discretion of the 
investigator only if no other cancer treatment was administered since the last dose of 
pembrolizumab, 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 (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.  
To supplement the routine trial monitoring outlined in this protocol, an external data 
monitoring committee (eDMC) will monitor the interim data from this trial (Cohort 1 only). 
Details regarding the role of the eDMC are provided in the eDMC Charter. 
An interim analysis (see Section 8.7) of the safety and efficacy data from the first 20 patients 
enrolled in Cohort 1 will be performed to inform planning of other studies in the 
pembrolizumab development program. This analysis will be performed by the Clinical 
Biostatistics department of the Sponsor. 
Upon study completion, participants are discontinued and may be enrolled in a 
pembrolizumab extension study, if available. 
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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.
Trial Diagram
*Participants may roll over if extension study is available 
Abbreviations: ECOG = Eastern Cooperative Oncology Group; IV = intravenous; IVRS = interactive voice 
response system; IWRS = Integrated web response system; PD = progressive disease;
Q3W = every 3 weeks; Q9W = every 9 weeks; Q12W – every 12 weeks; RECIST = Response Evaluation 
Criteria in Solid Tumors; 
Figure 1
Trial Diagram
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3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
Intravenous administration of pembrolizumab in subjects with HCC with no curative option 
after disease progression on sorafenib or intolerance of sorafenib (Cohort 1) and, separately, 
in subjects with HCC who had not received treatment for systemic disease in the advanced 
setting (Cohort 2):
Primary Objective(s) & Hypothesis(es)
(1) Objective:  To estimate the ORR, per RECIST 1.1 assessed by central imaging 
vendor. 
Hypothesis:  No hypothesis testing will be performed. 
Secondary Objective(s) & Hypothesis(es)
(1) Objective: To evaluate the duration of response (DOR), disease control rate (DCR),
time to progression (TTP), and progression-free survival (PFS) per RECIST 1.1 
assessed by central imaging vendor, and OS.  
(2) Objective:  To determine the safety and tolerability of pembrolizumab monotherapy.  
Exploratory Objectives 
(1) Objective: To evaluate ORR, DOR, DCR, TTP, and PFS per irRECIST assessed by 
the central imaging vendor.
(2) Objective:  To evaluate PFS, ORR, DOR, DCR, and TTP per modified RECIST for 
HCC (mRECIST) assessed by central imaging vendor review.  
(3) Objective: To evaluate ORR, DOR, DCR, TTP, and PFS according to investigator-
assessed scans per RECIST 1.1.
(4) Objective: To identify
molecular (genomic, metabolic and/or proteomic) 
determinants of response or resistance (e.g., PD-L1 IHC, gene expression profiling, 
or genomic variation) to pembrolizumab and other treatments in this study, using 
blood and /or tumor tissue to define novel predictive and pharmacodynamic 
biomarkers and better understand the mechanism of action of pembrolizumab.
(5) 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.
(6) Objective: For Cohort 1 only, to explore the relationship between cause of sorafenib 
discontinuation (intolerant vs. radiographic progression of disease) and response to 
pembrolizumab.
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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 in the world 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. HCC is resistant to most traditional 
chemotherapy agents, and the median survival for patients with advanced disease is typically 
6–9 months without therapy.
The oral tyrosine kinase inhibitor sorafenib is the current standard of care worldwide for 
treatment of patients with advanced HCC in the first line based on a large Phase 3 trial in a 
Western population.
In this trial, time to progression 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 [3], 
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]. 
Several recent randomized clinical trials comparing other agents to sorafenib in the first-line 
setting have been negative, although lenvatinib was non-inferior with respect to overall 
survival [5], and has already been approved in Japan for first-line HCC; however sorafenib 
remains the only Food and Drug Administration (FDA)-approved systemic therapy for 1L 
HCC patients in the United States.
In parts of Asia, the FOLFOX regimen (folinic acid, 
5-fluorouracil, and oxaliplatin) has also been approved, based on a randomized trial 
comparing FOLFOX4 to doxorubicin [6]. In this trial, there was a non-significant 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 without a curative option remains crucial. All other agents assessed 
as first-line therapy as well as several other agents assessed in the second-line setting have 
failed to show improved survival over sorafenib or placebo [7].
Currently, regorafenib is the only globally approved second-line therapy following sorafenib 
treatment in patients with advanced HCC [8]. Recently, cabozantinib has demonstrated 
improved overall survival versus placebo in patients with advanced HCC who failed prior 
sorafenib treatment [9]. While these both have demonstrated improved survival, the benefits 
remain modest with associated side effects.  Several large randomized trials again failed to 
show a significant survival advantage against placebo in the second line, including brivanib 
[10], everolimus [11], and ramucirumab [12]. Chemotherapy drugs including capecitabine 
and the gemcitabine/oxaliplatin (GEMOX) combination have also been used in the second 
line in small trials [13] [14]. Nivolumab received accelerated approval for the second-line 
treatment of HCC in 2017 [15].
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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 PD-1 
and its ligands, programmed death ligand 1 (PD-L1) and programmed death ligand 2 
(PD-L2).  KEYTRUDA® (pembrolizumab) has recently been approved in the United States 
for the treatment of patients with unresectable or metastatic melanoma and disease 
progression following treatment with ipilimumab or a BRAF inhibitor, if BRAF V600 
mutation-positive.  Pembrolizumab was also recently approved for the treatment of patients 
with metastatic non-small cell lung cancer (NSCLC) whose tumors express PD-L1 as 
determined by a Food and Drug 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 [16].  Accumulating evidence shows a correlation between tumor-
infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in various 
malignancies [17] [18] [19] [20] [21].  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) 
[22] [23].  
The structure of murine PD-1 has been identified [24].  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 [22] [25] [26] [27].  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 [28] [29].  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 [30] [31].  Expression has also been shown during thymic development on 
CD4–/CD8– (double negative) T-cells as well as subsets of macrophages and dendritic cells 
[32].  
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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 [33] 
[34] [35] [28]. 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 [28].  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 [36].
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 [37] [38] [39] [40] [41] [42]. 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 extends survival [43]. HCC patients with higher tumoral expression of PD-L1 had
a significantly poorer prognosis than patients with lower expression, and tumor expression of 
PD-L1 is an independent predictor for postoperative recurrence in HCC patients [44]. 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 [45]. 
The Phase I/II trial of the anti–PD-1 antibody, nivolumab, in subjects with advanced HCC 
demonstrated an ORR by blinded independent central review of 14%, with several durable 
responses.  Responses were seen both in viral-mediated cancers and those without an 
underlying viral etiology.  Responses were also seen in those with tumors positive or 
negative for PD-L1 tumor staining by immunohistochemistry.  Results showed the safety 
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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. These data provide 
additional preliminary evidence that anti-PD-1 therapy can yield durable responses with an 
acceptable toxicity profile in patients with advanced HCC [15].
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. 
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 [46]. As discussed above, HCC 
patients with higher tumor expression of PD-L1 have a significantly poorer prognosis than 
patients with lower expression [44].  In addition, high expression levels of PD-1 on T-cells, 
both on tumor infiltrating lymphocytes and peripheral blood mononuclear cells, also correlate 
with increased stage and higher recurrence rates in HCC patients after surgical resection [45].  
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 [47].  Seventeen patients were evaluable for response, and 3 
partial responses were seen 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, the interim analysis of a Phase 1/2 trial of the anti–PD-1 antibody, 
nivolumab, in subjects with advanced HCC demonstrated an ORR of 14.3% [48].  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 [49].
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 the 200 mg 
Q3W dose is summarized below. Keynote-001, an open-label Phase 1 study, was conducted 
to evaluate the safety, tolerability, pharmacokinetics (PK) and 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 
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(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 the efficacy and safety profiles across doses. 
An integrated body of evidence suggests that 200 mg Q3W is expected to provide a similar 
response to 2 mg/kg Q3W, 10 mg/kg Q3W and 10 mg/kg Q2W.  Previously, a flat 
pembrolizumab exposure-response relationship for efficacy and safety has been found in 
subjects with melanoma in the range of doses between 2 mg/kg and 10 mg/kg.  Exposures for 
200 mg Q3W are expected to lie within this range and will be close to those obtained with 
2 mg/kg Q3W dose.  
A population PK model, which characterized the influence of body weight and other patient 
covariates on exposure, has been developed.  The PK profile of pembrolizumab is consistent 
with that of other humanized monoclonal antibodies, which typically have a 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.  Pharmacokinetic 
properties of pembrolizumab, and specifically the weight-dependency in clearance and 
volume of distribution are consistent with no 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.
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Rationale for Endpoints
4.2.3.1
Efficacy Endpoints
4.2.3.1.1 Primary Efficacy Endpoints
The primary efficacy objective of this study is to evaluate the anti-tumor activity of 
pembrolizumab in subjects after disease progression on sorafenib or intolerance of sorafenib 
(Cohort 1) or who had not received treatment for systemic disease in the advanced setting 
(Cohort 2).  The ORR will be used as the primary endpoint per RECIST 1.1 criteria as 
assessed by the central imaging vendor.  
4.2.3.1.2 Secondary Efficacy Endpoints
The secondary efficacy objectives of this study are to evaluate DOR, and determine the
safety and tolerability of pembrolizumab in subjects with HCC. DCR, TTP, and PFS per 
RECIST 1.1 will also be assessed by the central imaging vendor; and OS will also be 
examined.
4.2.3.1.3 Exploratory Efficacy Endpoints
Exploratory efficacy objectives of this study are to explore ORR, DOR, DCR, TTP and PFS 
per 1) irRECIST assessed by the central imaging vendor and 2) investigator assessment using 
RECIST 1.1 3) measurements based on RECIST 1.1 assessed by the central imaging vendor
and 4) mRECIST by the central imaging vendor, to assess these different evaluations in an 
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 between 
cause of sorafenib discontinuation (intolerance vs. radiographic progression to disease) and 
response to pembrolizumab in terms of overall survival will also be explored.
4.2.3.2
Immune-related RECIST
RECIST 1.1 will be adapted to account for the unique tumor response characteristics seen 
with pembrolizumab treatment.  Immunotherapeutic agents such as pembrolizumab may 
produce anti-tumor effects by potentiating endogenous cancer-specific immune responses.  
The response patterns seen with such an approach may extend beyond the typical time course 
of responses seen with cytotoxic agents, and can manifest a clinical response after an initial 
increase in tumor burden or even the appearance of new lesions.  Standard RECIST 1.1 may, 
thus, not provide an accurate response assessment of immunotherapeutic agents such as 
pembrolizumab. 
Based on an analysis of patients with melanoma enrolled in Keynote 001, 7% of evaluable 
patients experienced delayed or early tumor pseudoprogression.  Of note, patients who had 
progressive disease by RECIST 1.1 but not by immune-related response criteria had longer 
OS than patients with progressive disease by both criteria.  Additionally, the data suggest that 
RECIST 1.1 may underestimate the benefit of pembrolizumab in approximately 15% of 
patients.  These findings support the need to apply a modification to RECIST 1.1 that takes 
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into account the unique patterns of atypical response in immunotherapy and enable treatment 
beyond initial radiographic progression. 
Immune-related RECIST (irRECIST) is RECIST 1.1 adapted to account for the unique tumor 
response seen with immuno-therapeutics as described in Nishino et al., CCR 2013 [1].  The 
assessment of unidimensional target lesions and response categories per irRECIST are 
identical to RECIST 1.1.  However, MSD has implemented an adaptation related to new 
lesions, non-target and tumor burden assessment in order to confirm radiographic 
progression. 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 7.1.4.1.6.  
4.2.3.3
Safety Endpoints
The safety objective of this trial is to characterize the safety and tolerability of 
pembrolizumab in subjects after disease progression on sorafenib or intolerance of sorafenib 
(Cohort 1) or who had not received treatment for systemic disease in the advanced setting 
(Cohort 2). The primary safety analysis will be based on subjects who have toxicities as 
defined by CTCAE, version 4.0 (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. 
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.
4.2.3.4
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 adverse events 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 
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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 blood-soluble 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 (ie, mutations, methylation 
status, microsatellite instability etc.).  Key molecular changes of interest to immune-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).
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 
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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 (eg, 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 NSLC.   Preliminary data indicates that this 
association may also be true in additional cancer types (ie, 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 immunoassay 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 (PCR) 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.  
4.2.3.5
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 
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.
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Benefit/Risk
It cannot be guaranteed that subjects in clinical trials will directly 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).  
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 and with no curative option after disease
progression on sorafenib or intolerance of sorafenib (Cohort 1) or who had not received 
treatment for systemic disease in the advanced setting (Cohort 2) will be enrolled in this trial.
Subject Inclusion Criteria
In order to be eligible for participation in this trial, the subject must:
1. Be willing and able to provide written informed consent for the trial.  The subject 
may also provide consent for Future Biomedical Research (FBR).  However, the 
subject may participate in the main trial without participating in FBR.
2. Be 18 years of age on day of signing informed consent.
3. For Cohort 1 only: Have histologically or cytologically confirmed diagnosis of HCC 
(fibrolamellar and mixed hepatocellular/cholangiocarcinoma subtypes are not 
eligible) 
based 
on 
pathology 
report.
For Cohort 2 only: Have an 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).
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6. Have a predicted life expectancy of greater than 3 months.
7. Have measurable disease 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. For Cohort 1 only: Have documented objective radiographic progression after 
stopping treatment with sorafenib or else intolerance to sorafenib.  
The definition of sorafenib intolerance will be:
Any Grade ≥2 drug-related AE which, 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.  
10. Subjects with chronic infection by HCV who are untreated are allowed on study.  In 
addition, subjects with successful HCV treatment (defined as sustained virologic 
response [SVR] 12 or SVR 24) are allowed as long as 4 weeks have passed between 
completion of HCV therapy and start of study drug.
11. Have a negative urine or serum pregnancy test within 72 hours prior to receiving the 
first dose of study medication (Cycle 1, Day 1) (female subjects of childbearing 
potential).  If the urine test is positive or cannot be confirmed as negative, a serum 
pregnancy test will be required.  
12. Be willing to use an adequate method of contraception for the course of the study 
through 120 days after the last dose of study medication (male and female subjects of 
childbearing potential [see Section 5.7.2]).
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception 
for the subject.
13.  Demonstrate adequate organ function as defined in Table 1.
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Table 1
Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count
≥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
Coagulation
INR or PT
aPTT (Cohort 1 only)
≤1.5×ULN unless subject is receiving anticoagulant 
therapy as long as PT or aPTT (cohort 1) is within 
therapeutic range of intended use of anticoagulants
Abbreviations: ALT=alanine aminotransferase; aPTT=activated partial thromboplastin time; AST=aspartate 
aminotransferase; EPO = erythropoietin; GFR=glomerular filtration rate; INR=international normalized 
ratio; PT=prothrombin time; PTT=partial thromboplastin time; SGOT=serum glutamic oxaloacetic 
transaminase; SGPT=serum glutamic pyruvic transaminase; ULN=upper limit of normal
Subject Exclusion Criteria
The subject must be excluded from participating in the trial if the subject:
1. Is currently participating and receiving study therapy 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 (ie, to 
Grade ≤1 or baseline) and from adverse events due to any prior therapy. 
2. For Cohort 1 only: 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 trial treatment.  
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4. Has clinically apparent ascites on physical examination. 
Note: ascites detectable on imaging studies only IS allowed.
5. Portal vein invasion at the main portal (Vp4), inferior vena cava, or cardiac 
involvement of HCC based on imaging.  
6. Has had encephalopathy in the last 6 months.  Subjects on rifaximin or lactulose to 
control their encephalopathy are not allowed.
7. Had a solid organ or hematologic transplant.
8. For Cohort 1 only: Had prior systemic therapy for HCC other than sorafenib, or 
intercurrent local therapy to the liver tumor between sorafenib and study drug.  
For Cohort 2 only: Had prior systemic therapy in the advanced disease setting.
9. Has active autoimmune disease that has required systemic treatment in past 2 years 
(ie, with use of disease-modifying agents, corticosteroids, or immunosuppressive 
drugs).  Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a 
form of systemic treatment.
10. 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.
11. Has received locoregional therapy to liver (transcatheter chemoembolization [TACE], 
transcatheter embolization [TAE], radiation, radioembolization, or ablation) or major 
surgery to liver or other site within 6 weeks in Cohort 1 and 4 weeks in Cohort 2 prior 
to the first dose of study drug.  Minor surgery (eg, simple excision, tooth extraction) 
must have occurred at least 7 days prior to the first dose of trial treatment (Cycle 1, 
Day 1).  Subjects must have recovered adequately (ie., Grade ≤1 or baseline) from the 
toxicity and/or complications from any intervention prior to starting therapy.
12. Has a diagnosed additional malignancy within 5 years for Cohort 1 and 3 years for 
Cohort 2 prior to first dose of trial 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 cervical and/or breast cancers.
13. Has radiographically detectable (even if asymptomatic and/or previously treated) 
central nervous system (CNS) metastases and/or carcinomatous meningitis as 
assessed by local site investigator.
14. Has a known history of, or any evidence of, interstitial lung disease or active non-
infectious pneumonitis.
15. Has an active infection requiring systemic therapy
16. Has a known severe hypersensitivity (≥Grade 3) to pembrolizumab, its active 
substance and/or any of its excipients.  (Refer to the Investigator’s Brochure for a list 
of excipients.).
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17. 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.
18. Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.
19. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the screening visit through 120 days after 
the last dose of trial treatment.
20. Has received prior immunotherapy including anti–PD-1, anti–PD-L1, or anti–PD-L2 
agents, or if the subject has previously participated in MSD pembrolizumab clinical 
trials.
21. Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies).
22. Has untreated active Hepatitis B
Note:  To qualify for enrollment, antiviral therapy for HBV must be given for at least 
3 months, and HBV viral load must be less than 100 IU/mL prior to first dose of 
study drug. Those on active HBV therapy with viral loads under 100 IU/mL should 
stay on the same therapy throughout trial treatment. Those subjects who are anti-HBc 
(+) and negative for HBsAg, and have an HBV viral load under 100 IU/mL
irrespective of their anti-HBS value do not require HBV anti-viral prophylaxis but 
need close monitoring.
23. For Cohort 1 only: Has dual infection with HBV/HCV or other hepatitis combinations 
at 
study 
entry.
For Cohort 2 only: Has dual active HBV infection (HBsAg (+) and/or detectable 
HBV DNA) and HCV infection (detectable HCV RNA) at study entry.
24. Has received a live vaccine within 30 days of planned start of study therapy (Cycle 1, 
Day 1).
Note: Killed virus vaccines used for seasonal influenza vaccines for injection are 
allowed; however intranasal influenza vaccines (eg, FluMist®) are live attenuated 
vaccines and are not allowed.
Trial Treatment(s)
The treatment to be used in this trial is outlined below in Table 2.  
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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
IV = intravenous; Q3W = every 3 weeks.
Trial treatment should begin within 3 days of allocation. However, every effort should be 
made to begin trial treatment on the day of allocation.
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 to be used in this trial is provided in Section 4.0 
Background & Rationale.  Details on preparation and administration of pembrolizumab are 
provided in the Pharmacy Manual.
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 one body 
system simultaneously. Therefore, early recognition and initiation of treatment is critical to 
reduce complications. Based on existing clinical trial data, most irAEs were reversible and 
could be managed with interruptions of pembrolizumab administration of corticosteroids 
and/or other supportive care.  For suspected irAEs, ensure adequate evaluation to confirm 
etiology or exclude other causes.  Additional procedures or tests such as bronchoscopy, 
endoscopy, or skin biopsy may be included as part of the evaluation.  Based on the severity 
of irAEs, withhold or permanently discontinue pembrolizumab and administer 
corticosteroids.  Dose modification and toxicity management guidelines for irAEs associated 
with pembrolizumab are provided in Table 3.
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Table 3
Dose Modification and Toxicity Management Guidelines for Immune-related AEs Associated with Pembrolizumab
General instructions:
1.
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks.
2.
For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and corticosteroid 
has been tapered. Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids cannot be 
reduced to ≤10 mg prednisone or equivalent per day within 12 weeks. 
3.
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive treatment should be 
initiated if irAEs cannot be controlled by corticosteroids.
Immune-related 
AEs (irAEs)
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with 
corticosteroid and/or other 
therapies
Monitor and follow-up
Pneumonitis 
Grade 2
Withhold 
Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper

Monitor participants for signs and symptoms of 
pneumonitis

Evaluate 
participants 
with 
suspected 
pneumonitis with radiographic imaging and 
initiate corticosteroid treatment

Add prophylactic antibiotics for opportunistic 
infections
Grade 3 or 4, or 
recurrent Grade 2
Permanently 
discontinue
Diarrhea / Colitis 
Grade 2 or 3
Withhold
Administer corticosteroids (initial
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper

Monitor participants for signs and symptoms of 
enterocolitis (ie, diarrhea, abdominal pain, blood 
or mucus in stool with or without fever) and of 
bowel perforation (ie, peritoneal signs and 
ileus).

Participants with ≥ Grade 2 diarrhea suspecting 
colitis should consider GI consultation and 
performing endoscopy to rule out colitis. 

Participants with diarrhea/colitis should be 
advised to drink liberal quantities of clear fluids.  
If sufficient oral fluid intake is not feasible, fluid 
and electrolytes should be substituted via IV 
infusion.
Grade 4
Permanently 
discontinue
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Immune-related 
AEs (irAEs)
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 
participants 
with 
T1DM 
Administer anti-hyperglycemic in 
participants with hyperglycemia 

Monitor participants for hyperglycemia or other 
signs and symptoms of diabetes.
Hypophysitis
Grade 2
Withhold
Administer 
corticosteroids 
and 
initiate hormonal replacements as 
clinically indicated.  

Monitor for signs and symptoms of hypophysitis 
(including 
hypopituitarism 
and 
adrenal 
insufficiency)
Grade 3 or 4 
Withhold 
or 
permanently 
discontinue1
Hyperthyroidism 
Grade 2
Continue 
Treat with non-selective beta-
blockers 
(eg, 
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 (eg, levothyroxine or 
liothyronine) per standard of care

Monitor for signs and symptoms of thyroid 
disorders. 
Nephritis and 
Renal dysfunction
Grade 2
Withhold 
Administer 
corticosteroids 
(prednisone 
1-2 
mg/kg 
or 
equivalent) followed by taper.

Monitor changes of renal function
Grade 3 or 4 
Permanently 
discontinue
Myocarditis
Grade 1 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
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Immune-related 
AEs (irAEs)
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with 
corticosteroid and/or other 
therapies
Monitor and follow-up
All other immune-
related AEs
Intolerable/ 
persistent Grade 2
Withhold
Based on type and severity of AE 
administer corticosteroids 

Ensure adequate evaluation to confirm etiology 
and/or exclude other causes
Grade 3
Withhold 
or 
discontinue 
based 
on the type of event.  
Events that require 
discontinuation 
include 
and 
not 
limited to:  Gullain-
Barré
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 participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may be resumed 
when AE resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM).
AE = GI = irAE = IV = 
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Dosing interruptions are permitted in the case of medical/surgical events or for logistical 
reasons not related to study therapy (eg, 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
Cohort 1
In addition to overdose, hepatic ECIs will include any of the following events. All of these 
events will require holding pembrolizumab treatment, notification of the Sponsor within 
24 hours, and a hepatology consultation. Refer to Section 7.2.3.2 for reporting guidelines and 
the definition of hepatic ECIs.
Immediate assessment
All subjects

All subjects should be evaluated according to directions below within 
72 hours of alert for 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, Tbil, Dbil, ALP, -glutamyl transpeptidase (GGT), 
INR, and 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.
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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 (eg, esophageal or 
gastric varices)

New onset of clinically detectable ascites

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
Other subjects may be eligible for treatment interruption (and potential re-start) of 
pembrolizumab after discussion with the Sponsor (Section 5.8.1).  
Diagnosis and Management of Non-Overdose Hepatic ECIs
HCC subjects are at risk for a range of complications that can cause hepatic 
laboratory abnormalities with or without clinical decompensation. Those with a 
history of chronic HCV or HBV infection also have the potential to experience 
virologic flares. Immune-related hepatitis has been observed in ~1% of subjects who 
received pembrolizumab. The following section provides further guidance on the 
diagnosis and management of potential hepatic complications among HCC subjects. 
a.
Hepatitis B Flare
Hepatitis B flares are characterized by rapid elevations of ALT and AST to 
>5×ULN and/or >3× baseline. ALT elevation to ≥10×ULN is common. In the 
absence of hepatic decompensation, ALT/AST elevations are typically isolated 
(ie, 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 to 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, pembrolizumab dosing may be interrupted 
for up to 12 weeks. 
Subjects should undergo weekly laboratory tests 
including: AST, ALT, ALP, Tbil, Dbil, INR, HBsAg, and 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 to 3 weeks.
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
If ALT returns to normal or Grade 1 (if normal at baseline), or to baseline 
grade (if Grade 2 at baseline) within 12 weeks, and subjects are clinically 
stable, subjects may restart pembrolizumab treatment. If these conditions are 
not met, then pembrolizumab treatment should be permanently discontinued.
b. Hepatitis C Recurrence or Flare
Subjects who achieved SVR 12 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 (ie, 
limited/no elevations of bilirubin/ALP).
Among subjects with uncontrolled hepatitis C, virologic flares are possible. 
Hepatitis C flares are characterized by rapid elevations of ALT and AST to 
>5×ULN and/or >3× baseline along with a rise in HCV RNA. ALT elevation to 
≥10×ULN and a 1 log elevation in HCV RNA level are common. In the absence 
of hepatic decompensation, ALT/AST elevations are typically isolated (ie, 
limited/no elevations of bilirubin/ALP). Laboratory abnormalities secondary to 
flare or recurrence are typically observed for 3 to 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 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 considered.
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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 
pembrolizumab
treatment.
If these conditions are not met, then 
pembrolizumab treatment should be permanently discontinued.
c.
Immune-related hepatitis 
i. Description: Immune-related hepatitis due to pembrolizumab should be 
suspected if 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

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 pembrolizumab treatment and alert the sponsor as per ECI 
criteria above for ALT, AST, bilirubin, and hepatic decompensation. 

Start IV corticosteroid (methylprednisolone 125 mg) followed by oral 
corticosteroid (1-2 mg/kg/day). 

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.  Pembrolizumab 
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 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.
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d. Other Hepatic Events of Clinical Interest

Infection should 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. 

For all of these cases, subjects may resume pembrolizumab treatment if they 
are clinically stable after appropriate therapy or discontinue the causative
agent, as long as laboratory values have returned to Grade 1 or baseline (if 
normal or Grade 1 at start) or to baseline grade within 3 weeks. 

Treatment
must be permanently discontinued if the subject is
off 
pembrolizumab therapy for infection, obstruction, or drug/alcohol-related 
toxicity for more than 3 weeks, or if they have esophageal bleeding, or 
become Child-Pugh C at any point.  
Cohort 2
Hepatic ECIs have been described in Section 7.2.3.2. All of these HECIs will require holding 
pembrolizumab treatment and notification of the Sponsor within 24 hours. All cases of 
retreatment and permanent discontinuation must be reported to the Sponsor and recorded in 
the database.
Immediate assessment in case of HECI:
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
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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
Measure HCV RNA viral load (applies only for participants who have current active 
HCV infection or had infection in the past)
o
HBV DNA, HBsAg, HBeAg, anti-HBc (total and IgM), anti-HBe, and anti-HBs 
(Note: participants should be questioned about compliance with the use of anti-viral 
agents)
o
Other laboratories or imaging studies as clinically indicated
o
Consider liver biopsy if indicated 
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 participants who received pembrolizumab. The 
following section provides further guidance on the diagnosis and management of potential 
hepatic complications among HCC subjects in this study (Table 4).
Table 4
Guidance for Diagnosis and Management of Hepatic Events of Clinical Interest 
Event
Diagnosis
Management
Hepatitis 
B 
consider flare or 
change in HBV 
immunologic 
status
1) Rapid elevation of 
ALT to >5×ULN 
and/or >3× baseline
Interrupt treatment for up to 12 weeks 
Check for compliance if HBV is detectable
Measure safety labs for AST, ALT, ALP, T 
Bili, D Bili, INR on weekly basis
Measure HBsAg, HBV DNA on weekly
basis (if detected at the time of onset of 
ECI)
Evaluate the following every 2 to 3 weeks:

anti-HBe, HBe antigen, anti-HBs, and 
HBV DNA levels (if not detected at the 
onset of ECI)
Restart treatment only if ALT returns to 
normal or Grade 1 (if normal at baseline), or 
to baseline grade (if Grade 2 at baseline) 
within 12 weeks, and the participant is 
clinically stable, otherwise the participant 
should be permanently discontinued
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Event
Diagnosis
Management
Hepatitis
C 
exacerbation 
in 
participants with 
positive baseline 
HCV RNA 
Rapid 
elevation 
of 
ALT 
to 
>5×ULN 
and/or >3x baseline 
Interrupt study treatment for up to 12 weeks
Assess use of injection or inhalation drugs
Check HCV genotype at the time of first 
detection of HCV RNA to rule out new 
infection 
Measure safety labs for AST, ALT, ALP, T 
Bili, D Bili, INR on weekly basis
Measure HCV RNA levels every 2 weeks
Consider starting HCV anti-viral therapy; 
discuss risk benefit with sponsor before 
starting.
Restart treatment only if ALT returns to 
normal or G1 (if normal at baseline), or to 
baseline grade (if G2 at baseline) within 12 
weeks, and the participant is clinically 
stable, otherwise, the participant should be 
permanently discontinued
Relapse of HCV
infection
for 
participants with 
successfully 
treated or 
new 
HCV infection on 
study intervention
If HCV RNA was TND 
at baseline, and now 
has 
confirmed 
detectable HCV RNA 
(2 specimens, 1 week 
apart)
Immune-related 
Hepatitis
If any of the HECI 
criteria 
is 
met 
as 
defined in the protocol 
Section 8.4.7
Note: Immune-related 
hepatitis is a diagnosis 
made after excluding 
other 
possible 
etiologies such as Viral 
flare, 
biliary 
or 
vascular 
obstruction, 
infection, medications, 
and alcohol use usually 
immune-related 
hepatitis response to 
dechallenge 
and/or 
steroids 
and 
occurs 
with rechallenge
Interrupt study treatment for up to 12 weeks
Start IV corticosteroid 60 mg/day of 
prednisone or equivalent followed by oral 
corticosteroid
Monitor with biweekly laboratory tests 
including AST, ALT, T Bili, D Bili, ALP, 
and INR
Restart study treatment only if: 
a) Abnormal laboratory values resolve to 
Grade ≤1 or baseline (if abnormal at 
baseline); then steroids may be tapered
b) Taper steroid  over 28 days
c) Steroid treatment is tapered to 
prednisone <10 mg/day or equivalent
within 12 weeks
Permanently Discontinue participant if:
a) Laboratory abnormalities do not resolve 
within 3 weeks
b) Steroids cannot be lowered to ≤10 
mg/day (or prednisone equivalent) 
within 12 weeks
c) Evidence of decompensation to CP C 
status 
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Event
Diagnosis
Management
Other Causes
Rule out infection with 
blood, 
urine,
and 
ascites 
culture 
–
antibiotics should be 
started if infection is 
found
If total bilirubin is 
elevated, 
imaging 
should be obtained to 
rule 
out 
vascular 
compromise, 
biliary 
obstruction, 
and/or 
tumor progression by 
imaging
Ruled out alcohol use 
and hepatotoxic drugs 
including herbal and 
alternative medications
Interrupt treatment for up to 12 weeks 
Restart study treatment only if laboratory 
values have returned to Grade 1 or baseline 
(if normal or Grade 1 at start) or to baseline 
grade within 3 weeks
If biliary obstruction is present, consultation 
with 
a 
gastroenterologist 
and/or 
an 
interventional radiologist should be obtained 
to see if the obstruction may be relieved 
Abbreviations: 
ALP=alkaline 
phosphatase; 
ALT=alanine 
aminotransferase; 
AST=aspartate 
aminotransferase; D Bili=direct bilirubin; DNA=deoxyribonucleic acid; ECI=events of clinical interest; 
HBe=hepatitis B early antibody; HBs = hepatitis B surface; HBsAg= hepatitis B surface antigen; 
HBV=hepatitis B virus;
HCV=hepatitis C virus; HECI=hepatic events of clinical interest; 
RNA=ribonucleic acid; INR=international normalized ratio; T Bili=total bilirubin; ULN=upper limit of 
normal
Permanent Discontinuation Criteria for Subjects with Non-overdose Hepatic ECI
Therapy should also be permanently discontinued for any of the following: 

ALT >20×ULN (confirmed within 1 week)

CP score of >9 points

Hepatic Encephalopathy

If ascites is not due to PD and not manageable by intervention within 3 days
Recurrence of a severe or life-threatening event, or of any of the laboratory abnormalities 
listed above, that are presumed to be immune-related.
Timing of Dose Administration
Cycle 1 Day 1 treatment with pembrolizumab should begin on the day of allocation, but no 
later than 3 days from the date the subject is allocated to trial treatment. However, every 
effort should be made to begin trial treatment on the day of allocation.
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For all additional cycles of pembrolizumab, 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 trial 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
Pembrolizumab will be administered as a 30 minute IV infusion every 3 weeks.  Sites should 
make every effort to target infusion timing to be as close to 30 minutes as possible.  
However, given the variability of infusion pumps from site to site, a window of –5 minutes 
and +10 minutes is permitted (ie, infusion time is 30 minutes: –5 min/+10 min).
The Pharmacy Manual contains specific instructions for the preparation of the 
pembrolizumab infusion fluid and administration of infusion solution.
All trial treatments will be administered on an outpatient basis.
Trial Blinding 
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered.
Randomization or Treatment Allocation
Treatment allocation will occur centrally using an interactive voice response 
system/integrated web response system (IVRS/IWRS).  All enrolled subjects will be 
allocated to receive pembrolizumab 200 mg IV Q3W as monotherapy in an unblinded 
fashion.  
Stratification
No stratification based on age, sex or other characteristics will be used in this trial.
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 
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medical care.  All concomitant medication will be recorded on the case report form (CRF) 
including all prescription, over-the-counter (OTC), and IV medications and fluids.
If 
changes occur during the trial period, documentation of drug dosage, frequency, route, and 
date should also 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 radiation 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.
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/local therapy for tumor control.
Radiation for pain or palliation is 
acceptable.  

Live vaccines within 30 days prior to the first dose of trial treatment (Cycle 1 
Day 1) 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 vaccine (BCG), and typhoid (oral) vaccine. 
The killed virus vaccines used for seasonal influenza vaccines for injection are 
allowed; however live attenuated intranasal influenza vaccines (eg, 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 
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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 (eg,
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 trial
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 (ie, drugs with a warning of hepatotoxicity in the 
package insert) should be avoided during the dosing period.  Investigators are 
encouraged to review each medication for potential hepatotoxicity by searching the 
www.livertox.nih.gov website.
Listed below are specific restrictions for concomitant therapy during the course of the trial.
The following medications/therapies should be avoided during the dosing period and for 
14 days thereafter:
Known hepatotoxic drugs, including but not limited to: 

Etifoxine

Isoniazid

Nitrofurantoin

Ketoconazole

Amiodarone

Phenytoin
Herbal Supplements/Alternative Medicines

No herbal supplements or alternative medicines are allowed during this study.  
The exclusion criteria describe other medications that are prohibited in this trial.  
There are no prohibited therapies during the post-treatment follow-up phase.
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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 below.  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 trial treatment. 
Note: if after the evaluation the event is determined not to be related, the investigator does 
not need to follow the treatment guidance (as outlined below). Refer to Section 5.2.1.2 for 
dose interval modification. 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event. 

Hepatic:
Guidance for Diagnosis and Management of Hepatic Events of Clinical Interest can 
be found in Section 5.2.1.3.  

Pneumonitis: 
o
For Grade 2 events, treat with systemic corticosteroids.  When symptoms 
improve to Grade 1 or less, steroid taper should be started and continued over 
no less than 4 weeks.
o
For Grade 3-4 events, immediately treat with intravenous steroids. 
Administer additional anti-inflammatory measures, as needed.
o
Add prophylactic antibiotics for opportunistic infections in the case of 
prolonged steroid administration.

Diarrhea/Colitis:
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such 
as diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of 
bowel perforation (such as peritoneal signs and ileus).  
o
All subjects who experience diarrhea/colitis should be advised to drink liberal 
quantities of clear fluids.  If sufficient oral fluid intake is not feasible, fluid 
and electrolytes should be substituted via IV infusion.  For Grade 2 or higher 
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diarrhea, consider GI consultation and endoscopy to confirm or rule out 
colitis.
o
For Grade 2 diarrhea/colitis, administer oral corticosteroids. 
o
For Grade 3 or 4 diarrhea/colitis, treat with intravenous steroids followed by 
high dose oral steroids.  
o
When symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks.

Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or 
≥ Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic 
acidosis (DKA)
o
For new onset T1DM or Grade 3-4 Hyperglycemia

Insulin replacement therapy is recommended for T1DM and for 
Grade 3-4 hyperglycemia associated with metabolic acidosis or 
ketonuria. 

Evaluate patients with plasma glucose and a metabolic panel, urine 
ketones, HbA1c and C-peptide. 

Hypophysitis:
o
For Grade 2 events, treat with corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 
4 weeks.
Replacement of appropriate hormones may be required as the 
steroid dose is tapered.
o
For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed 
by oral corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. Replacement 
of appropriate hormones may be required as the steroid dose is tapered.

Hyperthyroidism or Hypothyroidism: 
Thyroid disorders can occur at any time during treatment. Monitor patients for 
changes in thyroid function (at the start of treatment, periodically during treatment, 
and as indicated based on clinical evaluation) and for clinical signs and symptoms of 
thyroid disorders.
o
Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism):

In hyperthyroidism, non-selective beta-blockers (eg, propranolol) are 
suggested as initial therapy.

In hypothyroidism, thyroid hormone replacement therapy, with 
levothyroxine or liothyronine, is indicated per standard of care.
o
Grade 3-4 hyperthyroidism 

Treat with an initial dose of IV corticosteroid followed by oral 
corticosteroids.  When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks.  
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Replacement of appropriate hormones may be required as the steroid 
dose is tapered.

Renal Failure or Nephritis:
o
For Grade 2 events, treat with corticosteroids.
o
For Grade 3-4 events, treat with systemic corticosteroids.
o
When symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks.

Management of Infusion Reactions:
Signs and symptoms usually develop during or shortly after drug infusion and 
generally resolve completely within 24 hours of completion of infusion.
Pembrolizumab may cause severe or life-threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis.  Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion.  
Dose modification and toxicity management guidelines on pembrolizumab associated 
infusion reaction are provided in Table 5.  
Table 5
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 
(eg, 
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 
pembrolizumab 
with:
Diphenhydramine 50 mg PO (or 
equivalent 
dose 
of 
antihistamine).
Acetaminophen 
500-1000 mg 
PO
(or equivalent dose of 
antipyretic).
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NCI CTCAE Grade
Treatment
Premedication at subsequent 
dosing
Grades 3 or 4
Grade 3:
Prolonged 
(ie, 
not 
rapidly 
responsive 
to 
symptomatic 
medication 
and/or 
brief 
interruption 
of 
infusion); 
recurrence 
of 
symptoms 
following initial improvement; 
hospitalization indicated for other 
clinical 
sequelae 
(eg, 
renal 
impairment, 
pulmonary 
infiltrates)
Grade 4:
Life-threatening; 
pressor 
or 
ventilatory support indicated
Stop Infusion.
Additional appropriate medical therapy may 
include but is not limited to:
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.
*In cases of anaphylaxis, epinephrine should be 
used immediately.
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.
For further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) at 
http://ctep.cancer.gov
Abbreviations: CTCAE= Common Toxicity Criteria for Adverse Events; IV=intravenous; NCI=National Cancer Institute; 
NSAIDs=non-steroidal anti-inflammatory drugs; PO=by mouth
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).  
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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 pembrolizumab (MK-3475) and for 
120 days after the last dose. Subjects must comply with one of the following:  
(1) practice abstinence† from heterosexual activity; 
OR
(2) use (or have their partner use) acceptable contraception during heterosexual activity.  
Acceptable methods of contraception are‡:
Single method (one of the following is acceptable):
• intrauterine device (IUD)
• vasectomy of a female subject’s sole 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 
(eg, calendar, ovulation, sympto-thermal, post-ovulation methods, etc.) and withdrawal are 
not acceptable methods of contraception. 
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‡If a contraceptive method listed above is restricted by local regulations/guidelines, then it 
does not qualify as an acceptable method of contraception for subjects participating at sites in 
this country/region.
Subjects should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate 
in the study, subjects of childbearing potential must adhere to the contraception requirement 
(described above) from the day of study medication initiation (or 14 days prior to the 
initiation of trial treatment [Cycle 1 Day 1] for oral contraception) throughout the study 
period up to 120 days 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.  
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 
it may 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 (a woman who is ≥45 years of age and has not had menses for greater 
than 1 year will be considered postmenopausal), or 3) not heterosexually active for the 
duration of the study. 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
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Subjects should start using birth control from study Visit 1 throughout the study period up to
120 days after the last dose of study therapy.
Subjects should be informed that taking the study medication may involve unknown risks to
the fetus (unborn baby) if pregnancy were to occur during the study. In order to participate
in the study they must adhere to the contraception requirement (described above) for the
duration of the study and during the follow-up period defined in Section 7.2.2 – Reporting of
Pregnancy and Lactation to the Sponsor. If there is any question that a subject will not
reliably comply with the requirements for contraception, that subject should not be entered
into the study.
Use in Pregnancy
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, the 
subject will immediately be removed from the trial treatment.  The site will contact the 
subject at least monthly and document the subject’s status until the pregnancy has been 
completed or terminated.  The outcome of the pregnancy will be reported to the Sponsor 
without delay and within 24 hours if the outcome is a serious adverse experience (eg, 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
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the 
trial plan is violated, or for administrative and/or other safety reasons.  Specific details 
regarding discontinuation or withdrawal procedures; including specific details regarding 
withdrawal from Future Biomedical Research, are provided in Section 7.1.5 – Other 
Procedures.
In this trial, a subject may discontinue treatment but continue to participate in survival follow 
up, as long as the subject does not withdraw consent.  Once a subject has discontinued initial 
treatment, he/she may be eligible for retreatment if deemed medically appropriate and the 
subject meets the criteria, as outlined in Section 7.1.6.  
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A subject must be discontinued from the trial for any of the following reasons:
●
The subject or legal representative (such as a parent or legal guardian) withdraws 
consent.

The subject is lost to follow-up.
A subject must be discontinued from treatment (but may continue to be monitored in the 
trial) for any of the following reasons:

The subject or legal representative (such as a parent or legal guardian) withdraws 
consent for treatment

Confirmed radiographic PD (irPD) as outlined in Section 7.1.4 (exception if Sponsor 
approves treatment continuation)

Unacceptable adverse events as described in Section 7.2.

Intercurrent illness that prevents further administration of treatment

Investigator’s decision to withdraw the subject

The subject has a confirmed positive urine or serum pregnancy test

Noncompliance with trial treatment or procedure requirements

Administrative reasons

Completed 35 treatments with pembrolizumab
o
Note: 35 treatments (approx. 2 years) are calculated from the first dose. Subjects 
who stop pembrolizumab after receiving 35 treatments may be eligible for 
retreatment if they progress after stopping trial 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.
The End of Treatment and Follow-up visit procedures are listed in Section 7.1.6 and the Trial 
Flow Chart in Section 6.0. After the end of treatment, each subject will be followed for a 
minimum of 30 days for adverse event monitoring (serious adverse events will be collected 
for up to 90 days after the end of treatment as described in Section 7.2.3). Subjects who 
discontinue trial treatment for a reason other than disease progression will move into the 
Follow-up Phase of the study and should be assessed every 12 weeks (84±7 days) by
radiologic imaging to monitor disease status, or more frequently if clinically indicated.  
Disease status will be monitored until the subject experiences PD, initiates a non-study 
cancer treatment, withdraws consent from participation in the study, or becomes lost to 
follow-up. After documented PD each subject will be followed (eg, by telephone or visit) for 
OS until death, withdrawal of consent from participating in the study, or the end of the study, 
whichever occurs first.
Discontinuation of Study Therapy after Complete Response
Discontinuation of treatment may be considered for subjects who have attained confirmed 
CR that have received at least 8 trial treatments (approx. 6 months) pembrolizumab and had 
at least 2 treatments with pembrolizumab beyond the date when the initial CR was declared.  
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Subjects who stop then experience radiographic PD may be eligible for up to 17 additional 
treatments (approx. 1 year) with pembrolizumab in the Second Course Phase at the discretion 
of the investigator if:
•
No cancer treatment was administered since the last dose of pembrolizumab
•
The subject meets the parameters listed in the Inclusion/Exclusion criteria
•
The trial is ongoing
Subjects will resume therapy at the same dose and schedule as at the time of initial 
discontinuation. 
Additional details are provided in Section 7.1.6.2.1.  Response or 
progression in this Second Course Phase will not count towards the primary endpoint in this 
trial.
Subject Replacement Strategy
A subject who discontinues from the trial will not be replaced.
Beginning and End of the Trial
The overall trial begins when the first subject signs the informed consent form.  The overall 
trial ends when the last subject completes the last study-related phone-call or visit,
discontinues from the trial or is lost to follow-up (i.e. the subject is unable to be contacted by 
the investigator).
Clinical Criteria for Early Trial Termination
Early trial termination will be the result of the criteria specified below:
The clinical trial may be terminated early if the extent (incidence and/or severity) of 
emerging effects/clinical endpoints is such that the risk/benefit ratio to the trial population as 
a whole is unacceptable.  In addition, further recruitment in the trial or at (a) particular trial 
site(s) may be stopped due to insufficient compliance with the protocol, GCP, and/or other 
applicable regulatory requirements, procedure-related problems, or the number of 
discontinuations for administrative reasons is too high.
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6.0 TRIAL FLOW CHART
Initial Treatment with Pembrolizumab
Trial Period:
Screen-
ing 
Phase
Treatment Cycles (3-Week Cycles)
End of 
Treatment
Post-treatment
Treatment Cycle/Title:
Screen-
ing
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
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 (to include 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 statusc
X
Clinical 
Procedures/Assessments
Review adverse eventsd
X
X
X
X
X
X
X
X
X
X
X
X
Full physical examination
X
X
X
Directed physical examination
X
X
X
X
X
X
X
X
Child-Pugh scoree
Xf
Height, weight, and vital signs 
(T, P, RR, BP)g
X
X
X
X
X
X
X
X
X
X
12-Lead electrocardiogram
X
Upper endoscopy 
Xh
ECOG performance status
Xf
X
X
X
X
X
X
X
X
X
Pembrolizumab administration
Xc
X
X
X
X
X
X
X
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Trial Period:
Screen-
ing 
Phase
Treatment Cycles (3-Week Cycles)
End of 
Treatment
Post-treatment
Treatment Cycle/Title:
Screen-
ing
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
Every 12 Weeks
Scheduling Window (Days)b
-28 to -1
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±7
LOCAL 
Laboratory 
Assessments
Pregnancy testi
X
Xj
X
X
X
X
X
X
X
X
X
PT/INR and aPTT (Cohort 1 only)
Xf
X
X
X
X
X
X
X
X
X
CBC with differentialk
Xf
X
X
X
X
X
X
X
X
X
Chemistry panel and liver panelk
Xf
X
X
X
X
X
X
X
X
X
Urinalysisl
Xf
X
X
X
X
X
T3, FT4, and TSHl
Xf
X
X
X
X
X
X
AFPm
Xf
X
X
X
X
X
X
X
X
X
C-Reactive protein
(Cohort 1 
only)n
X
X
X
X
Anti-HCV (Cohort 1 only)
X
If Anti-HCV positive: (Cohort 1 
only)
HCV genotype
X
HCV viral loado
X
X
X
X
X
X
X
X
X
X
Anti-HBc (total and IgM), anti-
HBs, HBV viral load, HBsAg
(Cohort 1 only)
X
If (1) HBsAg+ or (2) anti-HBc+, 
anti-HBs-, and HBsAg- and viral 
load <100 IU/mL: (Cohort 1 only)
Anti-HDV (Cohort 1 only)
X
Anti-HBe  and HBeAg (Cohort 
1 only)
X
HBsAg and HBV viral load
(Cohort 1 only)o
X
X
X
X
X
X
X
X
X
Anti-HBc 
(total), 
anti-HBe, 
anti-HBs, and HBe antigen
(Cohort 1 only)o
X
X
X
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Trial Period:
Screen-
ing 
Phase
Treatment Cycles (3-Week Cycles)
End of 
Treatment
Post-treatment
Treatment Cycle/Title:
Screen-
ing
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
Every 12 Weeks
Scheduling Window (Days)b
-28 to -1
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±7
CENTRAL 
Laboratory 
Assessments
Anti-HCV (Cohort 2 only)
X
If Anti-HCV positive: (Cohort 2
only)
HCV genotype
X
HCV viral load p
X
Anti-HBc (total and IgM) p, anti-
HBsp, HBV viral loadp, HBsAgp
(Cohort 2 only)
X
If (1) HBsAg+ or (2) anti-HBc+, 
anti-HBs-, and HBsAg- and viral 
load <100 IU/mL: (Cohort 2 only)
Anti-HDV (Cohort 2 only)
X
Anti-HBe and HBeAg (Cohort 
2 only)p
X
Blood for genetic analysesq
X
Blood 
for 
biomarker 
studies 
(serum and plasma)n
X
X
X
X
Blood for ctDNA (plasma)v
X
X
X
X
Blood for RNA analysisn
X
X
X
X
Tumor 
tissue 
for 
biomarker 
analysisr
X
Efficacy Measurements
Tumor imaging
Xs
Xt
Xu
X
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Trial Period:
Screen-
ing 
Phase
Treatment Cycles (3-Week Cycles)
End of 
Treatment
Post-treatment
Treatment Cycle/Title:
Screen-
ing
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
Every 12 Weeks
Scheduling Window (Days)b
-28 to -1
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±7
a.
In subjects that experience site-assessed PD or start a new anti-cancer therapy, contact should be made (example; by telephone) Q12W to assess for survival status.
b.
Cycle 1 treatment must be given within 3 days of allocation.  The window for each visit is ±3 days unless otherwise noted.  
c.
After documented local site assessed disease progression, or the start of new anticancer treatment; contacts are approximately every 12 weeks by telephone. Updated 
survival status may be requested by the Sponsor at any time during the course of the study.  Upon Sponsor notification, all participants who do not/will not have a 
scheduled study visit or study contact during the Sponsor defined time period will be contacted for their survival status (excluding participants that have a previously 
recorded death event in the collection tool). 
d.
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 until the hepatic ECIs resolve.
e.
If any of the hepatic ECI criteria are met, collect the Child-Pugh Score until the hepatic ECIs resolve.
f.
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.
g.
Height will be measured at Visit 1 only.
h.
Upper endoscopy to be performed at any time within 12 months before the first dose of study drug. 
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 a 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.  In Cohort 2, pregnancy testing is to be done only at screening and whenever an 
expected menstrual cycle is missed or when pregnancy is otherwise suspected; unless there is a country-specific regulation to have monthly testing.
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, urinalysis and thyroid function tests will be performed every other cycle.
m.
For Cohort 1, AFP will be measured every 3 weeks (21 +/-7 days) calculated from the date of allocation. For Cohort 2, AFP will be measured every 9 weeks (63 +/-7 
days) calculated from the date of allocation.
n.
Whole blood samples should be collected pre-dose at Cycle 1, Cycle 2, Cycle 5, and again at discontinuation or progression of disease.  These samples can be taken up to 
72 hours prior to dosing.  
o.
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 HBe 
antigen 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.  
08LLR6

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Trial Period:
Screen-
ing 
Phase
Treatment Cycles (3-Week Cycles)
End of 
Treatment
Post-treatment
Treatment Cycle/Title:
Screen-
ing
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
Every 12 Weeks
Scheduling Window (Days)b
-28 to -1
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±7
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. 
p.
For Cohort 2, HCV RNA, anti-HBc (total and IgM), HBSAg, anti-HBs, and HBV DNA will be tested only at screening. Participants must have baseline results within 28 
days of first dose. Post baseline tests will be done in case of HECI, following HECI management guidance provided in section 5.2.1.3 for cohort 2. All additional post-
baseline laboratory tests should be performed by a central laboratory, if possible.
q.
Details for collection of blood for genetic testing can be found in: Section 7.1.3.5 Planned Genetic Analysis Sample Collection.
r.
Tissue is not required for enrollment, but is strongly encouraged if available. Newly obtained tissue is preferred (ie, after sorafenib treatment in Cohort 1 only); 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 Future 
Biomedical Research (FBR) consent. FNA samples are acceptable if available.
s.
Screening tumor imaging will be performed within 21 days prior to allocation.  Confirmation of baseline measurable disease per RECIST 1.1 by the central imaging 
vendor is required prior to subject allocation. Imaging at screening should include the chest, abdomen, and pelvis, as detailed in the Site Imaging Manual.
t.
The first on-study imaging time point will be performed at 9 weeks (63±7 days) calculated from the date of allocation and will continue to be performed Q9W (63±7 
days), or earlier if clinically indicated. Imaging details can be found in the Site Imaging Manual. 
u.
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.
v.
For cohort 1, plasma for ctDNA should be collected pre-dose only at C1D1. For cohort 2, plasma for ctDNA should be collected at C1D1, C2D1, C5D1, and then every 3 
cycles after that until EOT
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Second Course Treatment
Trial Period:
Treatment Cycles
End of 
Treatment
Post-treatment
Treatment Cycle/Title:
1
2
3
4
5
6
7
8 and 
Beyond
Discon
Safety 
Follow
Up
Follow-up 
Visits
Survival Follow Upa
At Time of 
Discon
30 Days 
Post-
Discon
Every12 We
eks Post 
Discon
Every 12 Weeks
Scheduling Window (Days)b
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 7
± 7
± 7
Administrative Procedures
Eligibility criteria
X
Concomitant medication review
X
X
X
X
X
X
X
X
X
X
Clinical Procedures/Assessments
Review adverse eventsc
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 Scored
Xe
Weight, and vital signs (T, P, RR, BP)
X
X
X
X
X
X
X
X
X
ECOG performance statuse
X
X
X
X
X
X
X
X
X
Post-study anticancer therapy status
X
X
X
Survival statusf
X
Trial Treatment Administration
Pembrolizumab
X
X
X
X
X
X
X
X
LOCAL Laboratory Assessments
Pregnancy testg
X
X
X
X
X
X
X
X
X
X
PT/INR and aPTT (Cohort 1 only)
Xe
X
X
X
X
X
X
X
X
X
CBC with differentialh
Xe
X
X
X
X
X
X
X
X
X
Chemistry panelh
Xe
X
X
X
X
X
X
X
X
X
Urinalysisi
Xe
X
X
X
X
X
T3, FT4, and TSHi
Xe
X
X
X
X
X
X
AFPj
Xe
X
X
X
X
X
X
X
X
Anti-HCV (Cohort 1 only)k
X
If Anti-HCV positive: (Cohort 1 only)
HCV viral loadl
X
X
X
X
X
X
X
X
X
HCV genotype
X
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Trial Period:
Treatment Cycles
End of 
Treatment
Post-treatment
Treatment Cycle/Title:
1
2
3
4
5
6
7
8 and 
Beyond
Discon
Safety 
Follow
Up
Follow-up 
Visits
Survival Follow Upa
At Time of 
Discon
30 Days 
Post-
Discon
Every12 We
eks Post 
Discon
Every 12 Weeks
Scheduling Window (Days)b
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 7
± 7
± 7
If (1) HBsAg+ or (2) anti-HBc+, anti-
HBs-, HBsAg-
and viral load <100 
IU/mL (Cohort 1 only)
HBsAg and HBV viral loadl
X
X
X
X
X
X
X
X
X
Anti-HBc (total), anti-HBe , anti-HBs, 
and HBe antigenl
X
X
Central Laboratory Assessments
Efficacy Measurements
Anti-HCV (Cohort 2 only)k
X
If Anti-HCV positive: (Cohort 2 only)
HCV viral load m
X
HCV genotype
X
Anti-HBc (total and IgM), anti-HBs, 
HBV viral load, HBsAg (Cohort 2 only)m
X
If (1) HBsAg+ or (2) anti-HBc+, anti-
HBs-, HBsAg-
and viral load <100 
IU/mL (Cohort 2 only)
Anti-HDV (Cohort 2 only)
X
Anti-HBe and HBeAg (Cohort 2 only)m
X
Tumor imaging
Xn
Xn
Xo
X
a.
In subjects that experience site assessed PD or starts a new anti-cancer therapy contact should be made (by telephone or visit) Q12W to assess for survival status.
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 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 pembrolizumab.
f.
After documented local site assessed disease progression, or the start of new anticancer treatment; contacts are approximately every 12 weeks by telephone. Updated 
survival status may be requested by the Sponsor at any time during the course of the study.  Upon Sponsor notification, all participants who do not/will not have a 
scheduled study visit or study contact during the Sponsor defined time period will be contacted for their survival status (excluding participants that have a previously 
08LLR6

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Trial Period:
Treatment Cycles
End of 
Treatment
Post-treatment
Treatment Cycle/Title:
1
2
3
4
5
6
7
8 and 
Beyond
Discon
Safety 
Follow
Up
Follow-up 
Visits
Survival Follow Upa
At Time of 
Discon
30 Days 
Post-
Discon
Every12 We
eks Post 
Discon
Every 12 Weeks
Scheduling Window (Days)b
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 7
± 7
± 7
recorded death event in the collection tool).  
g.
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.  A serum test can be done if urine is not appropriate. Additionally, if urine test is positive or is not evaluable, a serum test is required. Subjects must be 
excluded/discontinued in the event of a positive test results. Pregnancy tests (serum and/or urine tests) should be repeated if required by local guidelines.  In Cohort 2, 
pregnancy testing is to be done only at screening and whenever an expected menstrual cycle is missed or when pregnancy is otherwise suspected; unless there is a 
country-specific regulation to have monthly testing.
h.
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, GGT, total bilirubin, alkaline phosphatase, direct bilirubin, and total protein. .
i.
While on treatment, urinalysis and thyroid function tests will be performed every other cycle. Thyroid evaluations must be available and reviewed before the next 
scheduled visit
j.
For Cohort 1, AFP will be measured every 3 weeks (21 +/-7 days) calculated from the date of allocation. For Cohort 2, AFP will be measured every 9 weeks (63 +/-7 
days) calculated from the date of allocation. AFP evaluations must be available and reviewed before the next scheduled visit.
k.
If anti-HCV was negative prior to retreatment in the Second Course Phase, anti-HCV must be performed.
l.
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 
treatment, or earlier if clinically indicated.  Anti-HBc (total), anti-HBe, anti-HBs, and HBe antigen 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.
m.
For Cohort 2, HCV RNA, anti-HBc (total and IgM), HBSAg, anti-HBs, and HBV DNA will be tested only at screening. Participants must have baseline results within 
28 days of first dose. Post baseline tests will be done in case of HECI, following HECI management guidance provided in section 5.2.1.3 for cohort 2.  All additional 
post-baseline laboratory tests should be performed by a central laboratory, if possible.
n.
Tumor imaging should be performed within 21 days prior to starting or restarting treatment with pembrolizumab and continue to be performed every 9 weeks (63±7 
days) calculated from the first dose of retreatment, or more frequently if clinically indicated. 
o.
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.
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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 are considered to be clinically significant by the investigator.  
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.  As well, any 
autoimmune disorders, regardless of onset date, should be recorded.  
Disease details regarding the subject’s HCC will be recorded separately and not listed as 
medical history.
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 
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medications.  Prior anti-cancer treatment for HCC will be recorded separately and not listed 
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 7.2.3.
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.  
7.1.1.9
Assignment of Treatment/Randomization Number
All eligible subjects will be allocated by non-random assignment, and will receive a 
treatment number referred to as an allocation number.  The allocation number identifies the 
subject for all procedures occurring after treatment allocation to pembrolizumab.  Once an 
allocation number is assigned to a subject, it can never be re-assigned to another subject. 
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A single subject cannot be assigned more than 1 allocation number.
7.1.1.10 Trial Compliance (Medication/Diet/Activity/Other)
Interruptions from the protocol-specified treatment plan for greater than 12 weeks between 
pembrolizumab 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 pembrolizumab infused will be compared to the total volume prepared to 
determine compliance with each dose of pembrolizumab administered.  The instructions for 
preparing and administering pembrolizumab are provided in the Pharmacy Manual.  
Administration of trial medication will be witnessed by the investigator, 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 pembrolizumab 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 encephalopathy should be noted on 
every examination. After the first dose of trial treatment new clinically significant abnormal 
findings should be recorded as AEs.  
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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 encephalopathy should be noted on every examination. New clinically significant 
abnormal findings should be recorded as AEs.  
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 five factors, three of which assess the synthetic function of the 
liver (ie, Tbil level, serum albumin, and coagulation parameters [INR or PT]) and two of
which are based on clinical assessment (ie, degree of ascites and degree of hepatic 
encephalopathy).
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 Procedure
Manual.  
Refer to the Trial Flow Chart - Section 6.0 for the schedule of laboratory assessments.
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7.1.3.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
Laboratory tests for hematology, chemistry, and urinalysis are specified in Table 6.
Table 6
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
aPTT (Cohort 1 only)
WBC (total and 
differential)b
Aspartate aminotransferase
Specific gravity 
Total T3 or Free T3, FT4, and 
TSHc,d
RBC
Bicarbonatee
Microscopic exam, if 
abnormal results are 
noted
Anti-HCVf
Absolute 
lymphocyte countb
Calcium
HCV viral loadf
Absolute 
neutrophil  countb
Chloride
HCV genotypef
Creatinine
anti-HBsf
Glucose
Phosphorus
HBsAgf
Potassium
Anti-HBcf (total and IgM)  
Sodium
HBeAgf
Total bilirubin  
anti-HBef
Direct bilirubin
HBV viral loadf
Anti-HDVf
AFPd
Total protein
CRP (Cohort 1 only)
GGT
Blood urea nitrogen
a.
Perform on women of childbearing potential only 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.
Report % or absolute results per standard of practice.  Report the results in the same manner throughout the study.
c.
T3 is preferred; if not available free T3 may be tested. 
d.
If the local laboratory is unable to perform these tests, the site should submit the sample to the central laboratory for  
testing. Details are provided in the Laboratory Manual.
e.
If this test is not done as part of local standard of care, this test does not need to be performed. 
f.
All hepatitis tests will be done centrally
AFP = alpha-fetoprotein; aPTT = activated partial thrombin time; CRP = C-reactive protein; FT4 = free thyroxine; 
GGT = gamma-glutamyl transferase; HBc = Hepatitis B core; HBeAg = Hepatitis B e antigen; HBe = hemoglobin E; 
HBs = hepatitis B surface; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HCV = hepatitis C virus; HDV
= hepatitis D virus; IgM = gamma M immunoglobulin; INR = insulin receptor; PT = prothrombin time; RBC = red blood 
cells; T3 = triothyronine; TSH = thyroid-stimulating hormone (thyrotropin); WBC = white blood cells.
Laboratory tests for screening should be performed within 7 days prior to the first dose of 
trial treatment. An exception is hepatitis serologies and thyroid tests, which may be 
performed within 28 days prior to first dose. Subjects eligible for retreatment with 
pembrolizumab should have imaging performed within 21 days and laboratory test 
performed within 7 days prior to the first dose of trial treatment in the Second Course Phase. 
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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 with the exception of 
AFP, CRP (cohort 1 only), and thyroid function test.
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 Trial Flow Chart (Section 6.0).  Unresolved abnormal laboratory values that 
are drug-related AEs should be followed until resolution.  Laboratory tests do not need to be 
repeated after the end of treatment if laboratory results are within normal range.
7.1.3.1.1 Pregnancy Tests
All women who are being considered for participation in the trial, and who are not surgically 
sterilized or postmenopausal, must be tested for pregnancy within 72 hours 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.  
7.1.3.2
Central Laboratory Assessments
Sample collection timing, storage and shipment instructions for the central laboratory 
assessments will be provided in the Laboratory Manual.
7.1.3.3
Blood Samples for RNA Analysis, and Biomarker Studies 
Information about sample collection, storage and shipment for blood, plasma, and serum is 
provided in the 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.  
7.1.3.4
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 in 
Cohort 1 only) to an archival sample.  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. Fine needles aspirate (FNA) samples are acceptable if 
available. 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.  
7.1.3.5
Planned Genetic Analysis Sample Collection
Sample collection, storage and shipment instructions for Planned Genetic Analysis samples 
will be provided in the Procedure Manual. This sample should be drawn for planned analysis 
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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.  
7.1.3.6
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 DNA 

Leftover RNA 

Leftover plasma and serum from Biomarker Studies
Efficacy Measurements
7.1.4.1
Tumor Imaging and Assessment of Disease
The process for image collection and transmission to the central imaging vendor can be 
found in the Site Imaging Manual (SIM).  Tumor imaging should be acquired by computed 
tomography (computed tomography [CT], strongly preferred).  Magnetic resonance imaging 
(MRI) should be used when CT is contraindicated or for imaging in the brain. MRI of the 
abdomen may also be used if it is the local standard of care. The same imaging technique 
regarding modality and use of contrast must 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 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 allocation. 
Although RECIST 1.1 references a maximum of 5 target lesions in total and 2 per organ, 
MSD 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 for retrospective review.  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.  
7.1.4.1.1 Initial Tumor Imaging
Initial tumor imaging at screening must be performed within 21 days prior to the date of 
allocation.  The site study team must review screening images to confirm the subject has 
measurable disease per RECIST 1.1.  Prior to allocation, the screening images must be 
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submitted to the central imaging vendor for confirmation 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 allocation, 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 9 weeks (63±7 days) from the 
date of allocation.  Subsequent tumor imaging should be performed Q9W (63±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 (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, whichever occurs first.  All supplemental imaging must be 
submitted to the central imaging vendor for retrospective review.  
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 ≥4 weeks after the first indication of 
response, or at the next scheduled scan (ie, 9 weeks later), whichever is clinically indicated.  
Subjects will then return to regular scheduled imaging every 9 weeks (63±7 days), starting 
with the next scheduled imaging time point.  Subjects who obtain a local 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 7.1.4.1.6), disease progression should be confirmed by the site at least 
4 weeks after site-assessed 1st 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 7.1.4.1.6.  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 7.1.4.1.6.  
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.  
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7.1.4.1.4 Second Course (Retreatment) Tumor Imaging
A scan must be performed within 21 days prior to restarting treatment with pembrolizumab.  
Local reading (investigator assessment with site radiology reading) will be used to determine 
eligibility.  Imaging should be submitted to the central imaging vendor for retrospective 
verification.  
The first on-study imaging assessment should be performed 12 weeks (84±7 days) after the 
restart of treatment.  Subsequent tumor imaging should be performed every 9 weeks 
(63±7 days), or more frequently if clinically indicated.  
Per irRECIST 1.1 (Section 7.1.4.1.6), 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 
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 
9 weeks (63±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 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 (eg, discontinuation of study therapy).  Confirmation of 
PR and CR for RECIST 1.1 will be taken from central imaging retrospectively.  
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, and protects against premature assessment of 
progression based on benign changes due to cirrhosis. Details are fully described in [50]. 
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.
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
New lesions in the liver must meet 1 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
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 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 progressive disease (PD) takes into account the observation that some 
subjects can have a transient tumor flare in the first few months after the start of 
immunotherapy, and then experience subsequent disease response.  Subjects that are deemed 
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 initial evidence of radiological PD by RECIST 1.1 as determined by the 
site, it is at the discretion of the PI whether to continue a subject on trial treatment until 
repeat imaging is obtained (using irRECIST for subject management, see Table 7 and Figure
2).  This clinical judgment decision by the site investigator should be based on the subject’s 
overall clinical condition, including performance status, clinical symptoms, and laboratory 
data.
Subjects may receive trial 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
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4) Absence of progressive tumor at critical anatomical sites (eg, cord compression) 
requiring urgent alternative medical intervention.   
Any subject deemed clinically unstable should be discontinued from trial treatment at site-
assessed first radiologic evidence of PD and is not required to have repeat imaging for PD 
confirmation.
In determining whether or not the tumor burden has increased or decreased per irRECIST, 
the local site investigator should consider all target and non-target lesions as well as any 
incremental new lesion(s).
Scenarios where PD is not confirmed at repeat imaging if ALL of the following occur by 
irRECIST: 

Target lesion sum of diameters is <20% or <5 mm absolute increase compared to 
nadir,

Non-target disease resulting in initial PD is qualitatively stable or improved,

New lesion resulting in initial PD is qualitatively stable or improved,

No incremental new lesion(s) since last evaluation, and

No incremental new non-target lesion progression since last evaluation.  
If repeat imaging does not confirm PD by irRECIST as assessed by the local site investigator
and the subject continues to be clinically stable, treatment may continue and follow the 
regular imaging schedule. 
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, or

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 (ie, 2 scans at least 4 weeks apart 
demonstrating progressive disease) per irRECIST, but the subject is achieving a clinically 
meaningful benefit and there is no further increase in the tumor burden at the confirmatory 
tumor imaging, an exception to continue treatment may be considered following consultation 
with the Sponsor. In this case, if treatment is continued, tumor imaging should continue to 
be performed following the intervals as outlined in Section 6.0 Trial Flow Chart; 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 central imaging vendor.  
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Additional details about irRECIST are referenced in MSD Tip Sheet for RECIST 1 1 and 
irRECIST.  
Table 7
Imaging and Treatment after First Radiologic Evidence of Progressive Disease
Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
First 
radiologic 
evidence of PD 
by RECIST 1.1 
Repeat 
imaging 
at >4 weeks at 
site to confirm 
PD
May continue trial 
treatment 
at 
the 
local 
site 
Investigator’s 
discretion 
while 
awaiting 
confirmatory tumor 
imaging by site by 
irRECIST.
Repeat imaging at 
>4 weeks 
to 
confirm 
PD 
per 
physician 
discretion only
Discontinue treatment
Repeat 
tumor 
imaging 
confirms PD by 
irRECIST at the 
local site
No 
additional 
imaging required
Discontinue 
treatment 
(exception 
is 
possible 
upon 
consultation 
with 
sponsor)
No 
additional 
imaging required
N/A
Repeat 
tumor 
imaging 
shows 
SD, PR or CR by 
irRECIST by the 
local site
Continue 
regularly 
scheduled 
imaging 
assessments 
Continue
trial 
treatment
at 
the 
local 
site 
Investigator’s 
discretion
Continue regularly 
scheduled imaging 
assessments 
May 
restart 
trial 
treatment if condition 
has improved and/or 
clinically stable per 
Investigator’s 
discretion. Next tumor 
image should occur 
according 
to 
the 
regular 
imaging 
schedule outlined in 
the protocol.
CR = complete response; irRECIST = immune-related response evaluation criteria in solid tumors; N/A = not applicable; 
PD = progressive disease; PFS = progression-free survival; PR = partial response; SD = stable disease.
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Abbreviations: CIV=central imaging vendor; irRECIST=immune-related Response Evaluation Criteria in Solid 
Tumors; PD=progressive disease; PI=principal investigator.
Figure 2
Imaging and Treatment for Clinically Stable Subjects after First Radiologic 
Evidence of Progressive Disease Assessed by the Site
Other Procedures
7.1.5.1
Withdrawal/Discontinuation
Subjects who discontinue/withdraw from treatment prior to completion of the treatment 
regimen should be encouraged to continue to be followed for all remaining study visits.
When a subject discontinues/withdraws from participation in the trial, all applicable activities 
scheduled for the end of treatment visit should be performed at the time of discontinuation.  
Any adverse events which are present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements outlined in Section 7.2 - Assessing and 
Recording Adverse Events.
Subjects 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).
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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@MSD.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
This is an open label trial; there is no blinding for this trial.
Section 5.8 outlines the criteria for allowing subjects who are discontinued from treatment to 
continue to be monitored in the trial.
7.1.5.3
Calibration of Critical Equipment
The investigator or qualified designee has the responsibility to ensure that any critical device
or instrument used for a clinical evaluation/test during a clinical trial that provides important 
information about inclusion/exclusion criteria and/or safety or efficacy parameters shall be 
suitably calibrated and maintained to ensure that the data obtained is reliable and/or 
reproducible.  Documentation of equipment calibration must be retained as source 
documentation at the trial site.
Critical Equipment for this trial includes:

Laboratory equipment – as required for inclusion labs and trial assessments

Imaging equipment – as required for study objectives
See protocol-specified guidance in the Trial Administrative Binder, Procedures Manual, and 
Site Imaging Manual.
Visit Requirements
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures.
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7.1.6.1
Screening
Approximately 28 days prior to treatment allocation, 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.  
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 and thyroid 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).
7.1.6.2.1 Second Course Phase (Retreatment Period) 
Subjects who stop pembrolizumab with stable disease (SD) or better may be eligible for up to 
17 additional trial treatments (approximately 1 year) if they progress after stopping trial 
treatments.  Retreatment with pembrolizumab 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 pembrolizumab after attaining an investigator-
determined CR according to RECIST 1.1

Was treated with at least 8 trial treatments (approximately 6 months) 
with pembrolizumab before discontinuing therapy

Received at least two treatments with pembrolizumab beyond the date 
when the initial CR was declared
OR
o
Had SD, PR or CR and stopped pembrolizumab after 35 trial treatments 
(approximately 2 years) for reasons other than disease progression or 
intolerability
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
And
o
Experienced an investigator-determined confirmed radiographic disease 
progression after stopping their initial treatment with pembrolizumab, and

Did not receive any anti-cancer treatment since the last dose of 
pembrolizumab.

Has a performance status of 0 or 1 on the ECOG Performance Scale.

Demonstrates adequate organ function as detailed in Section 5.1.2.

The subject meets all of the inclusion criteria and none of the safety 
parameters listed in the exclusion criteria.

Female subject of childbearing potential should have a negative serum 
or urine pregnancy test within 72 hours prior to receiving retreatment 
with study medication (Day 1).  

Female subjects of childbearing potential must be willing to use an 
adequate method of contraception as outlined in Section 5.7.2 –
Contraception, for the course of the study 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.

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 120 days after the last dose of study therapy.

Note: Abstinence is acceptable if this is the usual lifestyle and 
preferred contraception for the subject.

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.

The trial is ongoing.
Subjects who enter the Second Course Phase will be retreated at the same dose frequency as 
when they last received pembrolizumab.  Pembrolizumab will be administered for up to an 
additional 17 trial treatments (approximately 1 year).
Visit requirements for the second course phase are outlined in the Second Course Phase Trial 
Flow Chart (Section 6.2).
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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.  
Subjects who are eligible for retreatment with pembrolizumab 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
(or if the subject begins retreatment with pembrolizumab as detailed in Section 7.1.6.2.1). 
Information regarding post-study anti-cancer treatment will be collected if new treatment is 
initiated.  
Subjects who are eligible to receive retreatment with pembrolizumab according to the criteria 
in Section 7.1.4.1.4 will move from the Follow-up Phase to the Second Course Phase when 
they experience disease progression. Details are provided in the Trial Flow Chart (Section 
6.0) for retreatment with pembrolizumab.
7.1.6.3.3 Survival Follow Up
Subjects, who experience confirmed disease progression (by site assessment) or start a new 
anti-cancer therapy, will move into the Survival Follow-up Phase.  Subjects should be 
contacted (eg, 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 status may be requested during the course of the study by the Sponsor. For 
example, updated survival status may be requested prior to but not limited to an eDMC 
review, interim and/or final analysis. Upon Sponsor notification, all participants who do 
not/will not have a scheduled study visit or study contact during the Sponsor-defined time 
period will be contacted for their survival status (excluding participants that have a 
previously recorded death event in the collection tool).
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Assessing and Recording Adverse Events
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavourable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the 
use of the Sponsor’s product, is also an adverse event.
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  
Examples of this may include, but are not limited to, teething, typical crying in infants and 
children and onset of menses or menopause occurring at a physiologically appropriate time.
Sponsor's product includes any pharmaceutical product, biological product, device, 
diagnostic agent or protocol-specified procedure, whether investigational (including placebo 
or active comparator medication) or marketed, manufactured by, licensed by, provided by or 
distributed by the Sponsor for human use.
Adverse events may occur during clinical trials, or as prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal.
Progression of the cancer under study is not considered an adverse event. 
All adverse events that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure. From the time of treatment allocation/randomization through 30 days following 
cessation of treatment, all adverse events must be reported by the investigator. Such events 
will be recorded at each examination on the Adverse Event case report forms/worksheets.  
The reporting timeframe for adverse events meeting any serious criteria is described in 
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, trial treatment should be discontinued and the 
subject should be observed closely for signs of toxicity.  Appropriate supportive treatment 
should be provided if clinically indicated.
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If an adverse event(s) is associated with (“results from”) the overdose of Sponsor's product or 
vaccine, the adverse event(s) is reported as a serious adverse event, even if no other 
seriousness criteria are met.
If a dose of Sponsor's product or vaccine meeting the protocol definition of overdose is taken 
without any associated clinical symptoms or abnormal laboratory results, the overdose is 
reported as a non-serious Event of Clinical Interest (ECI), using the terminology “accidental 
or intentional overdose without adverse effect.”
All reports of overdose with and without an adverse event must be reported by the 
investigator within 24 hours to the Sponsor either by electronic media or paper. Electronic 
reporting procedures can be found in the EDC data entry guidelines. Paper reporting 
procedures can be found in the Investigator Trial File Binder (or equivalent).
Reporting of Pregnancy and Lactation to the Sponsor
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them) that occurs during the trial.
Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure.  Pregnancies and lactations that occur from the time of treatment 
allocation/randomization through 120 days following cessation of Sponsor’s product, or 30 
days following cessation of treatment if the subject initiates new anticancer therapy, 
whichever is earlier, must be reported by the investigator.  All reported pregnancies must be 
followed to the completion/termination of the pregnancy. Pregnancy outcomes of 
spontaneous abortion, missed abortion, benign hydatidiform mole, blighted ovum, fetal 
death, intrauterine death, miscarriage and stillbirth must be reported as serious events 
(Important Medical Events). If the pregnancy continues to term, the outcome (health of 
infant) must also be reported.
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;
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●
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 8  for additional details regarding each of the above criteria.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any serious adverse event, or follow up to a serious adverse event, 
including death due to any cause, other than progression of the cancer under study (reference 
Section 7.2.3.3 for additional details), that occurs to any subject must be reported within 24 
hours to the Sponsor if it causes the subject to be excluded from the trial, or is the result of a 
protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 90 days 
following cessation of treatment, or 30 days following cessation of treatment if the subject 
initiates new anticancer therapy, whichever is earlier, any serious adverse event, or follow up 
to a serious adverse event, including death due to any cause other than progression of the 
cancer under study (reference Section 7.2.3.3 for additional details), whether or not related to 
the Sponsor's product, must be reported within 24 hours to the Sponsor either by electronic 
media or paper. Electronic reporting procedures can be found in the EDC data entry 
guidelines. Paper reporting procedures can be found in the Investigator Trial File Binder (or 
equivalent).
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to the Sponsor's product that is brought to the attention of the 
investigator at any time following consent through the end of the specified safety follow-up 
period specified in the paragraph above, or at any time outside of the time period specified in 
the previous paragraph also must be reported immediately to the Sponsor.  
All subjects with serious adverse events must be followed up for outcome.
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.
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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.
Cohort 1:
All of these events will require holding pembrolizumab treatment, notification of the 
event(s) to the Sponsor within 24 hours via electronic media or paper, and a 
hepatology consultation.  For dose interval modification, refer to Section 5.2.1.2.  For 
guidance related to the diagnosis and management of hepatic ECIs, refer to Section 
5.2.1.3.  
a.
ALT:
i. Among subjects with baseline ALT <2×ULN: ALT ≥5×ULN
ii. Among subjects with baseline ALT ≥2×ULN: ALT >3× the baseline
level
iii. ALT >500 U/L regardless of baseline level
b. AST:
i. Among subjects with baseline AST <2×ULN: AST ≥5×ULN
ii. Among subjects with baseline AST ≥2×ULN: AST >3× the baseline
level
iii. AST >500 U/L regardless of baseline level
c.
Total Bilirubin:
i. Among subjects with baseline levels <1.5 mg/dL:  a value of 
>2.0 mg/dL
ii. Among subjects with baseline levels that are ≥1.5 mg/dL: a value ≥2×
the baseline level 
iii. Total bilirubin >3.0 mg/dL regardless of baseline level
d. Regardless of laboratory values, hepatic decompensation diagnosed clinically, 
including:
i. New onset clinically detectable ascites
ii. Gastrointestinal bleeding suggestive of portal hypertension (eg,
esophageal or gastric varices)
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iii. Encephalopathy
Cohort 2:
Hepatic ECIs include any of the following events if the events are NOT 
considered due to disease progression, as judged by the investigator. All of these 
events will require holding study treatment, notification of the event(s) to the 
Sponsor within 24 hours after awareness via electronic media or paper.
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. Total Bilirubin:
i. Total bilirubin >3.0 mg/dL regardless of baseline level
c.
Regardless of laboratory values, hepatic decompensation diagnosed clinically, 
including:
i. New onset clinically detectable ascites requiring intervention for >3 
days
ii. 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 8
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 mild 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 an MSD 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 both Sponsor and non-Sponsor scientific 
experts who provide input with respect to the trial design, interpretation of trial results and 
subsequent peer-reviewed scientific publications.  
Executive Oversight Committee
The Executive Oversight Committee (EOC) comprises members of Sponsor Senior 
Management.  The EOC will receive and decide upon any recommendations made by the 
eDMC regarding the trial.  
Data Monitoring Committee
Cohort 1 only
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 (eg, 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, but prior to any final database lock, changes made to primary and/or key 
secondary hypotheses, or the statistical methods related to those hypotheses, then the 
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protocol will be amended (consistent with International Conference on Harmonisation (ICH)
Guideline E-9).  Changes to exploratory or other non-confirmatory analyses made after the 
protocol has been finalized, but prior to final database lock, will be documented in a 
supplemental statistical analysis plan (SAP [sSAP]) and referenced in the Clinical Study 
Report (CSR) for the study.  There will be a separate biomarker and PK analysis plan. Post 
hoc exploratory analyses will be clearly identified in the CSR.  
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below. The same statistical 
analysis plan and endpoints will apply to Cohort 1 and Cohort 2; the analyses will be done 
separately. The comprehensive plan is provided in Sections 8.2 to 8.12.  
Study Design Overview
A Phase 2 Study of Pembrolizumab (MK-3475) as Monotherapy in 
Subjects 
with 
Previously 
Systemically 
Treated 
Advanced 
Hepatocellular Carcinoma
Treatment Assignment
This is a single arm open-label study. 
Analysis Populations
Efficacy: All Subjects as Treated (ASaT)
Safety: All Subjects as Treated (ASaT)
Primary Endpoints
Objective Response Rate (ORR) based on RECIST 1.1 assessed by the 
central imaging vendor 
Statistical Methods for Key 
Efficacy Analyses
The estimate of the ORR, along with its 95% confidence interval (CI)
based on the Clopper-Pearson method [51], will be provided. 
Statistical Methods for Key 
Safety Analyses
Counts and percentages of subjects with AEs will be provided. 
Interim Analysis
For cohort 1 only, an interim analysis of the safety and efficacy data 
from the first 20 patients enrolled will be performed to inform planning 
of other studies in the pembrolizumab development program.  This 
analysis will be performed by the Clinical Biostatistics department of 
the Sponsor. 
Multiplicity
No multiplicity adjustment is planned in this Phase 2 study.
Sample Size and Power 
The planned sample size is 100 subjects for Cohort 1 and 50 subjects 
for Cohort 2. Section 8.9 provides the precision of the ORR estimates
for Cohort 1.
Responsibility for Analyses
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
This trial is being conducted as a non-randomized, open-label study, ie, subjects, 
investigators, and Sponsor personnel will be aware of subject treatment assignments after 
each subject is enrolled and treatment is assigned.
Except for the one interim analysis of the first 20 subjects enrolled to inform the 
pembrolizumab development program for Cohort 1, no other interim analysis is planned. 
Any other interim analysis will be documented.  
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Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.0.
Analysis Endpoints
Efficacy and safety endpoints that will be evaluated are listed below.
Efficacy Endpoints
8.4.1.1
Primary Efficacy Endpoint

Objective Response Rate
ORR is defined as the proportion of the subjects in the analysis population who have a CR or 
PR. 
Responses are based on assessments by the blinded central imaging vendor per 
RECIST 1.1.
8.4.1.2
Secondary Efficacy Endpoints

Duration of Response
For subjects who demonstrate CR or PR, based on assessments by the central imaging vendor 
per RECIST 1.1, DOR is defined as the time from first documented evidence of CR or PR 
until disease progression or death due to any cause, whichever occurs first.  

Disease Control Rate
DCR is defined as the percentage of subjects who have achieved CR, PR, or SD based on 
assessments by the central imaging vendor per RECIST 1.1.

Time To Progression
TTP is defined as the time from the first day of trial treatment to the first documented disease 
progression per RECIST 1.1 based on assessments by the central imaging vendor.  

Progression-Free Survival
PFS is defined as the time from the first day of trial treatment to the first documented disease 
progression per RECIST 1.1 based on assessments by the central imaging vendor or death 
due to any cause, whichever occurs first.  

Overall Survival (OS)
OS is defined as the time from first dose of study medication to death due to any cause.
8.4.1.3
Exploratory Efficacy Endpoints
The exploratory endpoints listed in Section 3.3, ie, ORR, DOR, DCR, TTP, and PFS per 
irRECIST and mRECIST, are defined in the same way as in Section 8.4.1.1 and Section 
8.4.1.2, except that disease progression will be assessed, and then confirmed (4 weeks later),
by the central imaging vendor per irRECIST and by the central imaging vendor per 
mRECIST, instead of per RECIST 1.1.  
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Safety Endpoints
Safety endpoints are described in Section 4.2.3.3 and Section 7.2.
Analysis Populations
Eligible subjects enter the study when the treatment allocation number is centrally assigned 
using IVRS/IWRS (see Section 5.3). 
Efficacy Analysis Populations
The All Subjects as Treated (ASaT) population will be used for the analysis of ORR, DCR, 
TTP, PFS, and OS. The ASaT population consists of all allocated subjects who received at 
least one dose of trial treatment.
The analysis population for DOR consists of responders (PR and CR).
Details on the approach to handling missing data are provided in Table 9.  
Safety Analysis Populations
The ASaT population will be used for the analysis of safety data in this study.  The ASaT 
population consists of all allocated subjects who received at least one dose of trial treatment. 
At least one laboratory or vital sign measurement obtained subsequent to at least one dose of 
trial treatment is required for inclusion in the analysis of each specific parameter.  To assess 
change from baseline, a baseline measurement is also required.
Statistical Methods
Statistical Methods for Efficacy Analyses
This section describes the statistical methods that address the primary and secondary 
objectives. 
For the primary efficacy endpoint of ORR, the point estimate and 95% confidence interval 
will be provided using the exact binomial method proposed by Clopper and Pearson (1934) 
[51]. Subjects in the primary analysis population (ASaT) without ORR data will be counted 
as non-responders. 
For DOR, Kaplan-Meier (KM) curves and median estimates from the KM curves will be 
provided if sample size permits.
For DCR, the point estimate and 95% confidence interval will be provided using exact 
binomial method proposed by Clopper and Pearson (1934) [51]. Subjects in the analysis 
population (ASaT) with missing DCR data are considered as subjects whose disease is not 
under control.
For TTP, PFS, and OS endpoints, KM curves and median estimates from the KM curves will 
be provided as appropriate. 
The efficacy analysis is summarized in Table 9.  
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Table 9
Analysis Strategy for Efficacy Variables
Endpoint/Variable
(Description, Time Point)
Statistical 
Method
Analysis 
Population
Missing Data 
Approach
Primary Endpoint 
ORR – RECIST 1.1 by central 
imaging vendor review
Exact method 
based on 
binomial
distribution
(Clopper-Pearson
method)
ASaT
Subjects with 
missing data are 
considered non-
responders
Key Secondary Endpoints
DOR – RECIST 1.1 by central 
imaging vendor review
Summary 
statistics using 
Kaplan-Meier 
method, if 
sample size 
permits
All 
responders
Non-responders are 
excluded from 
analysis. 
Responders are 
censored according 
to the censoring 
rules listed in 
Table 10.
DCR – RECIST 1.1 by central 
imaging vendor review
Exact method 
based on 
binomial
distribution
(Clopper-Pearson
method)
ASaT
Subjects with 
missing data are 
considered as
subjects with 
disease not under
control
TTP – RECIST 1.1 by central 
imaging vendor review
Summary 
statistics using 
Kaplan-Meier 
method
ASaT
Censored at last 
assessment
PFS – RECIST 1.1 by central 
imaging vendor review
Summary 
statistics using 
Kaplan-Meier 
method
ASaT
Censored at last 
assessment
OS
Summary 
statistics using 
Kaplan-Meier 
method
ASaT
Censored at last 
known alive date
Abbreviations: ASaT=all subjects as treated; DCR=disease control rate; DOR=duration of response; 
ORR=overall response rate; OS=overall survival; PFS=progression-free survival; RECIST=Response 
Evaluation Criteria in Solid Tumors; TTP=time to progression.
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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 
adequate disease 
assessments
Last adequate disease 
assessment prior to the after 
≥2 consecutive missed 
adequate disease assessments
Censor
(non-event)
Death or progression after 
≤1 missed adequate disease 
assessments
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 and have not been determined to be lost to follow up.
Abbreviations: DOR=duration of response; PD=progressive disease
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, laboratory tests, and vital signs.
Counts and percentages of subjects with AEs will be provided.
Demographic and Baseline Characteristics
The number and percentage of subjects screened, allocated, the primary reasons for screening 
failure, and the primary reasons for discontinuation will be displayed.  Demographic 
variables (eg, age, gender), baseline characteristics, primary and secondary diagnoses, and 
prior and concomitant therapies will be summarized either by descriptive statistics or 
categorical tables for all enrolled subjects.
Interim Analyses
An interim analysis of the safety and efficacy data from the first 20 patients enrolled in 
Cohort 1 will be performed after they finish their 9-week imaging scan or discontinued to 
inform planning of other studies in the pembrolizumab development program.  This analysis 
will be performed by the Clinical Biostatistics department of the Sponsor.  
Multiplicity
No multiplicity adjustment is planned in this study.
Sample Size 
In this study, approximately 100 subjects will be enrolled in Cohort 1 and 50 subjects will be 
enrolled in Cohort 2.  Table 11 shows the two-sided 95% confidence interval (CI) of ORR 
with 100 subjects for different observed response rates. 
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Table 11
Two-sided 95% Confidence Interval of ORR with 100 Subjects (Cohort 1)
Number of Observed Responders
ORR Estimates (%)
95% CI of ORR (%)
15
15
(8.6, 23.5)
17
17
(10.2, 25.8)
20
20
(12.7, 29.2)
25
25
(16.9, 34.7)
30
30
(21.2, 40.0)
35
35
(25.7, 45.2)
Subgroup Analyses and Effect of Baseline Factors
The estimate of the treatment effect for the primary endpoint will be estimated within each 
category of the following classification variables: 

Age category (≤65 vs. >65 years)

Sex (female vs. male)

Region (US vs non-US)

Etiology (uninfected vs. infected (HCV or HBV positive))

Macrovascular invasion (yes vs. no)

ECOG PS (0 vs. 1)

Alpha fetoprotein (AFP) (>200 IU/mL vs. ≤200 IU/mL)

Extrahepatic disease (yes vs. no)

Sorafenib intolerance versus progression (Cohort 1 only)
Compliance (Medication Adherence)
Drug accountability data for pembrolizumab will be collected during the study.
Any 
deviation from protocol-directed administration will be reported.
Extent of Exposure
Extent of Exposure for a subject is defined as number of cycles in which the subject receives 
the study medication infusion. Summary statistics will be provided on Extent of Exposure 
for the ASaT population.
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 
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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 12.  
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 12
Product Descriptions
Product Name & 
Potency
Dosage Form
Source/Additional Information
Pembrolizumab
50 mg/vial
Lyophilized powder for 
injection
Provided centrally by the Sponsor
Pembrolizumab 
100 mg/4 mL
Solution for infusion
Provided 
centrally 
by 
the 
Sponsor*
*Pembrolizumab 100 mg/4 mL solution will not be supplied at the initiation of the trial.  It is considered a 
back-up if there are supply issues with the pembrolizumab 50 mg/vial lyophilized powder.
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.  Pembrolizumab will be provided 
as non-kitted single vials.
Clinical Supplies Disclosure
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded. Treatment (name, strength or potency) is included in the label text; 
random code/disclosure envelopes or lists are not provided.
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 
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drug accountability and return, or local discard and destruction if appropriate.   Where local 
discard and destruction is appropriate, the investigator is responsible for ensuring that a local 
discard/destruction procedure is documented.
Standard Policies
Trial 
site 
personnel 
will 
have 
access 
to 
a 
central 
electronic 
treatment 
allocation/randomization system (IVRS/IWRS system) to allocate subjects, to assign 
treatment to subjects and to manage the distribution of clinical supplies. Each person 
accessing the IVRS system must be assigned an individual unique PIN.  They must use only 
their assigned PIN to access the system, and they must not share their assigned PIN with 
anyone.
10.0 ADMINISTRATIVE AND REGULATORY DETAILS
Confidentiality
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the institutional review board, ethics review committee (IRB/ERC) or similar 
or expert committee; affiliated institution and employees, only under an appropriate 
understanding of confidentiality with such board or committee, affiliated institution and 
employees.  Data generated by this trial will be considered confidential by the investigator, 
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;
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3. curriculum vitae or other summary of qualifications and credentials; and
4. other professional documentation.
Consistent with the purposes described above, this information may be transmitted to the 
Sponsor, and subsidiaries, affiliates and agents of the Sponsor, in your country and other 
countries, including countries that do not have laws protecting such information.  
Additionally, the investigator’s name and business contact information may be included 
when reporting certain serious adverse events to regulatory authorities or to other 
investigators.  By signing this protocol, the investigator expressly consents to these uses and 
disclosures.
If this is a multicenter trial, in order to facilitate contact between investigators, the Sponsor 
may share an investigator’s name and contact information with other participating 
investigators upon request.
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this trial.  The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
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.
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The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in Section 12.1 -
Code of Conduct for Clinical Trials.
The investigator also agrees to allow monitoring, audits, IRB/ERC review and regulatory 
authority inspection of trial-related documents and procedures and provide for direct access 
to all trial-related source data and documents.
The investigator agrees not to seek reimbursement from subjects, their insurance providers or 
from government programs for procedures included as part of the trial reimbursed to the 
investigator by the Sponsor.
The investigator shall prepare and maintain complete and accurate trial documentation in 
compliance with Good Clinical Practice standards and applicable federal, state and local 
laws, rules and regulations; and, for each subject participating in the trial, provide all data, 
and, upon completion or termination of the clinical trial, submit any other reports to the 
Sponsor as required by this protocol or as otherwise required pursuant to any agreement with 
the Sponsor.
Trial documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the trial site upon request for inspection, 
copying, review and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities.  The investigator agrees to promptly take any reasonable steps that are 
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.
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The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this trial.
Persons debarred from conducting or working on clinical trials by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s trials.  The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the trial is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will 
promptly notify that trial site’s IRB/IEC.
According to European legislation, a Sponsor must designate an overall coordinating 
investigator for a multi-center trial (including multinational).  When more than one trial site 
is open in an EU country, MSD, 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.  MSD, as Sponsor of this trial, will review this protocol and submit 
the information necessary to fulfill these requirements.  MSD 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 
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data are generated, documented, and reported in compliance with the protocol, accepted 
standards of Good Clinical Practice, and all applicable federal, state, and local laws, rules and 
regulations relating to the conduct of the clinical trial.
Data Management
The investigator or qualified designee is responsible for recording and verifying the accuracy 
of subject data.  By signing this protocol, the investigator acknowledges that his/her 
electronic signature is the legally binding equivalent of a written signature.  By entering 
his/her electronic signature, the investigator confirms that all recorded data have been 
verified as accurate.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
Publications
This trial is intended for publication, even if terminated prematurely. Publication may include 
any or all of the following: posting of a synopsis online, abstract and/or presentation at a 
scientific conference, or publication of a full manuscript.  The Sponsor will work with the 
authors to submit a manuscript describing trial results within 12 months after the last data 
become available, which may take up to several months after the last subject visit in some 
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. MSD 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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[8]
Bruix J, Qin S, Merle P, Granito A, Huang YH, Bodoky G, et al. Regorafenib for 
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Abou-Alfa GK, Meyer T, Cheng AL, El-Khoueiry AB, Rimassa L, Ryoo BY, et 
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the randomized phase III CELESTIAL trial [abstract]. J Clin Oncol. 2018 
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[10]
Llovet JM, Decaens T, Raoul JL, Boucher E, Kudo M, Chang C, et al. Brivanib in 
patients with advanced hepatocellular carcinoma who were intolerant to sorafenib 
or for whom sorafenib failed: results from the randomized phase III BRISK-PS 
study. J Clin Oncol. 2013 Oct 1;31(28):3509-16.
[11]
Zhu AX, Kudo M, Assenat E, Cattan S, Kang YK, Lim HY, et al. Effect of 
everolimus on survival in advanced hepatocellular carcinoma after failure of 
sorafenib: the EVOLVE-1 randomized clinical trial. JAMA. 2014 Jul 2;312(1):57-
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Zhu AX, Park JO, Ryoo BY, Yen CJ, Poon R, Pastorelli D, et al. Ramucirumab 
versus placebo as second-line treatment in patients with advanced hepatocellular 
carcinoma following first-line therapy with sorafenib (REACH): a randomised, 
double-blind, multicentre, phase 3 trial. Lancet Oncol. 2015 Jul;16(7):859-70.
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Granito A, Marinelli S, Terzi E, Piscaglia F, Renzulli M, Venerandi L, et al. 
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after sorafenib failure. Dig Liver Dis. 2015 Jun;47(6):518-22.
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Patrikidou A, Sinapi I, Regnault H, Fayard F, Bouattour M, Fartoux L, et al. 
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El-Khoueiry AB, Sangro B, Yau T, Crocenzi TS, Kudo M, Hsu C, et al. 
Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): 
an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. 
Lancet. 2017 Jun 24;389(10088):2492-2502.
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Disis ML. Immune regulation of cancer. J Clin Oncol 2010;28(29):4531-8.
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Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, et al. Tumor-
associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune 
evasion. Nat Med 2002;8(8):793-800.
[18]
Sharpe AH, Freeman GJ. The B7-CD28 superfamily. Nat Rev Immunol 
2002;2(2):116-26.
[19]
Brown JA, Dorfman DM, Ma F-R, Sullivan EL, Munoz O, Wood CR, et al. 
Blockade of programmed death-1 ligands on dendritic cells enhances T cell 
activation and cytokine production. J Immunol 2003;170(3):1257-66.
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[20]
Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and 
autoimmunity. Immunol Rev 2010;236:219-42.
[21]
Thompson RH, Dong H, Lohse CM, Leibovich BC, Blute ML, Cheville JC, et al. 
PD-1 is expressed by tumor-infiltrating immune cells and is associated with poor 
outcome for patients with renal cell carcinoma. Clin Cancer Res 2007;13(6):1757-
61.
[22]
Talmadge JE, Donkor M, Scholar E. Inflammatory cell infiltration of tumors: 
Jekyll or Hyde. Cancer Metastasis Rev 2007;26(3-4):373-400.
[23]
Usubütün A, Ayhan A, Uygur MC, Özen H, Toklu C, Ruacan S. Prognostic 
factors in renal cell carcinoma. J Exp Clin Cancer Res 1998;17(1):77-81.
[24]
Al-Shibli K, Al-Saad S, Andersen S, Donnem T, Bremnes RM, Busund L-T. The 
prognistic value of intraepithelial and stromal CD3-, CD117- and CD138-positive 
cells in non-small cell lung carcinoma. APMIS 2010;118:371-82.
[25]
Deschoolmeester V, Baay M, Van Marck E, Weyler J, Vermeulen P, Lardon F, et 
al. Tumor infiltrating lymphocytes: an intriguing player in the survival of 
colorectal cancer patients. BMC Immunol 2010;11:19.
[26]
Diez M, Pollán M, Enriquez JM, Dominguez P, Santana A, Tobaruela E, et al. 
Histopathologic prognostic score in colorectal adenocarcinomas. Anticancer Res 
1998;18(1B):689-94.
[27]
Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pagès C, 
et al. Type, density, and location of immune cells within human colorectal tumors 
predict clinical outcome. Science 2006;313(5795):1960-4.
[28]
Hiraoka N. Tumor-infiltrating lymphocytes and hepatocellular carcinoma: 
molecular biology. Int J Clin Oncol 2010;15(6):544-51.
[29]
Nobili C, Degrate L, Caprotti R, Franciosi C, Leone BE, Trezzi R, et al. Prolonged 
survival of a patient affected by pancreatic adenocarcinoma with massive 
lymphocyte and dendritic cell infiltration after interleukin-2 immunotherapy. 
Report of a case. Tumori 2008;94(3):426-30.
[30]
Chemnitz JM, Parry RV, Nichols KE, June CH, Riley JL. SHP-1 and SHP-2 
associate with immunoreceptor tyrosine-based switch motif of programmed death 
1 upon primary human T cell stimulation, but only receptor ligation prevents T 
cell activation. J Immunol 2004;173:945-54.
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Kloor M. Lymphocyte infiltration and prognosis in colorectal cancer. Lancet 
Oncol. 2009 Sep;10(9):840-1.
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Hillen F, Baeten CIM, van de Winkel A, Creytens D, van der Schaft DWJ, 
Winnepenninckx V, et al. Leukocyte infiltration and tumor cell plasticity are 
parameters of aggressiveness in primary cutaneous melanoma. Cancer Immunol 
Immunother 2008;57(1):97-106.
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[33]
Lee HE, Chae SW, Lee YJ, Kim MA, Lee HS, Lee BL, et al. Prognostic 
implications of type and density of tumour-infiltrating lymphocytes in gastric 
cancer. Br J Cancer 2008;99(10):1704-11.
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Leffers N, Gooden MJM, de Jong RA, Hoogeboom B-N, ten Hoor KA, Hollema 
H, et al. Prognostic significance of tumor-infiltrating T-lymphocytes in primary 
and metastatic lesions of advanced stage ovarian cancer. Cancer Immunol 
Immunother 2009;58(3):449-59.
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Nishimura H, Honjo T, Minato N. Facilitation of beta selection and modification 
of positive selection in the thymus of PD-1-deficient mice. J Exp Med. 2000 Mar 
6;191(5):891-8.
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Liotta F, Gacci M, Frosali F, Querci V, Vittori G, Lapini A, et al. Frequency of 
regulatory T cells in peripheral blood and in tumour-infiltrating lymphocytes 
correlates with poor prognosis in renal cell carcinoma. BJU Int 2011;107(9):1500-
6.
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Ropponen KM, Eskelinen MJ, Lipponen PK, Alhava E, Kosma V-M. Prognostic 
value of tumour-infiltrating lymphocytes (TILs) in colorectal cancer. J Pathol 
1997;182(3):318-24.
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Dudley ME, Wunderlich JR, Yang JC, Sherry RM, Topalian SL, Restifo NP, et al. 
Adoptive cell transfer therapy following non-myeloablative but lymphodepleting 
chemotherapy for the treatment of patients with refractory metastatic melanoma. J 
Clin Oncol 2005;23(10):2346-57.
[39]
Hunder NN, Wallen H, Cao J, Hendricks DW, Reilly JZ, Rodmyre R, et al. 
Treatment of metastatic melanoma with autologous CD4+ T cells against NY-
ESO-1. N Engl J Med 2008;358(25):2698-703.
[40]
Pölcher M, Braun M, Friedrichs N, Rudlowski C, Bercht E, Fimmers R, et al. 
Foxp3(+) cell infiltration and granzyme B(+)/Foxp3(+) cell ratio are associated 
with outcome in neoadjuvant chemotherapy-treated ovarian carcinoma. Cancer 
Immunol Immunother 2010;59(6):909-19.
[41]
Okazaki T, Maeda A, Nishimura H, Kurosaki T, Honjo T. PD-1 immunoreceptor 
inhibits B cell receptor-mediated signaling by recruiting src homology 2-domain-
containing tyrosine phosphatase 2 to phosphotyrosine. Proc Natl Acad Sci U S A 
2001;98(24):13866-71.
[42]
Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Annu Rev 
Immunol 2005;23:515-48.
[43]
Morales-Kastresana A, Sanmamed MF, Rodriguez I, Palazon A, Martinez-Forero 
I, Labiano S, et al. Combined immunostimulatory monoclonal antibodies extend 
survival in an aggressive transgenic hepatocellular carcinoma mouse model. Clin 
Cancer Res. 2013 Nov 15;19(22):6151-62.
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[44]
Gao Q, Wang XY, Qiu SJ, Yamato I, Sho M, Nakajima Y, et al. Overexpression 
of PD-L1 significantly associates with tumor aggressiveness and postoperative 
recurrence in human hepatocellular carcinoma. Clin Cancer Res. 2009 Feb 
1;15(3):971-9.
[45]
Shi F, Shi M, Zeng Z, Qi RZ, Liu ZW, Zhang JY, et al. PD-1 and PD-L1 
upregulation promotes CD8(+) T-cell apoptosis and postoperative recurrence in 
hepatocellular carcinoma patients. Int J Cancer. 2011 Feb 15;128(4):887-96.
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Hoshida Y, Villanueva A, Kobayashi M, Peix J, Chiang DY, Camargo A, et al. 
Gene expression in fixed tissues and outcome in hepatocellular carcinoma. N Engl 
J Med. 2008 Nov 6;359(19):1995-2004.
[47]
Sangro B, Gomez-Martin C, de la Mata M, Inarrairaegui M, Garralda E, Barrera P, 
et al. A clinical trial of CTLA-4 blockade with tremelimumab in patients with
hepatocellular carcinoma and chronic hepatitis C. J Hepatol. 2013 Jul;59(1):81-8.
[48]
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use. 2018 Jan. Distributed by Bristol-Myers Squibb Company.
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EI-Khoueiry AB, Melero I, Crocenzi TS, Welling TH, Yau T, Yeo W, et al. Phase 
1/2 safety and antitumor activity of nivolumab in patients with advanced 
Hepatocellular Carcinoma (HCC): CA209-040. Poster session presented at: 2015 
ASCO Annual Meeting; 2015 May 29 – Jun 2; Chicago, IL.
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Lencioni R, Llovet JM. Modified RECIST (mRECIST) assessment for 
hepatocellular carcinoma. Semin Liver Dis. 2010 Feb;30(1):52-60.
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case of binomial. Biometrika 1934;26(4):404-13.
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12.0 APPENDICES
Code of Conduct for Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing, and reporting these trials 
in compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design and conduct of clinical trials. In all cases, MSD clinical trials will be conducted 
in compliance with local and/or national regulations (including all applicable data protection laws and 
regulations), and International Council for Harmonisation Good Clinical Practice (ICH-GCP), and also in 
accordance with the ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD irrespective of the party (parties) employed for their execution (e.g., contract research organizations, 
collaborative research efforts). This Code is not intended to apply to trials that are observational in nature, or 
which are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the 
full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of MSD or comparator products. Alternatively, MSD 
may conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to 
determine patient preferences, etc.
The design (i.e., participant population, duration, statistical power) must be adequate to address the specific 
purpose of the trial and shall respect the data protection rights of all participants, trial site staff and, where 
applicable, third parties. All trial protocols are and will be assessed for the need and capability to enroll 
underrepresented groups. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
MSD’s clinical trials are conducted globally in many different countries and in diverse populations, including 
people of varying age, race, ethnicity, gender, and accounting for other potential disease related factors. MSD 
selects investigative sites based on medical expertise, access to appropriate participants, adequacy of facilities 
and staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial initiation, 
sites are evaluated by MSD personnel (or individuals acting on behalf of MSD) to assess the ability to 
successfully conduct the trial.
Where appropriate, and in accordance with regulatory authority guidance, MSD will make concerted efforts 
to raise awareness of clinical trial opportunities in various communities. MSD will seek to engage 
underrepresented groups and those disproportionately impacted by the disease under study. MSD will support 
clinical trial investigators to enroll underrepresented groups and expand access to those who will ultimately 
use the products under investigation.
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3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and Good Clinical Practice 
(GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data are verified versus 
source documentation according to standard operating procedures. Per MSD policies and procedures, if 
potential fraud, scientific/research misconduct, privacy incidents/breaches or Clinical Trial-related 
Significant Quality Issues are reported, such matters are investigated. When necessary, appropriate corrective 
and/or preventative actions are defined and regulatory authorities and/or ethics review committees are 
notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the pre-specified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important 
to patients, physicians, and payers. Some early phase or pilot trials are intended to be hypothesis-generating rather 
than hypothesis testing; in such cases, publication of results may not be appropriate since the trial may be 
underpowered and the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). In summary, authorship should reflect significant contribution to the design and 
conduct of the trial, performance or interpretation of the analysis, and/or writing of the manuscript. All named 
authors must be able to defend the trial results and conclusions. MSD funding of a trial will be acknowledged in 
publications.
III. Participant Protection
A. Regulatory Authority and Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics 
Committee [IEC])
All 
protocols 
and protocol 
amendments 
will 
be 
submitted 
by 
MSD 
for 
regulatory 
authority 
acceptance/authorization prior to implementation of the trial or amendment, in compliance with local and/or 
national regulations.
The protocol, protocol amendment(s), informed consent form, investigator’s brochure, and other relevant trial 
documents must be reviewed and approved by an IRB/IEC before being implemented at each site, in compliance 
with local and/or national regulations. Changes to the protocol that are required urgently to eliminate an 
immediate hazard and to protect participant safety may be enacted in anticipation of ethics committee approval. 
MSD will inform regulatory authorities of such new measures to protect participant safety, in compliance with 
local and/or national regulations.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance. 
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At 
a minimum, trial designs will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Participants may withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible, as well as all 
applicable data protection rights. Unless required by law, only the investigator, Sponsor (or individuals acting on 
behalf of MSD), ethics committee, and/or regulatory authorities will have access to confidential medical records 
that might identify the participant by name.
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D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD does not pay incentives to 
enroll participants in its trials. However, when enrollment is particularly challenging, additional payments may be 
made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent 
on chart review and medical evaluation to identify potentially eligible participants.
B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may 
wish to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards
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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 7.1.3.7 – 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 MSD 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 mailbox 
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(clinical.specimen.management@MSD.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 through 
appropriate mechanisms (e.g., scientific publications and/or presentations). Subjects will not 
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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
(ie, 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@MSD.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 13 describes the various definitions of hepatitis B as well as the treatment 
considerations for subjects with hepatitis B. 
Table 13
Hepatitis B Definitions and Treatment Considerations
Test
Patient Status
Eligible for KN-0224?
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 
pembrolizumab
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)
HBc = HBsAb = HBsAg = HBV = IgM = 
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ECOG Performance Status
GRADE ECOG PERFORMANCE STATUS
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work
2
Ambulatory and capable of all selfcare but unable to carry out any work 
activities; up and about more than 50% of waking hours
3
Capable of only limited selfcare; confined to bed or chair more than 50% of 
waking hours
4
Completely disabled; cannot carry on any selfcare; totally confined to bed or 
chair
5
Dead
*Oken M, Creech R, Tormey D, et al. Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol. 1982;5:649-655.
http://ecog-acrin.org/resources/ecog-performance-status
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Common Terminology Criteria for Adverse Events
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 bilirubin 1 (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 (secs)
<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 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
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
Grade IV:Coma (unresponsive to verbal or noxious stimuli)
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 3 below [52].  
CLT = cadaveric liver transplantation; LDLT = living donor liver transplantation; PEI = percutaneous ethanol 
injection; RF = radio frequency (ablation); TACE = transarterial chemoembolization. 
Figure 3
Barcelona Clinic Liver Cancer Staging System
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List of Abbreviations
Abbreviation/Term
Definition
1L
First line
2L
Second line
ADA
Anti-drug antibodies
AE
Adverse event
AFP
Alpha fetoprotein
ALC1
Antibodies to liver cytosol antigen
ALKM-1
Antibodies to liver/kidney microsomes
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
BCG
Bacille of Calmette-Guerin Vaccine (Tuberculosis Vaccine)
BCLC
Barcelona Clinic Liver Cancer scale
ß-HCG
Beta Human Chorionic Gonadotropin
BID
Twice daily
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
EPO
Erythropoeitin
ERC
Ethics review committee
FBR
Future biomedical research
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FDAMA
Food and Drug Administration Modernization Act
FFPE
Formalin-fixed, paraffin-embedded
FNA
Fine needle aspirate
FOLFOX
Chemotherapy regimen containing:  folinic acid, 5-fluorouracil, and 
oxaliplatin
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Abbreviation/Term
Definition
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
HDV
Hepatitis D virus
Anti-HDV
Hepatitis D antibody
HIV
Human immunodeficiency virus
IB
Investigator’s Brochure
ICF
Informed consent form
ICH
International Conference on Harmonisation
IHC
Immunohistochemistry
INR
International normalized ratio
irAE
Immune-related adverse event
irPD
radiographic progression of disease
IRB
Institutional Review Board
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
KM
Kaplan-Meier
mAb
Monoclonal antibody
mRECIST
Modified RECIST for HCC
miRNA
Micro RNA
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
PD-L2
Programmed death ligand 2
PFS
Progression-free survival
PI
Principal investigator
PK
Pharmacokinetic
PR
Partial response
PT
Prothrombin time
PS
Performance status
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Abbreviation/Term
Definition
RECIST
Response Evaluation Criteria in Solid Tumors
Q2W
Every 2 weeks
Q3W
Every 3 weeks
Q9W
Every 9 weeks
Q12W
Every 12 weeks
QD
Once daily
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
TACE
Transcatheter chemoembolization
TAE
Transarterial embolization
Tbil
Total bilirubin
TIL
Tumor infiltrating lymphocytes
TTP
Time to progression
ULN
Upper limit of normal
V
Volume of distribution
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13.0 SIGNATURES
Sponsor's Representative
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
Investigator
I agree to conduct this clinical trial in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol (including other manuals and documents 
referenced from this protocol).  I agree to conduct the trial in accordance with generally 
accepted standards of Good Clinical Practice.  I also agree to report all information or data in 
accordance with the protocol and, in particular, I agree to report any serious adverse events 
as defined in Section 7.0 – TRIAL PROCEDURES (Assessing and Recording Adverse 
Events).  I also agree to handle all clinical supplies provided by the Sponsor and collect and 
handle all clinical specimens in accordance with the protocol.  I understand that information 
that identifies me will be used and disclosed as described in the protocol, and that such 
information may be transferred to countries that do not have laws protecting such 
information.  Since the information in this protocol and the referenced Investigator’s 
Brochure is confidential, I understand that its disclosure to any third parties, other than those 
involved in approval, supervision, or conduct of the trial is prohibited.  I will ensure that the 
necessary precautions are taken to protect such information from loss, inadvertent disclosure 
or access by third parties.
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
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