Clinical trial NCT03713593
Conditions: Carcinoma, Hepatocellular
Keywords: receptor tyrosine kinase inhibitor programmed cell death 1 (PD-1, PD1) programmed cell death ligand 1 (PD-L1, PDL1) programmed cell death ligand 2 (PD-L2, PDL2)
Sponsor: Merck Sharp & Dohme LLC
Start date: 2018-12-31; Completion date: 2024-09-24
Enrollment: 794 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the safety and efficacy of lenvatinib (E7080/MK-7902) in combination with pembrolizumab (MK-3745) versus lenvatinib in combination with placebo as first-line therapy for the treatment of advanced hepatocellular carcinoma in adult participants.

The primary hypotheses of this study are that lenvatinib plus pembrolizumab is superior to lenvatinib plus placebo with respect to progression-free survival (PFS) and overall survival (OS).

Detailed description:

Arms: arm 1: Participants receive lenvatinib 12 mg (for participants with screening body weight ≥60 kg) or 8 mg (for participants with screening body weight \<60 kg) orally once a day (QD) plus pembrolizumab 200 mg by intravenous (IV) infusion on Day 1 of each 21-day cycle (Q3W). Pembrolizumab will be administered for up to 35 cycles (approximately 24 months). Lenvatinib will be administered until progressive disease or unacceptable toxicity. arm 2: Participants receive lenvatinib 12 mg (for participants with screening body weight ≥60 kg) or 8 mg (for participants with screening body weight \<60 kg) orally QD plus saline placebo by IV infusion on Day 1 Q3W. Saline placebo will be administered for up to 35 cycles (approximately 24 months). Lenvatinib will be administered until progressive disease or unacceptable toxicity.
Interventions: intervention 1: lenvatinib intervention 2: pembrolizumab intervention 3: saline placebo
Intervention descriptions: intervention 1: Administered orally once a day intervention 2: Administered as an IV infusion on Day 1 Q3W intervention 3: Administered as an IV infusion on Day 1 Q3W

Protocol documents:
Prot_SAP_000.pdf: 
Official Protocol Title:
NCT number:
Document Date:
A Phase 3 Multicenter, Randomized, Double-blinded, 
Active-controlled, Clinical Study to Evaluate the Safety 
and Efficacy of Lenvatinib (E7080/MK-7902) in 
Combination with Pembrolizumab (MK-3475) Versus 
Lenvatinib in First-line Therapy of Participants with 
Advanced Hepatocellular Carcinoma (LEAP-002)
NCT03713593
12-OCT-2022


PRODUCT: MK-7902  
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PROTOCOL/AMENDMENT NO.: MK-7902-002-03 (E7080-G000-311)
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12-OCT-2022
Title Page
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME LLC, RAHWAY, NJ, USA (MSD).
Protocol Title: A Phase 3 Multicenter, Randomized, Double-blinded, Active-controlled, 
Clinical Study to Evaluate the Safety and Efficacy of Lenvatinib (E7080/MK-7902) in 
Combination with Pembrolizumab (MK-3475) Versus Lenvatinib in First-line Therapy of 
Participants with Advanced Hepatocellular Carcinoma (LEAP-002)
Protocol Number: MK-7902-002-03 (E7080-G000-311)
Compound Number: MK-7902 (E7080/lenvatinib) and MK-3475 (pembrolizumab)
Sponsor Name:
Merck Sharp & Dohme LLC
(hereafter referred to as the Sponsor or MSD)
The study is cofunded by MSD and Eisai.
Legal Registered Address:
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Regulatory Agency Identifying Number(s):
IND
EudraCT
140284
2018-002983-26
Approval Date: 12 October 2022
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study 
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 3
12-OCT-2022
To space out clinic visits to every 6 weeks and imaging scans to every 
12 weeks.
Amendment 2
14-APR-2021
To remove pharmacokinetic (PK) objective and update pembrolizumab 
dose modification table.
Amendment 1
14-MAY-2019
To address feedback from regulatory authorities and align with 
MK-7902 program standard updates.
Original Protocol
20-SEPT-2018
Not applicable
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 03
Overall Rationale for the Amendments:
To space out clinic visits to every 6 weeks and imaging scans to every 12 weeks.
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
Title Page
Section 10.1.1 Code of 
Conduct for Clinical Trials
Throughout
Sponsor entity name and 
address change.
Merck Sharp & Dohme Corp. underwent an entity name and 
address change to Merck Sharp & Dohme LLC, Rahway, NJ, USA. 
This conversion resulted only in an entity name change and update 
to the address.
Synopsis
1.3 Schedule of Activities 
(SoA)
8.1.8.1 Timing of Dose 
Administration
10.7.1 Germany
10.7.2 United Kingdom
Treatment cycles were 
lengthened from 21 days to 42 
days.
The study scientific advisory committee recommended that 
switching from Q3W to Q6W visits for participants tolerating 
treatment would be clinically appropriate after the first 3 months of 
therapy. This decreases participant burden by reducing the number 
of site visits without compromising participant safety. Participants 
who require more frequent visits per investigator assessment will 
continue to be scheduled Q3W.
This change is supported by published literature describing the 
safety of the pembrolizumab + lenvatinib combination [Makker, 
V., et al 2021].
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Section # and Name
Description of Change 
Brief Rationale 
1.3 Schedule of Activities
4.1 Overall Design
8.10.3.2 Follow-up Visits
Imaging was changed from 
Q9W to Q12W.
Final analysis has now been completed for this study. Imaging 
window is being increased to every 12 weeks to be more in line 
with standard of care for subjects receiving lenvatinib 
monotherapy. All subjects have completed pembrolizumab/placebo 
treatment on this study.
1.3 Schedule of Activities
Note was added to indicate 
that home pregnancy testing 
should be conducted midcycle 
(Day 22).
Midcycle pregnancy tests were added because of the change from 
Q3W to Q6W visits.
8.3.7 Pregnancy Testing
This section was added to 
clarify pregnancy testing 
requirements and to add 
midcycle pregnancy tests.
Pregnancy testing information was clarified. Midcycle pregnancy 
tests were added because of the change from Q3W to Q6W visits.
8.4.5 Pregnancy and 
Exposure During 
Breastfeeding
Added information about 
reporting pregnancy 
complications.
To ensure accurate reporting of pregnancy events.
10.2 Appendix 2: Clinical 
Laboratory Tests
Removed details for 
pregnancy testing.
Details for pregnancy testing were added to Section 8.3.7.
8.3.6.2 Pregnancy Test
This section was removed.
The information that was in this section was redundant to that 
contained in Section 5.1 (Inclusion Criteria).
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Section # and Name
Description of Change 
Brief Rationale 
5.1 Inclusion Criteria
For Inclusion Criterion 9, the 
period of time for abstinence 
or contraception use after the 
last dose of lenvatinib was 
updated from 30 days to 7 
days.
To align with current lenvatinib guidance.
5.2 Exclusion Criteria
6.5.2 Prohibited 
Concomitant Medications
Removed the use of factor X 
inhibitors as an exclusion 
criterion and from prohibited 
concomitant medications.
To align with other lenvatinib protocols. Anti-Xa inhibitors do not 
require INR monitoring, and may be used with lenvatinib 
treatment.
6.7 Intervention After the 
End of the Study
Language added to allow 
participants to be enrolled into 
an extension study (if 
available).
Participants will be allowed to enroll into an extension study (if 
available).
6.6.1.9 Management of 
Osteonecrosis of the Jaw
This section was added.
To comply with the lenvatinib label requirements for osteonecrosis 
of the jaw.
6.6.5 Other Allowed Dose 
Interruptions for Lenvatinib
Language added indicating 
lenvatinib dose interruptions 
for scheduled dental surgery or 
invasive dental procedures are 
allowed.
To comply with the lenvatinib label requirements for osteonecrosis 
of the jaw.
8.3.1 Physical Examinations
Included oral examination.
To comply with the lenvatinib label requirements for osteonecrosis 
of the jaw.
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Section # and Name
Description of Change 
Brief Rationale 
6.6.1 Lenvatinib Dose 
Modification
Added cross-references to 
sections regarding 
management of 
gastrointestinal perforation and 
osteonecrosis of the jaw.
Added for completeness.
7.1 Discontinuation of Study 
Intervention
Removed unblinding as reason 
for discontinuation.
Participants are unblinded after final analysis.
8.1.10 Participant 
Blinding/Unblinding
Language added indicating 
participants may continue on 
study after unblinding of 
treatment assignment.
Participants are unblinded after final analysis, but may continue on 
study.
1.3 Schedule of Activities
8.8 Biomarkers
Removed serum biomarkers, 
plasma biomarkers, RNA, and 
stool collection from SoA.
Biomarker collections were streamlined to minimize burden to 
participants.
4.2.1.6 Planned Exploratory 
Biomarker Research
Removed text about stool 
samples.
Removed references to 
pembrolizumab and immune-
oncology.
Biomarker collections were streamlined to minimize burden to 
participants.
To allow flexibility and current treatment options for exploratory 
biomarker research.
4.4 Beginning and End of 
Study Definition
Clarified definitions for 
beginning and end of study.
Per Regulation (EU) No 536/2014 of the European Parliament and 
of the Council.
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Section # and Name
Description of Change 
Brief Rationale 
8.4 Adverse Events (AEs), 
Serious Adverse Events 
(SAEs), and Other 
Reportable Safety Events
Language added indicating 
investigators need to document 
SAE associated with 
medication error, misuse, or 
abuse.
Per Regulation (EU) No 536/2014 of the European Parliament and 
of the Council.
10.3 Definitions of 
Medication Error, Misuse, 
and Abuse
Definitions for medication 
error, misuse, and abuse were 
added.
Per Regulation (EU) No 536/2014 of the European Parliament and 
of the Council.
4.2.1.3 Patient-reported 
Outcomes
Added background 
information on patient-
reported outcomes.
Added for completeness and clarity.
4.2.1.3.3 EQ-5D-5L
Section name was corrected.
The section heading was incorrect.
8.9 Medical Resource 
Utilization and Health 
Economics
The section name was 
modified.
To reduce redundancy.
1.3 Schedule of Activities
8.10.4 Vital Status
These sections were updated to 
use vital status (rather than 
survival status).
Revised for clarity.
8.2.1.4 RECIST 1.1 
Assessment of Disease
Edited to delete unnecessary 
text.
To improve clarity.
10.1.4.1 Scientific Advisory 
Committee
This section was edited for 
clarity.
To clarify guidance.
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Section # and Name
Description of Change 
Brief Rationale 
10.7.4 China
This section was updated to 
clarify China-specific 
biomarker collection, testing, 
and analysis.
Biomarker sample collection, testing, and analysis are dependent 
on approval by the Human Genetic Resources Administration of 
China.
10.7.5 Japan
Clarified study intervention 
classification in Japan.
Per PMDA regulation.
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................19
1.1
Synopsis.................................................................................................................19
1.2
Schema ..................................................................................................................24
1.3
Schedule of Activities (SoA)................................................................................25
2
INTRODUCTION..........................................................................................................37
2.1
Study Rationale....................................................................................................37
2.2
Background ..........................................................................................................37
2.2.1
Pharmaceutical and Therapeutic Background .............................................38
2.2.1.1
Lenvatinib ..........................................................................................38
2.2.1.2
Pembrolizumab ..................................................................................38
2.2.1.3
Hepatocellular Carcinoma: Epidemiology and Current 
Therapeutic Options...........................................................................39
2.2.1.4
Immunotherapy Interventions in HCC...............................................41
2.2.1.5
Clinical Data on Lenvatinib and Pembrolizumab as Single Agents 
for the Treatment of HCC..................................................................41
2.2.1.6
Scientific Rationale for the Combination of Lenvatinib With 
Pembrolizumab ..................................................................................43
2.2.1.7
Clinical Data on Lenvatinib in Combination With Pembrolizumab 
for Treatment of Solid Tumors and HCC ..........................................43
2.2.2
Preclinical and Clinical Studies ...................................................................44
2.2.3
Ongoing Clinical Studies.............................................................................44
2.3
Benefit/Risk Assessment......................................................................................44
3
HYPOTHESIS, OBJECTIVES, AND ENDPOINTS .................................................45
4
STUDY DESIGN............................................................................................................47
4.1
Overall Design......................................................................................................47
4.2
Scientific Rationale for Study Design.................................................................48
4.2.1
Rationale for Endpoints ...............................................................................48
4.2.1.1
Efficacy Endpoints.............................................................................48
4.2.1.1.1
RECIST 1.1..............................................................................49
4.2.1.1.2
iRECIST...................................................................................49
4.2.1.1.3
Modified RECIST (mRECIST) ...............................................50
4.2.1.2
Safety Endpoints................................................................................50
4.2.1.3
Patient-reported Outcomes.................................................................50
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4.2.1.3.1
EORTC QLQ-C30 ...................................................................51
4.2.1.3.2
EORTC QLQ- HCC18.............................................................51
4.2.1.3.3
EQ-5D-5L ................................................................................51
4.2.1.4
Pharmacokinetic Endpoints ...............................................................51
4.2.1.5
Pharmacodynamic Endpoints.............................................................51
4.2.1.6
Planned Exploratory Biomarker Research.........................................51
4.2.1.7
Radiomic Biomarkers ........................................................................53
4.2.2
Rationale for the Use of Comparator/Placebo .............................................53
4.2.3
Rationale for Excluding Vp4 Patients..........................................................54
4.3
Justification for Dose...........................................................................................54
4.3.1
Lenvatinib ....................................................................................................54
4.3.2
Pembrolizumab ............................................................................................55
4.3.3
Maximum Dose/Exposure for This Study ...................................................56
4.4
Beginning and End of Study Definition .............................................................56
4.4.1
Clinical Criteria for Early Study Termination .............................................57
5
STUDY POPULATION ................................................................................................57
5.1
Inclusion Criteria.................................................................................................57
5.2
Exclusion Criteria................................................................................................61
5.3
Lifestyle Considerations......................................................................................64
5.3.1
Contraception...............................................................................................64
5.4
Screen Failures.....................................................................................................64
5.5
Participant Replacement Strategy......................................................................65
6
STUDY INTERVENTION............................................................................................65
6.1
Study Intervention(s) Administered...................................................................66
6.2
Preparation/Handling/Storage/Accountability .................................................68
6.2.1
Dose Preparation..........................................................................................68
6.2.2
Handling, Storage, and Accountability........................................................68
6.3
Measures to Minimize Bias: Randomization and Blinding..............................69
6.3.1
Intervention Assignment..............................................................................69
6.3.2
Stratification.................................................................................................69
6.3.3
Blinding........................................................................................................69
6.4
Study Intervention Compliance..........................................................................69
6.5
Concomitant Therapy..........................................................................................70
6.5.1
Allowed Concomitant Medication...............................................................70
6.5.2
Prohibited Concomitant Medications ..........................................................70
6.5.3
Drug-Drug Interactions................................................................................72
6.5.4
Rescue Medications and Supportive Care ...................................................72
6.6
Dose Modification (Escalation/Titration/Other)...............................................73
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6.6.1
Lenvatinib Dose Modification.....................................................................73
6.6.1.1
Management of Hypertension............................................................75
6.6.1.2
Management of Proteinuria................................................................77
6.6.1.3
Management of Diarrhea ...................................................................78
6.6.1.4
Management of Thromboembolic Events..........................................78
6.6.1.5
Management of Posterior Reversible Encephalopathy 
Syndrome/Reversible Encephalopathy Syndrome/ Reversible 
Posterior Leukoencephalopathy Syndrome .......................................79
6.6.1.6
Management of Hypocalcemia ..........................................................79
6.6.1.7
Management of Hemorrhage .............................................................79
6.6.1.8
Management of Gastrointestinal Perforation or Fistula Formation ...79
6.6.1.9
Management of Osteonecrosis of the Jaw .........................................80
6.6.2
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue).................................................................................................80
6.6.3
Guidance for Management of Hepatic Events of Clinical Interest..............85
6.6.3.1
Management of HECI for Lenvatinib Toxicity: ................................87
6.6.3.2
Management of HECI for Pembrolizumab/Placebo:.........................87
6.6.4
Dose Modifications for Overlapping Toxicities ..........................................89
6.6.5
Other Allowed Dose Interruptions for Lenvatinib.......................................90
6.7
Intervention After the End of the Study............................................................90
6.8
Clinical Supplies Disclosure................................................................................90
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................91
7.1
Discontinuation of Study Intervention...............................................................91
7.2
Participant Withdrawal From the Study...........................................................92
7.3
Lost to Follow-up .................................................................................................92
8
STUDY ASSESSMENTS AND PROCEDURES........................................................93
8.1
Administrative and General Procedures ...........................................................93
8.1.1
Informed Consent.........................................................................................93
8.1.1.1
General Informed Consent.................................................................94
8.1.2
Inclusion/Exclusion Criteria ........................................................................94
8.1.3
Participant Identification Card.....................................................................94
8.1.4
Medical History ...........................................................................................95
8.1.5
Prior and Concomitant Medications Review...............................................95
8.1.5.1
Prior Medications...............................................................................95
8.1.5.2
Concomitant Medications..................................................................95
8.1.6
Assignment of Screening Number...............................................................95
8.1.7
Assignment of Treatment/Randomization Number.....................................95
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8.1.8
Study Intervention Administration ..............................................................96
8.1.8.1
Timing of Dose Administration.........................................................96
8.1.8.1.1
Lenvatinib ................................................................................96
8.1.8.1.2
Pembrolizumab ........................................................................96
8.1.9
Discontinuation and Withdrawal .................................................................96
8.1.10
Participant Blinding/Unblinding..................................................................97
8.1.11
Calibration of Equipment.............................................................................97
8.2
Efficacy/Immunogenicity Assessments ..............................................................98
8.2.1
Tumor Imaging and Assessment of Disease................................................98
8.2.1.1
Initial Tumor Imaging........................................................................98
8.2.1.2
Tumor Imaging During the Study......................................................98
8.2.1.3
End-of-Treatment and Follow-up Tumor Imaging............................99
8.2.1.4
RECIST 1.1 Assessment of Disease..................................................99
8.2.1.5
iRECIST Assessment of Disease.....................................................100
8.2.1.6
Modified RECIST (mRECIST) Assessment of Disease..................101
8.2.2
Patient-reported Outcomes.........................................................................103
8.3
Safety Assessments.............................................................................................104
8.3.1
Physical Examinations...............................................................................104
8.3.1.1
Full Physical Examination...............................................................104
8.3.1.2
Directed Physical Examination........................................................104
8.3.2
Vital Signs..................................................................................................105
8.3.3
Electrocardiograms ....................................................................................105
8.3.4
Echocardiogram or Multiple Gated Acquisition Scan...............................105
8.3.5
Child-Pugh Score.......................................................................................106
8.3.6
Clinical Safety Laboratory Assessments ...................................................106
8.3.6.1
Laboratory Safety Evaluations (Hematology, Chemistry and 
Urinalysis)........................................................................................107
8.3.7
Pregnancy Testing......................................................................................107
8.3.8
Performance Assessments..........................................................................107
8.3.8.1
Eastern Cooperative Oncology Group (ECOG) Performance 
Scale.................................................................................................107
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Reportable Safety Events ..................................................................................107
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ........................................................108
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events....110
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information.110
8.4.4
Regulatory Reporting Requirements for SAE ...........................................110
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8.4.5
Pregnancy and Exposure During Breastfeeding ........................................111
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs..........................................................................................111
8.4.7
Events of Clinical Interest (ECIs)..............................................................112
8.5
Treatment of Overdose......................................................................................112
8.6
Pharmacokinetics...............................................................................................113
8.7
Pharmacodynamics............................................................................................113
8.8
Biomarkers .........................................................................................................113
8.8.1
Planned Genetic Analysis Sample Collection............................................113
8.9
Medical Resource Utilization and Health Economics.....................................114
8.10
Visit Requirements.............................................................................................114
8.10.1
Screening....................................................................................................114
8.10.2
Treatment Period........................................................................................115
8.10.3
Post-treatment Visit ...................................................................................115
8.10.3.1
Safety Follow-up Visit.....................................................................115
8.10.3.2
Follow-up Visits...............................................................................115
8.10.3.3
Survival Follow-up ..........................................................................115
8.10.4
Vital Status.................................................................................................116
9
STATISTICAL ANALYSIS PLAN ...........................................................................116
9.1
Statistical Analysis Plan Summary...................................................................116
9.2
Responsibility for Analyses/In-house Blinding ...............................................118
9.3
Hypotheses/Estimation ......................................................................................119
9.4
Analysis Endpoints.............................................................................................119
9.4.1
Efficacy Endpoints.....................................................................................119
9.4.2
Safety Endpoints........................................................................................119
9.5
Analysis Populations..........................................................................................120
9.5.1
Efficacy Analysis Populations...................................................................120
9.5.2
Safety Analysis Populations ......................................................................120
9.5.3
PRO Analysis Populations.........................................................................120
9.6
Statistical Methods.............................................................................................120
9.6.1
Statistical Methods for Efficacy Analyses.................................................120
9.6.1.1
Progression-free Survival.................................................................121
9.6.1.2
Overall Survival...............................................................................122
9.6.1.3
Objective Response..........................................................................122
9.6.1.4
Disease Control................................................................................123
9.6.1.5
Time to Progression.........................................................................123
9.6.1.6
Duration of Response.......................................................................123
9.6.2
Statistical Methods for Safety Analyses ....................................................125
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9.6.3
Statistical Methods for PRO Analyses.......................................................127
9.6.4
Statistical Methods for Pharmacokinetics (PK) Analyses .........................127
9.6.5
Summaries of Baseline Characteristics and Demographics.......................127
9.7
Interim Analyses ................................................................................................128
9.7.1
Safety Interim Analyses.............................................................................128
9.7.2
Efficacy Interim Analyses..........................................................................128
9.8
Multiplicity .........................................................................................................129
9.8.1
Progression-free Survival...........................................................................130
9.8.2
Overall Survival.........................................................................................130
9.8.3
Objective Response....................................................................................131
9.8.4
Safety Analyses..........................................................................................132
9.9
Sample Size and Power Calculations ...............................................................132
9.9.1
Sample Size and Power for Efficacy Analyses..........................................132
9.9.2
Sample Size and Power for Safety Analyses .............................................133
9.10
Subgroup Analyses.............................................................................................133
9.11
Compliance (Medication Adherence)...............................................................134
9.12
Extent of Exposure.............................................................................................134
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...................................................................................................135
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations......135
10.1.1
Code of Conduct for Clinical Trials...........................................................135
10.1.2
Financial Disclosure...................................................................................137
10.1.3
Data Protection...........................................................................................137
10.1.3.1
Confidentiality of Data ....................................................................138
10.1.3.2
Confidentiality of Participant Records.............................................138
10.1.3.3
Confidentiality of IRB/IEC Information..........................................138
10.1.4
Committees Structure.................................................................................138
10.1.4.1
Scientific Advisory Committee........................................................138
10.1.4.2
Executive Oversight Committee......................................................138
10.1.4.3
External Data Monitoring Committee .............................................139
10.1.5
Publication Policy......................................................................................139
10.1.6
Compliance with Study Registration and Results Posting Requirements .139
10.1.7
Compliance with Law, Audit, and Debarment ..........................................140
10.1.8
Data Quality Assurance .............................................................................140
10.1.9
Source Documents .....................................................................................141
10.1.10
Study and Site Closure...............................................................................141
10.2
Appendix 2: Clinical Laboratory Tests............................................................142
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................144
10.3.1
Definitions of Medication Error, Misuse, and Abuse................................144
10.3.2
Definition of AE ........................................................................................144
10.3.3
Definition of SAE ......................................................................................145
10.3.4
Additional Events Reported in the Same Manner as SAE.........................147
10.3.5
Recording AE and SAE .............................................................................147
10.3.6
Reporting of AE, SAE, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................151
10.4
Appendix 4: Medical Device Incidents: Definition and Procedures for 
Recording, Evaluating, Follow-up, and Reporting.........................................152
10.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing......................153
10.5.1
Definitions..................................................................................................153
10.5.2
Contraception Requirements......................................................................154
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................155
10.7
Appendix 7: Country-specific Requirements..................................................156
10.7.1
Germany.....................................................................................................156
10.7.2
United Kingdom.........................................................................................156
10.7.3
France.........................................................................................................157
10.7.4
China..........................................................................................................157
10.7.5
Japan ..........................................................................................................158
10.8
Appendix 8: Hepatitis B Definitions and Treatment Considerations ...........159
10.9
Appendix 9: ECOG Performance Status.........................................................160
10.10 Appendix 10: Child-Pugh Score .......................................................................161
10.11 Appendix 11: Barcelona Clinic Liver Cancer Staging System ......................163
10.12 Appendix 12: NYHA Criteria...........................................................................164
10.13 Appendix 13: Clinical Studies Evaluating Drug-Drug Interactions With 
Lenvatinib...........................................................................................................165
10.14 Appendix 14: Description of the iRECIST Process for Assessment of 
Disease Progression............................................................................................166
10.15 Appendix 15: American Association for the Study of Liver Diseases 
(AASLD) Liver Imaging Reporting and Data System (LI-RADS) 5 
Criteria................................................................................................................170
10.16 Appendix 16: Abbreviations .............................................................................171
11
REFERENCES.............................................................................................................174
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LIST OF TABLES
Table 1
Study Schedule of Activities..................................................................................25
Table 2
Adequate Organ Function Laboratory Values .......................................................60
Table 3
Study Interventions................................................................................................66
Table 4
Dose Modification for Lenvatinib Treatment-Related Toxicity............................73
Table 5
Dose Modification Guidelines for Lenvatinib-Related Adverse Events (for the 
Lenvatinib-Pembrolizumab Combination) ............................................................74
Table 6
Dose Modification and Toxicity Management Guidelines for Nonhepatic 
Immune-related Adverse Events Associated with Pembrolizumab 
Monotherapy, Coformulations or IO Combinations..............................................81
Table 7
Pembrolizumab Infusion Reaction Dose Modification and Treatment 
Guidelines ..............................................................................................................84
Table 8
Imaging and Treatment After First Radiologic Evidence of Progressive 
Disease.................................................................................................................102
Table 9
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events.....................................................................................109
Table 10
Censoring Rules for Primary and Sensitivity Analyses of PFS...........................122
Table 11
Censoring Rules for TTP .....................................................................................123
Table 12
Censoring Rules for DOR....................................................................................124
Table 13
Analysis Strategy for Key Efficacy Endpoints....................................................125
Table 14
Analysis Strategy for Safety Parameters..............................................................127
Table 15
Summary of Interim and Final Analyses Strategy...............................................128
Table 16
Efficacy Boundaries and Properties for Progression-free Survival Analyses .....130
Table 17
Efficacy Boundaries and Properties for Overall Survival Analyses....................131
Table 18
Possible Alpha-levels and Power for ORR Analysis...........................................132
Table 19
Two-sided 95% CIs of Differences in Incidence of AE Rates Between the 
Two Treatment Groups for 375 Participants in Each Treatment Arm.................133
Table 20
Protocol-required Safety Laboratory Assessments..............................................142
Table 21
Hepatitis B Definitions and Treatment Considerations .......................................159
Table 22
AASLD LI-RADS 5 Criteria ...............................................................................170
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LIST OF FIGURES
Figure 1
Study Diagram .......................................................................................................24
Figure 2
Imaging and Treatment for Clinically Stable Participants Treated With 
Pembrolizumab After First Radiologic Evidence of PD Assessed by the 
Investigator ..........................................................................................................103
Figure 3
Multiplicity Graph for Type I Error Control........................................................129
Figure 4
Barcelona Clinic Liver Cancer Staging System...................................................163
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 3 Multicenter, Randomized, Double-blinded, Active-controlled, 
Clinical Study to Evaluate the Safety and Efficacy of Lenvatinib (E7080/MK-7902) in 
Combination with Pembrolizumab (MK-3475) Versus Lenvatinib in First-line Therapy of 
Participants with Advanced Hepatocellular Carcinoma (LEAP-002)
Short Title: Phase 3 Study of Lenvatinib (E7080/MK-7902) plus Pembrolizumab (MK-
3475) for First-line Therapy of Advanced Hepatocellular Carcinoma
Acronym: LEAP-002
Hypotheses, Objectives, and Endpoints:
In first-line therapy of participants with advanced HCC following treatment with 
pembrolizumab plus lenvatinib versus treatment with placebo plus lenvatinib:
Primary Objectives
Primary Endpoints
- Objective: To compare progression-free 
survival (PFS) per Response Evaluation 
Criteria in Solid Tumors (RECIST) 1.1 
assessed by Blinded Independent Central 
Review (BICR) modified to follow a 
maximum of 10 target lesions and a 
maximum of 5 target lesions per organ.
- Hypothesis (H1): Pembrolizumab plus 
lenvatinib is superior to placebo plus 
lenvatinib with respect to PFS per RECIST 
1.1 assessed by BICR.
- PFS, defined as the time from 
randomization to the first documented 
disease progression or death due to any 
cause, whichever occurs first.
- Objective: To compare overall survival 
(OS). 
- Hypothesis (H2): Pembrolizumab plus 
lenvatinib is superior to placebo and 
lenvatinib with respect to OS.
- OS, defined as the time from 
randomization to death due to any cause.
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Secondary Objectives
Secondary Endpoints
- Objective: To compare objective response 
rate (ORR) per RECIST 1.1 as assessed by 
BICR. 
- Hypothesis (H3): Pembrolizumab plus 
lenvatinib is superior to placebo plus 
lenvatinib with respect to OR per RECIST 
1.1 assessed by BICR.
- Objective Response (OR): Complete 
response (CR) or partial response (PR).
- Objective: To evaluate duration of response 
(DOR), and disease control rate (DCR) per 
RECIST 1.1 as assessed by BICR.
- DOR, defined as the time from the first 
documented evidence of CR or PR until 
the first documented disease progression or 
death due to any cause, whichever occurs 
first.
- Disease Control (DC), defined as a best 
overall response of CR, PR, or stable 
disease (SD). SD must be achieved at ≥6 
weeks after randomization to be 
considered best overall response.
- Objective: To evaluate the safety and 
tolerability of pembrolizumab plus lenvatinib 
versus placebo plus lenvatinib.
- Adverse events (AEs), serious AEs 
(SAEs), immune-related (irAEs), and 
hepatic AEs.
- Study intervention discontinuations due 
to AEs.
- Objective: To evaluate TTP per 
RECIST 1.1 assessed by BICR.
- TTP, defined as the time from 
randomization to the first documented 
disease progression.
- Objective: To evaluate efficacy outcomes 
per modified RECIST 1.1 (mRECIST) 
assessed by BICR. 
- PFS, OR, DOR, DCR, and time to 
disease progression (TTP). 
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The study will be deemed positive if either OS or PFS null hypotheses are rejected.
Overall Design:
Study Phase
Phase 3
Primary Purpose
Treatment
Indication
The treatment of participants with advanced 
hepatocellular carcinoma
Population
Participants with advanced hepatocellular carcinoma
Study Type
Interventional
Intervention Model
Parallel
This is a multi-site study.
Type of Control
Active
Study Blinding
Double-blind
Masking
Investigator
Participant
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 44 months from the time the first 
participant signs the informed consent until the last 
participant’s last study-related telephone call or visit.
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Number of Participants:
Approximately 750 participants will be randomized to 1:1 to 1 of 2 treatment arms.
Intervention Groups and Duration:
Intervention 
Groups
Intervention 
Group Name
Drug
Dose 
Strength
Dose 
Frequency
Route of 
Admin.
Regimen/ 
Treatment 
Period
Use
Arm A
Pembrolizumab
200 mg
Every 3 
Weeks 
(Q3W)
Intravenous 
(IV) 
infusion
Day 1 of 
each 
42-day 
cycle
Experimental
Lenvatinib
12 mg (Body 
weight [BW] 
≥60 kg) or 
8 mg (BW 
<60 kg)*
Once Daily
Oral
Daily
Experimental
Arm B
Placebo
0 mg, 0.90% 
w/v NaCl
Q3W
IV infusion
Day 1 of 
each 
42-day 
cycle
Placebo
Lenvatinib
12 mg (BW 
≥60 kg) or 
8 mg (BW 
<60 kg)
Once Daily
Oral
Daily
Experimental
*Lenvatinib dosing is based on actual body weight at Screening and will be fixed for the duration of the study.
Abbreviations: BW=body weight; IV=intravenous; Q3W=every 3 weeks; w/v=weight/volume.
Total 
Number 
2 arms
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Duration of 
Participation
Each participant will participate in the study from the time the participant 
signs the Informed Consent Form (ICF) through the final protocol-specified 
contact.
After a screening phase of up to 28 days, each participant will be assigned 
to receive study intervention until disease progression is radiographically 
documented and verified by BICR. When clinically appropriate, 
participants can remain on study until confirmed by the site per modified 
Response Evaluation Criteria in Solid Tumors 1.1 for immune-based 
therapeutics (iRECIST), or unacceptable adverse event(s) (AEs), 
intercurrent illness that prevents further administration of treatment, 
investigator’s decision to discontinue the participant, noncompliance with 
study intervention or procedure requirements or administrative reasons 
requiring cessation of treatment, or until the participant has received 35 
administrations of pembrolizumab/placebo (approximately 2 years)
whichever occurs first. Participants who attain an investigator-determined 
CR may consider stopping treatment with pembrolizumab/placebo after at 
least 24 weeks of study intervention have been administered. In addition, if 
a confirmed CR per RECIST 1.1 is attained, at least 2 additional doses of 
pembrolizumab/placebo must be received after CR is first documented.  In 
the presence of clinical benefit, participants who complete 35 cycles of 
treatment with pembrolizumab/placebo (approximately 2 years) may 
continue to receive lenvatinib alone until progression or intolerable toxicity.
This protocol does not allow participants to cross over to the other arm if 
they experience progression.
After the end of treatment, each participant will be followed for the 
occurrence of AEs and spontaneously reported pregnancy as described 
under Section 8.4.
Participants who discontinue for reasons other than radiographic disease 
progression will have post-treatment follow-up imaging for disease status 
until disease progression is documented radiographically per RECIST 1.1
and verified by BICR. When clinically appropriate, participants can remain 
on study until confirmed by the site per iRECIST, or initiating a non-study 
cancer treatment, withdrawing consent, or becoming lost to follow-up, 
whichever occurs first. All participants will be followed by telephone for 
overall survival until death, withdrawal of consent, or the end of the study.
The end of the study will be the date of data cutoff for the final analysis or 
the time of last participant/last treatment, whichever occurs later.
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Study Governance Committees:
Steering Committee
No
Executive Oversight Committee
Yes
Data Monitoring Committee
Yes
Clinical Adjudication Committee
No
Study governance considerations are outlined in Appendix 1.
Study Accepts Healthy Volunteers: No
A list of abbreviations used in this document can be found in Appendix 16.
1.2
Schema
The study design is depicted in Figure 1.
Figure 1
Study Diagram
BW = body weight; ECOG PS = Eastern Cooperative Oncology Group performance status; HCC = hepatocellular 
carcinoma; IV = intravenous; Q3W = every 3 weeks; QD = once daily; PD = progressive disease; PO = per oral.
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1.3
Schedule of Activities (SoA)
Table 1
Study Schedule of Activities
Study Period
Screening
Treatment Period
42-Day Cycles
EOT
Post Treatment
Notes
Intervention 
Cycles/ Titles
1
2
3
4
5
6
7 to 
last
Cycle Day
1
8
15
1
15
1
1
1
1
1
Safety 
FUa,b
Imaging 
FUc
Survival 
FU
Scheduling 
Window (Days):
–28 to –1
±3
±3
±3
±3
±3
±3
±3
±3
±3
At 
D/C
30 Days 
and 90 
Days  
After Last 
Dose (+ 7 )
Q12W 
(± 7 )
Q12W 
(± 7 )
Administrative and General Procedures
Informed consent
X
Consent form can be signed at any 
time prior to any protocol-specific 
screening procedures being 
performed.
Additional consent is required at 
disease progression.
Inclusion/ 
exclusion
X
Participant ID 
card
X
Demographics
X
Medical/
surgical history
X
Prior/
concomitant 
medication 
review
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications will be 
recorded for 90 days after last dose (or 
for up to 120 days after last dose for 
SAEs).
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Study Period
Screening
Treatment Period
42-Day Cycles
EOT
Post Treatment
Notes
Intervention 
Cycles/ Titles
1
2
3
4
5
6
7 to 
last
Cycle Day
1
8
15
1
15
1
1
1
1
1
Safety 
FUa,b
Imaging 
FUc
Survival 
FU
Scheduling 
Window (Days):
–28 to –1
±3
±3
±3
±3
±3
±3
±3
±3
±3
At 
D/C
30 Days 
and 90 
Days  
After Last 
Dose (+ 7 )
Q12W 
(± 7 )
Q12W 
(± 7 )
Randomization 
and study 
intervention 
assignment via 
IRT
X
Participants will be randomized on 
C1D1 after confirmation of eligibility. 
All procedures and assessments on 
C1D1 should be performed after 
randomization.
For participants that have been 
enrolled and randomized: The TEA is 
to be completed as soon as possible 
for those participants that have been 
previously randomized. 
For participants yet to be randomized: 
The TEA form must be completed 
prior to randomization. The 
investigator must provide the rationale 
for treatment choice prior to 
randomization.
Subsequent 
antineoplastic 
treatment
X
X
X
All antineoplastic therapy will be 
recorded until time of death or 
termination of survival follow-up.
If a clinic visit is not feasible, 
follow-up information may be 
obtained via telephone or email.
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Study Period
Screening
Treatment Period
42-Day Cycles
EOT
Post Treatment
Notes
Intervention 
Cycles/ Titles
1
2
3
4
5
6
7 to 
last
Cycle Day
1
8
15
1
15
1
1
1
1
1
Safety 
FUa,b
Imaging 
FUc
Survival 
FU
Scheduling 
Window (Days):
–28 to –1
±3
±3
±3
±3
±3
±3
±3
±3
±3
At 
D/C
30 Days 
and 90 
Days  
After Last 
Dose (+ 7 )
Q12W 
(± 7 )
Q12W 
(± 7 )
Vital status
In participants who experience PD or 
start a new anticancer therapy, contact 
should be made (by telephone or visit) 
approximately every 12 weeks or 
more frequently, to assess for vital
status. All subsequent antineoplastic 
therapy will be recorded. Updated 
vital 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 vital status 
(excluding participants who have a 
death event previously recorded). 
Schedule of Study Intervention
Lenvatinib 
Dispensing
X
X
X
X
X
X
X
Lenvatinib 12 mg (BW≥60 kg) or 
8 mg (BW<60 kg) orally QD until PD 
or intolerable toxicity.
Pembrolizumab / 
placebo 
administration
X
X
X
X
X
X
X
Pembrolizumab 200 mg IV Q3W or 
normal saline placebo IV Q3W for 35 
cycles.
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Study Period
Screening
Treatment Period
42-Day Cycles
EOT
Post Treatment
Notes
Intervention 
Cycles/ Titles
1
2
3
4
5
6
7 to 
last
Cycle Day
1
8
15
1
15
1
1
1
1
1
Safety 
FUa,b
Imaging 
FUc
Survival 
FU
Scheduling 
Window (Days):
–28 to –1
±3
±3
±3
±3
±3
±3
±3
±3
±3
At 
D/C
30 Days 
and 90 
Days  
After Last 
Dose (+ 7 )
Q12W 
(± 7 )
Q12W 
(± 7 )
Efficacy Procedures
Tumor 
assessment –
chest, abdomen,
and pelvis 
(CT/MRI)c
X
X
X
Historical scans performed within 28 
days prior to randomization but before 
providing documented informed 
consent may be used if consistent with 
protocol requirements per BICR.
All imaging visits have a scheduling 
window of within 7 days.
Confirmation of all the following 
characteristics at screening is required 
prior to randomization:
-
Measurable disease per RECIST 
1.1 by BICR
-
Radiographic diagnosis of HCC 
per ASSLD guidelines (Appendix 
15) by Site,  
-
Absence of VP4 portal vein 
thrombosis, inferior vena cava 
thrombosis, and cardiac 
involvement. Imaging must 
include triphasic CT/MRI for liver 
evaluation. Details to be provided 
in BICR SIM. Progression should 
be confirmed by BICR prior to 
discontinuing study treatment.
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Study Period
Screening
Treatment Period
42-Day Cycles
EOT
Post Treatment
Notes
Intervention 
Cycles/ Titles
1
2
3
4
5
6
7 to 
last
Cycle Day
1
8
15
1
15
1
1
1
1
1
Safety 
FUa,b
Imaging 
FUc
Survival 
FU
Scheduling 
Window (Days):
–28 to –1
±3
±3
±3
±3
±3
±3
±3
±3
±3
At 
D/C
30 Days 
and 90 
Days  
After Last 
Dose (+ 7 )
Q12W 
(± 7 )
Q12W 
(± 7 )
For participants D/Cing for reasons 
other than BICR-confirmed PD, 
imaging should continue Q12W until 
BICR-confirmed PD.
Imaging at EOT is not required if the 
previous tumor imaging assessment 
was within 4 weeks prior to the EOT 
visit.
Clinical Procedures or Assessments
AE monitoring
X
X
X
X
X
X
X
X
X
X
X
X
X
X
AEs: monitored up to 90 days after 
last dose or 30 days after the last dose 
if the participant initiates new 
anticancer therapy.
SAEs: monitored up to 120 days after 
last dose, or 30 days after last dose if 
participant starts a new antineoplastic 
therapy, whichever is sooner.
Full physical 
examination
X
X
To be performed within 7 days prior 
to start of study treatment.
Directed physical 
examination
X
X
X
X
X
X
X
X
X
X
X
Child-Pugh 
Score
X
If any hepatic ECI criteria are met, 
document the Child-Pugh score with 
each visit until the hepatic ECIs 
resolve.
Vital signs 
(resting BP, 
pulse, RR, and 
temp) and weight
X
X
X
X
X
X
X
X
X
X
X
X
X
Additionally, participants with initial 
or recurrent systolic BP ≥160 mm Hg 
or diastolic BP ≥100 mm Hg must 
have their BP monitored until systolic 
BP is ≤150 mm Hg and diastolic BP is 
≤95 mm Hg for 2 consecutive 
treatment cycles. 
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Study Period
Screening
Treatment Period
42-Day Cycles
EOT
Post Treatment
Notes
Intervention 
Cycles/ Titles
1
2
3
4
5
6
7 to 
last
Cycle Day
1
8
15
1
15
1
1
1
1
1
Safety 
FUa,b
Imaging 
FUc
Survival 
FU
Scheduling 
Window (Days):
–28 to –1
±3
±3
±3
±3
±3
±3
±3
±3
±3
At 
D/C
30 Days 
and 90 
Days  
After Last 
Dose (+ 7 )
Q12W 
(± 7 )
Q12W 
(± 7 )
Height
X
NYHA
X
See Appendix 12.
12-lead ECG
X
X
X
X
X
X
X
X
X
C1D1 and C2D1: predose and 
approximately 2 hr-post-lenvatinib 
dose assessments are required.
Single 12-lead ECG. Participants must 
be in the recumbent position for 
5 minutes prior to the ECG.
MUGA or 
ECHO for LVEF 
assessment
X
X
Additional assessments as clinically 
indicated. Assessments should use the 
same method (MUGA or ECHO) 
throughout the study.
Gastro-
enterological 
endoscopy
X
Gastroenterological upper endoscopy 
at Screening period is necessary only 
if more than 3 months have passed 
since the previous assessment.
ECOG 
performance 
status
X
X
X
X
X
X
X
X
X
To be assessed within 7 days prior to 
starting study intervention.
Should be assessed prior to dosing at 
treatment visits.
Local Laboratory Procedures and Assessmentsd
Pregnancy test 
(WOCBP only)
X
X
X
X
X
X
X
X
X
X
WOCBP require negative test prior to 
randomization. If more than 24 hours 
have elapsed prior to first dose of 
study intervention, another pregnancy 
test is required prior to starting study 
intervention.
A serum or urine pregnancy test will 
be performed per Section 8.3.7.
Home pregnancy testing should be 
conducted midcycle (Day 22 of each 
treatment cycle), while taking oral 
study intervention(s).
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Study Period
Screening
Treatment Period
42-Day Cycles
EOT
Post Treatment
Notes
Intervention 
Cycles/ Titles
1
2
3
4
5
6
7 to 
last
Cycle Day
1
8
15
1
15
1
1
1
1
1
Safety 
FUa,b
Imaging 
FUc
Survival 
FU
Scheduling 
Window (Days):
–28 to –1
±3
±3
±3
±3
±3
±3
±3
±3
±3
At 
D/C
30 Days 
and 90 
Days  
After Last 
Dose (+ 7 )
Q12W 
(± 7 )
Q12W 
(± 7 )
PT/INR
X
X
X
X
X
X
X
X
X
Screening samples collected within 
7 days prior to first dose of study 
intervention.
CBC with 
Differential
X
X
X
X
X
X
X
X
X
X
X
To be assessed within 7 days prior to 
first dose of study intervention.
Clinical 
chemistry 
laboratory 
assessments
X
X
X
X
X
X
X
X
X
X
X
To be assessed within 7 days prior to 
first dose of study intervention. Every 
effort should be made to collect 
samples at the same time of day.
For lab details see Section 10.2, 
Appendix 2.
Urine dipstick 
testing
X
X
X
X
X
X
X
X
X
X
X
Performed locally within 7 days prior 
to start of intervention.
Testing to be performed on D1 of 
every cycle. D15 testing is mandatory 
in C1 and C2. Participants may return 
for testing if monitoring is required as 
follows: requires 24-hour urine 
protein analysis if new proteinuria 
(dipstick ≥2+) is detected on 
urinalysis; repeat testing for 
participants with proteinuria ≥2+ 
should be performed until the results 
have been 1+ or negative for 2 
consecutive treatment cycles.
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Study Period
Screening
Treatment Period
42-Day Cycles
EOT
Post Treatment
Notes
Intervention 
Cycles/ Titles
1
2
3
4
5
6
7 to 
last
Cycle Day
1
8
15
1
15
1
1
1
1
1
Safety 
FUa,b
Imaging 
FUc
Survival 
FU
Scheduling 
Window (Days):
–28 to –1
±3
±3
±3
±3
±3
±3
±3
±3
±3
At 
D/C
30 Days 
and 90 
Days  
After Last 
Dose (+ 7 )
Q12W 
(± 7 )
Q12W 
(± 7 )
T3/FT3, FT4, 
and TSH
X
X
X
X
X
X
Thyroid function tests will be assessed 
at Screening, followed by C2D1 and 
then every 2 cycles after that (ie,
C4D1, C6D1, C8D1, etc.).
Screening samples to be collected 
within 28 days prior to treatment 
initiation. 
After Cycle 1, participant will be 
dosed even if thyroid evaluations are 
not available prior to dosing; however,
the results must be available and 
reviewed before the next scheduled 
visit.
Free T3 (FT3) is acceptable where T3 
cannot be determined.
AFP
X
X
X*
X
X
Perform within 28 days prior to study 
treatment.
*AFP every 9 weeks (Screening, C4, 
C7, C10, etc.)
After Cycle 1, participant will be 
dosed even if AFP is not available 
prior to dosing; however, the results 
must be available and reviewed before 
the next scheduled visit.
HIV
X
Testing is not required unless 
mandated by local health authority.
Refer to Appendix 7 for country-
specific requirements.
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Study Period
Screening
Treatment Period
42-Day Cycles
EOT
Post Treatment
Notes
Intervention 
Cycles/ Titles
1
2
3
4
5
6
7 to 
last
Cycle Day
1
8
15
1
15
1
1
1
1
1
Safety 
FUa,b
Imaging 
FUc
Survival 
FU
Scheduling 
Window (Days):
–28 to –1
±3
±3
±3
±3
±3
±3
±3
±3
±3
At 
D/C
30 Days 
and 90 
Days  
After Last 
Dose (+ 7 )
Q12W 
(± 7 )
Q12W 
(± 7 )
Central Laboratory Assessments
Anti-HCV (IgG)
X
Perform within 28 days prior to study 
treatment.
If Anti-HCV
(IgG) positive:
If these conditions are met, the 
following test will be done within 
28 days prior to study intervention.
HCV 
genotype
X
Participant may be randomized if 
results are pending and participant 
meets all other eligibility criteria.
HCV viral 
loade
X
Anti-HBc (total 
and IgM), anti-
HBs, HBV viral 
load, HBsAge
X
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Study Period
Screening
Treatment Period
42-Day Cycles
EOT
Post Treatment
Notes
Intervention 
Cycles/ Titles
1
2
3
4
5
6
7 to 
last
Cycle Day
1
8
15
1
15
1
1
1
1
1
Safety 
FUa,b
Imaging 
FUc
Survival 
FU
Scheduling 
Window (Days):
–28 to –1
±3
±3
±3
±3
±3
±3
±3
±3
±3
At 
D/C
30 Days 
and 90 
Days  
After Last 
Dose (+ 7 )
Q12W 
(± 7 )
Q12W 
(± 7 )
If (1) HBsAg+ 
and/or HBV 
viral load 
detectable or (2) 
anti-HBc+, anti-
HBs-, HBsAg-
and viral load 
<100 IU/mL
If these conditions are met, the 
following tests will be done within 28 
days prior to study intervention.
Anti-HDV
X
HDV RNA
X
Anti-HBe 
and 
HBeAge
X
PK/Pharmacodynamic/Biomarker Assessment
Pembrolizumab 
PK blood 
samplef
X
X
X
Predose C1D1, C2D1, C8D1. 
Pembrolizumab 
ADAf
X
X
X
Predose C1D1, C2D1, C8D1. 
Lenvatinib PK 
blood samplef
X
X
X
C1D1: 0.5-4 hr and 6-10 hr post dose; 
C1D15: predose and 2-12 hr postdose; 
C2D1: predose, 0.5-4 hr and 6-10 hr
postdose
Note: all predose samples should be 
collected within 2 hrs of lenvatinib 
dosing.
Note: postdose samples not needed if 
lenvatinib administration is skipped.
Blood for genetic 
analysisg
X
Collect predose. See Section 8.8.1 for 
additional information.
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Study Period
Screening
Treatment Period
42-Day Cycles
EOT
Post Treatment
Notes
Intervention 
Cycles/ Titles
1
2
3
4
5
6
7 to 
last
Cycle Day
1
8
15
1
15
1
1
1
1
1
Safety 
FUa,b
Imaging 
FUc
Survival 
FU
Scheduling 
Window (Days):
–28 to –1
±3
±3
±3
±3
±3
±3
±3
±3
±3
At 
D/C
30 Days 
and 90 
Days  
After Last 
Dose (+ 7 )
Q12W 
(± 7 )
Q12W 
(± 7 )
Blood for 
circulating tumor 
nucleic acidsg
X
X
X
X
X
X
Collect predose C1D1, C2D1, C3D1, 
C5D1, and then D1 every 3 cycles
thereafter (C8D1, C11D1, C14D1,
etc.), and at EOT.
Tumor block or 
slidesg
X
Tissue is not required for enrollment, 
however submission of archival tissue 
is strongly encouraged, if available. 
Formalin-fixed, paraffin-embedded 
block specimens are preferred to 
slides.
Patient-Reported Outcomes
ePROs in the 
following order: 
EORTC QLQ-
C30, EORTC 
QLQ-HCC18, 
EQ-5D-5L
X
X
X
X
X
X
X*
X
X
Every effort should be made to 
administer PROs prior to drug 
administration, AE evaluation, and 
disease status notification.
All PROs are to be performed at C1, 
C2, C3, C4, C5, C6, C7, C8, C9, and 
C10.
*After C10 (Week 27), PROs are to 
be performed every 2 cycles (6 weeks) 
i.e. Cycle 12, 14, 16, 18. PROs are to 
be performed up to a year or EOT, 
whichever comes first, at D/C, and at 
the 30-day post-treatment 
discontinuation follow-up visit. A 
visit window of ±7 days will apply to 
PRO visit assessment. If the EOT visit 
occurs 30 days from the last dose of 
study treatment, a Safety Follow-up 
visit is not required; ePROs do not 
need to be repeated. 
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Study Period
Screening
Treatment Period
42-Day Cycles
EOT
Post Treatment
Notes
Intervention 
Cycles/ Titles
1
2
3
4
5
6
7 to 
last
Cycle Day
1
8
15
1
15
1
1
1
1
1
Safety 
FUa,b
Imaging 
FUc
Survival 
FU
Scheduling 
Window (Days):
–28 to –1
±3
±3
±3
±3
±3
±3
±3
±3
±3
At 
D/C
30 Days 
and 90 
Days  
After Last 
Dose (+ 7 )
Q12W 
(± 7 )
Q12W 
(± 7 )
Abbreviations: ADA = anti-drug antibody(ies); AE = adverse event; AFP = alpha fetaprotein; Anti-HBc = antihepatitis B core antibody, Total; Anti-HBe = antihepatitis B early antibody; Anti-HBs = 
antihepatitis B surface antibody; Anti-HDV = antihepatitis D antibody; BICR = blinded independent central review; BP = blood pressure; BW = body weight; CBC = complete blood count; CT = 
computed tomography; CX = Cycle X; D/C = discontinuation; DX = Day X, ECG = electrocardiogram; ECHO = echocardiogram; ECI = event of clinical interest; ECOG = Eastern Cooperative 
Oncology Group; EORTC QLQ= European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire; EOT = end of treatment; ePRO = electronic patient-reported outcome; 
EQ-5D-5L = European Quality of Life 5-dimension, 5-level Questionnaire; FT3 = free triiodothyronine; FU = follow-up; HBeAg = hepatitis B early antigen; HBsAg = hepatitis B surface antigen; 
HBV = hepatitis B virus; HCC = hepatocellular carcinoma; HCV = hepatitis C virus; HIV = human immunodeficiency virus; ID = identification; IgM = immunoglobulin M; INR = international 
normalized ratio; IRT = interactive response technology; LVEF = left ventricular ejection fraction; MRI = magnetic resonance imaging; MUGA = multigated acquisition; NYHA = New York Heart 
Association; PD = progressive disease; PE = physical examination; PK = pharmacokinetics; PRO = patient-reported outcome; PT = prothrombin time; Q3W = every 3 weeks; Q12W = every 12 
weeks; QD = once daily; RECIST 1.1 = Response Evaluation Criteria in Solid Tumors Version 1.1; RNA = ribonucleic acid; RR = respiratory rate; SAE = serious adverse event; SIM = site imaging 
manual; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone; WOCBP = women of childbearing potential.
a.
If EOT visit occurs ≥30 days from last dose of study treatment, a Safety Follow-up visit is not required. In this situation, all procedures required at both the EOT visit and the Safety Follow-up 
visit should be performed.
b. 
Safety FU will occur during 2 separate visits: 30 days AND 90 days after last dose. For participants continuing with imaging FU at ≥12W, if their 90-day safety FU visit falls within the same 
window as their imaging FU visit, these visits may be combined. All procedures required at the Safety FU visit at 90 days will be performed at the imaging FU at ≥12W.
c.
Following the primary analysis for the study:  follow-up visits and tumor assessments should be performed Q12W or more frequently if required by local standard of care.
d.
Clinical laboratory assessments may be conducted anytime within 72 hours prior to the scheduled visit, unless otherwise specified. Procedures/assessments should be performed prior to 
administration of study intervention.
e.
At screening, participants must have results within 28 days prior to first dose. In the case of hepatic ECIs, additional tests are to be performed as described in Section 6.6.3, Guidance for 
Management of Hepatic Events of Clinical Interest. All additional laboratory tests should be performed by a central laboratory, if possible.
f.
If ongoing PK and/or ADA sampling is deemed to be unnecessary by the Sponsor, it may be reduced or discontinued.
g.
See Section 10.7.4 for China-Specific requirement for submitting biomarker samples, including tissue, blood, and stool.
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2
INTRODUCTION
2.1
Study Rationale
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer deaths worldwide. 
Furthermore, incidence and mortality rates are increasing in most parts of the world, 
including in the United States (US). Patients with advanced HCC represent a group with high 
unmet need with low survival rates, few effective therapeutic options, and poor health-related 
quality of life (HRQoL).
Sorafenib, an oral antiangiogenic tyrosine kinase inhibitor (TKI), is a current standard of care 
worldwide for the first-line (1L) treatment of patients with advanced HCC. In a randomized, 
open-label, Phase 3 study (REFLECT), lenvatinib (also known as E7080 or MK-7902; 
hereafter referred to as lenvatinib), an oral multikinase inhibitor, showed noninferiority in 
terms of overall survival (OS) compared with sorafenib (median OS duration was 13.6 
months for lenvatinib vs 12.3 months for sorafenib) [Kudo, M., et al 2018]. Lenvatinib is 
now approved for the 1L treatment of advanced HCC in many parts of the world.  
Emerging data of successful immune activation show promising results in various 
malignancies, and provide the opportunity to explore immunotherapy in HCC as a 
therapeutic approach. Immunotherapy has been shown to produce antitumor effects in HCC, 
a tumor that has shown resistance to traditional forms of chemotherapy.
Recently, Phase 2 data from treatment with the programmed cell death 1 (PD-1) inhibitor, 
pembrolizumab, in second-line (2L) HCC (KEYNOTE-224) were published [Zhu, A. X., et 
al 2018]. These results included an objective response rate (ORR) of 17%, with responses 
seen in different viral hepatitis subtypes, and several participants with prolonged durations of 
response. Toxicity was comparable to that seen in participants treated with pembrolizumab in 
other indications.
Early data of the combination of lenvatinib and pembrolizumab in HCC also show
encouraging initial data with respect to both safety and efficacy [Ikeda, M., et al 2018]. The 
current study will evaluate lenvatinib plus pembrolizumab or placebo in a 1L HCC setting. 
The demonstrated clinical efficacy and acceptable safety profile of pembrolizumab in HCC, 
together with single-agent activity and safety of lenvatinib in 1L HCC, and preliminary 
safety and efficacy data with the combination strongly support further development of 
pembrolizumab and lenvatinib in participants with 1L advanced HCC.
2.2
Background
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody 
(mAb) with high specificity of binding to the PD-1 receptor, thus inhibiting its interaction 
with programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 2 (PD-L2). 
Based on preclinical in vitro data, pembrolizumab has high affinity and potent receptor 
blocking activity for PD-1. Pembrolizumab has an acceptable preclinical safety profile and is 
in clinical development as an intravenous (IV) immunotherapy for advanced malignancies. 
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Keytruda® (pembrolizumab) is indicated for the treatment of patients across a number of 
indications.
Lenvatinib is a potent multiple-receptor tyrosine kinase (RTK) inhibitor that selectively 
inhibits vascular endothelial growth factor (VEGF) receptors (VEGFR1 [FLT1], VEGFR2 
[KDR], and VEGFR3 [FLT4]) in addition to other proangiogenic and oncogenic pathway-
related RTKs, including fibroblast growth factor (FGF) receptors 1-4, platelet-derived growth
factor receptor α, KIT, and RET.
Refer to the respective Investigator’s Brochures (IBs) for detailed background information on 
pembrolizumab and lenvatinib.
2.2.1
Pharmaceutical and Therapeutic Background
2.2.1.1
Lenvatinib
Angiogenesis, the formation of new blood vessels from a preexisting vascular network, is 
essential for tumor growth and metastasis. VEGF and its family of receptors (VEGRs 1 
through 3) play a major role in tumor angiogenesis [Ferrara, N., et al 2003] [Ellis, L. M. and 
Hicklin, D. J. 2008] [Tammela, T. and Alitalo, K. 2010]. Accumulated evidence suggests that 
FGF and its RTK, FGFR, also play important roles in tumor angiogenesis [Cross, M. J. and
Claesson-Welsh L. 2001] [Lieu, C., et al 2011] [Limaverde-Sousa, G., et al 2014]. Among 
known kinase inhibitors in clinical use, lenvatinib is one of the only inhibitors currently 
labeled with a mechanism of action as an inhibitor of not only VEGFRs but also of FGFRs, 
both of which are currently believed to be very important for tumor angiogenesis. Lenvatinib
inhibited VEGF- and FGF-driven proliferation and tube formation of human umbilical vein 
endothelial cell in vitro. In vivo angiogenesis induced by overexpressed VEGF (KP-1/VEGF 
transfectants) or FGF (KP-1/FGF transfectants) was significantly suppressed with oral 
treatments of lenvatinib. Lenvatinib also showed significant antitumor activity in KP-
1/VEGF and in 5 of 7 different types of human tumor xenograft models at between 1 to 100 
mg/kg [Yamamoto, Y., et al 2014].
In vitro proliferation assay of 9 human HCC cell lines showed that lenvatinib selectively 
inhibited proliferation of FGF signal-activated HCC cells, including FGF19-expressing 
Hep3B2.1-7. Lenvatinib suppressed phosphorylation of FRS2, a substrate of FGFR1–4, in 
these cells in a concentration-dependent manner. Lenvatinib inhibited in vivo tumor growth 
in Hep3B2.1-7 and SNU-398 xenografts and decreased phosphorylation of FRS2 and Erk1/2 
within the tumor tissue. Lenvatinib also exerted antitumor activity and potently reduced 
tumor microvessel density in the PLC/PRF/5 xenograft model and 2 HCC patient-derived 
xenograft models. These results suggest that lenvatinib has antitumor activity across diverse 
HCC models, and that targeting of tumor FGF signaling pathways and antiangiogenic 
activity underlies its antitumor activity against HCC tumors [Matsuki, M., et al 2018].
2.2.1.2
Pembrolizumab
The importance of intact immune surveillance function in controlling neoplastic 
transformations has been known for decades [Disis, M. L. 2010]. Accumulating evidence 
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shows a correlation between tumor-infiltrating lymphocytes in cancer tissue and favorable 
prognosis in various malignancies. In particular, the presence of cluster of differentiation 
(CD) 8+ T-cells and the ratio of CD8+ effector T-cells/FoxP3+ regulatory T-cells correlates 
with improved prognosis and long-term survival in several solid malignancies, including
ovarian, colorectal, and pancreatic cancer; HCC; malignant melanoma; and renal cell 
carcinoma. Tumor-infiltrating lymphocytes can also be expanded ex vivo and reinfused, 
inducing durable objective tumor responses in cancers such as melanoma [Dudley, M. E., et
al 2005] [Hunder, N. N., et al 2008].
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control. The normal function of PD-1, expressed on the cell surface of activated T-
cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an 
immunoglobulin (Ig) superfamily member related to CD28 and cytotoxic T-lymphocyte-
associated protein 4 (CTLA-4) that has been shown to negatively regulate antigen receptor 
signaling upon engagement of its ligands (PD-L1 and/or PD-L2) [Greenwald, R. J., et al 
2005] [Okazaki, T., et al 2001].
The structure of murine PD-1 has been resolved [Zhang, X., et al 2004]. PD-1 and its family 
members are type I transmembrane glycoproteins containing an Ig-variable–type domain 
responsible for ligand binding and a cytoplasmic tail responsible for the binding of signaling 
molecules. The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an 
immunoreceptor tyrosine-based inhibition motif, and an immunoreceptor tyrosine-based 
switch motif. Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases, SHP-1 
and SHP-2, to the immunoreceptor tyrosine-based switch motif within its cytoplasmic tail, 
leading to the dephosphorylation of effector molecules such as CD3 zeta (CD3ζ), protein 
kinase C-theta (PKCθ), and zeta-chain-associated protein kinase (ZAP70), which are 
involved in the CD3 T-cell signaling cascade [Okazaki, T., et al 2001] [Chemnitz, J. M., et al 
2004] [Sheppard, K-A, et al 2004] [Riley, J. L. 2009]. The mechanism by which PD-1 down-
modulates T-cell responses is similar to, but distinct from, that of CTLA-4, because both 
molecules regulate an overlapping set of signaling proteins [Parry, R. V., et al 2005] 
[Francisco, L. M., et al 2010]. As a consequence, the PD-1/PD-L1 pathway is an attractive 
target for therapeutic intervention in HCC.
2.2.1.3
Hepatocellular Carcinoma: Epidemiology and Current Therapeutic 
Options
HCC is responsible for more than 700,000 new cases and 600,000 deaths annually 
[Dhanasekaran, R., et al 2012]. Most HCC arises in the setting of liver cirrhosis from varied 
causes, including viral hepatitis, excessive alcohol consumption, and metabolic syndrome. 
Additionally, HCC incidence varies by region, with the highest rates seen in Eastern Asia and 
sub-Saharan Africa (over 20 cases per 100,000 individuals). China accounts for 
approximately 50% (395,000 new cases annually) of all new HCC cases. Countries in the 
Mediterranean, including Italy, Spain, and Greece, have intermediate rates, ranging from 10 
to 20 cases per 100,000 [Lafaro, K. J., et al 2015], although the incidence in the European 
Union (EU) overall (and in Western Europe specifically), as well as in North and South 
America, is relatively low (<10/100,000) [Ferlay, J., et al 2015].
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The predominant risk factors for HCC vary in high- and low-rate regions. In most high-rate 
countries, particularly Asia and Africa, chronic hepatitis B virus (HBV) infection and 
aflatoxin exposure are the major risk factors [McGlynn, K. A., et al 2015]. In contrast, in 
lower-rate areas, such as the US, hepatitis C virus (HCV) infection, excessive alcohol 
consumption, and metabolic syndrome play more important roles. Exceptions to these 
regional patterns are seen in Japan and Egypt, where the predominant risk factor is HCV 
infection.
Several nonviral risk factors have also been associated with an increased risk for HCC, 
including alcohol consumption, metabolic syndrome, and hereditary hemochromatosis 
[Lafaro, K. J., et al 2015] [McGlynn, K. A., et al 2015]. The array of disorders associated 
with metabolic syndrome (eg, obesity, type II diabetes, nonalcoholic fatty liver disease, and 
nonalcoholic steatohepatitis) are also linked to an increased risk of HCC [Welzel, T. M., et al 
2013]. The prevalence of NAFLD in the US ranges from 5.4% to 24% and is the most 
common reason for abnormal liver function in the US [Abd El-Kader, S. M. 2015]. SEER 
data from 2000-2011 showed metabolic disorders to be the etiology with the highest 
population-attributable risk (32%) for the development of HCC in the US [Makarova-Rusher, 
O. V., et al 2016].
Surgical resection, transplantation, and ablation are potentially curative treatment options for 
patients with early-stage disease; however, about 70% of patients present with advanced, 
unresectable disease. As HCC is resistant to most traditional chemotherapy agents, the 
median survival for patients with advanced disease is typically 6 to 9 months without therapy
[Qin, S., et al 2013]. With improved treatment options for hepatitis C, HCC rates are forecast 
to stabilize in the US over time. However, because a high percentage of HCC in the US is 
attributed to metabolic disorders, which continue to increase, the overall HCC incidence rates 
will likely not decrease in the near future [Petrick, J. L., et al 2016]. 
In a large Phase 3 study of sorafenib versus placebo in 1L HCC in the Western population, 
sorafenib showed a median improvement of 2.8 months compared with placebo (10.7 months 
vs 7.9 months; hazard ratio [HR] 0.69; p<0.001), despite a low response rate of 2% [Llovet, 
Josep M., et al 2008]. The time to progression (TTP) was 5.5 months and OS was 10.7 
months in the treatment arm, compared with 2.8 and 7.9 months in the placebo arm, 
respectively. The HR for OS was 0.69 (95% confidence interval [CI]: 0.55-0.87, p<0.001)
[Llovet, Josep M., et al 2008].
In patients from the Asia-Pacific region taking sorafenib, the median improvement in OS 
compared with placebo was 2.3 months (6.5 months vs 4.2 months; HR 0.68; p=0.014), 
although OS was shorter in this study [Cheng, A.-L., et al 2009]. In parts of Asia, the 
FOLFOX regimen (folinic acid, 5 fluorouracil, and oxaliplatin) has also been approved, 
based on a randomized study comparing FOLFOX with doxorubicin [Qin, S., et al 2013]. In 
that study, there was a nonsignificant trend toward improved OS in the FOLFOX arm, with 
some imbalances in the populations favoring the FOLFOX arm. 
Lenvatinib was approved in Japan, US, EU, and China for first-line treatment of unresectable 
HCC (see Sec 2.2.1.5 for additional information). Currently, regorafenib is the only globally 
approved 2L therapy following sorafenib treatment in patients with HCC based on a data 
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from a Phase 3 study [Bruix, J., et al 2017]. Recently, cabozantinib has demonstrated 
improved OS versus placebo in patients with advanced HCC who failed prior sorafenib 
treatment [Abou-Alfa, G. K., et al 2018]. Ramucirumab also recently reported a positive trial 
for OS versus placebo in a high-risk HCC population with alpha fetoprotein (AFP) levels 
≥400 ng/mL [Zhu, A. X., et al 2018]. While these both have demonstrated improved survival, 
the benefits remain modest, with associated side effects; thus, continued investigation of 
additional agents for advanced HCC patients remains crucial.
2.2.1.4
Immunotherapy Interventions in HCC
As described above, HCC often develops in the setting of inflammation of various types. In a 
gene-expression profiling study, nontumoral tissue from patients with HCC with an 
inflammatory signature predicted worsened OS [Hoshida, Y., et al 2008]. HCC patients with 
higher tumor expression of PD-L1 have a significantly poorer prognosis than patients with 
lower expression [Gao, Q., et al 2009]. In addition, high expression levels of PD-1 on T-cells 
(both tumor-infiltrating lymphocytes and peripheral blood mononuclear cells) also correlate 
with higher recurrence rates in HCC patients after surgical resection [Shi, F., et al 2011].
Recently, as described above, immunotherapy has been shown to produce antitumor effects 
in HCC, a tumor that has shown resistance to traditional forms of chemotherapy. CTLA-4 
inhibition with tremelimumab was evaluated in a small study of HCV-associated HCC 
patients [Sangro, B., et al 2013]. Seventeen patients were evaluable for response, and 3 
partial responses (PRs) were seen, lasting for 3.6, 9.2, and 15.8 months. Stable disease (SD) 
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.
A Phase 1/2 study of the anti-PD-1 antibody, nivolumab, in participants with advanced HCC 
demonstrated an ORR by blinded independent committee review (BICR) in the dose-
expansion cohort of 19%, and an estimated survival rate in evaluable patients of 83% at 6 
months and 74% at 9 months with several durable responses [El-Khoueiry, A. B., et al 2017]. 
Responses were seen both in viral-mediated HCC 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 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 [El-Khoueiry, A. B., et al 
2017]. As discussed above, early data suggest comparable results with pembrolizumab in 
advanced HCC.
2.2.1.5
Clinical Data on Lenvatinib and Pembrolizumab as Single Agents for the 
Treatment of HCC
HCC stimulates the development of arterial vessels in the process of progression, and it also 
expresses high levels of VEGF [Yamaguchi, R., et al 1998] [Poon, R. T. P., et al 2004]. An 
angiogenesis inhibitor, therefore, which selectively inhibits VEGF receptors, could 
selectively treat HCC with less effect on background hepatic disease. While lenvatinib is 
expected to induce tumor necrosis and suppression of progression by inhibiting angiogenesis 
and blocking blood flow in HCC with high expression of VEGF, an additional incremental 
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benefit (compared with conventional anticancer agents) is that lenvatinib may have the 
potential for lower levels of toxicity in patients with HCC who have chronic hepatic disease. 
Because it selectively affects blood vessels, lenvatinib may also be less likely to induce 
resistance after long-term treatment since endothelial cells are unlikely to become resistant. 
Lenvatinib has a different TKI profile than sorafenib, inhibiting FGFR pathways in addition 
to VEGFR pathways, which may contribute to additional antitumor activity in patients with 
HCC.
Lenvatinib is currently being evaluated in several clinical trials, including patients with HCC, 
renal cell carcinoma, nonsmall cell lung cancer (NSCLC), endometrial cancer, glioma, 
melanoma, and ovarian cancer [Kudo, M., et al 2018]and lenvatinib IB. Lenvatinib was 
approved by Japan (on 23-MAR-2018), FDA (on 15-AUG-2018), the EC (on 20-AUG-
2018), and China (04-SEPT-2018) for first-line treatment of unresectable HCC based on 
results from the open-label Phase 3 clinical trial E7080-G000-304 (REFLECT) study. In data 
published from the REFLECT study, 954 patients with 1L HCC were randomly assigned to 
receive lenvatinib at 12 mg or 8 mg once daily (QD) depending on body weight (BW) (≥60 
kg or <60 kg, respectively [n=478]) or sorafenib at 400 mg twice a day (n=476). Lenvatinib 
showed noninferior median OS compared to sorafenib (13.6 months vs 12.3 months; HR: 
0.92; 95% CI: 0.79–1.06). Lenvatinib treatment also showed improvements when compared 
to sorafenib treatment in the following: ORR (24.1% vs 9.2%), progression-free survival 
(PFS) (7.4 months vs 3.7 months), and median TTP (8.9 months vs 3.7 months). The most 
common any-grade adverse events (AEs) for lenvatinib were hypertension (201 [42%]), 
diarrhea (184 [39%]), decreased appetite (162 [34%]), and decreased weight (147 [31%]). 
When comparing the AE profile to sorafenib, lenvatinib has a decreased frequency of 
palmar-plantar erythrodysaesthesia (128 [27%] vs 249 [52%]), but an increased frequency of 
hypertension (201 [42%]) vs 144 [30%]).
Recently, Phase 2 data from treatment of 104 participants with pembrolizumab in 2L HCC 
(KEYNOTE-224) were published [Zhu, A. X., et al 2018]. These results included an ORR of 
17%, with responses seen in different viral subtypes, and several participants with prolonged 
durations of response. The best overall responses were 1 complete response (CR) (1%), 17 
PRs (16%), 46 SD (44%), 34 progressive disease (PD) (33%), and 6 (6%) participants who 
did not have a postbaseline assessment on the cutoff date and were considered not to be 
assessable. Of the 18 responders, 12 (77%) responders showed a response for at least 9 
months, as estimated by the Kaplan-Meier method, and the median time to response was 2.1 
months (range, 2.1–4.1 months). Treatment-related AEs occurred in 76 (73%) of 104
participants; 16 (15%) were serious. Grade 3 treatment-related events were reported in 25 
(24%) of the 104 participants; the most common were increased aspartate aminotransferase 
(AST) concentration in 7 (7%), increased alanine aminotransferase (ALT) concentration in 4
(4%), and fatigue in 4 (4%) of participants. One (1%) Grade 4 treatment-related event of 
hyperbilirubinemia occurred. One death associated with ulcerative esophagitis was attributed 
to treatment. Immune-mediated hepatitis occurred in 3 (3%) participants, but there were no 
reported cases of viral flares. Immune-mediated hepatitis was comparable to that seen in 
participants treated with pembrolizumab in other indications.
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2.2.1.6
Scientific Rationale for the Combination of Lenvatinib With 
Pembrolizumab
In preclinical models, lenvatinib decreased the tumor-associated macrophage (TAM) 
population, which is known as an immune regulator in the tumor microenvironment. By 
decreasing TAMs, expression levels of cytokines and immune-regulating receptors were 
changed to increase immune activation. The immune-modulating effect of lenvatinib may 
result in a potent combination effect with PD-1/PD-L1 signal inhibitors. The effect of 
combining lenvatinib with anti-PD-1/PD-L1 mAbs has been investigated in the CT26 
colorectal cancer syngeneic model (anti-PD-L1 mAb) as well as the LL/2 lung cancer 
syngeneic model (anti-PD-1 mAb). Combination treatment with lenvatinib and either an anti-
PD-1 or anti-PD-L1 mAb showed significant and superior antitumor effects compared with 
either compound alone in these 2 syngeneic models [Kato, Y., et al 2015].
Antitumor activity of combination treatment of lenvatinib with anti-PD-1 mAb was also 
examined in H22 murine HCC cell syngeneic model. The result showed that combination 
treatment with lenvatinib and anti-PD-1 mAb was more effective than single-agent treatment 
in this model [Kato, Y., et al 2016].
Based on these results, an open-label, Phase 1b/2 study (Study E7080-A001-111) to assess 
the safety and preliminary antitumor activity of the combination of lenvatinib plus 
pembrolizumab in participants with selected solid tumors is currently ongoing.
2.2.1.7
Clinical Data on Lenvatinib in Combination With Pembrolizumab for 
Treatment of Solid Tumors and HCC
E7080-A001-111 is an open-label Phase 1b/2 study in participants with selected solid tumors 
(NSCLC, predominantly clear cell renal cell carcinoma, endometrial carcinoma, urothelial 
carcinoma, head and neck squamous cell carcinoma or melanoma [excluding uveal 
melanoma]), which is being conducted in the US. Phase 1b of this study determined the 
MTD and recommended Phase 2 dose as 20 mg lenvatinib QD in combination with 200 mg 
of pembrolizumab given IV every 3 weeks (Q3W). In Phase 2, participants are assigned by 
tumor type to up to 6 cohorts (10 or 20 evaluable participants per cohort) to receive the MTD 
to assess the safety and efficacy of the combination in the selected tumor types. This phase is 
ongoing.
Study E7080-J081-115 is being conducted for participants with selected solid tumors in 
Japan to confirm the tolerability and safety for combination regimen of lenvatinib plus 
pembrolizumab at the MTD determined in E7080-A001-111 (lenvatinib 20 mg QD and 
pembrolizumab 200 mg Q3W IV).
Data submitted to ASCO 2018 of a Phase 1b study of the combination of lenvatinib and 
pembrolizumab in HCC (Study E7080-J081-116/MK-3475-524) using weight-based dosing 
showed encouraging initial data (ASCO 2018) [Ikeda, M., et al 2018]. No dose-limiting 
toxicities (DLTs) were reported in Part 1. The MTD was determined as 12 mg (≥60 kg BW) 
or 8 mg (<60 kg BW) lenvatinib orally QD in combination with 200 mg IV Q3W of 
pembrolizumab. As of data cutoff, 22-MAR-2018, 30 patients were enrolled (Part 1, n = 6; 
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Part 2, n = 24). There was a manageable safety profile for the combination and notable 
antitumor activity. The ORR, excluding unconfirmed responses, was 3 (50.0%) for Part 1 and 
4 (20.0%) for Part 2 by modified Response Evaluation Criteria in Solid Tumors (mRECIST)
as assessed by investigator. See Section 4.3 – Justification for Dose for additional 
information.
2.2.2
Preclinical and Clinical Studies
Refer to the respective IBs for preclinical and clinical study data for pembrolizumab and 
lenvatinib.
2.2.3
Ongoing Clinical Studies
Refer to the respective IBs for ongoing clinical study data for pembrolizumab and lenvatinib.
2.3
Benefit/Risk Assessment
It cannot be guaranteed that participants in clinical studies will directly benefit from 
treatment during participation, as clinical studies are designed to provide information about 
the safety and effectiveness of an investigational medicine.
As discussed in Sections 2.2.1.1 and 2.2.1.2, both lenvatinib and pembrolizumab (alone and 
in combination), have shown promising efficacy in participants with HCC, and preliminary 
safety data of the combination of lenvatinib and pembrolizumab suggest toxicity is 
manageable. Given the limited treatment options for patients with advanced HCC, there is an 
unmet medical need for novel therapies in this setting. The existing data suggest that 
inhibiting angiogenesis in combination with PD-1 blockade is a promising therapeutic 
strategy, and the benefit:risk assessment for participants included in this study is considered 
to be favorable. No unexpected risks have been reported in HCC with other immune check 
point inhibitors other than transient elevations in ALT and AST. Additional details regarding 
specific benefits and risks for participants participating in this clinical study may be found in 
the accompanying IB and informed consent form (ICF) documents.
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3
HYPOTHESIS, OBJECTIVES, AND ENDPOINTS
In first-line therapy of participants with advanced HCC following treatment with 
pembrolizumab plus lenvatinib versus treatment with placebo plus lenvatinib:
Objectives
Endpoints
Primary
•
Objective: To compare progression-free 
survival (PFS) per Response Evaluation 
Criteria in Solid Tumors (RECIST) 1.1 
assessed by Blinded Independent Central 
Review (BICR) modified to follow a 
maximum of 10 target lesions and a 
maximum of 5 target lesions per organ.
•
Hypothesis (H1): Pembrolizumab plus 
lenvatinib is superior to placebo plus
lenvatinib with respect to PFS per 
RECIST 1.1 assessed by BICR.
•
PFS, defined as the time from 
randomization to the first documented 
disease progression or death due to any 
cause, whichever occurs first.
•
Objective: To compare overall survival 
(OS). 
•
Hypothesis (H2): Pembrolizumab plus 
lenvatinib is superior to placebo and 
lenvatinib with respect to OS.
•
OS, defined as the time from 
randomization to death due to any 
cause.
Secondary
•
Objective: To compare objective 
response rate (ORR) per RECIST 1.1 as 
assessed by BICR. 
•
Hypothesis (H3): Pembrolizumab plus 
lenvatinib is superior to placebo plus
lenvatinib with respect to OR per 
RECIST 1.1 assessed by BICR.
•
Objective Response (OR): Complete 
response (CR) or partial response (PR).
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Objectives
Endpoints
•
Objective: To evaluate duration of 
response (DOR), and disease control rate 
(DCR) per RECIST 1.1 as assessed by 
BICR.
•
DOR, defined as the time from the first 
documented evidence of CR or PR 
until the first documented disease 
progression or death due to any cause, 
whichever occurs first.
•
Disease Control (DC), defined as a
best overall response of CR, PR, or 
stable disease (SD). SD must be 
achieved at ≥6 weeks after 
randomization to be considered best 
overall response.
•
Objective: To evaluate the safety and 
tolerability of pembrolizumab plus 
lenvatinib versus placebo plus lenvatinib.
•
Adverse events (AEs), serious AEs 
(SAEs), immune-related (irAEs), and 
hepatic AEs.
•
Study intervention discontinuations
due to AEs.
•
Objective: To evaluate TTP per 
RECIST 1.1 assessed by BICR.
•
TTP, defined as the time from 
randomization to the first documented 
disease progression.
•
Objective: To evaluate efficacy outcomes 
per modified RECIST 1.1 (mRECIST)
assessed by BICR. 
•
PFS, OR, DOR, DCR, and time to 
disease progression (TTP). 
Tertiary/Exploratory
•
Objective: To evaluate efficacy outcomes 
per RECIST 1.1 and RECIST 1.1 
modified for immune-based therapeutics 
(iRECIST) as assessed by the 
investigator. 
•
PFS, OR, DOR, DCR, and TTP.
•
Objective: To identify molecular 
(genomic, metabolic, and/or proteomic) 
biomarkers that may be indicative of 
clinical response/resistance, safety, 
pharmacodynamic activity, and/or the 
mechanism of action of lenvatinib and 
pembrolizumab in all participants.
•
Molecular (genomic, metabolic, and/or 
proteomic) determinants of response or 
resistance to treatments, using blood 
and/or tumor tissue.
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Objectives
Endpoints
•
Objective: To evaluate score change from 
baseline of health-related quality of life 
(HRQoL) and to evaluate time to 
deterioration (TTD) using the European 
Organisation for Research and Treatment 
of Cancer (EORTC) Quality of Life 
Questionnaire—Core 30 (QLQ-C30) and 
the EORTC Quality of Life 
Questionnaire—HCC 18 (QLQ-HCC18).
•
HRQoL will be assessed using the 
global score of the EORTC QLQ-C30 
and EORTC QLQ-HCC18.
•
TTD evaluated for EORTC QLQ-C30 
and EORTC QLQ-HCC18 global 
health status/QOL. Details will be 
provided in sSAP.
•
Objective: To characterize health utilities 
using EuroQol-5-Dimension, 5-Level
Questionnaire (EQ-5D-5L).
•
HRQoL will be assessed using the 
EQ-5D-5L.
•
Objective: To identify novel radiomic 
biomarkers (based on combinations of 
imaging features) that may be useful as 
pre-treatment predictors of response, 
early indicators of response, or correlates 
of molecular biomarkers, based on 
analysis of tumor assessment images 
from all participants.
•
OR
The study will be deemed positive if either OS or PFS null hypotheses are rejected.
4
STUDY DESIGN
4.1
Overall Design
Specific procedures to be performed during the study, as well as their prescribed times and 
associated visit windows, are outlined in the SoA in Section 1.3. Details of each procedure 
are provided in Section 8.
This is a multicenter, randomized, active-controlled, parallel-group, double-blinded study of 
lenvatinib in combination with pembrolizumab (MK-3475) versus lenvatinib with placebo in 
first-line intervention in participants with advanced hepatocellular carcinoma. Approximately 
750 participants will be randomized in a 1:1 ratio to the following 2 treatment groups:

Arm A: Lenvatinib 12 mg (BW ≥60 kg) or 8 mg (BW <60 kg) orally once daily (QD) plus
pembrolizumab 200 mg IV Q3W

Arm B: Lenvatinib 12 mg (BW ≥60 kg) or 8 mg (BW <60 kg) orally QD plus placebo 
(normal saline) IV Q3W
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Lenvatinib dosing is based on actual body weight at Screening and will be fixed for the 
duration of the study. Pembrolizumab/placebo will be administered for up to 35 cycles. 
Lenvatinib will be administered until PD or unacceptable toxicity. This protocol does not 
allow participants to cross over to the other arm if they experience progression.
The primary objectives of this study are to compare the PFS and OS of lenvatinib plus 
pembrolizumab versus lenvatinib plus placebo. On-study imaging assessments will be 
performed every 12 weeks (Q12W) calculated from the date of randomization and 
independent of treatment delays. RECIST 1.1 will be used by the site for treatment decisions 
until the first radiologic evidence of progressive disease (PD). PD will also be confirmed by 
the BICR vendor. Participants who experience confirmed disease progression or start a new 
anticancer therapy will move into the Survival Follow-up Phase and should be contacted by 
telephone or visit approximately every 12 weeks, or more frequently to assess for survival 
status until death, withdrawal of consent, or the end of the study, whichever occurs first.
This study will use a group sequential design, using an independent, external Data 
Monitoring Committee (eDMC) to monitor safety and efficacy during the course of the 
study. There will be 2 planned interim analyses conducted: IA1, when approximately 335 OS 
events (63% of expected total OS events); and IA2, when approximately 452 OS events 
(85% of expected total OS events) have been observed (see Section 9.7). The final OS 
analysis will be conducted when approximately 532 OS events have been observed. There 
will be 2 PFS analyses conducted, the first at the time of the first OS interim analysis (IA1) 
and a final PFS analysis at the time of the second OS interim analysis (IA2). The results of 
the interim analyses will be reviewed by the eDMC, which will provide recommendations for 
the study in accordance with the eDMC charter and the SAP described in detail in Section 
9.0 - Statistical Analysis Plan (SAP).
4.2
Scientific Rationale for Study Design
4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
The study includes dual primary efficacy endpoints: PFS per RECIST 1.1 as assessed by 
BICR, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions 
per organ and OS.
Progression-free survival is an acceptable measure of clinical benefit for a late stage study 
that demonstrates superiority of a new antineoplastic therapy, especially if the magnitude of 
the effect is large and the therapy has an acceptable risk/benefit profile. The use of BICR and 
RECIST 1.1 to assess PFS is typically considered acceptable by regulatory authorities. 
Images will be read by a central imaging vendor blinded to treatment assignment to minimize 
bias in the response assessments.  In addition, the final determination of radiologic 
progression will be based on the central assessment of progression, rather than a local site 
investigator/radiology assessment. Real time determination of site-determined radiologic 
progression as determined by central review will be communicated to the site.
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The endpoint of OS is the standard for demonstrating superiority of antineoplastic therapy in 
clinical studies for HCC. PFS is being included as a dual primary endpoint because efficacy 
in PFS may be able to be established earlier than efficacy in OS, and given better efficacy 
seen in newer HCC therapies it may be a useful surrogate for OS. 
The secondary efficacy objectives of this study are to: 1) compare ORR per RECIST 1.1 
assessed by BICR and 2) evaluate duration of response (DOR), and disease control rate 
(DCR) per RECIST 1.1 assessed by BICR. 3) TTP per RECIST 1.1 assessed by BICR will 
also be evaluated and 4) Evaluating PFS, ORR, DOR, DCR, and TTP per mRECIST assessed 
by BICR are secondary objectives.
ORR is an acceptable measure of clinical benefit for a late-stage study that demonstrates 
superiority of a new antineoplastic therapy, especially if the magnitude of the effect is large 
and the therapy has an acceptable risk:benefit profile. Images will be read per RECIST 1.1 by
BICR to minimize bias in the response assessments. 
DCR and DOR per RECIST 1.1 assessed by BICR will serve as additional measures of 
efficacy and are commonly accepted endpoints by both regulatory authorities and the 
oncology community.
Measurable disease will be confirmed centrally at enrollment, prior to participant 
randomization, to ensure that the assessment of measurable disease is accurate. These 
endpoints have been chosen as ancillary markers of efficacy in a population with few 
treatment options.  
Exploratory efficacy objectives of this study include evaluating PFS, OR, DOR, DCR, and 
TTP per 1) iRECIST (modified RECIST for immune-based therapeutics) assessed by 
investigator, and 2) RECIST 1.1 assessed by investigator. 
4.2.1.1.1
RECIST 1.1
RECIST 1.1 will be used by the BICR when assessing images for efficacy measures and by 
the local site when determining eligibility (see Section 8.2.1.4). Although traditional 
RECIST 1.1 references a maximum of 5 target lesions in total and 2 per organ, this protocol 
has implemented a modification to RECIST 1.1 to allow a maximum of 10 target lesions in 
total and 5 per organ.
4.2.1.1.2
iRECIST
RECIST 1.1 will be adapted to account for the unique tumor response characteristics seen 
following treatment with pembrolizumab (see Section 8.2.1.5). Immunotherapeutic agents 
such as pembrolizumab may produce antitumor effects by potentiating endogenous cancer-
specific immune responses. The response patterns seen with such an approach may extend 
beyond the typical time course of responses seen with cytotoxic agents, and patients treated 
with pembrolizumab may manifest a clinical response after an initial increase in tumor 
burden or even the appearance of new lesions. Thus, standard RECIST 1.1 may not provide 
an accurate response assessment of immunotherapeutic agents such as pembrolizumab. 
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Based on an analysis of participants with melanoma enrolled in KEYNOTE-001 (KN001), 
7% of evaluable participants experienced delayed or early tumor pseudo-progression. Of 
note, participants who had progressive disease (PD) by RECIST 1.1 but not by the immune-
related response criteria [Wolchok, J. D., et al 2009] had longer overall survival than 
participants with PD by both criteria [Hodi, F. S., et al 2014]. Additionally, the data suggest 
that RECIST 1.1 may underestimate the benefit of pembrolizumab in approximately 15% of 
participants. These findings support the need to apply a modification to RECIST 1.1 that 
takes into account the unique patterns of atypical responses in immunotherapy and enables 
treatment beyond initial radiographic progression, if the participant is clinically stable.
Modified RECIST 1.1 for immune-based therapeutics (iRECIST) assessment has been 
developed and published by the RECIST Working Group, with input from leading experts 
from industry and academia, along with participation from the US Food and Drug 
Administration and the European Medicines Agency [Seymour, L., et al 2017]. The 
unidimensional measurement of target lesions, qualitative assessment of nontarget lesions, 
and response categories are identical to RECIST 1.1, until progression is seen by RECIST 
1.1. However, if a participant is clinically stable, additional imaging may be performed to 
confirm radiographic progression. iRECIST will be used by investigators to assess tumor 
response and progression and make treatment decisions .
4.2.1.1.3
Modified RECIST (mRECIST)
Modified RECIST for HCC (mRECIST) allows evaluation of treatment effects that are not 
reflected in simple total size changes of lesions. Specifically, mRECIST allows assessment of 
treatment-related tumor necrosis and assessment of viable tumor by assessment with arterial 
phase imaging. Details are fully described in [Lencioni, R. 2010], and key differences from 
RECIST 1.1 are listed in Section 8.2.1.6.
4.2.1.2
Safety Endpoints
Safety parameters commonly used for evaluating investigational systemic anticancer 
treatments are included as safety endpoints including, but not limited to, the incidence of, 
causality, and outcome of adverse events (AEs)/serious adverse events (SAEs); and changes 
in vital signs and laboratory values. AEs will be assessed as defined by CTCAE, Version 4.0.
4.2.1.3
Patient-reported Outcomes
Symptomatic improvement is considered a clinical benefit and accepted by health authorities 
as additional evidence of the risk-benefit profile of any new study intervention. In this study, 
HRQoL and disease-related symptoms will be investigated via the following assessment 
tools: EORTC QLQ-C30 and EORTC QLQ-HCC18 questionnaires. Health utilities will be 
evaluated using the EQ-5D-5L PRO instrument. These measures are not pure efficacy or 
safety endpoints because they are affected by both disease progression and treatment 
tolerability.
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4.2.1.3.1
EORTC QLQ-C30
EORTC QLQ-C30 is the most widely used cancer-specific, health-related, quality-of-life 
(QoL) instrument, which contains 30 items and measures 5 functional dimensions (physical, 
role, emotional, cognitive, and social), 3 symptom items (fatigue, nausea/vomiting, and pain), 
6 single items (dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, and financial 
impact), and a global health and QoL scale [Aaronson, N. K., et al 1993]. The EORTC QLQ-
C30 is a psychometrically and clinically validated instrument appropriate for assessing QoL 
in oncology studies [Aaronson, N. K., et al 1993].
4.2.1.3.2
EORTC QLQ- HCC18
The EORTC QLQ-HCC18 is a disease-specific questionnaire developed and validated to 
address measurements specific to HCC [Blazeby, J. M., et al 2004]. It is one of multiple 
disease-specific modules developed by the EORTC QLG (Quality of Life Group) designed 
for use in clinical trials, to be administered in addition to the QLQ-C30 to assess disease-
specific treatment measurements. It consists of 18 items containing 6 scales and 2 single 
items.
4.2.1.3.3
EQ-5D-5L
The EuroQoL-5D-5L (EQ-5D-5L) is a standardized instrument for use as a measure of health 
outcome and will provide data to develop health utilities for use in health economic analyses 
[Rabin, R. and de Charro, F. 2001]. The 5 health state dimensions in the EQ-5D-5L include 
the following: mobility, selfcare, usual activities, pain/discomfort, and anxiety/depression. 
Each dimension is rated on a 5-level scale (no problems, slight problems, moderate problems, 
severe problems, and extreme problems). The EQ-5D-5L also includes a graded (0 to 100) 
vertical visual analog scale on which the participant rates his or her general state of health at 
the time of the assessment. This instrument has been used extensively in cancer studies and 
published results from these studies support its validity and reliability [Pickard, A. S., et al 
2007].
4.2.1.4
Pharmacokinetic Endpoints
No pharmacokinetic endpoints will be evaluated in this study.
4.2.1.5
Pharmacodynamic Endpoints
No pharmacodynamic endpoints are planned for this study.
4.2.1.6
Planned Exploratory Biomarker Research
The mechanism of action of many antitumor agents is not completely understood and much 
remains to be learned regarding how best to leverage new drugs in treating patients. Thus, to 
aid future patients, it is important to investigate the determinants of response or resistance to 
cancer treatments administered, as well as determinants of AEs in the course of our clinical 
studies. These efforts may identify novel predictive/pharmacodynamic biomarkers and 
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generate information that may better guide single-agent and combination therapy with 
antineoplastic drugs. To identify novel biomarkers, biospecimens (ie, blood components, 
tumor material) will be collected to support analyses of cellular components (eg, protein, 
DNA, RNA, metabolites) and other circulating molecules. Investigations may include, but 
are not limited to:
Germline (blood) genetic analyses (eg, SNP analyses, whole exome sequencing, whole 
genome sequencing)
This research may evaluate whether genetic variation within a clinical study population 
correlates with response to the treatment(s) under evaluation. If genetic variation is found to 
predict efficacy or AEs, 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.
Genetic (DNA) analyses from tumor
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) contributing towards the development/progression of cancer 
and/or driving response to therapy. Key molecular changes of interest to immuno-oncology 
drug development include 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) may generate neo-antigen presentation in the tumor microenvironment. To 
conduct this type of research, it is important to identify tumor-specific mutations that occur 
across all genes in the tumor genome. Evaluation of molecular targets and signaling 
pathways including angiogenesis- or and growth factor related signaling pathways related to 
pembrolizumab and lenvatinib may also be explored. 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. Circulating tumor DNA and/or 
RNA may also be evaluated from blood samples.
Tumor and/or blood RNA analyses
Both genome-wide and targeted mRNA expression profiling and sequencing in tumor tissue 
and/or in blood may be performed to define gene signatures that correlate to clinical response 
to treatment with antitumor therapies. Specific gene sets (ie, those capturing interferon-
gamma transcriptional pathways) may be evaluated and new signatures may be identified. 
Individual genes may also be evaluated (eg, IL-10). MicroRNA profiling may also be 
pursued as well as exosomal profiling.
Proteomics and immunohistochemistry (IHC) using blood or tumor
Tumor and blood samples from this study may undergo proteomic analyses (eg, PD-L1 IHC). 
Therefore, tumor tissue may be subjected to proteomic analyses using a variety of platforms 
that could include, but are not limited to, immunoassays and liquid chromatography/mass 
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spectrometry. This approach could identify novel protein biomarkers that could aid in patient 
selection for antitumor therapy.
Other blood-derived biomarkers
In addition to expression on the tumor tissue, PD-L1 and other tumor derived proteins can be 
shed from tumor and released into the blood. Assays such as ELISA measure such proteins in 
serum. Correlation of expression with response to therapy may identify new approaches for 
predictive biomarkers in blood, representing a major advance from today’s reliance on 
assessing tumor biomarkers. This research would serve to develop such assays for future 
clinical use.
Other molecular changes of interest include the subtype of T-cells in the tumor 
microenvironment. The T-cell repertoire from tumor tissue and blood components may be 
evaluated.
Country-specific requirements are noted in Appendix 7.
4.2.1.7
Radiomic Biomarkers
Computed tomography (CT) images of tumors contain information that is not captured by 
traditional size measurements, including radiographic features related to density, texture, 
morphology, and higher-order pixel relationships. Analysis of these features, individually 
and in combination, is commonly referred to as “radiomics.” Radiomic signatures 
(combinations of radiographic features) have shown promising preliminary results in a 
variety of tumor types as novel biomarkers that are prognostic, predictive (of response to 
therapy), or indicative of molecular phenotypes.
CT scans will be obtained using typical standard-of-care techniques. Additional 
reconstructions of the images will be collected to allow maximal flexibility in analysis. Scans
may be analyzed using a variety of machine learning tools, including traditional radiomics 
with predefined feature sets and deep learning approaches in which features are discovered 
during model development in a data-driven fashion. The goal would be to discover radiomic 
biomarkers that correlate with survival, AEs, and molecular biomarkers.
4.2.2
Rationale for the Use of Comparator/Placebo
Participants will be randomized to receive IV pembrolizumab or placebo. Both treatment 
arms will receive lenvatinib. Cross over will not be allowed at time of documented disease 
progression.
The standard 1L therapy for HCC worldwide is sorafenib, which has shown a survival 
advantage compared to best supportive care, but with only a few months’ benefit in OS 
compared with placebo in a Western population [Llovet, Josep M., et al 2008]. Sorafenib has 
a median PFS of approximately 6 months and a median OS of approximately 12 months. 
Sorafenib has significant toxicity, with approximately 40% of patients permanently 
discontinuing due to toxicity [Iavarone, M., et al 2011]. The most frequent drug-related 
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Grade 3-4 AEs are diarrhea (8%) and Grade 3-4 palmar-plantar erythrodysaesthesia (8%)
[Llovet, Josep M., et al 2008].  
Lenvatinib, another antiangiogenic multikinase inhibitor, has a similar mechanism of action 
as sorafenib. In addition, it shows noninferior OS and an improved response rate and PFS 
compared with sorafenib in the 1L treatment of HCC. When comparing the AE profiles, 
lenvatinib has a decreased frequency of palmar-plantar erythrodysaesthesia compared to 
sorafenib, but an increased frequency of hypertension. PD-1 inhibitors have shown durable
responses in unselected HCC participants. In the Phase 2 study of pembrolizumab 
monotherapy in 2L HCC (KEYNOTE-224), the ORR is 16.3% [Zhu, A. X., et al 2018]. The 
anti-PD-1 antibody nivolumab received accelerated approval in the United States for 
treatment of 2L HCC. At the time of the study start, there are no therapeutic combinations yet 
approved for 1L treatment of HCC.
Lenvatinib has already been approved in the United States, the EU, Japan, and China and will 
likely become a standard of care in much of the world for 1L HCC. Given this, it is believed 
to be an appropriate comparator arm. A normal saline placebo for pembrolizumab is being 
used in this study to maintain the blinding.
4.2.3
Rationale for Excluding Vp4 Patients
Blockage or thrombosis of the main portal vein, or the portal vein branch contralateral to the 
primary involved lobe, is defined as Vp4. Patients with Vp4 constitute approximately 3% of 
the HCC patient population [Katagiri. S. 2014]). Vp4 patients have significantly increased 
rates of hepatic decompensation compared to other patients with lesser grades of tumor 
thrombosis [Kuo, Y. H., et al 2018]. The low prevalence and the high degree of morbidity 
and mortality may result in the uneven distribution of patients across the treatment and 
control cohorts, thereby biasing the data, as has happened with vascular invasion imbalance 
in other studies [Llovet, J. M., et al 2013]. Additionally, excluding Vp4 patients allows for 
comparability to previous and current pembrolizumab and lenvatinib therapeutic studies in 
HCC patients.
4.3
Justification for Dose
4.3.1
Lenvatinib
The starting dose of lenvatinib for this combination study will be 12 mg (BW ≥60 kg) or 8 
mg (BW <60 kg) orally QD. Based on dose modification results in an earlier Phase 1/2 study 
of lenvatinib in participants with HCC (E7080-J081-202) and population PK analyses 
showing higher lenvatinib area under the curve (AUC) and lower BW resulting in earlier 
drug withdrawal or dose reduction, 2 different starting doses were planned in a Phase 3 study 
of lenvatinib monotherapy in participants with unresectable HCC (E7080-G000-304): 12 mg 
for participants with BW ≥60 kg and 8 mg for subjects weighing <60 kg. The final PK model 
including data from E7080-G000-304 confirmed that lenvatinib was affected by body weight. 
The decrease in CL/F in subjects with low body weight resulted in an increase in lenvatinib 
AUC. The median value and range of individual AUCs at steady state for subjects in E7080-
G000-304 were comparable between the 8 mg starting dose group for BW <60 kg and the 12-
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mg dose group for BW ≥60 kg. Furthermore, a similar median OS was observed in both BW 
subgroups (BW ≥60 kg and <60 kg: 13.7 months and 13.4 months, respectively), and the HR 
favored lenvatinib in both subgroups (HR: 0.95 and 0.85, respectively). Lastly, the duration-
adjusted rate of treatment-emergent AEs (TEAEs) was similar for subjects treated with either 
starting dose. These findings support the appropriateness of the lower starting dose of 8 mg 
for subjects with BW <60 kg.
Study E7080-J081-116 (MK-3475-524) is a Phase 1b study to evaluate the tolerability and 
safety of lenvatinib (8 mg for participants <60 kg BW and 12 mg for participants ≥60 kg 
BW, orally) in combination with pembrolizumab (200 mg IV) in patients with unresectable 
HCC [Ikeda, M., et al 2018]. Tolerability was evaluated by assessing DLTs during the first 
cycle in participants who were ineligible for other therapies (3+3 design; Part 1). Once 
tolerability of lenvatinib plus pembrolizumab was confirmed, additional participants with no 
prior systemic therapy for unresectable HCC were enrolled (Part 2). As of 22-MAR-2018, 30 
participants were enrolled in the study (Part 1, n = 6; Part 2, n = 24) [Ikeda, M., et al 2018]. 
Participants had Barcelona Clinic Liver Cancer (BCLC) Stage B (n=9) or C (n=21), Child-
Pugh (CP) scores of 5 (n=26) or 6 (n=4), and 4 participants (13.3%) had received prior 
sorafenib. No DLTs were reported in Part 1, and the MTD was determined as lenvatinib 12 
mg (≥60 kg BW) or 8 mg (<60 kg BW) orally QD in combination with pembrolizumab 200 
mg IV Q3W. The toxicity profile for the combination was manageable. The most common 
TEAEs were decreased appetite (53.3%), hypertension (53.3%), diarrhea (43.3%), and 
fatigue (40.0%). The best overall response per investigator assessment by mRECIST was: 
Part 1, PR (n=4, 66.7%) and SD (n=2, 33.3%) and Part 2, CR (n=1, 5.0%), PR (n=6, 30.0%),
and SD (n= 13, 65.0%). The ORR (excluding unconfirmed responses) for Part 1 was (n=3, 
50.0%) and (n=4, 20.0%) for Part 2.
4.3.2
Pembrolizumab
The planned dose of pembrolizumab for this study is 200 mg every 3 weeks (Q3W). Based 
on the totality of data generated in the Keytruda development program, 200 mg Q3W is the 
appropriate dose of pembrolizumab for adults across all indications and regardless of tumor 
type. As outlined below, this dose is justified by:
•
Clinical data from 8 randomized studies demonstrating flat dose- and exposure-efficacy 
relationships from 2 mg/kg Q3W to 10 mg/kg every 2 weeks (Q2W),
•
Clinical data showing meaningful improvement in benefit-risk including overall survival 
at 200 mg Q3W across multiple indications, and
•
Pharmacology data showing full target saturation in both systemic circulation (inferred 
from pharmacokinetic [PK] data) and tumor (inferred from physiologically-based PK 
[PBPK] analysis) at 200 mg Q3W
Among the 8 randomized dose-comparison studies, a total of 2262 participants were enrolled 
with melanoma and non-small cell lung cancer (NSCLC), covering different disease settings 
(treatment naïve, previously treated, PD-L1 enriched, and all-comers) and different treatment 
settings (monotherapy and in combination with chemotherapy). Five studies compared 2 
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mg/kg Q3W versus 10 mg/kg Q3W (KN001 Cohort B2, KN001 Cohort D, KN002, KN010, 
and KN021), and 3 studies compared 10 mg/kg Q3W versus 10 mg/kg Q2W (KN001 Cohort 
B3, KN001 Cohort F2 and KN006). All of these studies demonstrated flat dose- and 
exposure-response relationships across the doses studied representing an approximate 5- to 
7.5-fold difference in exposure. The 2 mg/kg (or 200 mg fixed-dose) Q3W provided similar 
responses to the highest doses studied. Subsequently, flat dose-exposure-response 
relationships were also observed in other tumor types including head and neck cancer, 
bladder cancer, gastric cancer and classical Hodgkin Lymphoma, confirming 200 mg Q3W 
as the appropriate dose independent of the tumor type. These findings are consistent with the 
mechanism of action of pembrolizumab, which acts by interaction with immune cells, and 
not via direct binding to cancer cells.
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W. First, PK 
data in KN001 evaluating target-mediated drug disposition (TMDD) conclusively 
demonstrated saturation of PD-1 in systemic circulation at doses much lower than 200 mg 
Q3W. Second, a PBPK analysis was conducted to predict tumor PD-1 saturation over a wide 
range of tumor penetration and PD-1 expression. This evaluation concluded that 
pembrolizumab at 200 mg Q3W achieves full PD-1 saturation in both blood and tumor.
Finally, population PK analysis of pembrolizumab, which characterized the influence of 
body weight and other participant covariates on exposure, has shown that the fixed-dosing 
provides similar control of PK variability as weight based dosing, with considerable overlap 
in the distribution of exposures from the 200 mg Q3W fixed dose and 2 mg/kg Q3W dose. 
Supported by these PK characteristics, and given that fixed-dose has advantages of reduced 
dosing complexity and reduced potential of dosing errors, the 200 mg Q3W fixed-dose was 
selected for evaluation across all pembrolizumab protocols.
4.3.3
Maximum Dose/Exposure for This Study
The maximum dose for lenvatinib is 12 mg/day. Lenvatinib will be continued until disease 
progression or unacceptable toxicity. The maximum dose/exposure of pembrolizumab 
allowed in this study is 200 mg Q3W up to 2 years.
4.4
Beginning and End of Study Definition
The overall study begins when the first participant (or their legally acceptable representative) 
provides documented informed consent. 
The overall study ends when the last participant completes the last study-related contact, 
withdraws consent, or is lost to follow-up (ie, the participant is unable to be contacted by the 
investigator).
For purposes of analysis and reporting, the overall study ends when the Sponsor receives the 
last laboratory test result or at the time of final contact with the last participant, whichever 
comes last.
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If the study includes countries in the European Economic Area (EEA), the local start of the 
study in the EAA is defined as First Site Ready (FSR) in any Member State.
4.4.1
Clinical Criteria for Early Study Termination
The clinical study may be terminated early if the extent (incidence and/or severity) of 
emerging effects/clinical endpoints is such that the risk/benefit ratio to the study population 
as a whole is unacceptable. In addition, further recruitment in the study or at (a) particular 
study site(s) may be stopped due to insufficient compliance with the protocol, Good Clinical 
Practice (GCP), and/or other applicable regulatory requirements, procedure-related problems 
or the number of discontinuations for administrative reasons is too high.
5
STUDY POPULATION
This is a study in 1L therapy of participants of at least 18 years with advanced HCC.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
1. Have a HCC diagnosis confirmed by radiology, histology, or cytology (fibrolamellar and 
mixed hepatocellular/cholangiocarcinoma subtypes are not eligible).

Radiologic confirmation of diagnosis is provided by the study site. Clinically confirmed 
diagnosis of HCC as per the American Association for the Study of Liver Diseases 
(AASLD) criteria (Appendix 15) , which requires: 
-
Radiographically evident cirrhosis AND 
-
A liver mass that shows arterial phase hyperenhancement on triphasic CT or MRI,
AND EITHER:
o
Is ≥20 mm with either nonperipheral portal washout or an enhancing capsule 
OR
o
Is 10-19 mm with nonperipheral portal venous washout AND an enhancing 
capsule
2. Have 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 Appendix 11).
3. Have a Child-Pugh class A liver score within 7 days prior to first dose of study 
intervention (see Appendix 10).
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4. Have a predicted life expectancy of >3 months.
5. Have at least one measurable HCC lesion based on RECIST 1.1 as confirmed by the 
BICR vendor.  
Demographics
6. Have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 1
within 7 days prior to first dose of study intervention. 
7. Participant is male or female.
8. Participant is ≥18 years of age, at the time of providing the documented informed 
consent.
Male Participants
9. Male participants are eligible to participate if they agree to the following during the 
intervention period and for at least 7 days after the last dose of lenvatinib:

Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent 
on a long-term and persistent basis) and agree to remain abstinent
OR

Must agree to use contraception unless confirmed to be azoospermic (vasectomized or 
secondary to medical cause [Appendix 5]) as detailed below:
-
Agree to use a male condom plus partner use of an additional contraceptive 
method when having penile-vaginal intercourse with a WOCBP who is not 
currently pregnant. Note: Men with a pregnant or breastfeeding partner must 
agree to remain abstinent from penile-vaginal intercourse or use a male condom 
during each episode of penile-vaginal penetration.
-
Contraceptive use by men should be consistent with local regulations regarding 
the methods of contraception for those participating in clinical studies. 

Please note that 7 days after lenvatinib is stopped, if the participant is on 
pembrolizumab/placebo only, no male contraception measures are needed.
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Female Participants
10. A female participant is eligible to participate if she is not pregnant or breastfeeding, and 
at least one of the following conditions applies:

Is not a woman of childbearing potential (WOCBP)
OR
Is a WOCBP and using a contraceptive method that is highly effective (with a failure 
rate of <1% per year), with low user dependency, or be abstinent from heterosexual 
intercourse as their preferred and usual lifestyle (abstinent on a long term and 
persistent basis), as described in Appendix 5 during the intervention period and for at 
least 120 days post pembrolizumab/placebo or 30 days post lenvatinib, whichever 
occurs last. The investigator should evaluate the potential for contraceptive method 
failure (ie, noncompliance, recently initiated) in relationship to the first dose of study 
intervention.
-
A WOCBP must have a negative highly sensitive pregnancy test (urine or serum 
as required by local regulations) within 24 hours before the first dose of study 
intervention.
-
If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum 
pregnancy test is required. In such cases, the participant must be excluded from 
participation if the serum pregnancy result is positive.

Additional requirements for pregnancy testing during and after study intervention are 
located in Section 8.3.7.

The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy

Contraceptive use by women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.
Informed Consent
11. The participant (or legally acceptable representative if applicable) provides documented
informed consent/assent for the study. 
Additional Categories
12. Participants with past or ongoing HCV infection will be eligible for the study. The treated 
participants must have completed their treatment at least 1 month prior to starting study 
intervention.
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13. Participants with controlled hepatitis B will be eligible as long as they meet the following 
criteria:

Antiviral therapy for HBV must be given for at least 4 weeks and HBV viral load 
must be less than 100 IU/mL prior to first dose of study drug. Participants on active 
HBV therapy with viral loads under 100 IU/mL should stay on the same therapy 
throughout study treatment.  

Participants who are positive for antihepatitis B core antibody HBc, negative for 
hepatitis B surface antigen (HBsAg), and negative or positive for antihepatitis B 
surface antibody (HBs), and who have an HBV viral load under 100 IU/mL, do not 
require HBV antiviral prophylaxis.
14. Adequately controlled blood pressure (BP) with or without antihypertensive medications, 
defined as BP ≤150/90 mm Hg at Screening and no change in antihypertensive 
medications within 1 week before Cycle 1 Day 1.
15.  Have adequate organ function as defined in the following table (Table 2). Specimens 
must be collected within 7 days prior to the start of study intervention.
Table 2
Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
≥1500/µL
Platelets
≥75,000/µL
Hemoglobin
≥8 g/dL without transfusion or EPO dependency1
Renal
Creatinine OR
Measured or calculated2 creatinine clearance
(GFR can also be used in place of creatinine or 
CrCl)
≤1.5 × ULN OR
≥40 mL/min for participant with creatinine levels 
>1.5 × institutional ULN
Hepatic
Total bilirubin
≤2 mg/dL OR direct bilirubin ≤ULN for participants 
with total bilirubin levels >2 mg/dL
AST (SGOT) and ALT (SGPT)
≤5 × ULN
Amylase and lipase
≤ 1.5 × ULN
Albumin3
>3.0 g/dL
Coagulation
International normalized ratio (INR) OR 
prothrombin time (PT)
≤2 OR
≤1.5xULN
ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT)=aspartate aminotransferase 
(serum glutamic oxaloacetic transaminase); GFR=glomerular filtration rate; ULN=upper limit of normal.
1Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last 2 
weeks.
2Creatinine clearance (CrCl) should be calculated per institutional standard.
3No albumin supplement allowed within the last 14 days.
Note: This table includes eligibility-defining laboratory value requirements for treatment.
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Country-specific requirements are noted in Appendix 7.
5.2
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. Has had esophageal or gastric variceal bleeding within the last 6 months. All participants 
will be screened for esophageal or gastric varices unless such screening has been 
performed in the past 3 months before first dose of treatment. If varices are present, they 
should be treated according to institutional standards before starting study intervention; 
esophageal or gastric varices that require interventional treatment within 28 days prior to 
first dose of study drug are excluded.
2. Bleeding or thrombotic disorders or anticoagulants requiring therapeutic international 
normalized ratio (INR) monitoring, eg, warfarin or similar agents. Treatment with low 
molecular weight heparin is permitted.
3. Has clinically apparent ascites on physical examination that is not controlled with 
medication.
Note:  ascites detectable on imaging studies only are allowed.  
4. Portal vein invasion (Vp4), inferior vena cava, or cardiac involvement of HCC based on 
imaging.
5. Has had clinically diagnosed hepatic encephalopathy in the last 6 months unresponsive to 
therapy within 3 days. Participants on rifaximin or lactulose during screening to control 
their hepatic encephalopathy are not allowed.
6. Has medical contraindications that preclude all forms of contrast-enhanced imaging (CT 
or MRI).
7. Gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition that 
might affect the absorption of lenvatinib.
8. Has a preexisting Grade ≥3 gastrointestinal or nongastrointestinal fistula.
9. Clinically significant hemoptysis from any source or tumor bleeding within 2 weeks prior 
to the first dose of study drug.
10. Has significant cardiovascular impairment within 12 months of the first dose of study 
intervention such as history of congestive heart failure greater than New York Heart 
Association (NYHA) Class II, unstable angina, myocardial infarction or cerebrovascular 
accident stroke, or cardiac arrhythmia associated with hemodynamic instability.
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11. Has had major surgery to the liver within 4 weeks prior to the first dose of study 
intervention.
Note: If participant received major surgery, they must have recovered adequately from 
the toxicity and/or complications from the intervention prior to starting study treatment.
12. Has had a minor surgery (ie, simple excision) within 7 days prior to the first dose of study 
intervention (Cycle 1 Day 1).
13. Has serious nonhealing wound, ulcer, or bone fracture.
Prior/Concomitant Therapy
14. Has received any systemic chemotherapy, including anti-VEGF therapy, or any systemic 
investigational anticancer agents for advanced/unresectable HCC.
Note: Participants who have received local hepatic injection chemotherapy are eligible.
15. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an 
agent directed to another stimulatory or coinhibitory T-cell receptor (eg, CTLA-4, OX-
40, or CD137).
16. Has received locoregional therapy to liver (transcatheter chemoembolization, 
transcatheter embolization, hepatic arterial infusion, radiation, radioembolization, or 
ablation) within 4 weeks prior to the first dose of study intervention.
Note: Participant must show evidence of disease progression after locoregional therapy to 
be eligible.
17. Has received prior radiotherapy to a nonliver region within 2 weeks of start of study 
intervention. Participants must have recovered from all radiation-related toxicities, not 
require corticosteroids, and not have had radiation pneumonitis. A 2-week washout is 
permitted for palliative radiation (≤2 weeks of radiotherapy) to noncentral nervous 
system (CNS) disease.
18. Has received a live vaccine within 30 days prior to the first dose of study intervention. 
Examples of live vaccines include, but are not limited to, the following: measles, mumps, 
rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin 
(BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally 
killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, 
FluMist®) are live attenuated vaccines and are not allowed.
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Prior/Concurrent Clinical Study Experience
19. Is currently participating in or has participated in a study of an investigational agent or 
has used an investigational device within 4 weeks prior to the first dose of study 
intervention.
Note: Participants who have entered the Follow-up Phase of an investigational study may 
participate as long as it has been 4 weeks after the last dose of the previous 
investigational agent.
Diagnostic Assessments
20. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in 
dosing exceeding 10 mg daily of prednisone equivalent) or any other form of 
immunosuppressive therapy within 7 days prior the first dose of study intervention.
21. Has a known additional malignancy that is progressing or has required active treatment 
within the past 3 years.
Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the 
skin, or carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) that have 
undergone potentially curative therapy are not excluded.
22. Has a known history of, or any evidence of, CNS metastases and/or carcinomatous 
meningitis as assessed by local site investigator.
23. Has severe hypersensitivity (≥Grade 3) to study intervention and/or any of their
excipients.
24. Has an 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) is not considered a form of systemic 
treatment and is allowed.
25. Has a history of (non-infectious) pneumonitis that required steroids or has current 
pneumonitis.
26. Participants with proteinuria >1+ on urine dipstick testing will undergo 24-hour urine 
collection for quantitative assessment of proteinuria. Participants with urine protein 
≥1 g/24 hours will be ineligible.
27. Prolongation of corrected QT (QTc) interval to >480 ms (corrected by Fridericia 
Formula).
28. Left ventricular ejection fraction (LVEF) below the institutional normal range as 
determined by multigated acquisition scan (MUGA) or echocardiogram (ECHO).
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29. Has an active infection requiring systemic therapy, with the exception of HBV, HCV.
30. Has a known history of human immunodeficiency virus (HIV) infection. No HIV testing 
is required unless mandated by local health authority.
31. Has dual active HBV infection (HBsAg (+) and /or detectable HBV DNA) and HCV 
infection (anti-HCV Ab (+) and detectable HCV RNA) at study entry.  
32. Has known active tuberculosis (Bacillus tuberculosis).
33. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the study, interfere with the participant’s participation 
for the full duration of the study, or is not in the best interest of the participant to 
participate, in the opinion of the treating investigator.
34. Has a known psychiatric or substance abuse disorder that would interfere with the 
participants ability to cooperate with the requirements of the study.
Other Exclusions 
35. Is pregnant or breastfeeding or expecting to conceive or father children within the 
projected duration of the study, starting with the screening visit through 120 days after 
the last dose of study intervention.
36. Has had an allogenic tissue/solid organ transplant.
Country-specific requirements are noted in Appendix 7.
5.3
Lifestyle Considerations
5.3.1
Contraception
Lenvatinib and pembrolizumab may have adverse effects on a fetus in utero. The participant 
should adhere to the protocol-specified contraception requirements. Refer to Appendix 5 for 
approved methods of contraception.
Based on its mechanism of action, lenvatinib can cause fetal harm when administered to a 
pregnant woman. Lenvatinib may also result in reduced fertility in females of reproductive 
potential and may result in damage to male reproductive tissues leading to reduced fertility of 
unknown duration. In animal reproduction studies, oral administration of lenvatinib during 
organogenesis at doses below the recommended human dose resulted in embryotoxicity, 
fetotoxicity, and teratogenicity in rats and rabbits.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study, but 
are not subsequently randomized in the study. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the 
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Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any AEs or SAEs meeting reporting 
requirements as outlined in the data entry guidelines.
5.5
Participant Replacement Strategy
A participant who discontinues from study intervention OR withdraws from the study will 
not be replaced.
6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
Clinical supplies of lenvatinib and pembrolizumab will be packaged to support enrollment as 
required. Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
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6.1
Study Intervention(s) Administered
The study interventions to be used in this study are outlined in Table 3.
Table 3
Study Interventions
Arm 
Name
Arm 
Type
Intervention 
Name
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen/
Treatment 
Period/
Vaccination 
Regimen
Use
IMP or
NIMP/
AxMP
Sourcing
Arm A
Experi-
mental
Lenvatinib
Drug
Capsule
4 mg
12 mg (BW 
≥60 kg) or 
8 mg (BW 
<60 kg)
Oral
Once daily
Test 
Product
IMP
Centrally 
by Sponsor 
or locally 
by the 
study site, 
subsidiary, 
or designee
Arm A
Experi-
mental
Pembrolizumab
Drug
Vial
25 mg/mL
200 mg
IV Infusion
Day 1 of 
each cycle
Test 
Product
IMP
Centrally 
by Sponsor
Arm B
Active 
Compa-
rator
Lenvatinib
Drug
Capsule
4 mg
12 mg (BW 
≥60 kg) or 
8 mg (BW 
<60 kg) 
Oral
Once daily
Comparator
IMP
Centrally 
by Sponsor
or locally 
by the 
study site, 
subsidiary, 
or designee
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Arm 
Name
Arm 
Type
Intervention 
Name
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen/
Treatment 
Period/
Vaccination 
Regimen
Use
IMP or
NIMP/
AxMP
Sourcing
Arm B
Active 
Compar-
ator
Placebo
Drug
Vial
Normal Saline, 
0.90% w/v
0 mg
IV Infusion
Day 1 of 
each cycle
Placebo
IMP
Provided 
locally by 
the study 
site, 
subsidiary, 
or designee
BW = body weight; EEA =European Economic Area; IMP=investigational medicinal product; NIMP/AxMP=noninvestigational/auxiliary medicinal product; w/v = 
weight/volume.
The classification of IMP and NIMP/AxMP in this table is based on guidance issued by the European Commission and applies to countries in the EEA. Country differences with 
respect to the definition/classification of IMP and NIMP/AxMP may exist. In these circumstances, local legislation is followed.
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All study interventions will be administered on an outpatient basis.
All products indicated in Table 3 will be provided centrally by the Sponsor or locally by the 
study site, subsidiary or designee, depending on local country operational or regulatory 
requirements with the exception of placebo (normal saline), which will be provided locally.
For any commercially available product that is provided by the study site, subsidiary, or 
designee, every attempt will be made to source these supplies from a single lot/batch number. 
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product as per local guidelines unless otherwise instructed by the 
Sponsor.
Refer to Section 8.1.8 for details regarding administration of the study intervention.
Country-specific requirements are noted in Appendix 7.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
Details on preparation and administration of pembrolizumab/placebo are provided in the 
Pharmacy Manual. Lenvatinib is a capsule for oral administration and does not require 
preparation.
If a dose of lenvatinib is missed and cannot be taken within 12 hours from the scheduled 
administration, the participant should skip this dose and take the next dose at the scheduled 
time the next day. See Pharmacy Manual for additional information.
6.2.2
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
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investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Treatment allocation/randomization will occur centrally using an interactive response 
technology (IRT) system. There are 2 study intervention arms. Participants will be assigned 
randomly in a 1:1 ratio to lenvatinib + pembrolizumab study intervention and lenvatinib + 
placebo study intervention, respectively.
6.3.2
Stratification
Treatment allocation/randomization will be stratified according to the following factors:

Geographic region (Region 1: Asia vs. Region 2: Japan and Western regions, such as EU, 
North America, etc.)

Macroscopic portal vein invasion or extrahepatic spread or both (Yes vs. No) 

AFP: ≤400 ng/mL vs. >400 ng/mL

ECOG PS: 0 vs. 1
6.3.3
Blinding
A double-blinding technique with in-house blinding will be used. Pembrolizumab and 
placebo (normal saline) will be packaged identically by site pharmacy so that the blind is 
maintained. The participant, the investigator, and Sponsor personnel or delegate(s) who are 
involved in the study intervention administration or clinical evaluation of the participants are 
unaware of the group assignments.
6.4
Study Intervention Compliance
Interruptions from the protocol specified intervention for >28 consecutive days (lenvatinib)
or for >12 weeks (pembrolizumab or placebo) require consultation between the investigator 
and the Sponsor and written documentation of the collaborative decision on participant 
management.
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6.5
Concomitant Therapy
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing study. If there is a clinical indication for any medication specifically 
prohibited, discontinuation from study therapy or vaccination may be required. The 
investigator should discuss any questions regarding this with the Sponsor's Clinical Director. 
The final decision on any supportive therapy or vaccination rests with the investigator and/or 
the participant's primary physician. However, the decision to continue the participant on 
study intervention requires the mutual agreement of the investigator, the Sponsor, and the 
participant.
6.5.1
Allowed Concomitant Medication
Palliative and supportive care is permitted during the course of the study 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 on an exceptional case-by-case basis after consultation with the Sponsor if considered 
medically necessary by the treating physician, as long as the lesion is NOT a RECIST 1.1-
defined target lesion and is NOT administered for tumor control. Pembrolizumab/placebo
should be held during the course of palliative radiotherapy and should be resumed no earlier 
than the next scheduled administration of study intervention; however, lenvatinib can be 
continued per investigator discretion during the palliative radiation. The specifics of the 
radiation treatment, including the location, will be recorded on the case report form (CRF).
6.5.2
Prohibited Concomitant Medications
Participants are prohibited from receiving the following therapies during the Screening and 
Treatment Phase of this study:

Concurrent anticancer therapies such as chemotherapy, targeted therapies (eg, tyrosine 
kinase inhibitors), antitumor interventions (surgical resection, surgical debulking of 
tumor, etc.), or cancer immunotherapy not specified in this protocol

Investigational agents other than pembrolizumab or lenvatinib

Locoregional therapy

Radiation therapy
Note: Radiation for pain or palliation is acceptable (see Section 6.5.1).

Live vaccines within 30 days prior to the first dose of study intervention and while 
participating in the study. Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and 
typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live 
attenuated vaccines and are not allowed.
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
Systemic glucocorticoids for any purpose other than to modulate symptoms from an AE 
that is suspected to have an immunologic etiology. The use of physiologic doses of 
corticosteroids may be approved after consultation with the Sponsor. Exception: steroids 
may be used for premedication prior to imaging.

Anticoagulants that require INR monitoring, such as warfarin (treatments that do not 
require INR monitoring, such as low molecular weight heparin, are permitted).
Participants who, in the assessment of the Investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the study.
All treatments that the investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care. All concomitant medication will be recorded on the eCRF including all 
prescription, over-the-counter (OTC) products, herbal supplements, and IV medications and 
fluids. If changes occur during the study period, documentation of drug dosage, frequency, 
route, and date should also be included on the eCRF.
All concomitant medications received within 28 days prior to the first dose of study 
intervention and up to 90 days after the last dose of study intervention should be recorded. 
Concomitant medications administered 120 days after the last dose of study intervention 
should be recorded for SAEs and events of clinical interest (ECIs) as defined in Section 
8.4.7.
It is important for investigators to review each medication (prescription and nonprescription) 
the participant is taking before starting the study and at each study visit. 

At each visit, participants 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 study.
The following medications/therapies should be avoided during the dosing period and for 
14 days thereafter:
Herbal Supplements/Alternative Medicines 

Anticancer herbal supplements or alternative medicines (including approved traditional 
Chinese medicines for HCC) are strongly discouraged during the Screening and 
Treatment Phase of this study.
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The exclusion criteria describe other medications that are prohibited in this study.
There are no prohibited therapies during the post-treatment Follow-up Phase.
Country-specific requirements are noted in Appendix 7.
6.5.3
Drug-Drug Interactions
A clinical drug-drug interaction (DDI) study in cancer patients showed that plasma 
concentrations of midazolam (a sensitive CYP3A and Pgp substrate) were not altered in the 
presence of lenvatinib. No significant DDI is therefore expected between lenvatinib and other 
CYP3A4/Pgp substrates. Therefore, there are no DDI-related concomitant medication 
prohibitions or restrictions.  
Nonclinical studies identify CYP3A4 as the important CYP isozyme responsible for human 
hepatic metabolism of lenvatinib. However, clinical studies conducted showed that 
coadministration of lenvatinib with either inducers or inhibitors of CYP3A4/P-glycoprotein 
(P gp) are not of clinical concern. The main metabolic pathways for lenvatinib in humans 
were identified as enzymatic (CYP3A and aldehyde oxidase) and nonenzymatic processes 
(LENVIMA product information).
6.5.4
Rescue Medications and Supportive Care
Participants should receive appropriate supportive care measures as deemed necessary by the 
treating investigator. Suggested supportive care measures for the management of AEs with 
potential immunologic etiology are outlined along with the dose modification guidelines in 
Section 6.6.2, Table 6 and Section 6.6.3. Where appropriate, these guidelines include the 
use of oral or IV treatment with corticosteroids, as well as additional anti-inflammatory 
agents if symptoms do not improve with administration of corticosteroids. Note that several 
courses of steroid tapering may be necessary as symptoms may worsen when the steroid dose 
is decreased. For each disorder, attempts should be made to rule out other causes such as 
metastatic disease or bacterial or viral infection, which might require additional supportive 
care. The treatment guidelines are intended to be applied when the investigator determines 
the events to be related to pembrolizumab.
Note: If after the evaluation of the event, it is determined not to be related to pembrolizumab, 
the investigator does not need to follow the treatment guidance. Refer to Table 6 in Section
6.6.2 and Guidance for Management of Hepatic Events of Clinical Interest in Section 6.6.3
for guidelines regarding dose modification and supportive care.
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event.
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6.6
Dose Modification (Escalation/Titration/Other)
6.6.1
Lenvatinib Dose Modification
Lenvatinib dose reduction and interruption for participants who experience 
lenvatinib-pembrolizumab combination therapy-related toxicity will be in accordance with 
the dose-modification guidelines described in Table 4. An interruption of study intervention 
for more than 28 days will require Sponsor approval before treatment can be resumed.
Adverse events will be graded using NCI CTCAE Version 4.0. Investigators will decide the 
probability of the event being related to one or both drugs as to whether dose modification of 
one or both drugs is required.  
The starting dose of lenvatinib is 12 mg (BW ≥60 kg) or 8 mg (BW <60 kg) orally QD. Dose 
reductions of lenvatinib occur in succession based on the previous dose level. Dose 
reductions occur in succession based on the previous dose level (12, 8, and 4 mg QD, and 4 
mg every other day [QOD]) per Table 4. Once the dose has been reduced, it cannot be 
increased at a later date unless the dose has been mistakenly decreased; in this situation, the 
Sponsor’s approval is required to increase the dose.
Table 4
Dose Modification for Lenvatinib Treatment-Related Toxicity
Adjusted Dose To Be Administered
Initial Lenvatinib Dose 
(mg, QD)
Reduction 1
Reduction 2
Reduction 3
12 mg QD
8 mg QD
4 mg QD
4 mg QOD
8 mg QD
4 mg QD
4 mg QOD
Discontinue
QD = once daily; QOD = every other day. 
Refer to the subsections below for management of hypertension (Section 6.6.1.1), proteinuria 
(Section 6.6.1.2), diarrhea (Section 6.6.1.3), thromboembolic events (Section 6.6.1.4), 
posterior reversible encephalopathy syndrome/ reversible posterior leukoencephalopathy 
syndrome (PRES/RPLS; Section 6.6.1.5), hypocalcemia (Section 6.6.1.6), hemorrhage 
(Section 6.6.1.7), gastrointestinal perforation (Section 6.6.1.8), and osteonecrosis of the jaw 
(Section 6.6.1.9) as appropriate, before consulting the dose modification table (Table 5).
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Table 5
Dose Modification Guidelines for Lenvatinib-Related Adverse Events (for the 
Lenvatinib-Pembrolizumab Combination)
Lenvatinib Dose Reduction and Interruption Instructions
Dose adjustment for lenvatinib treatment-related toxicity is AFTER interruption and resolution of study intervention as 
detailed in the table below. Dose reductions occur in succession based on the previous dose level (12, 8, and 4 mg/day, 
and 4 mg every other day [QOD]).  
Nonhematologic Toxicities
Treatment-Related Toxicitya,b
Management
Dose Adjustment
Grade 1 or Tolerable Grade 2
Continue treatmentc
No change
Intolerable Grade 2c or Grade 3d,e,h
First occurrence
Interrupt until resolved to Grade 0-1 or baseline
Reduce lenvatinib by 1 dose level
Second occurrence
(same toxicity or new toxicity)
Interrupt until resolved to Grade 0-1 or baseline
Reduce lenvatinib by 1 more dose 
level
Third occurrencef
(same toxicity or new toxicity)
Interrupt until resolved to Grade 0-1 or baseline
Reduce lenvatinib by 1 more dose 
level
Fourth occurrence 
(same toxicity or new toxicity)
Interrupt until resolved to Grade 0-1 or baseline
Discontinue lenvatinib
Grade 4g,h:  Discontinue Lenvatinib
Hematologic Toxicities and Proteinuria
Treatment-Related Toxicitya
Management
Dose Adjustment
Grade 1 or Grade 2e
Continue treatmentc
No change
Grade 3e, i
First occurrence
Interrupt until resolved to Grade 0-2 or baseline
No change
Second occurrence 
(same toxicity or new toxicity)
Interrupt until resolved to Grade 0-2 or baseline
Reduce lenvatinib by 1 dose level
Third occurrence
(same toxicity or new toxicity)
Interrupt until resolved to Grade 0-2 or baseline
Reduce lenvatinib by 1 more dose 
level
Fourth occurrence f
(same toxicity or new toxicity)
Interrupt until resolved to Grade 0-2 or baseline
Reduce lenvatinib by 1 more dose 
level
Fifth occurrence
(same toxicity or new toxicity)
Interrupt until resolved to Grade 0-2 or baseline
Discontinue lenvatinib
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Lenvatinib Dose Reduction and Interruption Instructions
Dose adjustment for lenvatinib treatment-related toxicity is AFTER interruption and resolution of study intervention as 
detailed in the table below. Dose reductions occur in succession based on the previous dose level (12, 8, and 4 mg/day, 
and 4 mg every other day [QOD]).  
Grade 4j
First occurrence
Interrupt until resolved to Grade 0-2 or baseline
Reduce lenvatinib by 1 dose level
Second occurrence
(same toxicity or new toxicity)
Interrupt until resolved to Grade 0-2 or baseline
Reduce lenvatinib by 1 more dose 
level
Third occurrencef
(same toxicity or new toxicity)
Interrupt until resolved to Grade 0-2 or baseline
Reduce lenvatinib by 1 more dose 
level
Fourth occurrence
(same toxicity or new toxicity)
Interrupt until resolved to Grade 0-2 or baseline
Discontinue lenvatinib
Note: Grading according to CTCAE v4.0.
AE = adverse event; BMI = body mass index; CTCAE v4.0 = Common Terminology Criteria for Adverse Events Version 
4.03; QD = once daily.
a An interruption of lenvatinib for more than 28 days (due to treatment-related toxicities) will require Sponsor’s 
approval before treatment can be resumed. During treatment interruption, repeat AEs assessment at least every 
7 days (until restarting administration). 
b Initiate optimal medical management for nausea, vomiting, diarrhea, and/or hypothyroidism prior to any lenvatinib 
treatment, interruption, or dose reduction. 
c Grade 2 toxicities will be determined to be tolerable or intolerable by both the participant and investigator. If Grade 
2 toxicity is determined to be intolerable, the dose of study drug will be reduced with or without dose interruption. 
Interruption for Grade 3 toxicities is mandatory. 
d Obese participants (BMI >/= 30) with weight loss do not need to return to their baseline weight or within 10% of 
their baseline weight (ie, Grade 1 weight loss). These participants may restart study treatment at a lower dose once 
their weight loss remains stable for at least 1 week and they reach at least a BMI of 25. The new stable weight 
should be used for future dose reductions. 
e Not applicable to abnormal clinical laboratory values that are not clinically relevant based on the judgment of the 
investigator.
f
Not applicable for participants who start at 8 mg QD. 
g Excluding laboratory abnormalities judged to be nonlife-threatening, which should be managed as Grade 3. 
h For asymptomatic Grade ≥3 elevations of amylase and lipase, Sponsor should be consulted to obtain permission to 
continue treatment. 
i
For a Grade 3 thromboembolic event, with the exception of portal vein thrombosis developed during treatment, 
permanently discontinue lenvatinib. See Section 6.6.1.4
j
Applies to hematologic toxicities only.
6.6.1.1
Management of Hypertension
Hypertension is a recognized side effect of treatment with drugs inhibiting VEGF signaling. 
Investigators should therefore ensure that participants enrolled to receive treatment with 
lenvatinib have BP of ≤150/90 mm Hg at the time of study entry and, if known to be 
hypertensive, have been on a stable dose of antihypertensive therapy for at least 1 week 
before Cycle 1 Day 1. Early detection and effective management of hypertension are 
important to minimize the need for lenvatinib dose interruptions and reductions.
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Regular assessment of BP should be as detailed in the SoA (Section 1.3, Table 1). 
Hypertension will be graded using NCI CTCAE v4.0, based on BP measurements only (and 
not on the number of antihypertensive medications). If the participant’s initial BP 
measurement is elevated (ie, systolic BP ≥140 mm Hg or diastolic BP ≥90 mm Hg), the BP 
measurement should be repeated at least 5 minutes later. One BP assessment is defined as the 
mean value of 2 measurements at least 5 minutes apart. If the BP assessment (ie, the mean of 
the 2 BP measurements obtained at least 5 minutes apart) is elevated (systolic BP ≥140 mm 
Hg or diastolic BP ≥90 mm Hg), a confirmatory assessment should be obtained at least 30 
minutes later by performing 2 measurements (at least 5 minutes apart) to yield a mean value. 
Antihypertensive agents should be started as soon as elevated BP (systolic BP ≥140 mm Hg 
or diastolic BP ≥90 mm Hg) is confirmed on 2 assessments at least 30 minutes apart. The 
choice of antihypertensive treatment should be individualized to the participant’s clinical 
circumstances and follow standard medical practice. For previously normotensive 
participants, appropriate antihypertensive therapy should be started when systolic BP ≥140 
mm Hg or diastolic BP ≥90 mm Hg is first observed on 2 assessments at least 30 minutes 
apart. For those participants already on antihypertensive medication, treatment modification 
may be necessary if hypertension persists.  
Lenvatinib should be withheld in any instance where a participant is at imminent risk to 
develop a hypertensive crisis or has significant risk factors for severe complications of 
uncontrolled hypertension (eg, BP ≥160/100 mm Hg, significant risk factors for cardiac 
disease, intracerebral hemorrhage, or other significant comorbidities). Once the participant 
has been on the same antihypertensive medications for at least 48 hours and the BP is 
controlled, lenvatinib should be resumed as described below.
Participants who have had systolic BP ≥160 mm Hg or diastolic BP ≥100 mm Hg must have 
their BP monitored on Day 15 (or more frequently as clinically indicated) until systolic BP 
has been ≤150 mm Hg and diastolic BP has been ≤95 mm Hg for 2 consecutive treatment 
cycles. If a repeat event of systolic BP ≥160 mm Hg or diastolic BP ≥100 mm Hg occurs, the 
participant must resume evaluation until systolic BP has been ≤150 mm Hg and diastolic BP 
has been ≤95 mm Hg for 2 consecutive treatment cycles. A diary will be provided as a tool to 
aid the participant in collecting blood pressure evaluations between study visits.
The following guidelines should be followed for the management of systolic BP ≥160 mm 
Hg or diastolic BP ≥100 mm Hg confirmed on 2 BP assessments at least 30 minutes apart:
1. Continue study drug and institute antihypertensive therapy for participants not already 
receiving this.
2. For those participants already on antihypertensive medication, the dose of the current 
agent may be increased, if appropriate, or 1 or more agents of a different class of 
antihypertensive should be added. Study treatment can be continued without dose 
modification.
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3. If systolic BP ≥160 mm Hg or diastolic BP ≥100 mm Hg persists despite maximal 
antihypertensive therapy, then lenvatinib administration should be interrupted and 
restarted at 1 dose level reduction only when systolic BP ≤150 mm Hg and diastolic BP 
≤95 mm Hg and the participant has been on a stable dose of antihypertensive medication 
for at least 48 hours. 
•
If systolic BP ≥160 mm Hg or diastolic BP ≥100 mm Hg recurs on the first dose 
reduction despite optimal management of hypertension with antihypertensive 
medications (either by dose increase or the addition of a different class of 
antihypertensive), then lenvatinib administration should be interrupted and restarted 
at an additional dose reduction only when systolic BP ≤150 mm Hg and diastolic BP 
≤95 mm Hg and the participant has been on a stable dose of antihypertensive 
medication for at least 48 hours. 
•
If systolic BP ≥160 mm Hg or diastolic BP ≥100 mm Hg recurs on the second dose 
reduction despite optimal management of hypertension with antihypertensive 
medications (either by dose increase or the addition of a different class of 
antihypertensive), then lenvatinib administration should be interrupted and restarted 
at a third dose reduction only when systolic BP ≤150 mm Hg and diastolic BP ≤95 
mm Hg and the participant has been on a stable dose of antihypertensive medication 
for at least 48 hours.
•
Additional dose reduction should be discussed with the Sponsor.
The following guidelines should be followed for the management of Grade 4 hypertension 
(life-threatening consequences):
1. Institute appropriate medical management
2. Discontinue lenvatinib
6.6.1.2
Management of Proteinuria
Regular assessment of proteinuria should be conducted as detailed in the SoA (Section 1.3). 
Guidelines for assessment and management of proteinuria are as follows:
Detection and Confirmation
1. Perform urine dipstick testing per the SoA (Section 1.3).
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2. A 24-hour urine collection or an immediate spot urine protein-to-creatinine ratio (UPCR)
test is required in the following situations:
•
The first (initial) occurrence of ≥2+ proteinuria on urine dipstick while on lenvatinib.
•
A subsequent increase in severity of urine dipstick proteinuria occurring on the same 
lenvatinib dose level.
•
When there has been a lenvatinib dose reduction and at the new dose level the urine 
protein dipstick result is ≥2+.
3. A 24-hour urine collection (initiated as soon as possible and at least within 24 hours) to 
verify the grade of proteinuria is required when UPCR is ≥2.4.
Grading of Proteinuria
•
Grading according to NCI CTCAE v4.0 will be based on the 24-hour urinary protein 
result if one has been obtained. 
Management of Proteinuria
•
Management of lenvatinib administration will be based on the grade of proteinuria 
according to Table 5.
•
In the event of nephrotic syndrome, lenvatinib must be discontinued.
Monitoring
•
Urine dipstick testing for participants with proteinuria ≥2+ should be performed on 
Day 15 (or more frequently as clinically indicated) until the results have been 1+ or 
negative for 2 consecutive treatment cycles.
6.6.1.3
Management of Diarrhea
An antidiarrheal agent should be recommended to the participant at the start of lenvatinib and 
participants should be instructed and educated to initiate antidiarrheal treatment at the first 
onset of soft bowel movements. The choice of antidiarrheal agent should be individualized to 
the participant’s clinical circumstances and follow standard medical practice. If 
signs/symptoms of diarrhea persist despite optimal medical management, instructions 
contained in Table 5 should be followed.
6.6.1.4
Management of Thromboembolic Events
Participants should be advised to pay attention to symptoms suggestive of venous 
thromboembolic events, which include acute onset of shortness of breath, dyspnea, chest 
pain, cough, hemoptysis, tachypnea, tachycardia, cyanosis, deep vein thrombosis signs 
including lower-extremity swelling, and warmth to touch or tenderness. In case any of these 
symptoms appear, participants should be instructed to report such symptoms promptly to the 
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treating physician. If a thromboembolic event is confirmed, instructions contained in Table 5
should be followed. Appropriate supportive care should be provided together with close 
monitoring. If a participant experiences a Grade 3 or a life-threatening (Grade 4) 
thromboembolic reactions, including pulmonary embolism, lenvatinib must be discontinued.
Arterial thromboembolic events (eg, new onset, worsening, or unstable angina, myocardial 
infarction, transient ischemic attack, and cerebrovascular accident) of any grade require 
lenvatinib discontinuation.
6.6.1.5
Management of Posterior Reversible Encephalopathy Syndrome/Reversible 
Encephalopathy Syndrome/ Reversible Posterior Leukoencephalopathy 
Syndrome
PRES/RPLS is a neurological disorder that can present with headache, seizure, lethargy, 
confusion, altered mental function, blindness, and other visual or neurological disturbances. 
Mild to severe hypertension may be present. MRI is necessary to confirm the diagnosis of 
PRES/RPLS. Appropriate measures should be taken to control BP. In participants with signs 
or symptoms of PRES/RPLS, instructions in Table 5 should be followed. 
6.6.1.6
Management of Hypocalcemia
Serum calcium should be monitored per the SoA (Section 1.3). Corrected serum calcium 
should be used to assess the grade of hypocalcemia per CTCAE v4.0, using the following 
formula: 
Corrected calcium = ([4 – serum albumin in g/dL] × 0.8 + serum calcium)
The formula is not applicable when serum albumin concentration is normal (˃4 g/dL); in 
such situations, the total (uncorrected) serum calcium should be used instead. 
Hypocalcemia should be treated per institutional guidelines (eg, using appropriate calcium, 
magnesium, and vitamin D supplementation) until resolution.
6.6.1.7
Management of Hemorrhage
Instructions in Table 5 (Nonhematologic Toxicities) should be followed for the management 
of hemorrhage. Either resume at a reduced dose or discontinue lenvatinib depending on the 
severity and persistence of hemorrhage.
6.6.1.8
Management of Gastrointestinal Perforation or Fistula Formation
Lenvatinib should be discontinued in any participants who develop gastrointestinal 
perforation or life-threatening fistula.
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6.6.1.9
Management of Osteonecrosis of the Jaw
Perform an oral examination prior to treatment with lenvatinib and periodically during 
lenvatinib treatment. Advise participants regarding good oral hygiene practices. Avoid 
invasive dental procedures, if possible, while on lenvatinib treatment, particularly in 
participants at higher risk. For participants requiring invasive dental procedures, 
discontinuation of bisphosphonate treatment may reduce the risk of ONJ. Withhold 
lenvatinib if ONJ develops and restart based on clinical judgment of adequate resolution (See 
Section 6.6.5).
6.6.2
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue)
Dose Modification and Toxicity Management for Non-hepatic Immune-related AEs 
Associated with Pembrolizumab
AEs associated with pembrolizumab exposure may represent an immune-related response. 
These irAEs may occur shortly after the first dose or several months after the last dose of 
pembrolizumab treatment and may affect more than one body system simultaneously. 
Therefore, early recognition and initiation of treatment is critical to reduce complications. 
Based on existing clinical study data, most irAEs were reversible and could be managed with 
interruptions of pembrolizumab, administration of corticosteroids and/or other supportive 
care. For suspected irAEs, ensure adequate evaluation to confirm etiology or exclude other 
causes. Additional procedures or tests such as bronchoscopy, endoscopy, skin biopsy may be 
included as part of the evaluation. Based on the severity of irAEs, withhold or permanently 
discontinue pembrolizumab and administer corticosteroids. 
Dose Modification and Toxicity Management Guidelines for Non-hepatic irAEs associated 
with pembrolizumab monotherapy, coformulations, or IO combinations are provided in
Table 6.  
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Table 6
Dose Modification and Toxicity Management Guidelines for Nonhepatic Immune-related Adverse Events Associated with 
Pembrolizumab Monotherapy, Coformulations or IO Combinations
General instructions:
1.
Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive treatment should begin if the irAEs are 
not controlled by corticosteroids.
2.
Pembrolizumab monotherapy, coformulations or IO combinations must be permanently discontinued if the irAE does not resolve or the corticosteroid dose is not 
≤10 mg/day within 12 weeks of the last treatment. 
3.
The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks.
4.
If pembrolizumab monotherapy, coformulations or IO combinations have been withheld, treatment may resume after the irAE decreased to ≤Grade 1 after 
corticosteroid taper.
irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Pneumonitis 
Grade 2
Withhold 
•
Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper
•
Monitor participants for signs and symptoms of 
pneumonitis
•
Evaluate participants with suspected pneumonitis 
with radiographic imaging and initiate 
corticosteroid treatment
•
Add prophylactic antibiotics for opportunistic 
infections
Recurrent Grade 2 
or Grade 3 or 4 
Permanently 
discontinue
Diarrhea / Colitis 
Grade 2 or 3
Withhold
•
Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper
•
Monitor participants for signs and symptoms of 
enterocolitis (ie, diarrhea, abdominal pain, blood 
or mucus in stool with or without fever) and of 
bowel perforation (ie, peritoneal signs and ileus)
•
Participants with ≥Grade 2 diarrhea suspecting 
colitis should consider GI consultation and 
performing endoscopy to rule out colitis
•
Participants with diarrhea/colitis should be advised 
to drink liberal quantities of clear fluids. If 
sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via IV infusion.
Recurrent Grade 3 
or Grade 4
Permanently 
discontinue
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irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
T1DM or 
Hyperglycemia
New onset T1DM 
or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of β-cell 
failure
Withhold a
•
Initiate insulin 
replacement therapy for 
participants with T1DM
•
Administer 
antihyperglycemic in 
participants with 
hyperglycemia
•
Monitor participants for hyperglycemia or other 
signs and symptoms of diabetes
Hypophysitis
Grade 2
Withhold
•
Administer corticosteroids 
and initiate hormonal 
replacements as clinically 
indicated
•
Monitor for signs and symptoms of hypophysitis 
(including hypopituitarism and adrenal 
insufficiency)
Grade 3 or 4
Withhold or 
permanently 
discontinue a
Hyperthyroidism 
Grade 2
Continue
•
Treat with non-selective 
beta-blockers (eg, 
propranolol) or 
thionamides as 
appropriate
•
Monitor for signs and symptoms of thyroid 
disorders
Grade 3 or 4
Withhold or 
Permanently 
discontinue a
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
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irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Myocarditis
Grade 1 
Withhold
•
Based on severity of AE 
administer corticosteroids
•
Ensure adequate evaluation to confirm etiology 
and/or exclude other causes
Grade 2, 3 or 4
Permanently 
discontinue
All Other irAEs
Persistent Grade 2
Withhold
•
Based on severity of AE 
administer corticosteroids
•
Ensure adequate evaluation to confirm etiology or 
exclude other causes
Grade 3
Withhold or 
discontinue b
Recurrent Grade 3 
or Grade 4 
Permanently 
discontinue
AE(s)=adverse event(s); CTCAE=Common Terminology Criteria for Adverse Events; DRESS=Drug Rash with Eosinophilia and Systemic Symptom; GI=gastrointestinal; 
IO=immuno-oncology; ir=immune-related; IV=intravenous; SJS=Stevens-Johnson Syndrome; T1DM=type 1 diabetes mellitus; TEN=Toxic Epidermal Necrolysis; 
ULN=upper limit of normal.
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations.
a
The decision to withhold or permanently discontinue pembrolizumab monotherapy, coformulations or IO combinations is at the discretion of the investigator or treating 
physician. If control achieved or ≤ Grade 2, pembrolizumab monotherapy, coformulations or IO combinations may be resumed.
b
Events that require discontinuation include, but are not limited to: Guillain-Barre Syndrome, encephalitis, myelitis, DRESS, SJS, TEN and other clinically important irAEs 
(eg, vasculitis and sclerosing cholangitis).
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Dose Modification and Toxicity Management of Infusion Reactions Related to 
Pembrolizumab
Pembrolizumab may cause severe or life-threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion. 
Dose modification and toxicity management guidelines on pembrolizumab associated 
infusion reaction are provided in Table 7.
Table 7
Pembrolizumab Infusion Reaction Dose Modification and Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at 
Subsequent Dosing
Grade 1
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated
Increase monitoring of vital signs as 
medically indicated until the participant is 
deemed medically stable in the opinion of 
the investigator
None
Grade 2
Requires therapy or infusion 
interruption but responds 
promptly to symptomatic 
treatment (eg, antihistamines, 
NSAIDs, narcotics, IV fluids); 
prophylactic medications 
indicated for ≤24 hrs
Stop Infusion
Additional appropriate medical therapy 
may include but is not limited to:
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Increase monitoring of vital signs as 
medically indicated until the participant is 
deemed medically stable in the opinion of 
the investigator.
If symptoms resolve within 1 hour of 
stopping drug infusion, the infusion may 
be restarted at 50% of the original infusion 
rate (eg, from 100 mL/hr to 50 mL/hr). 
Otherwise dosing will be held until 
symptoms resolve and the participant 
should be premedicated for the next 
scheduled dose.
Participants who develop Grade 2 toxicity 
despite adequate premedication should be 
permanently discontinued from further 
treatment with pembrolizumab/placebo.
Participant may be 
premedicated 1.5 h (±30 
minutes) prior to infusion of 
pembrolizumab/placebo
with:
Diphenhydramine 50 mg 
PO (or equivalent dose of 
antihistamine).
Acetaminophen 500-1000 
mg PO (or equivalent dose 
of analgesic).
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NCI CTCAE Grade
Treatment
Premedication at 
Subsequent Dosing
Grades 3 or 4
Grade 3:
Prolonged (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:
Epinephrine**
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Increase monitoring of vital signs as 
medically indicated until the participant is 
deemed medically stable in the opinion of 
the investigator.
Hospitalization may be indicated.
**In cases of anaphylaxis, epinephrine 
should be used immediately.
Participant is permanently discontinued 
from further treatment with 
pembrolizumab/placebo.
No subsequent dosing
Appropriate resuscitation equipment should be available at the bedside and a physician readily available 
during the period of drug administration.
For further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) 
at http://ctep.cancer.gov
Other Allowed Dose Interruption for Pembrolizumab/Placebo
Pembrolizumab/placebo may be interrupted for situations other than treatment-related AEs 
such as medical / surgical events or logistical reasons not related to study therapy. 
Participants should be placed back on pembrolizumab/placebo within 3 weeks of the 
scheduled interruption, unless otherwise discussed with the Sponsor. The reason for 
interruption should be documented in the participant's study record.
Country-specific requirements are noted in Appendix 7.
6.6.3
Guidance for Management of Hepatic Events of Clinical Interest
Hepatic ECIs (HECIs) have been described in Section 8.4.7. All of these HECIs will require 
holding study intervention and notification of the Sponsor within 24 hours. All cases of 
retreatment after interruption of study intervention for HECI must be reported to the Sponsor 
and recorded in the database.
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Immediate assessment in case of HECI:
All Participants
All participants should be considered for evaluation according to the directions below within 
72 hours of the alert for a nonoverdose ECI. For laboratory assessments of HECIs, central 
laboratory is preferred; local laboratory is acceptable if central laboratory is not available.
Procedures:
-
Consider obtaining a consultation with a hepatologist
-
Obtain a workup for hepatitis if there is no underlying hepatitis, including hepatitis A, B, 
C, D, E, Epstein-Barr virus, and cytomegalovirus
-
Assess for ingestion of drugs/supplements with hepatotoxic potential
-
Assess for alcohol ingestion
-
Assess for potential bacterial infection, biliary obstruction, or occult gastrointestinal 
bleeding
-
Repeat ALT, AST, total bilirubin, direct bilirubin, alkaline phosphatase, -glutamyl 
transpeptidase, INR, and complete blood count with differential
-
Measure HCV RNA viral load (applies only for participants who have current active 
HCV infection or had infection in the past)
-
HBV DNA, HBsAg, HBeAg, anti-HBc (total and IgM), anti-HBe, and anti-HBs 
regardless of prior HBV status (Note: participants should be questioned about compliance 
with the use of antiviral agents)
-
Other laboratories or imaging studies as clinically indicated
-
Consider liver biopsy if indicated
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 approximately 1% to 2% of participants who received 
pembrolizumab. The following section provides further guidance on the diagnosis and 
management of potential hepatic complications among HCC participants in this study. The 
recommendation is to hold both lenvatinib and pembrolizumab/placebo interventions and 
initiate “Management of HECI for Lenvatinib Toxicity”. If toxicity does not improve within 
1 to 2 days or worsens, follow “Management of HECI for Pembrolizumab/Placebo” below.
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6.6.3.1
Management of HECI for Lenvatinib Toxicity:
Lenvatinib Dose Reduction and Interruption Instructions
Dose reductions occur in succession based on the previous dose level (12, 8, and 4 mg/day, and 4 mg every 
other day [QOD]). Any dose reduction below 4 mg QOD must be discussed with the Sponsor. Once the dose 
has been reduced, it cannot be increased at a later date.
Lenvatinib Induced
HECI
Management
Dose Adjustment
First occurrence
Interrupt for up to 28 days. Restart only if resolved to 
Grade 0-1 or baseline within 28 days; otherwise, 
permanently discontinue lenvatinib.
Reduce lenvatinib by 1 
dose level.
Second occurrence
(same toxicity or new 
toxicity)
Interrupt for up to 28 days. Restart only if resolved to 
Grade 0-1 or baseline within 28 days; otherwise,
permanently discontinue lenvatinib.
Reduce lenvatinib by 1 
more dose level.
Third occurrence
(same toxicity or new 
toxicity)a
Interrupt for up to 28 days. Restart only if resolved to 
Grade 0-1 or baseline within 28 days; otherwise,
permanently discontinue lenvatinib.
Reduce lenvatinib by 1 
more dose level.
Fourth occurrence 
(same toxicity or new 
toxicity)
Interrupt for up to 28 days. Restart only if resolved to 
Grade 0-1 or baseline within 28 days; otherwise,
permanently discontinue lenvatinib.
Discontinue lenvatinib.
a Not applicable for participants who start at 8 mg QD.
6.6.3.2
Management of HECI for Pembrolizumab/Placebo:
Diagnosis
Management
Hepatitis B 
consider flare or 
change in HBV 
immunologic 
status
Rapid elevation of ALT to 
>5×ULN and/or >3× baseline
Interrupt pembrolizumab/placebo intervention for 
up to 12 weeks.
Start antiviral therapy or check for compliance if 
HBV is detectable.
Measure safety labs for AST, ALT, ALP, T Bili, D 
Bili, and INR on weekly basis.
Measure HBsAg and HBV DNA on weekly basis 
(if detected at the time of onset of ECI).
Evaluate the following every 2-3 weeks:
•
anti-HBe, HBe antigen, anti-HBs, and HBV 
DNA levels (if not detected at the onset of ECI)
Restart pembrolizumab/placebo intervention only if 
ALT returns to normal or Grade 1 (if normal at 
baseline), or to baseline grade (if Grade 2 at 
baseline) within 12 weeks, and the participant is 
clinically stable; otherwise, the participant should 
be permanently discontinued.
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Diagnosis
Management
Hepatitis C 
exacerbation in 
participants with 
HCV RNA 
positive
Rapid elevation of ALT to 
>5×ULN and/or >3x baseline 
Interrupt pembrolizumab/placebo intervention for 
up to 12 weeks.
Assess use of injection or inhalation drugs.
Recheck HCV genotype at the time of relapse of 
HCV RNA to rule out new infection.
Measure safety labs for AST, ALT, ALP, T Bili, D 
Bili, and INR on weekly basis
Measure HCV RNA levels every 2 weeks.
Please discuss risk benefit with Sponsor prior to 
starting HCV antiviral therapy.
Restart pembrolizumab/placebo intervention only if 
ALT returns to normal or Grade 1 (if normal at 
baseline), or to baseline grade (if Grade 2 at 
baseline) within 12 weeks, and the participant is 
clinically stable; otherwise, the participant should 
be permanently discontinued.
Relapse of HCV
infection for 
participants with 
successfully 
treated or new 
HCV infection 
If HCV RNA was TND at 
baseline, and now has confirmed 
detectable HCV RNA (2 
specimens, 1 week apart)
Immune-related 
Hepatitis
If any of the HECI criteria is met 
as defined in the protocol Section 
8.4.7
Note: 
Immune-related hepatitis is a 
diagnosis made after excluding 
other possible etiologies such as 
viral flare, biliary or vascular 
obstruction, infection, 
medications, and alcohol use 
usually immune-related hepatitis 
response to dechallenge and/or 
steroids and reoccurs with 
rechallenge
Interrupt pembrolizumab/placebo 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 pembrolizumab/placebo intervention
only if: 
a)
Abnormal laboratory values resolve to Grade 
≤1 or baseline (if abnormal at baseline)
b)
Taper steroid over 28 days
c)
Steroid treatment is tapered to prednisone <10 
mg/day or equivalent
Permanently Discontinue 
pembrolizumab/placebo intervention 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)
Decompensation to CP-C status
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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
Restart pembrolizumab/placebo 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.
6.6.4
Dose Modifications for Overlapping Toxicities
Based on the known toxicity profiles of pembrolizumab and lenvatinib, certain treatment-
related AEs are uniquely associated with one drug versus the other. For example, 
hypertension, arterial thrombotic events, proteinuria, and hemorrhagic events are known risks 
for lenvatinib treatment, while immune-related AEs are risks for pembrolizumab treatment. 
However, certain AEs, such as diarrhea, hypothyroidism, and liver enzyme elevation, may be 
initially considered attributable to either study drug. Therefore, evaluation of attribution is 
important for determining the study drug most likely related to the AE, or an alternative 
etiology, and subsequently proper clinical management. The following aspects should be 
considered:
1. Timing of AE onset 
Since lenvatinib is dosed daily and continuously due to a relatively short half-life (~28 
hours), and pembrolizumab is dosed Q3W due to a long half-life, lenvatinib can be 
interrupted to assess whether an AE improves/resolves with dechallenge (ie, interruption 
of treatment) based on the following 2 scenarios:
•
If an AE is identified during a treatment cycle (ie, between 2 pembrolizumab doses), 
only lenvatinib dose interruption is needed. 
•
If an AE is identified at the beginning of a treatment cycle, lenvatinib can be 
interrupted and dosing of pembrolizumab should be held.
If the participant recovers from an AE in response to lenvatinib interruption (ie, positive 
dechallenge), the event is more likely to be related to lenvatinib. Otherwise, after 
excluding other alternative explanations, an immune-related AE should be considered. 
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2. Severity of AE
If an AE is suspected to be treatment-related and is severe/life-threatening at the time of 
onset or is rapidly worsened, action including interrupting both drugs and initiating treatment 
with a corticosteroid (with exception of hypothyroidism, TIDM) and other supportive care 
should be taken promptly.
6.6.5
Other Allowed Dose Interruptions for Lenvatinib 
If the participant is receiving treatment with lenvatinib and requires surgery during the study, 
the stop time and restart time of lenvatinib should be as follows:
•
For minor procedures: stop lenvatinib at least 2 days before the procedure and restart it at 
least 2 days after, once there is evidence of adequate healing and no risk of bleeding.
•
For major procedures: stop lenvatinib at least 1 week (5 half-lives) prior to surgery and 
then restart it at least 1 week after, once there is evidence of adequate healing and no risk 
of bleeding.
•
For scheduled dental surgery or invasive dental procedures, stop lenvatinib for at least 
1 week before the procedure, then restart lenvatinib when deemed clinically appropriate.
6.7
Intervention After the End of the Study
Upon study completion, participants are to be discontinued and may be enrolled in an 
extension study using pembrolizumab in combination with lenvatinib, if available.
6.8
Clinical Supplies Disclosure
This study is blinded but supplies are provided open label; therefore, an unblinded 
pharmacist or qualified study site personnel will be used to blind supplies. Study intervention
identity (name, strength, or potency) is included in the label text; random code/disclosure 
envelopes or lists are not provided.
The emergency unblinding call center will use the intervention/randomization schedule for 
the study to unblind participants and to unmask study intervention identity. The emergency 
unblinding call center should only be used in cases of emergency (see Section 8.1.10). In the 
event that the emergency unblinding call center is not available for a given site in this study, 
the central electronic intervention allocation/randomization system (IRT) should be used to 
unblind participants and to unmask study intervention identity. The Sponsor will not provide 
random code/disclosure envelopes or lists with the clinical supplies.
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7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
Discontinuation of study intervention does not represent withdrawal from the study.
As certain data on clinical events beyond study intervention discontinuation may be 
important to the study, they must be collected through the participant’s last scheduled follow-
up, even if the participant has discontinued study intervention. Therefore, all participants 
who discontinue study intervention prior to completion of the protocol-specified treatment 
period will still continue to participate in the study as specified in Section 1.3 and Section 
8.10.3.
Participants may discontinue study intervention at any time for any reason or be dropped 
from the study intervention at the discretion of the investigator should any untoward effect 
occur. In addition, a participant may be discontinued from study intervention by the 
investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or 
for administrative and/or other safety reasons. Specific details regarding procedures to be 
performed at study intervention discontinuation are provided in Section 8.1.9.
A participant must be discontinued from study intervention but continue to be monitored in 
the study for any of the following reasons:
•
The participant or participant’s legally acceptable representative requests to discontinue 
study intervention.
•
The participant has a medical condition or personal circumstance that, in the opinion of 
the investigator and/or Sponsor, places the participant at unnecessary risk from continued 
administration of study intervention.
•
The participant has a confirmed positive serum pregnancy test.
•
Confirmed radiographic disease progression outlined in Section 8.2.1 (exception if the 
Sponsor approves treatment continuation)
•
Any progression or recurrence of any malignancy, or any occurrence of another 
malignancy that requires active treatment
•
Discontinuation of pembrolizumab/placebo for recurrent Grade 2 pneumonitis
•
Discontinuation of pembrolizumab/placebo may be considered for participants who have 
attained a confirmed complete response (CR) and have been treated for at least 8 cycles 
(at least 24 weeks), receiving at least 2 doses of pembrolizumab or matching placebo
beyond the date when the initial CR was declared.
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•
Completion of 35 treatments (approximately 2 years) with pembrolizumab/placebo
Note: The number of treatments is calculated starting with the first dose of 
pembrolizumab/placebo. In the presence of clinical benefit, participants who complete 
35 cycles of treatment with lenvatinib + pembrolizumab/placebo (approximately 2 years) 
may continue to receive lenvatinib alone until disease progression or intolerable toxicity.
•
Participant has any of the following nonoverdose hepatic ECIs: 
-
ALT >20×ULN (confirmed within 1 week)
-
Drug-related total bilirubin >10 x ULN
-
CP score of >9 points if not improved to CP score <9 by intervention within 3 days
-
Hepatic encephalopathy not manageable by therapy 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
-
If ascites is not manageable by intervention within 3 days
For participants who are discontinued from study intervention but continue to be monitored 
in the study, all visits and procedures, as outlined in the SoA, should be completed.
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study treatment or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study are outlined in Section 8.1.9. The procedures to be performed should a participant 
repeatedly fail to return for scheduled visits and/or if the study site is unable to contact the 
participant are outlined in Section 7.3.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
•
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
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•
The investigator or designee must make every effort to regain contact with the participant 
at each missed visit (eg, telephone calls and/or a certified letter to the participant’s last 
known mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
•
Note: A participant is not considered lost to follow-up until the last scheduled visit for the 
individual participant. The missing data for the participant will be managed via the 
prespecified statistical data handling and analysis guidelines.
8
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and their timing are summarized in the SoA.
•
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
•
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified or trained staff. Delegation of study site personnel responsibilities 
will be documented in the Investigator Study File Binder (or equivalent).
•
All study-related medical (or dental) decisions must be made by an investigator who is a 
qualified physician (or dentist when appropriate).
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of ICF may be utilized for screening or baseline 
purposes provided the procedure met the protocol-specified criteria and were performed 
within the time frame defined in the SoA.
•
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, Hepatitis C), and thus local regulations 
may require that additional informed consent be obtained from the participant. In these 
cases, such evaluations/testing will be performed in accordance with those regulations.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
8.1
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented consent from each potential participant or each participant’s legally 
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acceptable representative prior to participating in a clinical study. If there are changes to the 
participant’s status during the study (eg, health or age of majority requirements), the 
investigator the investigator or medically qualified designee must ensure the appropriate 
consent is in place.
8.1.1.1
General Informed Consent
Consent must be documented by the participant’s dated signature or by the participant’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 participant before 
participation in the study.
The initial ICF, any subsequent revised written ICF, and any written information provided to 
the participant must receive the Institutional Review Board/Independent Ethics Committee’s 
(IRB/IEC’s) approval/favorable opinion in advance of use. The participant or his/her legally 
acceptable representative should be informed in a timely manner if new information becomes 
available that may be relevant to the participant’s willingness to continue participation in the 
study. The communication of this information will be provided and documented via a revised 
consent form or addendum to the original consent form that captures the participant’s dated 
signature or by the participant’s legally acceptable representative’s dated signature.
The participant or his/her legally acceptable representative will be asked to sign consent at 
the point of initial radiographic disease progression.
Specifics about a study and the study population will be added to the consent form template 
at the protocol level.
The informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, 
and Sponsor requirements.
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator who is a qualified 
physician to ensure that the participant qualifies for the study.
8.1.3
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant provides written informed consent. At the time of intervention
allocation/randomization, site personnel will add the intervention/randomization number to 
the participant identification card.
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The participant identification card also contains contact information for the emergency 
unblinding call center so that a healthcare provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
8.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee. The medical 
history will collect all active conditions and any condition diagnosed within the prior 10 
years that the investigator considers to be clinically significant. Details regarding the disease 
for which the participant has enrolled in this study will be recorded separately and not listed 
as medical history.
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant 
within 28 days before starting the study. Treatment for the disease for which the participant 
has enrolled in this study will be recorded separately and not listed as a prior medication.
For all participants with a history of hepatitis B or hepatitis C, information on past and /or 
present antiviral treatment will be collected.
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study through the Safety Follow-up visit.
8.1.6
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur prior to randomization. Each participant 
will be assigned only 1 screening number. Screening numbers must not be re-used for 
different participants.
Any participant who is screened multiple times will retain the original screening number 
assigned at the initial screening visit. Specific details on the screening/rescreening visit 
requirements are provided in Section 8.10.1.
8.1.7
Assignment of Treatment/Randomization Number
All eligible participants will be randomly allocated and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment allocation/randomization. Once a 
treatment/randomization number is assigned to a participant, it can never be re-assigned to 
another participant.
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A single participant cannot be assigned more than 1 treatment/randomization number.
The investigator must provide the rationale for not using sorafenib prior to randomization.
Treatment Eligibility Assessment (TEA)
The TEA is included in the study to document investigator assessment of participant 
suitability for potential treatment and rationale. These data may be required to support 
reimbursement efforts.
8.1.8
Study Intervention Administration
Administration of pembrolizumab will be witnessed by the investigator and/or study staff. 
Lenvatinib may be administered at home except on Day 1 of Cycles 1 and 2. Please refer to 
Section 8.1.8.1 for further detail.
Study treatment should begin within 3 days of randomization.
8.1.8.1
Timing of Dose Administration
8.1.8.1.1
Lenvatinib
Lenvatinib is provided as 4-mg capsules. Lenvatinib 12 mg (BW ≥60 kg) or 8 mg (BW <60 
kg) once daily will be taken orally with water (with or without food) at approximately the 
same time each day in each 42-day cycle. However, on Day 1 of Cycles 1 and 2, lenvatinib 
will be administered 0 to 4 hours after completion of pembrolizumab administration. 
If a lenvatinib dose is missed and cannot be taken within 12 hours, then that dose should be 
skipped and the next dose should be taken at the usual time of administration.
8.1.8.1.2
Pembrolizumab
Pembrolizumab/placebo will be administered as a 30-minute IV infusion on Day 1 of each 
42-day cycle. 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).
After Cycle 1 Day 1, pembrolizumab/placebo may be administered up to 3 days before or 
after the scheduled Day 1 of each subsequent cycle due to administrative reasons.
8.1.9
Discontinuation and Withdrawal
Participants who discontinue study intervention prior to completion of the treatment period
should be encouraged to continue to be followed for all remaining study visits.
When a participant withdraws from participation in the study, all applicable activities 
scheduled for the discontinuation visit (End of Treatment Visit) should be performed (at the 
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time of withdrawal). Any AEs that are present at the time of withdrawal should be followed 
in accordance with the safety requirements outlined in Section 8.4 .
8.1.10
Participant Blinding/Unblinding
STUDY INTERVENTION IDENTIFICATION INFORMATION IS TO BE UNMASKED 
ONLY IF NECESSARY FOR THE WELFARE OF THE PARTICIPANT. EVERY 
EFFORT SHOULD BE MADE NOT TO UNBLIND.
For emergency situations where the investigator or medically qualified designee (consistent 
with local requirements) needs to identify the drug used by a participant and/or the dosage 
administered, he/she will contact the emergency unblinding call center by telephone and 
make a request for emergency unblinding. As requested by the investigator or medically 
qualified designee, the emergency unblinding call center will provide the information to 
him/her promptly and report unblinding to the Sponsor. Prior to contacting the emergency 
unblinding call center to request unblinding of a participant’s treatment assignment, the 
investigator who is a qualified physician should make reasonable attempts to enter the 
intensity/toxicity grade of the AEs observed, the relation to study intervention, the reason 
thereof, etc., in the medical chart. If it is not possible to record this assessment in the chart 
prior to the unblinding, the unblinding should not be delayed.
In the event that unblinding has occurred, the circumstances around the unblinding (eg, date, 
reason, and person performing the unblinding) must be documented promptly, and the 
Sponsor Clinical Director notified as soon as possible.
Once an emergency unblinding has taken place, the principal investigator, site personnel, and 
Sponsor personnel may be unblinded so that the appropriate follow-up medical care can be 
provided to the participant.
Participants whose treatment assignment has been unblinded by the investigator or medically 
qualified designee and/or nonstudy treating physician may be allowed to continue study 
intervention and should continue to be monitored in the study.
Additionally, the investigator or medically qualified designee must go into the IRT system 
and perform the unblind in the IRT system to update drug disposition. In the event that the 
emergency unblinding call center is not available for a given site in this study, the IRT 
system should be used for emergency unblinding in the event that this is required for 
participant safety.
At the end of the study, random code/disclosure envelopes or lists and unblinding logs are to 
be returned to the Sponsor or designee.
8.1.11
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
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calibrated and/or maintained to ensure that the data obtained is reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
8.2
Efficacy/Immunogenicity Assessments
8.2.1
Tumor Imaging and Assessment of Disease
The process for image collection and transmission to the BICR vendor can be found in the 
site imaging manual (SIM). Tumor imaging is strongly preferred to be acquired by CT. For 
the abdomen and pelvis, contrast-enhanced MRI may be used when CT with iodinated 
contrast is contraindicated, or when mandated by local practice. Triple phase imaging of the 
liver is required, as described in the SIM. MRI is the strongly preferred modality for imaging 
the brain. The same imaging technique regarding modality, ideally the same scanner, and the 
use of contrast should be used in a participant throughout the study to optimize the 
reproducibility of the assessment of existing and new tumor burden and improve the 
accuracy of the assessment of response or progression based on imaging. Note: for the 
purposes of assessing tumor imaging, the term “investigator” refers to the local investigator 
at the site and/or the radiological reviewer at the site or at an offsite facility.
All scheduled images for all study participants from the sites will be submitted to the BICR. 
In addition, images (including via other modalities) that are obtained at an unscheduled time 
point to determine disease progression, as well as imaging obtained for other reasons, but 
which demonstrate radiologic progression, should also be submitted to the central imaging 
vendor.
When the investigator identifies radiographic progression per RECIST 1.1, the BICR will 
perform expedited verification of radiologic PD and communicate the results to the study site 
and Sponsor (see Section 8.2.1.4 and Figure 2). Treatment should continue until PD has been 
verified. Regardless of whether PD is verified, if the investigator considers the participant 
has progressed, but elects to implement iRECIST, the investigator will assess for 
confirmation of progression by iRECIST at subsequent time points. Images should continue 
to be submitted to the BICR. 
8.2.1.1
Initial Tumor Imaging
The screening images must be submitted to the central imaging vendor for retrospective 
review.
Tumor imaging performed as part of routine clinical management is acceptable for use as 
screening tumor imaging if it is of diagnostic quality and performed within 28 days prior to 
the date of randomization and can be assessed by the central imaging vendor.
8.2.1.2
Tumor Imaging During the Study
The first on-study imaging assessment should be performed at 9 weeks ( 63 days ±7 days]) 
from the date of randomization. Subsequent tumor imaging should be performed every
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9 weeks ( 63 days ±7 days) or more frequently if clinically indicated. Imaging timing should 
follow calendar days and should not be adjusted for delays in cycle starts. Imaging should 
continue to be performed until disease progression is identified by the investigator and 
verified by the BICR vendor (unless the investigator elects to continue treatment and follow
iRECIST), the start of new anticancer treatment, withdrawal of consent, or death, or 
notification by the Sponsor, whichever occurs first. All supplemental imaging must be 
submitted to the central imaging vendor.
Objective response should be confirmed by a repeat imaging assessment. Tumor imaging to 
confirm PR or CR should be performed at least 4 weeks after the first indication of a 
response is observed. Participants will then return to regular scheduled imaging, starting with 
the next scheduled imaging time point. Participants who receive additional imaging for 
confirmation do not need to undergo the next scheduled tumor imaging if it is less than 4 
weeks later; tumor imaging may resume at the subsequent scheduled imaging time point. 
Note: Response does not typically need to be verified in real time by the central imaging 
vendor.
Per iRECIST (Section 8.2.1.5), disease progression should be confirmed by the site 4 to 8 
weeks after central verification of site-assessed first radiologic evidence of PD in clinically 
stable participants. Participants who have unconfirmed disease progression may continue on 
treatment at the discretion of the investigator until progression is confirmed by the site 
provided they have met the conditions detailed in Section 8.2.1.5. Participants who receive 
confirmatory imaging do not need to undergo the next scheduled tumor imaging if it is less 
than 4 weeks later; tumor imaging may resume at the subsequent scheduled imaging time 
point, if clinically stable. Participants who have confirmed disease progression by iRECIST, 
as assessed by the site, will discontinue study treatment. Exceptions are detailed in Section
8.2.1.5.
8.2.1.3
End-of-Treatment and Follow-up Tumor Imaging
For participants who discontinue study intervention, tumor imaging should be performed at 
the time of treatment discontinuation (±4 week window). If previous imaging was obtained 
within 4 weeks prior to the date of discontinuation, then imaging at treatment discontinuation 
is not mandatory. For participants who discontinue study intervention due to documented 
disease progression, this is the final required tumor imaging if the investigator elects not to 
implement iRECIST.
For participants who discontinue study intervention without documented disease progression, 
every effort should be made to continue monitoring disease status by tumor imaging using 
the same imaging schedule used while on treatment (every 9 weeks) until the start of a new 
anticancer treatment, disease progression, pregnancy, death, withdrawal of consent, or the 
end of the study, whichever occurs first.
8.2.1.4
RECIST 1.1 Assessment of Disease
RECIST 1.1 will be used as the primary measure for assessment of tumor response, date of 
disease progression, and as a basis for all protocol guidelines related to disease status (eg, 
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discontinuation of study intervention). Although RECIST 1.1 references a maximum of 5 
target lesions in total and 2 per organ, this protocol allows a maximum of 10 target lesions in 
total and 5 per organ, if clinically relevant to enable a broader sampling of tumor burden.
Initial tumor imaging showing site-assessed PD should be submitted immediately for BICR 
verification of PD. The site will be notified if the BICR verifies PD using RECIST 1.1. 
Figure 2 illustrates the imaging flow involving verification of PD for clinically stable 
participants.
8.2.1.5
iRECIST Assessment of Disease
iRECIST is based on RECIST 1.1, but adapted to account for the unique tumor response seen 
with immunotherapeutic drugs. iRECIST will be used by the investigator to assess tumor 
response and progression, and make treatment decisions. When clinically stable, participants 
should not be discontinued until progression is confirmed by the investigator, working with 
local radiology, according to the rules outlined in Appendix 14. This allowance to continue 
treatment despite initial radiologic PD takes into account the observation that some 
participants can have a transient tumor flare in the first few months after the start of 
immunotherapy, and then experience subsequent disease response. This data will be captured 
in the clinical database.
Clinical stability is defined as the following:
•
Absence of symptoms and signs indicating clinically significant progression of disease
•
No decline in ECOG performance status
•
No requirements for intensified management, including increased analgesia, radiation, or 
other palliative care
Any participant deemed clinically unstable should be discontinued from study intervention at
central verification of site-assessed first radiologic evidence of PD, and is not required to 
have repeat tumor imaging for confirmation of PD by iRECIST.
If the investigator decides to continue treatment, the participant may continue to receive 
study intervention and the tumor assessment should be repeated 4 to 8 weeks later to confirm 
PD by iRECIST, per investigator assessment. Images should continue to be sent in to the 
central imaging vendor for potential retrospective BICR.
If repeat imaging does not confirm PD per iRECIST, as assessed by the investigator, and the 
participant continues to be clinically stable, study intervention may continue and follow the 
regular imaging schedule. If PD is confirmed, participants will be discontinued from study 
intervention.
If a participant has confirmed radiographic progression (iCPD) as defined in Appendix 14, 
study intervention should be discontinued; however, if the participant is achieving a 
clinically meaningful benefit, an exception to continue study intervention may be considered 
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following consultation with the Sponsor. In this case, if study intervention is continued, 
tumor imaging should continue to be performed following the intervals as outlined in 
Section1.3 and submitted to the central imaging vendor.
A description of the adaptations and iRECIST process is provided in Appendix 14, with 
additional details in the iRECIST publication [Seymour, L., et al 2017]. A summary of 
imaging and treatment requirements after first radiologic evidence of progression is provided 
in Table 8 and illustrated as a flowchart in Figure 2.
8.2.1.6
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. Details are fully described in [Lencioni, R. 2010]. 
RECIST 1.1 by the BICR vendor will still be the primary measure of the tumor response.
Extrahepatic lesion assessment, as well as response categories and definitions, are identical to 
RECIST 1.1. Key differences from RECIST 1.1 include:
•
Lesions within the liver parenchyma are measured so as to include only the portion 
showing increased contrast enhancement in the arterial phase.
•
New lesions in the liver must meet one of the following conditions to be considered 
indicators of progression:
-
At least 10 mm in longest diameter, and showing typical HCC enhancement 
(enhancement during the arterial phase and washout during the portal venous phase)
-
At least 10 mm in longest diameter with atypical enhancement, but showing at least 
10 mm of growth on a subsequent scan
-
Porta hepatis lymph nodes should never be selected as target lesions, and should only 
be followed as nontarget lesions if their short axis measurement at screening is 
≥20 mm.
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Table 8
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 that has 
been verified by the 
BICR vendor.
Repeat imaging 
at 4 to 8 weeks 
to confirm PD.
May continue study 
intervention at the 
investigator’s 
discretion while 
awaiting 
confirmatory tumor 
imaging by site by 
iRECIST.
Repeat imaging at 4 
to 8 weeks to 
confirm PD per 
investigator’s 
discretion only.
Discontinue 
treatment.
Repeat tumor imaging 
confirms PD (iCPD) by 
iRECIST per 
investigator assessment.
No additional 
imaging 
required.
Discontinue 
treatment 
(exception is 
possible upon 
consultation with 
Sponsor).
No additional 
imaging required.
Not applicable.
Repeat tumor imaging 
shows iUPD by 
iRECIST per 
investigator assessment.
Repeat imaging 
at 4 to 8 weeks 
to confirm PD. 
May occur at 
next regularly 
scheduled 
imaging visit.
Continue study 
intervention at the 
investigator’s 
discretion.
Repeat imaging at 4 
to 8 weeks to 
confirm PD per 
investigator’s 
discretion only.
Discontinue 
treatment.
Repeat tumor imaging 
shows iSD, iPR, or iCR 
by iRECIST per 
investigator assessment.
Continue 
regularly 
scheduled 
imaging 
assessments.
Continue study 
intervention at the 
investigator’s 
discretion.
Continue regularly 
scheduled imaging 
assessments.
May restart 
study 
intervention if 
condition has 
improved and/or 
clinically stable 
per 
investigator’s 
discretion. Next 
tumor imaging 
should occur 
according to the 
regular imaging 
schedule.
Abbreviations: BICR=blinded independent central review; iCPD=iRECIST confirmed progressive disease; 
iCR=iRECIST complete response; iPR=iRECIST partial response; iRECIST=modified Response Evaluation 
Criteria in Solid Tumors 1.1 for immune-based therapeutics; iSD=iRECIST stable disease; iUPD=iRECIST 
unconfirmed progressive disease; PD=progressive disease; RECIST 1.1=Response Evaluation Criteria in 
Solid Tumors 1.1.
Note: If progression has been centrally verified, further management is by the site, based on iRECIST. If 
pembrolizumab/placebo has been discontinued, iRECIST would not be applicable for lenvatinib alone. Any 
further imaging should still be submitted to the BICR vendor, but no rapid review will occur. If RECIST 1.1 
disease progression has not been centrally verified, the site should continue treatment. Whether or not 
treatment continues, imaging should be collected and submitted to the BICR vendor with verification of 
progression request until RECIST 1.1 progression is verified by BICR.
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Figure 2
Imaging and Treatment for Clinically Stable Participants Treated With 
Pembrolizumab After First Radiologic Evidence of PD Assessed by the Investigator
CIV = central imaging vendor; iRECIST = RECIST 1.1 modified for immune-based therapeutics; PD = 
progressive disease RECIST 1.1 = Response Evaluation Criteria in Solid Tumors Version 1.1.
8.2.2
Patient-reported Outcomes
The EORTC QLQ-C30, EORTC QLQ-HCC18, and EQ-5D-5L questionnaires will be 
administered by trained site personnel and completed electronically by participants in the 
following order: EORTC QLQ-C30, EORTC QLQ-HCC18, and then EQ-5D-5L. See SoA 
(Section 1.3) for ePRO administration schedule.
It is best practice and strongly recommended that electronic patient-reported outcomes 
(ePROs) are administered to randomized participants prior to drug administration, AE
evaluation, and disease status notification. If the participant does not complete the ePROs at a
scheduled time point, the MISSMODE form must be completed to capture the reason the 
assessment was not performed. If at the time of enrollment of a participant, the translated 
version of the EORTC QLQ-C30 and/or EORTC QLQ-HCC18 questionnaires are not 
available for that language/country, and therefore cannot be completed by the participant at 
Cycle 1 Day 1, then the EORTC QLQ-C30 and/or EORTC QLQ-HCC18 will not be required 
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for this participant at any point during the study. The other study PRO measures must be
completed as scheduled. 
NOTE: For some sites, the translated EORTC QLQ-C30 and/or EORTC QLQ-HCC18 might 
become available after study startup and should be administered to participants at their time 
of enrollment; for some sites, the EORTC QLQ-C30 and/or EORTC QLQ-HCC18 
translation might not be available for the entire duration of the study.
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided. The total amount of blood/tissue to be drawn/collected over the course of the study 
(from prestudy to poststudy visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per participant, can be found in laboratory 
manual.
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
A complete physical examination (full physical or symptom-directed) including oral 
examination will be conducted by an investigator or medically qualified designee (consistent
with local requirements) per institutional standard. Height and weight will also be measured 
and recorded.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.3.1.1
Full Physical Examination
The investigator or qualified designee will perform a complete physical examination during 
the Screening period. Clinically significant abnormal findings should be recorded as medical 
history. The time points for full physical examination are described in Section 1.3. 
Assessment for possible ascites and hepatic encephalopathy should be noted on every 
examination. After the first dose of study intervention, new clinically significant abnormal 
findings should be recorded as AEs. Height and weight will also be measured and recorded.
8.3.1.2
Directed Physical Examination
For cycles that do not required a full physical examination as defined in Section 1.3, the 
investigator or qualified designee will perform a directed physical examination as clinically 
indicated prior to the administration of the study intervention. Assessment for possible 
ascites and hepatic encephalopathy should be noted on every examination. New clinically
significant abnormal findings should be recorded as AEs.
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8.3.2
Vital Signs
Vital sign measurements (ie, systolic and diastolic BP [mm Hg], pulse [beats per minute], 
respiratory rate [per minute], body temperature [in centigrade]), and weight [kg]) will be 
obtained at the visits designated in the SoA (Section 1.3) by a validated method.
Blood pressure and pulse will be measured after the participant has been resting for 5 
minutes. All BP measurements should be performed on the same arm, preferably by the same 
person.
Only 1 BP measurement is needed for participants with systolic BP <140 mm Hg and 
diastolic BP <90 mm Hg. If the participant’s initial BP measurement is elevated (ie, systolic 
BP ≥140 mm Hg or diastolic BP ≥90 mm Hg), the BOP measurement should be repeated at 
least 5 minutes later. One BP assessment is defined as the mean value of 2 measurements at 
least 5 minutes apart. If the BP assessment (ie, the mean of the 2 BP measurements obtained 
at least 5 minutes apart) is elevated (systolic BP ≥140 mm Hg or diastolic BP ≥90 mm Hg), a 
confirmatory assessment should be obtained at least 30 minutes later by performing 
2 measurements (at least 5 minutes apart) to yield a mean value.
Under exceptional circumstances, participants will have the option of having BP measured 
between visits obtained locally by a health care professional. A diary will be provided as a 
tool to aid the participant in collecting BP evaluations between study visits.
8.3.3
Electrocardiograms
Electrocardiograms (ECGs) will be obtained as designated in the SoA (Section 1.3). 
Complete, standardized, 12-lead ECG recordings that permit all 12 leads to be displayed on a 
single page with an accompanying lead II rhythm strip below the customary 3 × 4 lead 
format are to be used. In addition to a rhythm strip, a minimum of 3 full complexes should be 
recorded from each lead simultaneously. Participants must be in the recumbent position for a 
period of 5 minutes prior to the ECG. The Fridericia correction method for calculating QTc 
will be used.
QTc prolongation has been seen in some lenvatinib studies. Drugs known to prolong the QTc 
interval (including class Ia and III antiarrhythmics) must be used cautiously. Please refer to 
the IB.
An ECG abnormality may meet the criteria of an AE as described in this protocol (see 
Appendix 3) and the CRF Completion Guidelines. In these instances, the AE corresponding 
to the ECG abnormality will be recorded on the appropriate CRF.
8.3.4
Echocardiogram or Multiple Gated Acquisition Scan
A MUGA scan (using technetium-based tracer) or an ECHO will be performed to assess 
LVEF as designated in the SoA (Section 1.3). MUGA or ECHO scans should be performed 
locally in accordance with the institution’s standard practice. MUGA scans are the preferred 
modality; however, whichever modality is used for an individual participant at baseline 
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should be repeated for all subsequent LVEF assessments for that participant. LVEFs as 
assessed by the institution will be entered onto the CRF. Investigator assessment will be 
based upon institutional reports.
8.3.5
Child-Pugh Score
Originally developed in 1973, the Child-Pugh score was used to estimate the risk of operative 
mortality in participants with bleeding esophageal varices. It has since been modified, 
refined, and become a widely used tool to assess prognosis in patients with chronic liver 
disease and cirrhosis. The score considers 5 factors, 3 of which assess the synthetic function 
of the liver (ie, Tbili level, serum albumin, and coagulation parameters [INR or PT]) and 2 of 
which are based on clinical assessment (ie, degree of ascites and degree of hepatic 
encephalopathy).
8.3.6
Clinical Safety Laboratory Assessments
•
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the 
SoA for the timing and frequency.
•
The investigator or medically qualified designee (consistent with local requirements) 
must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the case report form 
(CRF). The laboratory reports must be filed with the source documents. Clinically 
significant abnormal laboratory findings are those which are not associated with the 
underlying disease, unless judged by the investigator to be more severe than expected for 
the participant's condition.
•
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.
•
If laboratory values from nonprotocol specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).
•
For any laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 90 days after the last dose of study intervention, every 
attempt should be made to perform repeat assessments until the values return to normal or 
baseline or if a new baseline is established as determined by the investigator.
Details regarding specific laboratory procedures/assessments to be performed in this study 
are provided below. The total amount of blood/tissue to be drawn/collected over the course 
of the study (from prestudy to poststudy visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per participant, can be found in the study 
procedures manual. Refer to the SoA (Section 1.3) for the timing of laboratory assessments.
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8.3.6.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
Laboratory tests for hematology, chemistry, and urinalysis are specified in Appendix 2.
8.3.7
Pregnancy Testing
•
Pregnancy testing:
-
Pregnancy testing requirements for study inclusion are described in Section 5.1.
-
Pregnancy testing (urine or serum) should be conducted at every protocol treatment 
cycle, as per SoA.
-
Home pregnancy testing should be conducted midcycle (Day 22 of each treatment 
cycle), while taking oral study intervention(s) as per SoA.
-
Pregnancy testing (urine or serum) should be conducted for the time required to 
eliminate systemic exposure after the last dose of each study intervention(s) and 
should correspond with the time frame for the participant’s contraception, as noted in 
Section 5.1. The length of time required to continue pregnancy testing for each study 
intervention is: as follows:
◦
MK-3475: 120 days
◦
Lenvatinib: 30 days
-
Additional serum or urine pregnancy tests may be performed, as determined 
necessary by the investigator or required by local regulation, to establish the absence 
of pregnancy at any time during the participant’s participation in the study.
8.3.8
Performance Assessments
8.3.8.1
Eastern Cooperative Oncology Group (ECOG) Performance Scale
The investigator or qualified designee will assess ECOG status (see Appendix 9) at screening
(within 7 days of starting study intervention), prior to the administration of each dose of 
study intervention and during the follow-up period as specified in the SoA (Section 1.3).
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Reportable 
Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 4.
Progression of the cancer under study is not considered an AE as described in Section 8.4.7
and Appendix 4.
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Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant's legally authorized 
representative).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators need to document if an SAE was associated with a medication error, misuse, or 
abuse. Investigators remain responsible for following up AEs, SAEs, and other reportable 
safety events for outcome according to Section 8.4.3.
The investigator, who is a qualified physician, will assess events that meet the definition of 
an AE or SAE as well as other reportable safety events with respect to seriousness, 
intensity/toxicity and causality.
Adverse events will not be collected for participants during the prescreening period (for 
determination of archival tissue status) as long as that participant has not undergone any 
protocol-specified procedure or intervention. If the participant requires a blood draw, fresh 
tumor biopsy, etc., the participant is first required to provide consent to the main study, and 
AEs will be captured according to guidelines for standard AE reporting.
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
All AEs, SAEs, and other reportable safety events that occur after the consent form is signed 
but before treatment allocation/randomization must be reported by the investigator if the 
participant is receiving placebo run-in or other run-in treatment, if the event cause the 
participant to be excluded from the study, or is the result of a protocol-specified intervention, 
including but not limited to washout or discontinuation of usual therapy, diet, or a procedure.
•
All AEs from the time of treatment allocation/randomization through 90 days, or 30 days 
following cessation of study intervention if the participant initiates new anticancer 
therapy, must be reported by the investigator.
•
All AEs meeting serious criteria, from the time of treatment allocation/randomization 
through 120 days following cessation of study intervention or 30 days following 
cessation of study intervention if the participant initiates new anticancer therapy, 
whichever is earlier, must be reported by the investigator.
•
All pregnancies and exposure during breastfeeding, from the time of treatment 
allocation/randomization through 120 days following pembrolizumab/placebo or 30 days 
following cessation of lenvatinib, whichever occurs last, must be reported by the 
investigator. If the participant initiates new anticancer therapy following discontinuation 
of study intervention, the time period for reporting pregnancies and exposure during 
breastfeeding is reduced to 30 days following cessation of study intervention.
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•
Additionally, any SAE brought to the attention of an investigator at any time outside of 
the time period specified above must be reported immediately to the Sponsor if the event 
is considered drug-related.
Investigators are not obligated to actively seek AE or SAE or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a
death, at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 9.
Table 9
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation 
through Protocol-
Specified Follow-
up Period
Reporting Time Period:
After the Protocol-
Specified Follow-up 
Period
Timeframe to 
Report Event 
and Follow-up 
Information to 
SPONSOR:
Non-Serious 
Adverse Event 
(NSAE) 
Report if:
- due to protocol-
specified 
intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other run-
in treatment
Report all
Not required
Per data entry 
guidelines
Serious Adverse 
Event (SAE) 
including Cancer 
and Overdose
Report if:
- due to protocol-
specified 
intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other run-
in treatment
Report all
Report if:
- drug/vaccine related.
(Follow ongoing to 
outcome)
Within 24 hours 
of learning of 
event
Pregnancy/
Lactation 
Exposure
Report if:
- due to 
intervention
- causes exclusion
Report all
Previously reported –
Follow to 
completion/termination; 
report outcome
Within 24 hours 
of learning of 
event
Events of Clinical 
Interest
Report if
-due to 
intervention
-causes exclusion
Hepatic ECIs 
except those 
considered due to 
disease 
progression as 
judged by the 
investigator
Not required
Within 24 hours 
of learning of 
event
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Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation 
through Protocol-
Specified Follow-
up Period
Reporting Time Period:
After the Protocol-
Specified Follow-up 
Period
Timeframe to 
Report Event 
and Follow-up 
Information to 
SPONSOR:
Event of Clinical 
Interest (Do not 
require regulatory 
reporting)
Report if:
- due to 
intervention
- causes exclusion
Report
- non-hepatic
ECIs and those 
not requiring 
regulatory 
reporting
Not required
Within 
5 calendar days 
of learning of 
event
ECIs = events of clinical interest.
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AE and/or SAE and other reportable 
safety events. Open-ended and nonleading verbal questioning of the participant is the 
preferred method to inquire about AE occurrence.
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AE, SAE, and other reportable safety events 
including pregnancy and exposure during breastfeeding, events of clinical interest (ECI), 
cancer, and overdose will be followed until resolution, stabilization, until the event is 
otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). In 
addition, the investigator will make every attempt to follow all nonserious AEs that occur in 
randomized participants for outcome. Further information on follow-up procedures is given 
in Appendix 3.
8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. All 
AEs will be reported to regulatory authorities, IRB/IECs, and investigators in accordance 
with all applicable global laws and regulations (ie, per ICH Topic E6 (R2) Guidelines for 
Good Clinical Practice [GCP]).
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and Sponsor policy and 
forwarded to investigators as necessary.
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An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.4.5
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding (spontaneously reported to the 
investigator or their designee) that occurs in a participant during the study is reportable to the 
Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy.
Any pregnancy complication will be reported as an AE or SAE.
The medical reason (example: maternal health or fetal disease) for an elective termination of 
a pregnancy will be reported as an AE or SAE. Prenatal testing showing that the fetus will be 
born with severe abnormalities/congenital anomalies that leads to an elective termination of a 
pregnancy will be reported as an SAE for the fetus.
Pregnancy outcomes of ectopic pregnancy, spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth 
must be reported as serious events (Important Medical Events). If the pregnancy continues to 
term, the outcome (health of infant) must also be reported.
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
Efficacy endpoints as outlined in this section will not be reported to the Sponsor as described 
in Section 8.4.1.
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study.
The Sponsor/designee will monitor unblinded aggregated efficacy endpoint events and safety 
data to ensure the safety of the participants in the study. Any suspected endpoint that upon 
review is not progression of the cancer under study will be forwarded to Global 
Pharmacovigilance as an SAE within 24 hours of determination that the event is not 
progression of the cancer under study. 
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8.4.7
Events of Clinical Interest (ECIs)
Selected nonserious and SAEs are also known as ECIs and must be reported to the Sponsor. 
Events of clinical interest for this study include: 
1. An overdose of Sponsor's product, as defined in Section 8.5, that is not associated with 
clinical symptoms or abnormal laboratory results. 
2. Hepatic ECIs include any of the following events if the events are considered not due to 
disease progression as judged by the investigator. All of these events (if not associated 
with disease progression under study) will require holding study treatment, notification of 
the event(s) to the Sponsor within 24 hours after awareness via electronic media or paper.
For dose interval modification, refer to Section 6.6.1 and 6.6.2. For guidance related to the 
diagnosis and management of hepatic ECIs, refer to Section 6.6.3.
•
ALT:
-
Among subjects with Baseline ALT <2×ULN:  ALT ≥5×ULN
-
Among subjects with Baseline ALT ≥2×ULN:  ALT >3× the Baseline level
-
ALT >500 U/L regardless of baseline level
•
Total Bilirubin:
-
Total bilirubin >3.0 mg/dL
•
Regardless of laboratory values, hepatic decompensation diagnosed clinically, including:
-
New onset clinically detectable ascites requiring intervention for >3 days
-
Hepatic Encephalopathy
8.5
Treatment of Overdose
For this study, an overdose of pembrolizumab will be defined as any dose of 1000 mg or 
greater (≥5 times the indicated dose).  An overdose of lenvatinib will be defined as any dose 
≥20% over the prescribed dose described in the protocol.
No specific information is available on the treatment of overdose of pembrolizumab or 
lenvatinib. In the event of overdose, the participant should be observed closely for signs of 
toxicity. Appropriate supportive treatment should be provided if clinically indicated.
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8.6
Pharmacokinetics
To evaluate the immunogenicity and exposure of pembrolizumab in this indication, sample 
collections for analysis of antidrug antibodies (ADA) and PK are currently planned as shown 
in Section 1.3 (SoA). Blood samples for PK and ADA collected may be stored only at this 
time. Further analysis may be performed if required and reported separately if conducted. If 
ongoing PK and/or ADA sampling is deemed to be unnecessary by the Sponsor, it may be 
reduced or discontinued.
To evaluate the exposure of lenvatinib when coadministered with pembrolizumab blood 
samples will be collected as specified in the SoA (Section 1.3) from all participants. Study 
sites must have appropriately trained staff and adequate equipment for procuring and 
processing specimens. Instructions for the collection, handling, and shipping procedures of 
PK samples will be provided in the laboratory manual. 
Sample collection, storage, and shipment instructions for plasma samples will be provided in 
the operations/laboratory manual.
8.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
8.8
Biomarkers
To identify novel biomarkers, the following biospecimens to support exploratory analyses of 
cellular components (eg, protein, RNA, DNA, metabolites) and other circulating molecules 
will be collected from all participants as specified in the SoA:
•
Blood for genetic analysis
•
Blood for circulating tumor nucleic acids analysis
•
Tumor tissue
Sample collection, storage, and shipment instructions for the exploratory biomarker 
specimens will be provided in the laboratory manual.
Country-specific requirements are noted in Appendix 7.
8.8.1
Planned Genetic Analysis Sample Collection
Samples should be collected for planned analysis of associations between genetic variants in 
germline/tumor DNA and drug response. If a documented law or regulation prohibits (or 
local IRB/Independent Ethics Committee [IEC] does not approve) sample collection for these 
purposes, then such samples should not be collected at the corresponding sites. 
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8.9
Medical Resource Utilization and Health Economics
Medical resource utilization and health economics data, associated with medical encounters, 
will be collected in the CRF by the investigator and study-site personnel for all participants 
throughout the study. Protocol-mandated procedures, tests, and encounters are excluded.
The data collected may be used to conduct exploratory economic analyses and will include:
All-cause hospitalizations and emergency room visits must be reported in the eCRF, from the 
time of treatment allocation/randomization through 90 days following cessation of study 
intervention, or 30 days following cessation of study intervention, if the participant initiates 
new anticancer therapy, whichever is earlier.
8.10
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.10.1
Screening
Approximately 28 days prior to treatment randomization, potential participants will be 
evaluated to determine that they fulfill the entry requirements as set forth in Section 5.
Written consent must be obtained prior to performing any protocol-specific procedure. 
Results of a test performed prior to the participant signing consent as part of routine clinical 
management are acceptable in lieu of a screening test if performed within the specified time 
frame. Screening procedures are to be completed within 28 days prior to the first dose of 
study intervention except for the following:
•
Laboratory tests are to be performed within 7 days prior to the first dose of study 
intervention. Exceptions are hepatitis, AFP, and thyroid testing, which may be done up to 
28 days prior to the first dose of study intervention.
•
Evaluation of ECOG is to be performed within 7 days prior to the first dose of study 
intervention.
•
For WOCBP, a urine or serum pregnancy test will be performed within 24 hours prior to 
the first dose of study intervention. If urine pregnancy results cannot be confirmed as 
negative, a serum pregnancy test will be required (performed by the local study site 
laboratory).
•
Tissue is not required for enrollment, however submission of archival tissue is strongly 
encouraged, if available. Formalin-fixed, paraffin-embedded block specimens are 
preferred to slides.
Participants may be rescreened after initially failing to meet the inclusion/exclusion criteria. 
Results from assessments during the initial screening period are acceptable in lieu of a repeat 
screening test if performed within the specified time frame and the corresponding 
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inclusion/exclusion criteria is met. Participants who are rescreened will retain their original 
screening number.
8.10.2
Treatment Period
Visit requirements are outlined in the SoA (Section 1.3). Specific procedure-related details 
are provided in Section 8.1.
8.10.3
Post-treatment Visit
8.10.3.1
Safety Follow-up Visit
Safety Follow-up will occur during 2 separate visits: 30 days AND 90 days after last dose. 
One mandatory Safety Follow-up Visit should be conducted approximately 30 days after the 
last dose of study intervention or before the initiation of a new anticancer treatment, 
whichever comes first. If End-of-treatment visit occurs ≥30 days from last dose of study 
treatment, the 30-day Safety Follow-up visit is not required. In this situation, all procedures 
required at both the End-of-treatment visit and the 30-day Safety Follow-up visit should be 
performed at the end-of-treatment visit. End of treatment is defined as the date when the 
participant discontinues all study interventions. 
For participants continuing with imaging follow-up at ≥12W, if their 90-day Safety Follow-
up Visit falls within the same window as their imaging follow-up visit, these visits may be 
combined. All procedures required at the Safety Follow-up Visit at 90 days will be 
performed at the imaging follow-up at ≥12W.
8.10.3.2
Follow-up Visits
Participants who discontinue study intervention for a reason other than disease progression 
will move into the Follow-up Phase and should be assessed Q12W to monitor disease status; 
if a clinic visit is not feasible, the participant may be contacted by telephone or email. Every 
effort should be made to collect information regarding disease status until the start of new 
anticancer therapy, disease progression, death, end of study. Information regarding poststudy 
anticancer treatment will be collected if new treatment is initiated. Participants will also be 
asked to complete HRQoL questionnaires as outlined in Section 8.2.2.
All participants who discontinue study intervention prior to disease progression will continue 
to undergo tumor assessments Q12W in the Follow-up Period until disease progression is 
documented and confirmed by BICR or a new anticancer therapy is initiated, unless the 
participant withdraws consent. Following the primary analysis for the study, tumor 
assessments should be performed Q12W or more frequently per local standard of care.
8.10.3.3
Survival Follow-up
Participants who experience confirmed disease progression or start a new anticancer therapy 
will move into the Survival Follow-up Phase and should be contacted by telephone or visit 
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approximately every 12 weeks or more frequently to assess for survival status until death, 
withdrawal of consent, or the end of the study, whichever occurs first.
8.10.4
Vital Status
To ensure current and complete survival information (vital status) is available at the time of 
database locks, updated vital status may be requested during the study by the Sponsor. For 
example, updated vital status may be requested before but not limited to, an eDMC review, 
interim and/or final analysis. Upon Sponsor notification, all participants who do not/will not 
have a scheduled study visit or study contact during the Sponsor-defined time period will be 
contacted for their vital status.
9
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study. If, after the 
study has begun, but prior to any unblinding/final database lock, changes are made to 
primary and/or key secondary hypotheses, or the statistical methods related to those 
hypotheses, then the protocol will be amended (consistent with International Conference on
Harmonisation [ICH] Guideline E-9). Changes to exploratory or other nonconfirmatory 
analyses made after the protocol has been finalized, but prior to unblinding/final database 
lock, will be documented in a supplemental SAP (sSAP) and referenced in the clinical study 
report (CSR) for the study. Post hoc exploratory analyses will be clearly identified in the 
CSR. Other planned analyses (ie, those specific to the analysis of PK data or PROs) will be 
documented in a sSAP or separate analysis plans.
9.1
Statistical Analysis Plan Summary
Key elements of the SAP are summarized below; the comprehensive plan is provided in 
Sections 9.2 through 9.12.
Study Design Overview
A Phase 3 Multicenter, Randomized, Double-blinded, Active-controlled, 
Clinical Study to Evaluate the Safety and Efficacy of Lenvatinib 
(E7080/MK-7902) in Combination with Pembrolizumab (MK-3475) Versus 
Lenvatinib in First-line Therapy of Participants with Advanced
Hepatocellular Carcinoma (LEAP-002)
Treatment Assignment
Participants will be randomized in a 1:1 ratio to receive lenvatinib in 
combination with pembrolizumab or lenvatinib plus placebo (control arm).
This is a double-blind study. 
Treatment allocation/randomization will be stratified according to the 
following factors:

Geographic region (Region 1: Asia vs. Region 2: Japan and Western 
regions, such as European Union (EU), North America, etc.)

Macroscopic portal vein invasion or Extrahepatic spread or both (Yes vs. 
No)

AFP: ≤400 ng/mL vs. >400 ng/mL

ECOG PS: 0 vs. 1
Analysis Populations
Efficacy: Intention-to-Treat (ITT)
Safety: All Participants as Treated (APaT)
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Primary
Endpoints/Hypotheses
1)  Progression-free Survival (PFS) per RECIST 1.1 assessed by BICR
modified to follow a maximum of 10 target lesions and a maximum of 5 
target lesions per organ
2)  Overall survival (OS)
Statistical Methods for
Key Efficacy Analyses
The dual primary hypotheses will be evaluated by comparing lenvatinib in 
combination with pembrolizumab to lenvatinib on PFS and OS using
stratified log-rank tests. Estimation of the HR will be done using a
stratified Cox regression model. Event rates over time will be estimated
within each treatment group using the Kaplan-Meier method. Stratified 
Miettinen and Nurminen method [Miettinen, O. and Nurminen, M. 1985]
with weights proportional to the stratum size will be used for comparison of 
the objective response (OR) between the treatment arms.  
Statistical Methods for
Key Safety Analyses
The analysis of safety results will follow a tiered approach. The tiers differ 
with respect to the analyses that will be performed. There are no Tier 1 
events in this study. Tier 2 parameters will be assessed via point estimates 
with 95% confidence intervals provided for between-group comparisons; 
only point estimates by treatment group are provided for Tier 3 safety 
parameters. The 95% confidence intervals for the between-treatment 
differences in percentages will be provided using the Miettinen and 
Nurminen method, an unconditional, asymptotic method [Miettinen, O. and 
Nurminen, M. 1985].
Interim Analyses
Two efficacy interim analyses will be performed in this study. Results will 
be reviewed by an external Data Monitoring Committee. Details are 
provided in Section 9.7.
First Interim Analysis (IA1)
◦
Timing: To be performed when approximately 335 OS events (63% of 
expected total OS events) are observed. With 21 months enrollment, the 
IA1 is expected approximately at Month 27, at which time approximately 
474 PFS events are expected to have been accumulated. 
◦
Purpose:  The first interim efficacy analysis for both OS and PFS. Only if 
OS or PFS are significant, the analysis of the secondary endpoint of ORR 
(a single analysis) will also be performed.
Second Interim Analysis (IA2)
◦
Timing: To be performed when approximately 452 OS events (85% of 
expected total OS events) have been observed, projected to occur at 
approximately Month 36, at which time approximately 571 PFS events 
are expected to have been accumulated. 
◦
Purpose: the second efficacy IA for OS and final efficacy analysis for 
PFS.
Final analysis
◦
Timing: When approximately 532 OS events have been observed, 
estimated to be 44 months after start of randomization.
◦
Purpose: Final efficacy analysis for OS.
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Multiplicity
The multiplicity strategy in this study will be applied to the 2 primary 
hypotheses (superiority of lenvatinib in combination with pembrolizumab in 
OS and superiority of lenvatinib in combination with pembrolizumab in 
PFS) and the secondary hypothesis of superiority of lenvatinib in 
combination with pembrolizumab in OR. The overall Type I error across the 
3 hypotheses above is strongly controlled at 2.5% (one-sided). The 
multiplicity strategy will follow the graphical approach of Maurer and Bretz 
[Maurer, W. and Bretz, F. 2013] as described in Section 9.8, with initially 
0.2% allocated to PFS hypotheses and 2.3% allocated to OS hypotheses. 
Within the PFS and OS hypotheses that are analyzed following a group 
sequential approach, the Type I error rates for the interim and final analyses
will be controlled through the Lan-DeMets O’Brien-Fleming approximation 
alpha-spending functions specified for these endpoints as described in 
Section 9.8. The OR analysis does not use the group sequential approach.
The secondary OR hypothesis is tested using only the OR data collected at 
the time of the first interim OS analysis, whenever the Type I error becomes 
available for the OR analysis.
Sample Size and Power
The sample size is approximately 750.
The analysis of the OS endpoint is event driven. The testing of the OS 
hypothesis is conducted upon accumulating a preset number of events. The 
study is designed and will be conducted to accumulate approximately 532 OS 
events (unless superiority in OS is demonstrated at an interim analysis).
For the primary endpoint OS, the study has approximately 90% power to 
demonstrate that pembrolizumab + lenvatinib is superior to lenvatinib at a 
one-sided 2.3% alpha level, if the underlying HR of OS is 0.75. For the 
primary endpoint PFS, the timing of the interim and final analysis will be 
driven by the accumulation of the OS events required for IA1 (interim PFS 
analysis) and IA2 (final PFS analysis). The study is anticipated to have 
approximately 92% power for the PFS hypothesis to demonstrate that 
lenvatinib in combination with pembrolizumab is superior to lenvatinib at a 
one-sided 0.2% alpha level, if the underlying HR of PFS is 0.70.
9.2
Responsibility for Analyses/In-house Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
This study will be conducted as a double-blind study under in-house blinding procedures. 
The official, final database will not be unblinded until medical/scientific review has been 
performed, protocol deviations have been identified, and data have been declared final and 
complete.
The Clinical Biostatistics department will generate the randomized allocation schedule(s) for 
study treatment assignment for this protocol, and the randomization will be implemented in 
an interactive voice response system.
The eDMC will serve as the primary reviewer of the unblinded results of the efficacy and 
safety analyses and will make recommendations for discontinuation of the study or 
modification to an EOC (see Section 10.1.4.2) of the Sponsor. Depending on the 
recommendation of the eDMC, the Sponsor may prepare a regulatory submission. If the 
eDMC recommends modifications to the design of the protocol or discontinuation of the 
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study, the EOC and limited additional Sponsor personnel may be unblinded to results at the 
treatment level in order to act on these recommendations. Additional logistical details will be 
provided in the eDMC Charter.
9.3
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.0.
9.4
Analysis Endpoints
9.4.1
Efficacy Endpoints
Primary
•
Progression-free survival (PFS) – RECIST 1.1 assessed by BICR, modified to follow a 
maximum of 10 target lesions and a maximum of 5 target lesions per organ: the time 
from randomization to the first documented disease progression or death due to any 
cause, whichever occurs first. See Section 9.6.1.1 for the definition of censoring.
•
Overall Survival: the time from randomization to death due to any cause.
Secondary
•
Objective Response (OR) – RECIST 1.1 assessed by BICR: a confirmed CR or PR.
•
Duration of Response (DOR) – RECIST 1.1 assessed by BICR: the time from first 
documented evidence of CR or PR until PD or death due to any cause, whichever occurs 
first, in participants who demonstrate CR or PR. See Section 9.6.1.6 for the definition of 
censoring.
•
Disease Control (DC)-RECIST 1.1 assessed by BICR: CR, PR, or SD after ≥6 weeks.
•
Time to Progression (TTP)-RECIST 1.1 assessed by BICR: the time from 
randomization to the first documented disease progression. See Section 9.6.1.5 for 
definition of censoring.
•
PFS, OR, DOR, DC, and TTP – mRECIST assessed by BICR.
9.4.2
Safety Endpoints
Safety and tolerability will be assessed by clinical review of all relevant parameters,
including AEs, laboratory values, and vital signs.
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9.5
Analysis Populations
9.5.1
Efficacy Analysis Populations
The analyses of efficacy endpoints other than DOR are based on the intention-to-treat (ITT) 
population. All randomized participants will be included in this population. Participants will 
be analyzed in the treatment group to which they are randomized. The DOR analysis will be 
based on the population of responders (participants that achieved complete or partial 
response).
9.5.2
Safety Analysis Populations
Safety Analyses will be conducted in the All Participants as Treated (APaT) population, 
which consists of all randomized participants who received at least 1 dose of study treatment. 
Participants will be included in the treatment group corresponding to the study treatment they 
actually received for the analysis of safety data using the APaT population. This will be the 
treatment group to which they are randomized except for participants who take incorrect 
study treatment for the entire treatment period; such participants will be included in the 
treatment group corresponding to the study treatment actually received. Any participant who 
receives the incorrect study medication for 1 cycle, but receives the correct treatment for all 
other cycles, will be analyzed according to the correct treatment group and a narrative will be 
provided for any events that occur during the cycle for which the participant is incorrectly 
dosed.
At least 1 laboratory or vital sign measurement obtained after at least 1 dose of study 
treatment is required for inclusion in the analysis of each specific parameter. To assess 
change from baseline, a baseline measurement is also required.
9.5.3
PRO Analysis Populations
The PRO analyses are based on the PRO FAS population, defined as participants who have at 
least one PRO assessment available and have received at least one dose of study intervention.
9.6
Statistical Methods
9.6.1
Statistical Methods for Efficacy Analyses
This section describes the statistical methods that address the primary and secondary efficacy 
objectives. Methods related to exploratory objectives will be described in the sSAP. Efficacy 
results that will be deemed to be statistically significant after consideration of the Type I 
error control strategy are described in Section 9.8. Nominal p-values will be computed for 
other efficacy analyses, but should be interpreted with caution due to potential issues of 
multiplicity. The 4 stratification factors used for randomization, including geographic region 
(Region 1: Asia vs Region 2: Japan and Western regions), macroscopic portal vein invasion 
or extrahepatic spread or both (Yes vs. No), AFP (≤400 ng/mL vs >400 ng/mL), and ECOG 
PS (0 vs 1), will be applied to all stratified efficacy analyses, in particular, stratified log-rank 
test, stratified Cox model, and stratified Miettinen and Nurminen method                  
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[Miettinen, O. and Nurminen, M. 1985]. If required, some of the small strata among the 16 
strata formed by the 4 factors might be pooled for analyses in a meaningful way; the pooling 
strategy will be documented in the sSAP prior to the data base lock for the first interim 
analysis and used for all stratified analyses.
9.6.1.1
Progression-free Survival
The nonparametric Kaplan-Meier method will be used to estimate the PFS curve in each 
treatment group. The hypotheses of treatment difference in PFS will be tested by the 
stratified log-rank test. A stratified Cox proportional hazard model with Efron’s method of tie 
handling will be used to estimate the magnitude of the treatment difference (ie, HR) between 
the treatment arms. The HR and its 95% CI from the stratified Cox model with Efron’s 
method of tie handling and with a single treatment covariate will be reported. 
Since disease progression is assessed periodically, PD can occur any time in the time interval 
between the last assessment where PD was not documented and the assessment when PD is 
documented. For the primary analysis, for the participants who have PD, the true date of 
disease progression will be approximated by the date of the first assessment at which PD is 
objectively documented per RECIST 1.1 by the BICR vendor, regardless of discontinuation 
of study drug. Additional analyses will be performed for comparison of PFS per RECIST 1.1 
and iRECIST by investigator assessment and PFS analysis for PD per mRECIST by the 
BICR vendor.
In order to evaluate the robustness of the PFS endpoint per RECIST 1.1 via BICR modified 
to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ by the 
imaging vendor, 1 primary analysis and 2 sensitivity analyses with a different set of 
censoring rules will be performed. For the primary analysis, if the events (PD or death) are 
after more than 1 missed disease assessment, the data are censored at the last disease 
assessment prior to missing visits. Also, data after new anticancer therapy are censored at the 
last disease assessment prior to the initiation of new anticancer therapy. The first sensitivity 
analysis follows ITT principles. That is, PDs/deaths are counted as events regardless of 
missed study visits or initiation of new anticancer therapy. The second sensitivity analysis
considers discontinuation of treatment or initiation of an anticancer treatment after
discontinuation of study-specified treatments, whichever occurs later, to be a PD event for 
participants without documented PD or death. If a participant meets multiple criteria for 
censoring, the censoring criterion that occurs earliest will be applied. The censoring rules for 
primary and sensitivity analyses are summarized in Table 10.
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Table 10
Censoring Rules for Primary and Sensitivity Analyses of PFS
Situation
Primary Analysis
Sensitivity Analysis 1
Sensitivity Analysis 2
PD or death documented 
after ≤1 missed disease 
assessment, and before 
new anticancer therapy, 
if any
Progressed at date of 
documented PD or death
Progressed at date of 
documented PD or 
death
Progressed at date of 
documented PD or death
PD or death documented 
after ≥2 consecutive 
missed disease 
assessments or after new 
anticancer therapy
Censored at last disease 
assessment prior to 
the earlier date of ≥2 
consecutive missed 
disease assessment and 
new anticancer therapy, if 
any
Progressed at date of 
documented PD or 
death
Progressed at date of 
documented PD or death
No PD and no death; 
and new anticancer 
therapy is not initiated
Censored at last disease 
assessment 
Censored at last 
disease assessment 
Progressed at treatment 
discontinuation due to 
reasons other than 
complete response; 
otherwise censored at last 
disease assessment if still 
on study or completed 
study therapy 
No PD and no death; 
new anticancer therapy 
is initiated
Censored at last disease 
assessment before new 
anticancer therapy
Censored at last 
disease assessment 
Progressed at date of new 
anticancer therapy 
PD = progressive disease; PFS = progression-free survival.
9.6.1.2
Overall Survival
The nonparametric Kaplan-Meier method will be used to estimate the survival curves. The 
hypotheses of treatment difference in survival will be tested by the stratified log-rank test. A 
stratified Cox proportional hazard model with Efron’s method of tie handling will be used to 
estimate the magnitude of the treatment difference (ie, the HR). The HR and its 95% CI from 
the stratified Cox model with a single treatment covariate will be reported. 
9.6.1.3
Objective Response 
The stratified Miettinen and Nurminen method [Miettinen, O. and Nurminen, M. 1985] with 
weights proportional to the stratum size will be used for comparison of the objective response 
rates between the treatment arms. A 95% CI for the difference in response rates between the 
treatment arms will be provided.
The ORR analysis will be conducted according to the hypotheses testing plan as described in 
Section 9.7 – Interim Analyses and Section 9.8 – Multiplicity. 
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9.6.1.4
Disease Control 
The Stratified Miettinen and Nurminen method [Miettinen, O. and Nurminen, M. 1985] with 
weights proportional to the stratum size will be used for comparison of the DC rates between 
the treatment arms. A 95% CI for the difference in response rates between the treatment arms
will be provided. 
9.6.1.5
Time to Progression
The nonparametric Kaplan-Meier method will be used to estimate the TTP curve in each 
treatment group. A stratified Cox proportional hazard model with Efron’s method of tie 
handling will be used to estimate the magnitude of the treatment difference (ie, HR) between 
the treatment arms. The hazard ratio and its 95% CI from the stratified Cox model with 
Efron’s method of tie handling and with a single treatment covariate will be reported.  
Since disease progression is assessed periodically, PD can occur any time in the time interval 
between the last assessment where PD was not documented and the assessment when PD is 
documented. For the analysis, for the participants who have PD, the true date of disease 
progression will be approximated by the date of the first assessment at which PD is 
objectively documented per RECIST 1.1 by the BICR vendor, regardless of discontinuation 
of study drug. Unlike the PFS analysis, death is not considered an event. Censoring rules for 
TTP are summarized in Table 11.
Table 11
Censoring Rules for TTP
Situation
Primary Analysis
Death only
Censored at date of randomization or date of last non-
PD disease assessment, whichever is later
No PD and no death; new anticancer 
treatment is not initiated
Censored at last non-PD disease assessment
No PD and no death; new anticancer 
treatment is initiated
Censored at last non-PD disease assessment before new 
anticancer treatment
PD documented after ≤1 missed
disease assessment
Progressed at date of documented PD
PD documented after ≥2 missed
disease assessments
Censored at last disease assessment prior to the ≥2 
consecutive missed disease assessments
PD = progressive disease; TTP = time to progression.
9.6.1.6
Duration of Response
Participants who achieved CR or PR and are alive, have not progressed, have not initiated 
new anticancer treatment, and have not been determined to be lost to follow-up are 
considered ongoing responders at the time of analysis.
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The nonparametric Kaplan-Meier method will be used to estimate the DOR curve in each 
treatment group; estimates and 95% CIs at specific duration time points will be provided. 
Censoring rules for DOR are summarized in Table 12.
Table 12
Censoring Rules for DOR
Situation
Date of Progression or Censoring
Outcome
No progression nor death, no new 
anticancer therapy initiated
Last adequate disease assessment
Censor
(nonevent)
No progression nor death, new anticancer 
therapy initiated
Last adequate disease assessment before new 
anticancer therapy initiated
Censor
(nonevent)
Death or progression after ≥2 consecutive 
missed disease assessments or after new 
anticancer therapy
Earlier date of last adequate disease 
assessment prior to ≥2 missed adequate 
disease assessments and new anticancer 
therapy, if any
Censor
(nonevent)
Death or progression after ≤1 missed 
adequate disease assessments and before 
new anticancer therapy, if any
PD or death
End of 
response
(Event)
DOR = duration of response; PD = progressive disease.
Participants are considered to have an ongoing response if alive, have not progressed, have not started a new 
anticancer therapy, and have not been determined to be lost to follow-up.
Table 13 summarizes the primary analysis approach for primary (PFS and OS) and key 
secondary (OR) efficacy endpoints. Sensitivity analysis methods are described above for 
each endpoint.
Analyses of the DC, TTP, and DOR data will be performed at the time of the interim and 
final analysis of OS.
The strategy to address multiplicity issues with regard to multiple efficacy endpoints, 
multiple populations, and interim analyses is described in Section 9.7 – Interim Analyses and 
in Section 9.8 – Multiplicity.
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Table 13
Analysis Strategy for Key Efficacy Endpoints
Endpoint/Variable
(Description, Time Point)
Statistical Methoda
Analysis 
Population
Missing Data
Approach
Primary Hypothesis (H1)
PFS per RECIST 1.1 by the 
BICR vendor modified to 
follow a maximum of 10 
target lesions and a maximum 
of 5 target lesions per organ
Test: Stratified Log-
rank test 
Estimation: Stratified 
Cox model with 
Efron’s tie handling 
method
ITT
•
Primary censoring rule
•
Sensitivity analysis 1
•
Sensitivity analysis 2 
(More details are in 
Table 10)
Primary Hypothesis (H2)
OS
Test: Stratified Log-
rank test 
Estimation: Stratified 
Cox model with 
Efron’s tie handling 
method
ITT
Censored at last known alive 
date
Secondary Hypothesis (H3)
OR per RECIST 1.1 by the BICR
vendor
Stratified M & N 
methodb
ITT
Participants with missing 
response data are considered 
nonresponders
BICR = blinded independent central review; ITT = intention-to-treat; OR = objective response; 
OS = overall survival; PFS = progression-free survival.
a Statistical models are described in further detail in the text. For stratified analyses, the stratification factors used for
randomization (see Section 6.3.2)will be applied to the analysis model.
b Miettinen and Nurminen method [Miettinen, O. and Nurminen, M. 1985]
9.6.2
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters,
including AEs, laboratory tests, vital signs, and ECG measurements.
The analysis of safety results will follow a tiered approach (Table 14). The tiers differ with 
respect to the analyses that will be performed. Adverse events (specific terms as well as 
system organ class terms) and events that meet predefined limits of change (PDLCs) in 
laboratory, vital signs, and ECG parameters are either prespecified as “Tier 1” endpoints, or 
will be classified as belonging to “Tier 2” or “Tier 3” based on the number of events 
observed.
Tier 1 Events
Safety parameters or adverse events of special interest (AEOSI) that are identified a priori
constitute “Tier 1” safety endpoints that will be subject to inferential testing for statistical 
significance. AEOSI that are immune-mediated or potentially immune-mediated are well 
documented and will be evaluated separately; however, these events have been characterized 
consistently throughout the pembrolizumab clinical development program and determination 
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of statistical significance is not expected to add value to the safety evaluation. Similarly, the 
combination of pembrolizumab and lenvatinib has not been associated with any new safety 
signals. Finally, there are no known AEs associated with participants with HCC for which 
determination of a p value is expected to impact the safety assessment. Therefore, there are 
no Tier 1 events expected in this study.
Tier 2 Events
Tier 2 parameters will be assessed via point estimates with 95% CIs provided for differences 
in the proportion of participants with events using the Miettinen and Nurminen (M&N) 
method [Miettinen, O. and Nurminen, M. 1985], an unconditional, asymptotic method.
Membership in Tier 2 requires that at least 10% of participants in any treatment group exhibit 
the event; all other adverse experiences and PDLCs will belong to Tier 3. The threshold of at 
least 10% of participants was chosen for Tier 2 event because the population enrolled in this 
study are in critical conditions and usually experience various AEs of similar types regardless 
of treatment; events reported less frequently than 10% of participants would obscure the 
assessment of overall safety profile and add little to the interpretation of potentially 
meaningful treatment differences. In addition, Grade 3 to 5 AE (≥5% of participants in one of 
the treatment groups) and SAE (≥5% of participants in one of the treatment groups) will be 
considered Tier 2 endpoints. Because many 95% CIs may be provided without adjustment for 
multiplicity, the CIs should be regarded as a helpful descriptive measure to be used in safety 
review, not a formal method for assessing the statistical significance of the between-group 
differences.
Tier 3 Events
Safety endpoints that are not Tier 1 or 2 events are considered Tier 3 events. Only point 
estimates by treatment group are provided for Tier 3 safety parameters.
Continuous Safety Measures 
Continuous measures such as changes from baseline in laboratory, vital signs, and ECG 
parameters that are not prespecified as Tier 1 endpoints will be considered Tier 3 safety 
parameters. Summary statistics for baseline, on-treatment, and change from baseline values 
will be provided by treatment group in table format.
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Table 14
Analysis Strategy for Safety Parameters
Safety 
Tier
Safety Endpoint
95% CI for Treatment 
Comparison
Descriptive 
Statistics
Tier 2
Any AEs (≥10% of participants in one of the 
treatment groups)
X
X
Any Grade 3 to 5 AE (≥5% of participants in one of 
the treatment groups)
X
X
Any serious AE (≥5% of participants in one of the 
treatment groups)
X
X
Tier 3
Any AEs
X
Discontinuation due to AE
X
Change from baseline results (laboratory test toxicity 
grade)
X
AE = adverse event; CI = confidence interval; X = results will be provided.
The rainforest plots including the treatment difference and its 95% CI will be applied for Tier2 AEs.
9.6.3
Statistical Methods for PRO Analyses
To evaluate the treatment effect on the health-related QoL outcomes at prespecified time 
points, a constrained longitudinal data analysis (cLDA) model will be applied, with the PRO 
score as the response variable, and the treatment by time interaction and stratification factors 
as covariates. Least square mean (LS mean) change from baseline will be summarized. 
Groupwise comparisons will be performed and model-based LS mean score will be provided 
by treatment group and study visit.
Participants post-baseline EORTC QLQ-C30 scores will be classified as “improvement”, 
“stable”, or “deterioration” according to a predefined threshold (e.g. 10-point or greater 
change from baseline). The number and proportion of participants with “improved”, “stable”, 
or “deteriorated” symptoms/scales will be summarized by treatment group.
Time to deterioration is defined as the time from the baseline PRO assessment to 
deterioration or death, whichever occurs first [Yang, J. C., et al 2013]. The Kaplan-Meier 
method will be used to estimate times to deterioration survival curve for each treatment arm, 
and the Cox proportional hazards regression model will be used to estimate the magnitude of 
treatment difference. 
Details of PRO analyses will be described in the sSAP.
9.6.4
Statistical Methods for Pharmacokinetics (PK) Analyses
No pharmacokinetic endpoints will be evaluated in this study.
9.6.5
Summaries of Baseline Characteristics and Demographics
The comparability of the treatment groups for each relevant characteristic will be assessed by 
the use of tables and/or graphs. No statistical hypothesis tests will be performed on these 
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characteristics. The number and percentage of participants randomized and the primary 
reason for discontinuation will be displayed. Demographic variables (such as age), baseline 
characteristics, primary and secondary diagnoses, and prior and concomitant therapies will be 
summarized by treatment either by descriptive statistics or categorical tables. The reasons for 
exclusion from the ITT population (if any) will be summarized.
9.7
Interim Analyses
9.7.1
Safety Interim Analyses
The eDMC) will conduct regular safety monitoring. The timing of the safety monitoring will 
be specified in the eDMC charter. 
9.7.2
Efficacy Interim Analyses
Two interim efficacy analyses are planned in addition to the final analysis for this study. 
Results of the interim analyses will be reviewed by the eDMC. Details on the boundaries for 
establishing statistical significance with regard to efficacy are discussed further in Section 
9.8.
The analyses planned, endpoints evaluated, and drivers of timing are summarized in 
Table 15.
Table 15
Summary of Interim and Final Analyses Strategy
Analyses
Key 
Endpoints
Timing
Estimated Time 
after First 
Participant 
Randomized
Primary Purpose of 
Analysis
IA1
PFS
OS 
OR (if Type I 
error 
available)
when approximately 335 
OS events (63% of 
expected total OS events) 
are observed
~27 months 
Interim PFS and OS 
analyses 
ORR analysis if Type I 
error available
IA2
PFS
OS
when approximately 452 
OS events (85% of 
expected total OS events) 
have been observed
~36 months 
Final PFS and interim 
OS analyses
Final 
Analysis
PFS 
OS
when approximately 532 
OS events have been 
observed
~44 months 
Final OS analysis
IA1 = interim analysis 1; IA2 = interim analysis 2; ORR = objective response rate; OS = overall survival; 
PFS = progression-free survival.
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Results of the interim analyses will be reviewed by the eDMC. If the OS null hypothesis is 
rejected prior to the final analysis, the eDMC may recommend stopping the study early for 
efficacy. Details on how the above planned analyses are incorporated into establishing Type I 
error control and efficacy boundaries are discussed further in Section 9.8 – Multiplicity.
9.8
Multiplicity
The study uses the graphical method of Maurer and Bretz [Maurer, W. and Bretz, F. 2013] to 
control multiplicity for multiple hypotheses as well as interim analyses. According to this 
approach, study hypotheses may be tested more than once, and when a particular null 
hypothesis is rejected, the alpha allocated to that hypothesis can be reallocated to other 
hypothesis tests.
Figure 3 shows the initial one-sided α allocation for each hypothesis in the box representing 
the hypothesis. The weights for reallocation from each hypothesis to the others are 
represented in the boxes on the lines connecting hypotheses.
Figure 3
Multiplicity Graph for Type I Error Control
ORR = objective response rate; OS = overall survival; PFS = progression-free survival
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9.8.1
Progression-free Survival
The initial α-level for testing PFS is 0.002. If the null hypothesis for OS is rejected, Figure 3
shows that 0.5 of OS initial α=0.023 (ie, α=0.0115) is reallocated to PFS hypothesis testing. 
If the null hypothesis for OS and the null hypothesis for ORR are both rejected, then α=0.023 
is reallocated to PFS hypothesis testing. Thus, the PFS null hypothesis may be tested at 
α=0.002, α=0.0135 (if only the OS null hypothesis is rejected), or α=0.025 (if both the ORR 
and OS null hypotheses are rejected). Table 16 shows the boundary properties for 3 possible 
1-sided α-levels for the final analysis, which were derived using a Lan-DeMets O’Brien-
Fleming spending function. Note that the final row indicates the total power to reject the null 
hypothesis for PFS. If the actual number of events at the PFS analyses differ from those 
specified in the table, the bounds will be adjusted using the Lan-DeMets O’Brien-Fleming 
spending function accordingly. Also, note that if the OS null hypothesis is rejected at an 
interim or final analysis, PFS interim and final analysis tests will be compared to the updated 
PFS bounds considering the α reallocation from the OS hypothesis.
Table 16
Efficacy Boundaries and Properties for Progression-free Survival Analyses
Analysis
Value
α level=0.002
α level=0.0135
α level=0.025
IA1: 83%a
Z
3.1972
2.4731
2.2006
N: 750
p (1-sided)b
0.0007
0.0067
0.0139
Events: 474
HR at boundc
0.7454
0.7965
0.8169
Month: 27.5
P(Cross) if HR=1d
0.0007
0.0067
0.0139
P(Cross) if HR=0.7e
0.7559
0.9207
0.9538
IA2
Z
2.9135
2.2721
2.0334
N: 750
p (1-sided)
0.0018
0.0115
0.0210
Events: 571
HR at bound
0.7835
0.8266
0.8434
Month: 35.6
P(Cross) if HR=1
0.0020
0.0135
0.0250
P(Cross) if HR=0.7
0.9150
0.9782
0.9882
HR = hazard ratio; IA1 = Interim Analysis 1.
a Expected percentage of events with respect to the number of events expected at the final analysis.
b p (1-sided) is the nominal α for testing.
c HR at bound is the approximate HR required to reach an efficacy bound.
d P (Cross if HR=1) is the probability of crossing a bound under the null hypothesis.
e P (Cross if HR=0.7) is the probability of crossing a bound under the alternative hypothesis.
9.8.2
Overall Survival
The OS hypothesis may be tested at α=0.023 (initially allocated α) or α=0.025 (if both the 
ORR and PFS null hypotheses are rejected). Table 17 demonstrates the bounds and properties 
for OS hypothesis testing derived using a Lan-DeMets O’Brien-Fleming spending function 
with the initial α-level of 0.023 or α=0.025 (if both the ORR and PFS null hypotheses are 
rejected) for the final analysis. If the actual number of OS events at the interim and final 
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analyses differs from those specified in the table, the bounds will be adjusted using the Lan-
DeMets O’Brien-Fleming spending function accordingly.
Table 17
Efficacy Boundaries and Properties for Overall Survival Analyses
Analysis
Value
α level=0.023
α level=0.025
IA1: 63%a
Z
2.6372
2.5939
N: 750
p (1-sided) b
0.0042
0.0047
Events: 335
HR at boundc
0.7495
0.7531
Month: 27.4
P(Cross) if HR=1d
0.0042
0.0047
P(Cross) if HR=0.75e
0.4987
0.5161
IA2: 85%
Z
2.2448
2.2085
N: 750
p (1-sided)
0.0124
0.0136
Events: 452
HR at bound
0.8095
0.8124
Month: 35.6
P(Cross) if HR=1
0.0137
0.0151
P(Cross) if HR=0.75
0.7975
0.8080
Final
Z
2.0808
2.0478
N: 750
p (1-sided)
0.0187
0.0203
Events: 532
HR at bound
0.8348
0.8372
Month: 43.6
P(Cross) if HR=1
0.0230
0.0250
P(Cross) if HR=0.75
0.9000
0.9060
HR = hazard ratio; IA1 = Interim Analysis 1; IA2 = Interim Analysis 2.
a Expected percentage of events with respect to the number of events expected at the final analysis.
b.p (1-sided) is the nominal α for testing.
c HR at bound is the approximate HR required to reach an efficacy bound.
d.P (Cross if HR=1) is the probability of crossing a bound under the null hypothesis.
e.P (Cross if HR=0.7) is the probability of crossing a bound under the alternative hypothesis.
9.8.3
Objective Response 
The OR hypothesis is not allocated any α initially and can only be tested when either the PFS 
or OS endpoint is successful. The OR data obtained at the time of IA1 will be locked and 
tested at the time when α to test the OR hypothesis becomes available; it will be retested if 
available α increases. Specifically, if the OR test does not achieve statistical significance at 
IA1, the p-value from IA1 can be compared to an updated α-level at a later time. The power 
and smallest statistically significant detectable difference at the 3 possible α-levels, assuming 
underlying 19% and 30% response rates in the lenvatinib and pembrolizumab plus lenvatinib 
groups, respectively, are shown in Table 18 with 750 randomized participants.
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Table 18
Possible Alpha-levels and Power for ORR Analysis
Value
α level= 0.002
α level=0.0115
α level=0.025
Smallest Statistically Significant 
Detectable Difference in ORR
0.0903
0.0712
0.0614
Power if Difference in ORR=0.11
0.74
0.89
0.94
ORR = objective response rate.
9.8.4
Safety Analyses
The eDMC has responsibility for assessment of overall risk:benefit. When prompted by 
safety concerns, the eDMC can request corresponding efficacy data. External DMC review of 
efficacy data to assess the overall risk:benefit to study participants will not require a 
multiplicity adjustment typically associated with a planned efficacy interim analysis. 
However, to account for any multiplicity concerns raised by the eDMC review of unplanned 
efficacy data prompted by safety concerns, a sensitivity analysis for efficacy endpoints 
adopting a conservative multiplicity adjustment will be prespecified in the sSAP. This 
analysis will be performed if requested by the eDMC.
9.9
Sample Size and Power Calculations
9.9.1
Sample Size and Power for Efficacy Analyses
The study will randomize 750 participants in a 1:1 ratio into the pembrolizumab plus 
lenvatinib or placebo plus lenvatinib arms. For the OS endpoint, based on a target number of 
532 events and 2 interim analyses at approximately 63% and 85% of the target number of 
events, the study has approximately 90% power to detect an HR of 0.75 at an overall alpha 
level of 2.3% (1-sided). For the PFS endpoint, based on the expected number of 571 events at 
the final analysis and 1 interim analysis at approximately 83% of the target number of events, 
the study has approximately 92% power to detect an HR of 0.70 at an overall alpha level of 
0.2% (1-sided).
The sample size and power calculations for PFS and OS assume the following:
•
PFS follows an exponential distribution with a median of 7.3 months for the control 
group.
•
OS follows an exponential distribution in both arms with a median of 14.5 months for the 
control group. The HR of 0.75 would result in 19.3 months for median OS for the 
combination group. Constant HR for PFS and OS endpoints.
•
Enrollment period of 21 months with a ramp-up period of 9 months.
•
A monthly drop-out rate of 0.01 and 0.001 for PFS and OS, respectively.
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With these assumptions, the final OS analysis will take place 44 months after the start of 
randomization.
Based on the 750 participants, the power of the ORR testing at the reallocated from PFS 
α=0.002 is approximately 74% to detect a difference between an underlying 19% ORR in the 
control arm and a 30% ORR in the experimental arm.
9.9.2
Sample Size and Power for Safety Analyses
For safety comparisons, risk differences between any 2 treatment groups are summarized in 
Table 19 for a variety of hypothetical observed incidence rates. The table demonstrates the 
width of the corresponding 95% CIs for different incidence rates in the treatment groups. 
These calculations assume there are 375 participants for each treatment group.
Table 19
Two-sided 95% CIs of Differences in Incidence of AE Rates Between the Two 
Treatment Groups for 375 Participants in Each Treatment Arm
Incidence of Adverse Event
Risk Difference
Treatment Group 1 (%)
Treatment Group 2 (%)
Percentage Points
95% Confidence Intervala
5.1
12.3
-7.2
(-11.2, -3.2)
11
20.2
-9.2
(-14.4, -4.0)
24.9
36.6
-11.7
(-18.3, -5.1)
43.9
56.5
-12.6
(-19.7, -5.5)
55.7
68
-12.3
(-19.2, -5.4)
Incidences presented here are hypothetical and do not represent actual adverse experiences in either group.
a Based on an asymptotic method [Farrington, C. P. 1990].
9.10
Subgroup Analyses
To determine whether the treatment effect is consistent across various subgroups, the 
between-group treatment effect for OS, PFS, and ORR (with a nominal 95% CI) will be 
estimated and plotted by treatment group within each category of the following classification 
variables:
•
Stratification factors
-
Geographic region (Region 1: Asia vs. Region 2: Japan and Western regions, such as 
EU, North America, etc.)
-
Macroscopic portal vein invasion or extrahepatic spread or both (Yes vs. No) 
-
AFP: ≤400 ng/mL versus >400 ng/mL
-
ECOG PS: 0 vs. 1
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•
Age category (<65, ≥65 years)
•
Sex (female, male)
•
Etiology (HCV, HBV, and uninfected)
•
Macrovascular invasion (Yes, No) 
•
Extrahepatic spread (Yes, No)
•
Current disease overall BCLC stage (B, C)
•
CP score (5 vs 6)
9.11
Compliance (Medication Adherence)
Drug accountability data for study treatment will be collected during the study. Any 
deviation from protocol-directed administration will be reported.
9.12
Extent of Exposure
Extent of exposure for a participant is defined as number of cycles in which the participant 
receives the study intervention. Summary statistics will be provided on extent of exposure for 
the APaT population.
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Code of Conduct for Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing and reporting these trials 
in compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design of clinical trials. In all cases, MSD clinical trials will be conducted in compliance 
with local and/or national regulations (eg, International Council for Harmonisation Good Clinical Practice [ICH-
GCP]) and 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 (eg, 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 (ie, participant population, duration, statistical power) must be adequate to address the specific
purpose of the trial. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
MSD selects investigative sites based on medical expertise, access to appropriate participants, adequacy of 
facilities and staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial 
initiation, sites are evaluated by MSD personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and general principles of 
Good Clinical Practice (GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data 
are verified versus source documentation according to standard operating procedures. Per MSD policies and 
procedures, if fraud, scientific/research misconduct, or serious GCP-noncompliance is suspected, the issues 
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are investigated. When necessary, the clinical site will be closed, the responsible regulatory authorities and 
ethics review committees notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the prespecified 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. Ethics Committee Review (Institutiona Review Board [IRB]/Independent Ethics Committee [IEC])
All clinical trials will be reviewed and approved by an IRB/IEC before being initiated at each site. Significant 
changes or revisions to the protocol will be approved by the ethics committee prior to implementation, except 
changes required urgently to protect participant safety that may be enacted in anticipation of ethics committee 
approval. For each site, the ethics committee and MSD will approve the participant informed consent form.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance. 
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At 
a minimum, trial designs will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Participants may withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible. Unless required by 
law, only the investigator, Sponsor (or representative), ethics committee, and/or regulatory authorities will have 
access to confidential medical records that might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
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 to identify potentially eligible participants.
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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 (eg, to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
10.1.2
Financial Disclosure
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required. It is the investigator's/subinvestigator's 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
10.1.3
Data Protection
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information that would make the participant identifiable will not be transferred.
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
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10.1.3.1
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the IRB, IEC, or similar or expert committee; affiliated institution and 
employees, only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution and employees. Data generated by this study will be 
considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol.
10.1.3.2
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF report form data. By signing the consent form, the participant agrees 
to this process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules 
and regulations.
10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
10.1.4
Committees Structure
10.1.4.1
Scientific Advisory Committee
This study was developed in collaboration with a SAC. The SAC is comprised of both 
Sponsor and non-Sponsor scientific experts who provide scientific and strategic guidance on 
various aspects of the clinical trial and/or development, which may include study design, 
interpretation of study results, and subsequent peer-reviewed scientific publications.
10.1.4.2
Executive Oversight Committee
The Executive Oversight Committee (EOC) is comprised of members of Sponsor Senior 
Management. The EOC will receive and decide upon any recommendations made by the
eDMC regarding the study.
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10.1.4.3
External Data Monitoring Committee
To supplement the routine study monitoring outlined in this protocol, an external DMC will 
monitor the interim data from this study. The voting members of the committee are external 
to the Sponsor. The members of the DMC must not be involved with the study in any other 
way (eg, they cannot be study investigators) and must have no competing interests that could 
affect their roles with respect to the study.
The DMC will make recommendations to the EOC regarding steps to ensure both participant 
safety and the continued ethical integrity of the study. Also, the DMC will review interim 
study results, consider the overall risk and benefit to study participants (Section 9.7 -Interim
Analyses) and recommend to the EOC whether the study should continue in accordance with 
the protocol.
Specific details regarding composition, responsibilities, and governance, including the roles 
and responsibilities of the various members and the Sponsor protocol team; meeting 
facilitation; the study governance structure; and requirements for and proper documentation 
of DMC reports, minutes, and recommendations will be described in the DMC charter that is 
reviewed and approved by all the DMC members.
10.1.5
Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments.  
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
10.1.6
Compliance with Study Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Amendments Act (FDAAA) of 2007 
and the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, the Sponsor 
of the study is solely responsible for determining whether the study and its results are subject
to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries. MSD, as Sponsor of this study, will 
review this protocol and submit the information necessary to fulfill these requirements. MSD 
entries are not limited to FDAAA or the EMA clinical trial directive mandated trials. 
Information posted will allow participants to identify potentially appropriate studies for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate study locations and study site contact information.
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By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this study or its results to those 
registries. 
10.1.7
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of GCP
(eg, International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals for Human Use GCP: Consolidated Guideline and other generally 
accepted standards of good clinical practice); and all applicable federal, state and local laws, 
rules and regulations relating to the conduct of the clinical study. The Code of Conduct, a 
collection of goals and considerations that govern the ethical and scientific conduct of 
clinical investigations sponsored by MSD, is provided in this appendix under the Code of 
Conduct for Clinical Studies.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority. 
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
10.1.8
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
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The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including signed ICF, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the Sponsor. No records may be 
transferred to another location or party without written notification to the Sponsor.
10.1.9
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available.
10.1.10
Study and Site Closure
The Sponsor or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor will 
promptly notify that study site’s IRB/IEC.
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10.2
Appendix 2: Clinical Laboratory Tests
•
The tests detailed in Table 20 will be performed by the local laboratory with the 
exception of hepatitis testing, which will be performed by the central laboratory.
•
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Sections 5.1 and 5.2 of the protocol.
•
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations.
Table 20
Protocol-required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count 
WBC count with Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Chemistry
Sodium 
Potassium
Chloride
Carbon dioxide 
(CO2 or 
Bicarbonate)a
Blood Urea 
Nitrogen (BUN)b
Creatininec
Glucose
Calcium 
Total Protein
Albumin
Total bilirubin (Tbil) 
and direct bilirubin 
(Dbil)d
Aspartate 
Aminotransferase
(AST)/ Serum 
Glutamic-
oxaloacetic 
Transaminase 
(SGOT)
Alanine 
Aminotransferase 
(ALT)/ Serum 
Glutamic pyruvic 
Transaminase 
(SGPT)
Alkaline 
phosphatase
Magnesium
Phosphorous 
Amylase
Lipasee
Lactate 
Dehydrogenase
Triglycerides
GGT
Urinalysis/Urine 
dipstick testing
•
Specific gravity
•
pH, glucose, protein, blood (or hemoglobin), ketones, by dipstickf
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Laboratory 
Assessments
Parameters
Other Tests
•
Serology Anti-HCV (IgG), HCV viral load, HCV genotype, anti-HBs, HBsAg, 
Anti-HBc (total and IgM), Anti-HBe, HBeAg, HBV viral load, HDV RNA, and 
Anti-HDVg
•
PT/INR
•
AFP
•
Serum or urine Pregnancy test 
•
Thyroid-stimulating Hormone (TSH)h, Free thyroxine (FT4)h, Triiodothyronine 
(T3)h
•
Serology HIV antibody as required by local health authority or institutional 
regulations. Refer to Appendix 7 for country-specific information.
Abbreviations: AFP = alpha fetaprotein; Anti-HBc = antihepatitis B core antibody, Total; Anti-HBs = antihepatitis B 
surface antibody; Anti-HDV = antihepatitis D antibody; GGT = gamma-glutamyl transferase; HBeAg = hepatitis B early 
antigen; HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = human immunodeficiency virus; 
IgM = immunoglobulin M; INR = international normalized ratio; PT = prothrombin time; RBC = red blood cells; WBC = 
white blood cells.
a
Performed only if considered local standard of care.
b
Urea is acceptable if BUN is not available as per institutional standard.
c
GFR (measured or calculated) or creatinine clearance can be used in place of creatinine.
d
Perform only if Tbil is above ULN.
e
After Cycle 1, retrospective review of lipase results is allowed when the results are not available prior to dosing.
f
If urine protein is ≥2+ (first occurrence or a subsequent increase in severity of urine dipstick proteinuria occurring 
on the same lenvatinib dose level), then a 24-hour urine collection should be done to quantify the 24-hour urine 
protein excretion.
g
All study-required laboratory assessments will be performed by a local laboratory, with the exception of hepatitis 
testing (Anti- HCV (IgG), HCV viral load, HCV genotype, anti- HBs, hepatitis B surface antigen [HBsAg], Anti-
HBc (total and IgM), Anti-HBe, HBeAg, HBV viral load, HDV RNA and Anti-HDV), which will be done centrally.
h
Free T4, T3, and TSH levels will be performed as indicated in Section 1.3 (SoA). T3: T3 is preferred; if not 
available, Free T3 may be tested. There may be instances when sites are unable to obtain the thyroid function 
testing results prior to scheduled dosing. After Cycle 1, review of thyroid function test results after dosing is 
acceptable.
The investigator (or medically qualified designee) must document their review of each 
laboratory safety report.
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definitions of Medication Error, Misuse, and Abuse
Medication error
This is an unintended failure in the drug treatment process that leads to or has the potential to 
lead to harm to the patient.
Misuse
This refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the terms of the product information.
Abuse
This corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product for a perceived psychological or physiological reward or desired nontherapeutic 
effect.
10.3.2
Definition of AE
AE definition
•
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.
•
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.
•
NOTE: For purposes of AE definition, study intervention (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, device, 
diagnostic agent, or protocol specified procedure whether investigational (including 
placebo or active comparator product) or marketed, manufactured by, licensed by, 
provided by, or distributed by the Sponsor for human use in this study.
Events meeting the AE definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.
•
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.
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•
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.
•
For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”
•
Any new cancer (that is not a condition of the study). 
Note: Progression of the cancer under study is not a reportable event. Refer to Section 
8.4.6 for additional details.
Events NOT meeting the AE definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
•
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
•
Surgery planned prior to informed consent to treat a pre-existing condition that has not 
worsened.
•
Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.3
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a. Results in death
b. Is life-threatening
•
The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
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c.
Requires inpatient hospitalization or prolongation of existing hospitalization
•
Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not an SAE. A pre-existing condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
d. Results in persistent or significant disability/incapacity
•
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
•
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
•
In offspring of participant taking the product regardless of time to diagnosis.
f.
Other important medical events
•
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
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10.3.4
Additional Events Reported in the Same Manner as SAE
Additional events that require reporting in the same manner as SAE
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor in the same 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
10.3.5
Recording AE and SAE
AE and SAE recording
•
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.
•
The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.
•
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
•
There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.
•
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity
•
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
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The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) according to the NCI Common Terminology Criteria for Adverse 
Events (CTCAE), version 4.0. Any AE that changes CTCAE grade over the course of a given 
episode will have each change of grade recorded on the AE CRFs/worksheets.
•
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated.
•
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (ADL).
•
Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting selfcare 
ADL.
•
Grade 4: Life-threatening consequences; urgent intervention indicated.
•
Grade 5: Death related to AE.
Assessment of causality
•
Did the Sponsor’s product cause the AE?
•
The determination of the likelihood that the Sponsor’s product caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed 
document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test product and the AE based upon the available information.
•
The following components are to be used to assess the relationship between the 
Sponsor’s product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Sponsor’s 
product caused the AE:
-
Exposure: Is there evidence that the participant was actually exposed to the 
Sponsor’s product such as: reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite 
in bodily specimen?
-
Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the Sponsor’s product? Is the time of onset of the AE compatible 
with a drug-induced effect (applies to studies with investigational medicinal product)?
-
Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors.
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-
Dechallenge: Was the Sponsor’s product discontinued or dose/exposure/frequency 
reduced?
◦
If yes, did the AE resolve or improve?
◦
If yes, this is a positive dechallenge.
◦
If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent 
disability; (2) the AE resolved/improved despite continuation of the Sponsor’s 
product; (3) the study is a single-dose drug study; or (4) Sponsor’s product(s) is/are 
only used 1 time.)
-
Rechallenge: Was the participant re-exposed to the Sponsor’s product in this study?
◦
If yes, did the AE recur or worsen?
◦
If yes, this is a positive rechallenge.
◦
If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or 
permanent disability, or (2) the study is a single-dose drug study; or (3) Sponsor’s 
product(s) is/are used only 1 time.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE SPONSOR’S PRODUCT, OR IF RE-EXPOSURE 
TO THE SPONSOR’S PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR AS PER DOSE 
MODIFICATION GUIDELINES IN THE PROTOCOL, AND IF REQUIRED, THE 
INIRB/IEC.
•
Consistency with study intervention profile: Is the clinical/pathological presentation of 
the AE consistent with previous knowledge regarding the Sponsor’s product or drug class 
pharmacology or toxicology?
•
The assessment of relationship will be reported on the case report forms/worksheets by 
an investigator who is a qualified physician according to his/her best clinical judgment, 
including consideration of the above elements.
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•
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Sponsor’s product relationship).
-
Yes, there is a reasonable possibility of Sponsor’s product relationship:
◦
There is evidence of exposure to the Sponsor’s product. The temporal sequence of 
the AE onset relative to the administration of the Sponsor’s product is reasonable. 
The AE is more likely explained by the Sponsor’s product than by another cause.
-
No, there is not a reasonable possibility of Sponsor's product relationship:
◦
Participant did not receive the Sponsor’s product OR temporal sequence of the 
AE onset relative to administration of the Sponsor’s product is not reasonable OR
the AE is more likely explained by another cause than the Sponsor’s product. 
(Also entered for a participant with overdose without an associated AE.)
•
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.
•
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.
•
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.
•
For studies in which multiple agents are administered as part of a combination regimen, 
the investigator may attribute each AE causality to the combination regimen or to a single 
agent of the combination. In general, causality attribution should be assigned to the 
combination regimen (ie, to all agents in the regimen). However, causality attribution 
may be assigned to a single agent if in the investigator’s opinion, there is sufficient data 
to support full attribution of the AE to the single agent.
Follow-up of AE and SAE
•
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
•
New or updated information will be recorded in the CRF.
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•
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
10.3.6
Reporting of AE, SAE, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool
•
The primary mechanism for reporting to the Sponsor will be the electronic data collection 
(EDC) tool.
-
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
-
If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper AE Reporting form.
◦
Reference Section 8.4.1  for reporting time requirements.
•
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
•
After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.
•
If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).
•
Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF
•
If the EDC tool is not operational, facsimile transmission or secure e-mail of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.
•
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
•
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
•
Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
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10.4
Appendix 4: Medical Device Incidents: Definition and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
Not applicable.
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10.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing
10.5.1
Definitions
Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below).
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
•
Premenarchal
•
Premenopausal female with 1 of the following:
-
Documented hysterectomy
-
Documented bilateral salpingectomy
-
Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.
•
Postmenopausal female
-
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
-
A high follicle stimulating hormone (FSH) level in the postmenopausal range may be 
used to confirm a postmenopausal state in women not using hormonal contraception 
or hormone replacement therapy (HRT). However, in the absence of 12 months of 
amenorrhea, confirmation with 2 FSH measurements in the postmenopausal range is 
required.
-
Females on HRT and whose menopausal status is in doubt will be required to use 1 of 
the nonhormonal highly effective contraception methods if they wish to continue their 
HRT during the study. Otherwise, they must discontinue HRT to allow confirmation 
of postmenopausal status before study enrollment.
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10.5.2
Contraception Requirements
Contraceptives allowed during the study includea:
Highly Effective Contraceptive Methods That Have Low User Dependency
Failure rate of <1% per year when used consistently and correctly.
•
Progestogen-only subdermal contraceptive implantb
•
Intrauterine hormone-releasing system (IUS)c
•
Intrauterine device (IUD)
•
Bilateral tubal occlusion
•
Azoospermic partner (vasectomized or secondary to medical cause)
This is a highly effective contraception method provided that the partner is the sole male sexual partner 
of the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective
method of contraception should be used. A spermatogenesis cycle is approximately 90 days.
Note: Documentation of azoospermia can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
Sexual Abstinence
•
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study intervention. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the 
preferred and usual lifestyle of the participant.
a
Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for participants of clinical studies.
b
If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable 
contraceptive implants are limited to those which inhibit ovulation.
c
IUS is a progestin releasing IUD.
Note: The following are not acceptable methods of contraception:
-
Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and lactational amenorrhea method (LAM).
-
Male condom with cap, diaphragm, or sponge with spermicide.
-
Male and female condom should not be used together (due to risk of failure with friction).
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
Not applicable.
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10.7
Appendix 7: Country-specific Requirements
10.7.1
Germany
Section 1.3 Schedule of Activities
Study 
Period
Screeninga
Treatment Period
42-Day Cycles
EOT
Notes
Intervention 
Cycles/ 
Titles
1
2
3
4
5
6
7 to 
last
Cycle Day
1
8
15
1
15
1
1
1
1
1
Scheduling 
Window 
(Days):
–28 to –1
±3
±3
±3
±3
±3
±3
±3
±3
±3
At DC
HIV
X
Testing is 
required
a. All screening procedures should be performed within 28 days of allocation, unless otherwise noted.
Section 5.2 Exclusion Criteria
30. Participant has a known history of human immunodeficiency virus (HIV) infection. 
Testing for HIV is required at screening.
Appendix 2 Clinical Laboratory Tests
Other Screening Tests: Serology (HIV Antibody).
10.7.2
United Kingdom
Section 1.3 Schedule of Activities
Study 
Period
Screeninga
Treatment Period
42-Day Cycles
EOT
Notes
Intervention 
Cycles/ 
Titles
1
2
3
4
5
6
7 to 
last
Cycle Day
1
8
15
1
15
1
1
1
1
1
Scheduling 
Window 
(Days):
–28 to –1
±3
±3
±3
±3
±3
±3
±3
±3
±3
At DC
HIV
X
Testing is 
required
a. All screening procedures should be performed within 28 days of allocation, unless otherwise noted.
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Section 5.2 Exclusion Criteria
30. Participant has a known history of human immunodeficiency virus (HIV) infection. 
Testing for HIV is required at screening.
Section 6.5.2 Prohibited Concomitant Medications

Live vaccines while participating in the study, and within 90 days of the last dose of 
study intervention.
-
Examples of live vaccines include, but are not limited to, the following: measles, 
mumps, rubella, chickenpox, yellow fever, intranasal seasonal influenza, rabies, 
BCG, and typhoid (oral).
-
Note: Seasonal influenza vaccines for injection are generally killed virus vaccines and 
are allowed.
Appendix 2 Clinical Laboratory Tests
Other Screening Tests: Serology (HIV Antibody).
10.7.3
France
Section 6.6.2 Pembrolizumab Dose Modification
Stevens-Johnson Syndrome is a permanent discontinuation criterion for pembrolizumab for 
France.
10.7.4
China
Biomarker sample collection, testing, and analysis as described in the following sections will 
be dependent on approval by the Human Genetic Resources Administration of China for 
participants enrolled in China:
•
Section 1.3: Schedule of Activities
•
Section 4.2.1.6: Planned Exploratory Biomarker Research
•
Section 5: Inclusion Criteria, Exclusion Criteria
•
Section 8.8: Biomarkers
Future biomedical research will not be conducted in China.
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10.7.5
Japan
Section 6.1 Study Intervention(s) Administered
Lenvatinib used in this study is categorized as “product(s) used in the clinical trial other than 
test product(s)” in Japan local regulation.
Intravenous solution, not provided by the Sponsor, as placebo for infusion in this protocol, is 
not categorized as “product(s) used in the clinical trial” in Japan.
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10.8
Appendix 8: Hepatitis B Definitions and Treatment Considerations
Table 21 describes the various definitions of treatment considerations and eligibility for study 
participation, along with the definitions of hepatitis B.
Table 21
Hepatitis B Definitions and Treatment Considerations
Test
Patient Status
Eligible for
MK-7902-002?
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 4 weeks prior to 
start of study treatment 
without evidence of a 
flare during that period 
Exclude if:
(a) <4 weeks of 
therapy; (b) HBV viral 
load not under control 
during this time frame; 
(c) Documented HBV 
flare in the past 
4 weeks
HBsAg (–)
Total anti-HBc (+)
IgM anti-HBc (–)
HBsAb (–)
HBV viral load 
(negative)
Unclear. Could be:
•
Resolved infection
•
False positive anti-HBc 
•
Low level infection
•
Resolving acute 
infection
Yes
No
HBsAg (–)
Total anti-HBc (+)
IgM anti-HBc (–)
HBsAb (–)
HBV viral load (+)
•
Low level infection
•
Resolving acute 
infection
Yes
Yes (as above)
Anti-HBc = antihepatitis B core antibody, HBsAb = hepatitis B surface antibody; HBsAg = hepatitis B surface antigen; 
HBV = hepatitis B virus; IgM = immunoglobulin M.
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10.9
Appendix 9: ECOG Performance Status
Developed by the Eastern Cooperative Oncology Group,
, Group Chair.*
GRADE
ECOG PERFORMANCE STATUS
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work
2
Ambulatory and capable of all selfcare but unable to carry out any work 
activities; up and about more than 50% of waking hours
3
Capable of only limited selfcare; confined to bed or chair more than 50% of 
waking hours
4
Completely disabled; cannot carry on any selfcare; totally confined to bed or 
chair
5
Dead
*Oken M, Creech R, Tormey D, et al. Toxicity and response criteria of the Eastern Cooperative 
Oncology Group. Am J Clin Oncol. 1982;5:649-655
http://ecog-acrin.org/resources/ecog-performance-status
PPD
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10.10 Appendix 10: 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 5 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 bilirubina (mg/dL)
<2.0
2.0 to 3.0
>3.0
Serum albumin (g/dL)
>3.5
2.8 to 3.5
<2.8
INRb,c
Or
Prothrombin time,
prolongation (seconds)
<1.7
<4.0 above ULN
1.7 to 2.3
4.0-6.0 above ULN
> 2.3
>6.0 above ULN
Ascites
None
Mild (easily controlled by 
medication)
Moderate to Severe 
(poorly controlled)
Hepatic encephalopathyd
None 
Grade I-II (mild or 
moderate)
Grade III-IV (severe or 
coma)
a
In primary sclerosing cholangitis and primary biliary cirrhosis, the bilirubin references are changed to 
reflect the fact that these diseases feature high conjugated bilirubin levels. The upper limit for 1 point is 68 
μmol/L (4 mg/dL) and the upper limit for 2 points is 170 μmol/L (10 mg/dL).
b
Different textbooks and publications use different measures. Some older reference works substitute PT 
prolongation for INR
c
For patients on anticoagulants (eg, Coumadin), only 1 point is assigned irrespective of the patient’s INR 
and PT value.
d
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. 
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•
Grade I:
Trivial lack of awareness; euphoria or anxiety; shortened attention span; 
impaired performance of addition or subtraction
•
Grade II:
Lethargy or apathy; minimal disorientation for time or place; subtle 
personality change; inappropriate behavior
•
Grade III: Somnolence to semi-stupor, but responsive to verbal stimuli
Confusion; Gross disorientation
•
Grade IV: Coma (unresponsive to verbal or noxious stimuli)
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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10.11 Appendix 11: Barcelona Clinic Liver Cancer Staging System
The Barcelona Clinic Liver Cancer staging system is shown in Figure 4 below [Llovet, J. M., 
et al 2008].
Figure 4
Barcelona Clinic Liver Cancer Staging System
CLT = cadaveric liver transplantation; HCC = hepatocellular carcinoma; LDLT = living donor liver 
transplantation; PEI = percutaneous ethanol injection; PST = performance status test; RF = radio frequency 
(ablation); TACE = transarterial chemoembolization.
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10.12 Appendix 12: NYHA Criteria
The New York Heart Association (NYHA) Cardiac Disease Classification provides a 
functional and therapeutic classification for the prescription of physical activity for cardiac 
participants. On the basis of NYHA definitions, participants are to be classified as follows:
Class
Definition
Class I
Participants with no limitation of activities; they suffer no symptoms from 
ordinary activities.
Class II
Participants with slight, mild limitation of activity; they are comfortable with rest 
or with mild exertion.
Class III
Participants with marked limitation of activity; they are comfortable only at rest.
Class IV
Participants who should be at complete rest, confined to bed or chair; any physical 
activity brings on discomfort and symptoms occur at rest.
Adapted from The Criteria Committee of the New York Heart Association, 1994 [Dolgin, M., et al 1994].
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10.13 Appendix 13: Clinical Studies Evaluating Drug-Drug Interactions With 
Lenvatinib
Nonclinical studies identify CYP3A4 as a potentially important Cytochrome P450 isozyme 
responsible for metabolism of lenvatinib. Clinical studies were conducted to test these 
findings. 
Simultaneous CYP3A4/P-glycoprotein (P-gp) inhibition by ketoconazole slightly (15% to 
19%) increases systemic exposure to lenvatinib [Shumaker, R., et al 2015]. Since no change 
was observed in half-life, tmax, or lag time (tlag), the slight increase in systemic exposure is 
probably related to a decrease in first-pass metabolism. However, since the magnitude of 
change is small, coadministration of lenvatinib with CYP3A4/P-gp inhibitors is not of 
clinical concern. 
The influence of P-gp inhibition on lenvatinib PK has been investigated. P gp inhibition was 
accomplished by coadministering a single dose of rifampin with a single dose of lenvatinib. 
Preliminary results suggest P-gp inhibition increases systemic exposure to lenvatinib 26% to 
32%. Thus, coadministration of lenvatinib with P-gp inhibitors only causes a small increase 
in lenvatinib exposure. 
The influence of simultaneous P-gp and CYP3A4 induction on lenvatinib PK has been 
investigated. Examination of simultaneous P-gp and CYP3A4 induction on lenvatinib PK 
was accomplished by administering rifampin QD for 21 days [Shumaker, R. C., et al 2014]. 
A single dose of lenvatinib was coadministered with the 15th dose of rifampin. Based on 
preliminary data, simultaneous P-gp and CYP3A4 induction minimally altered lenvatinib 
exposure, as mean Cmax increased about 8% while the area under the concentration-time 
curve (AUC) decreased about 7%. Co-administration of lenvatinib with CYP3A4/P-gp
inducers is not of clinical concern.
The main metabolic pathways for lenvatinib in humans were identified as enzymatic 
(CYP3A and aldehyde oxidase) and nonenzymatic processes (Lenvima® Package Insert).
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10.14 Appendix 14: Description of the iRECIST Process for Assessment of Disease 
Progression
Assessment at Screening and Prior to RECIST 1.1 Progression
Until radiographic disease progression based on RECIST 1.1, there is no distinct iRECIST 
assessment.
Assessment and Decision at RECIST 1.1 Progression
For participants who show evidence of radiological PD by RECIST 1.1 as determined by the 
investigator, the investigator will decide whether to continue a participant on study 
intervention until repeat imaging is obtained (using iRECIST for participant management 
(see Table 8 and Figure 2). This decision by the investigator should be based on the 
participant’s overall clinical condition.
Clinical stability is defined as the following:
•
Absence of symptoms and signs indicating clinically significant progression of disease
•
No decline in ECOG performance status
•
No requirements for intensified management, including increased analgesia, radiation, or 
other palliative care
Any participant deemed clinically unstable should be discontinued from study intervention at
central verification of site-assessed first radiologic evidence of PD, and is not required to 
have repeat tumor imaging for confirmation of PD by iRECIST.
If the investigator decides to continue treatment, the participant may continue to receive 
study intervention and the tumor assessment should be repeated 4 to 8 weeks later to confirm 
PD by iRECIST, per investigator assessment. Images should continue to be sent in to the 
central imaging vendor for potential retrospective BICR.
Tumor flare may manifest as any factor causing radiographic progression per RECIST 1.1, 
including:
•
Increase in the sum of diameters of target lesion(s) identified at baseline to ≥20% and 
≥5 mm from nadir
Note: The iRECIST publication uses the terminology “sum of measurements,” but “sum 
of diameters” will be used in this protocol, consistent with the original RECIST 1.1 
terminology.
•
Unequivocal progression of nontarget lesion(s) identified at baseline
•
Development of new lesion(s)
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iRECIST defines new response categories, including iUPD (unconfirmed progressive 
disease) and iCPD (confirmed progressive disease). For purposes of iRECIST assessment, 
the first visit showing progression according to RECIST 1.1 will be assigned a visit (overall) 
response of iUPD, regardless of which factors caused the progression.
At this visit, target and nontarget lesions identified at baseline by RECIST 1.1 will be 
assessed as usual.
New lesions will be classified as measurable or nonmeasurable, using the same size 
thresholds and rules as for baseline lesion assessment in RECIST 1.1. From measurable new 
lesions, up to 5 lesions total (up to 2 per organ), may be selected as New Lesions – Target. 
The sum of diameters of these lesions will be calculated, and kept distinct from the sum of 
diameters for target lesions at baseline. All other new lesions will be followed qualitatively 
as New Lesions – Non-target.
Assessment at the Confirmatory Imaging
On the confirmatory imaging, the participant will be classified as progression confirmed 
(with an overall response of iCPD), or as showing persistent unconfirmed progression (with 
an overall response of iUPD), or as showing disease stability or response (iSD/iPR/iCR).
Confirmation of Progression
Progression is considered confirmed, and the overall response will be iCPD, if ANY of the 
following occurs:
•
Any of the factors that were the basis for the iUPD at the previous visit show worsening
-
For target lesions, worsening is a further increase in the sum of diameters of ≥5 mm, 
compared to any prior iUPD time point
-
For nontarget lesions, worsening is any significant growth in lesions overall, 
compared to a prior iUPD time point; this does not have to meet the “unequivocal” 
standard of RECIST 1.1
-
For new lesions, worsening is any of these:
◦
An increase in the new lesion sum of diameters by ≥5 mm from a prior iUPD time 
point
◦
Visible growth of new nontarget lesions
◦
The appearance of additional new lesions
•
Any new factor appears that would have triggered PD by RECIST 1.1
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Persistent iUPD
Progression is considered not confirmed, and the overall response remains iUPD, if:
•
None of the progression-confirming factors identified above occurs AND
•
The target lesion sum of diameters (initial target lesions) remains above the initial PD 
threshold (by RECIST 1.1)
Additional imaging for confirmation should be scheduled 4 to 8 weeks from the imaging on 
which iUPD is seen. This may correspond to the next visit in the original visit schedule. The 
assessment of the subsequent confirmation imaging proceeds in an identical manner, with 
possible outcomes of iCPD, iUPD, and iSD/iPR/iCR.
Resolution of iUPD
Progression is considered not confirmed, and the overall response becomes iSD/iPR/iCR, if:
•
None of the progression-confirming factors identified above occurs, AND
•
The target lesion sum of diameters (initial target lesions) is not above the initial PD 
threshold.
The response is classified as iSD or iPR (depending on the sum of diameters of the target 
lesions), or iCR if all lesions resolve.
In this case, the initial iUPD is considered to be pseudo-progression, and the level of 
suspicion for progression is “reset.” This means that the next visit that shows radiographic 
progression, whenever it occurs, is again classified as iUPD by iRECIST, and the 
confirmation process is repeated before a response of iCPD can be assigned.
Management Following the Confirmatory Imaging
If repeat imaging does not confirm PD per iRECIST, as assessed by the investigator, and the 
participant continues to be clinically stable, study treatment may continue and follow the 
regular imaging schedule. If PD is confirmed, participants will be discontinued from study 
treatment.
NOTE: If a participant has confirmed radiographic progression (iCPD) as defined above, but 
the participant is achieving a clinically meaningful benefit or if RECIST 1.1 PD has not been 
verified centrally, an exception to continue study intervention may be considered following 
consultation with the Sponsor. In this case, if study intervention is continued, tumor imaging 
should continue to be performed following the intervals as outlined in Section 1.3 and 
submitted to the central imaging vendor.
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Detection of Progression at Visits After Pseudo-progression Resolves
After resolution of pseudo-progression (ie, achievement of iSD/iPR/iCR), iUPD is indicated 
by any of the following events:
•
Target lesions
-
Sum of diameters reaches the PD threshold (≥20% and ≥5 mm increase from nadir) 
either for the first time, or after resolution of previous pseudo-progression. The nadir 
is always the smallest sum of diameters seen during the entire study, either before or 
after an instance of pseudo-progression.
•
Nontarget lesions
-
If nontarget lesions have never shown unequivocal progression, their doing so for the 
first time results in iUPD.
-
If nontarget lesions have shown previous unequivocal progression, and this 
progression has not resolved, iUPD results from any significant further growth of 
non-target lesions, taken as a whole.
•
New lesions
-
New lesions appear for the first time
-
Additional new lesions appear
-
Previously identified new target lesions show an increase of ≥5 mm in the new lesion 
sum of diameters, from the nadir value of that sum
-
Previously identified non-target lesions show any significant growth
If any of the events above occur, the overall response for that visit is iUPD, and the iUPD 
evaluation process (see Assessment at the Confirmatory Imaging above) is repeated. 
Progression must be confirmed before iCPD can occur.
The decision process is identical to the iUPD confirmation process for the initial PD, with 
one exception: If new lesions occurred at a prior instance of iUPD, and at the confirmatory 
imaging the burden of new lesions has increased from its smallest value (for new target 
lesions, the sum of diameters is ≥5 mm increased from its nadir), then iUPD cannot resolve 
to iSD or iPR. It will remain iUPD until either a decrease in the new lesion burden allows 
resolution to iSD or iPR, or until a confirmatory factor causes iCPD.
Additional details about iRECIST are provided in the iRECIST publication [Seymour, L., et 
al 2017].
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10.15 Appendix 15: American Association for the Study of Liver Diseases (AASLD)
Liver Imaging Reporting and Data System (LI-RADS) 5 Criteria
AASLD LI-RADS 5 Criteria for radiographic diagnosis of hepatocellular carcinoma using 
CT/MRI. Cirrhosis is required for radiographic diagnosis.
Table 22
AASLD LI-RADS 5 Criteria
Table source: [Marrero, J. A., et al 2018].
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10.16 Appendix 16: Abbreviations
Abbreviation
Expanded Term
1L
First-line
2L
Second-line
AASLD
American Association for the Study of Liver Diseases
ADA
Anti-drug antibodies
ADL
Activities of daily living
AE
Adverse event 
AEOSI
Adverse event of special interest
AFP
Alpha fetoprotein
ALT
Alanine aminotransferase
Anti-HBc
Hepatitis B core antibody, Total
Anti-HBc, IgM
Hepatitis B core antibody, IgM
Anti-HBe
Hepatitis B early antibody
Anti-HBs
Hepatitis B surface antibody
Anti-HCV
Hepatitis C antibody
Anti-HDV
Hepatitis D antibody
APaT
All Participants as Treated
AST
Aspartate aminotransferase
AUC
Area under the concentration-time curve
BCG
Bacillus Calmette–Guérin
BCLC
Barcelona Clinic Liver Cancer
BICR
Blinded independent central [imaging] review(ers)
BP
Blood pressure
BW
Body weight
C1D1
Cycle 1 Day 1
CD
Cluster of differentiation
CI
Confidence interval
CNS
Central nervous system
CR
Complete response
CRF
Case Report Form 
CP
Child-Pugh
CR
Complete response
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTLA-4
Cytotoxic T-lymphocyte-associated protein 4
CYP
Cytochrome P450
D/C
Discontinuation/Discontinuing
DC
Disease Control
DCR
Disease control rate
DLT
Dose-limiting toxicity
DMC
Data Monitoring Committee 
DNA
Deoxyribonucleic acid 
DOR
Duration of response
EC
European Commission
ECG
Electrocardiogram 
ECHO
Echocardiogram
ECOG PS
Eastern Cooperative Oncology Group performance status
ECI
Event of clinical interest
eCRF
Electronic Case Report Form
EDC
Electronic data collection 
EMA
European Medicines Agency
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Abbreviation
Expanded Term
EOC
Executive Oversight Committee 
EORTC
European Organisation for the Research and Treatment of Cancer
EQ-5D-5L
European Quality of Life 5-dimension, 5-level Questionnaire
EU
European Union
EuroQOL
European Quality of Life
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FGF
Fibroblast growth factor
FGFR
Fibroblast growth factor receptor
FOLFOX
chemotherapy regimen containing: folinic acid, 5 fluorouracil, and oxaliplatin
GCP
Good Clinical Practice 
HBeAg
Hepatitis B early antigen
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCC
Hepatocellular carcinoma
HCV
Hepatitis C virus
HECI
Hepatic event of clinical interest
HGRAC
Human Genetics Resources Administration of China
HIV
Human immunodeficiency virus
HR
Hazard ratio
HRQoL
Health-related Quality of Life
HRT
Hormone replacement therapy
HDV
Hepatitis D virus
IA1
Interim Analysis 1
IA2
Interim Analysis 2
IB
Investigator’s Brochure 
ICF
Informed Consent Form 
ICH
International Conference on Harmonization
iCPD
iRECIST confirmed radiographic progression
IEC
Independent Ethics Committee
Ig
Immunoglobulin
IHC
Immunohistochemistry
IND
Investigational New Drug 
INR
International normalized ratio
IPCW
Inverse probability of censoring weight
iPD
iRECIST confirmed progressive disease
IRB
Institutional Review Board
irAE
Immune-related adverse events
iRECIST
Modified Response Evaluation Criteria in Solid Tumors 1.1 for immune-based 
therapeutics
IRT
Interactive response technology
ITT
Intention-to-treat
iUPD
iRECIST unconfirmed progressive disease
IV
Intravenous(ly)
LVEF
Left ventricular ejection fraction
mAB
Monoclonal antibody
mRECIST
Modified Response Evaluation Criteria in Solid Tumors 1.1
MRI
Magnetic resonance imaging
MTD
Maximum tolerated dose 
MUGA
Multigated acquisition
NSAID
Nonsteroidal anti-inflammatory drug
NSCLC
Nonsmall cell lung cancer
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Abbreviation
Expanded Term
NYHA
New York Heart Association
ONJ
Osteonecrosis of the jaw
OR
Objective Response
ORR
Objective response rate
OS
Overall survival
PD
Progressive disease
PD-1
Programmed death
PD-L1
Programmed cell death ligand 1
PD-L2
Programmed cell death ligand 2
PFS
Progression-free survival
P-gp
p-Glycoprotein
PK
Pharmacokinetic(s)
PMDA
Pharmaceuticals and Medical Devices Agency
PR
Partial response
PS
Performance Status
PRES/RPLS
Posterior reversible encephalopathy syndrome/ reversible posterior 
leukoencephalopathy syndrome
Q12W
Every 12 weeks
Q3W
Every 3 weeks
Q9W
Every 9 weeks
QD
Once daily
QLQ
Quality of life Questionnaire
QOD
Every other day
QoL
Quality of life
RBC
Red blood cell
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
Ribonucleic acid
RTK
Receptor tyrosine kinase
SAC
Scientific Advisory Committee
SAE
Serious adverse event 
SAP
Statistical analysis plan
SD
Stable disease
SGOT
Serum glutamic-oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transaminase
SIM
Site imaging manual
SoA
Schedule of activities
sSAP
Supplemental SAP
TEA
Treatment eligibility assessment
TEAE
Treatment-emergent AEs
TTD
Time to deterioration
TTP
Time to progression
ULN
Upper limit of normal
US
United States
VEGF
Vascular endothelial growth factor
VEGFR
Vascular endothelial growth factor receptor
Vp4
Main portal of portal vein
WOCBP
Woman/women of childbearing potential 
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11
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MK-7902-002-03-FINAL PROTOCOL
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PRODUCT:  MK-7902  
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PROTOCOL/AMENDMENT NO.: MK-7902-002-03 (E7080-G000-311)
MK-7902-002-03-FINAL PROTOCOL
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