Conditions: Advanced Melanoma
Keywords: programmed cell death 1 (PD-1, PD1) programmed cell death ligand 1 (PD-L1, PDL1) programmed cell death ligand 2 (PD-L2, PDL2)
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 103
Healthy volunteers: no

Brief summary:
This study will evaluate the safety and efficacy of combination therapy of lenvatinib (E7080/MK-7902) and pembrolizumab following approximately 2 years of pembrolizumab therapy and approximately 2 years or more lenvatinib therapy in adult participants with unresectable or advanced melanoma who have been exposed to anti-programmed cell death ligand 1 (PD-1/L1) agents approved for unresectable or metastatic melanoma. No statistical hypothesis will be tested in this study.

Detailed description:

Arms:
arm 1: Participants receive lenvatinib 20 mg 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.

Interventions: intervention 1: lenvatinib intervention 2: pembrolizumab
Intervention descriptions: intervention 1: Administered orally once a day during each 21-day cycle. intervention 2: Administered as an IV infusion on Day 1 Q3W.

Protocol document:
Prot_SAP_000.pdf: 
Official Protocol Title:
NCT number:
Document Date:
A Multicenter, Open-label, Phase 2 Trial to Assess 
the Efficacy and Safety of Lenvatinib (E7080/
MK-7902) in Combination with Pembrolizumab 
(MK-3475) in Participants with Advanced Melanoma 
Previously Exposed to an Anti-PD-1/L1 Agent
NCT03776136
15-JUL-2022


PRODUCT: MK-7902 
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PROTOCOL/AMENDMENT NO.: MK-7902-004-05 (E7080-G000-225)
MK-7902-004-05/(E7080-G000-225) FINAL PROTOCOL
15-JUL-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 Multicenter, Open-label, Phase 2 Trial to Assess the Efficacy and Safety of 
Lenvatinib (E7080/MK-7902) in Combination with Pembrolizumab (MK-3475) in 
Participants with Advanced Melanoma Previously Exposed to an Anti-PD-1/L1 Agent
(LEAP-004)
Protocol Number: MK-7902-004-05 (E7080-G000-225)
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 co-funded 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
140155
EudraCT
2018-002518-10
Approval Date: 15 July 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
7902-004-05
15-JUL-2022
Merck Sharp & Dohme Corp. underwent an entity name and address change to 
Merck Sharp & Dohme LLC, Rahway, NJ, USA.
7902-004-04
09-JUN-2021
To update the pembrolizumab dose modification and toxicity management 
guidelines for irAEs and table, to add MK-7902 program-level updates.
7902-004-03
19-MAR-2020
Amendment 3
7902-004-02
01-APR-2019
Amendment 2
7902-004-01
07-DEC-2018
Amendment 1
7902-004-00
11-SEP-2018
Original Protocol
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 05
Overall Rationale for the Amendments:
Sponsor underwent an entity name change and update to the address.
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
Title Page
Section 10.1.1 Code of 
Conduct for Clinical Trials
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.
Section 10.1.1 Code of 
Conduct for Clinical Trials
The Code of Conduct for Clinical Trials 
was updated.
To align with the current Code of Conduct.
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................14
1.1
Synopsis.................................................................................................................14
1.2
Schema ..................................................................................................................18
1.3
Schedule of Activities (SoA)................................................................................19
2
INTRODUCTION..........................................................................................................33
2.1
Study Rationale....................................................................................................33
2.2
Background ..........................................................................................................33
2.2.1
Pharmaceutical and Therapeutic Background .............................................34
2.2.1.1
Lenvatinib ..........................................................................................34
2.2.1.2
Pembrolizumab ..................................................................................34
2.2.1.3
Pembrolizumab Plus Lenvatinib........................................................35
2.2.1.4
Melanoma: Epidemiology and Current Therapeutic Options............36
2.2.1.5
Scientific Rationale for the Combination of Lenvatinib with 
Pembrolizumab ..................................................................................38
2.2.1.6
Clinical Data on Lenvatinib in Combination with 
Pembrolizumab for the Treatment of Melanoma...............................38
2.2.2
Preclinical and Clinical Studies ...................................................................39
2.3
Benefit/Risk Assessment......................................................................................39
3
HYPOTHESIS, OBJECTIVES, AND ENDPOINTS .................................................39
4
STUDY DESIGN............................................................................................................41
4.1
Overall Design......................................................................................................41
4.2
Scientific Rationale for Study Design.................................................................42
4.2.1
Rationale for Endpoints ...............................................................................42
4.2.1.1
Efficacy Endpoints.............................................................................42
4.2.1.1.1
RECIST 1.1..............................................................................43
4.2.1.1.2
RECIST 1.1 for Immune-based Therapeutics (iRECIST) .......43
4.2.1.2
Safety Endpoints................................................................................44
4.2.1.3
Pharmacokinetic Endpoints ...............................................................44
4.2.1.4
Pharmacodynamic Endpoints.............................................................44
4.2.1.5
Planned Exploratory Biomarker Research.........................................44
4.3
Justification for Dose...........................................................................................46
4.3.1
Pembrolizumab ............................................................................................46
4.3.2
Lenvatinib ....................................................................................................47
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4.3.3
Maximum Dose/Exposure for This Study ...................................................47
4.4
Beginning and End of Study Definition .............................................................47
4.4.1
Clinical Criteria for Early Study Termination .............................................48
5
STUDY POPULATION ................................................................................................48
5.1
Inclusion Criteria.................................................................................................48
5.2
Exclusion Criteria................................................................................................52
5.3
Lifestyle Considerations......................................................................................55
5.3.1
Meals and Dietary Restrictions....................................................................55
5.3.2
Contraception...............................................................................................55
5.3.3
Pregnancy.....................................................................................................56
5.3.4
Use in Nursing Women................................................................................56
5.4
Screen Failures.....................................................................................................56
5.5
Participant Replacement Strategy......................................................................56
6
STUDY INTERVENTION............................................................................................57
6.1
Study Intervention(s) Administered...................................................................57
6.2
Preparation/Handling/Storage/Accountability .................................................59
6.2.1
Dose Preparation..........................................................................................59
6.2.2
Handling, Storage, and Accountability........................................................59
6.3
Measures to Minimize Bias: Randomization and Blinding..............................60
6.3.1
Intervention Assignment..............................................................................60
6.3.2
Stratification.................................................................................................60
6.3.3
Blinding........................................................................................................60
6.4
Study Intervention Compliance..........................................................................60
6.5
Concomitant Therapy..........................................................................................60
6.5.1
Allowed Concomitant Medications .............................................................61
6.5.2
Prohibited Concomitant Medications ..........................................................61
6.5.3
Drug Interactions .........................................................................................62
6.5.4
Rescue Medications and Supportive Care ...................................................62
6.5.5
Hematopoietic Growth Factors....................................................................62
6.6
Dose Modification (Escalation/Titration/Other)...............................................63
6.6.1
Pembrolizumab ............................................................................................63
6.6.1.1
Immune-Related Events and Dose Modification (Withhold, 
Treat, Discontinue) ............................................................................63
6.6.1.2
Dose Modification and Toxicity Management of Infusion 
Reactions Related to Pembrolizumab................................................67
6.6.2
Lenvatinib ....................................................................................................70
6.6.2.1
Management of Hypertension............................................................71
6.6.2.2
Management of Proteinuria................................................................73
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6.6.2.3
Management of Diarrhea ...................................................................74
6.6.2.4
Management of Hepatotoxicity..........................................................74
6.6.2.5
Management of Thromboembolic Events..........................................74
6.6.2.6
Management of Posterior Reversible Encephalopathy 
Syndrome/Reversible Encephalopathy Syndrome/Reversible 
Posterior Leukoencephalopathy Syndrome .......................................75
6.6.2.7
Management of Hypocalcemia ..........................................................75
6.6.2.8
Management of Hemorrhage .............................................................75
6.6.2.9
Management of Gastrointestinal Perforation or Fistula 
Formation...........................................................................................75
6.6.2.10
Management of Osteonecrosis...........................................................75
6.6.3
Dose Modifications for Overlapping Toxicities ..........................................76
6.6.4
Other Allowed Dose Interruptions for Lenvatinib and 
Pembrolizumab ............................................................................................77
6.7
Intervention After the End of the Study............................................................77
6.8
Clinical Supplies Disclosure................................................................................77
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................77
7.1
Discontinuation of Study Intervention...............................................................77
7.2
Participant Withdrawal From the Study...........................................................79
7.3
Lost to Follow-up .................................................................................................80
8
STUDY ASSESSMENTS AND PROCEDURES........................................................80
8.1
Administrative and General Procedures ...........................................................81
8.1.1
Informed Consent.........................................................................................81
8.1.1.1
General Informed Consent.................................................................81
8.1.2
Inclusion/Exclusion Criteria ........................................................................81
8.1.3
Participant Identification Card.....................................................................82
8.1.4
Medical History ...........................................................................................82
8.1.5
Prior and Concomitant Medications Review...............................................82
8.1.5.1
Prior Medications...............................................................................82
8.1.5.2
Concomitant Medications..................................................................82
8.1.6
Assignment of Screening Number...............................................................82
8.1.7
Assignment of Treatment/Randomization Number.....................................83
8.1.8
Study Intervention Administration ..............................................................83
8.1.8.1
Timing of Dose Administration.........................................................83
8.1.8.1.1
Lenvatinib ................................................................................83
8.1.8.1.2
Pembrolizumab ........................................................................83
8.1.8.2
Compliance ........................................................................................83
8.1.9
Discontinuation and Withdrawal .................................................................84
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8.1.10
Participant Blinding/Unblinding..................................................................84
8.1.11
Calibration of Equipment.............................................................................84
8.1.12
Demography.................................................................................................84
8.1.13
Subsequent Antineoplastic Treatment .........................................................84
8.2
Efficacy/Immunogenicity Assessments ..............................................................84
8.2.1
Tumor Imaging and Assessment of Disease................................................84
8.2.1.1
Initial Tumor Imaging........................................................................85
8.2.1.2
Tumor Imaging During the Study......................................................86
8.2.1.3
End-of-treatment and Follow-up Imaging .........................................86
8.2.1.4
RECIST 1.1........................................................................................87
8.2.1.5
RECIST 1.1 for Immune-based Therapeutics (iRECIST) .................87
8.3
Safety Assessments...............................................................................................89
8.3.1
Physical Examinations.................................................................................90
8.3.2
Vital Signs....................................................................................................90
8.3.3
Electrocardiograms ......................................................................................91
8.3.4
Echocardiogram or Multiple Gated Acquisition Scan.................................91
8.3.5
Clinical Safety Laboratory Assessments .....................................................91
8.3.5.1
Hematology and Clinical Chemistry..................................................92
8.3.5.2
Urine Dipstick....................................................................................92
8.3.5.3
Pregnancy Test...................................................................................92
8.3.6
Eastern Cooperative Oncology Group Performance Status.........................92
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Reportable Safety Events ....................................................................................93
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................93
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety 
Events...........................................................................................................95
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event 
Information ..................................................................................................95
8.4.4
Regulatory Reporting Requirements for SAE .............................................95
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................95
8.4.6
Disease-related Events and/or Disease-related Outcomes Not 
Qualifying as AEs or SAEs..........................................................................96
8.4.7
Events of Clinical Interest (ECIs)................................................................96
8.5
Treatment of Overdose........................................................................................96
8.6
Pharmacokinetics.................................................................................................97
8.6.1
Blood Collection for Serum Pembrolizumab...............................................97
8.6.2
Blood Collection for Plasma Lenvatinib......................................................98
8.7
Pharmacodynamics..............................................................................................98
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8.8
Planned Genetic Analysis Sample Collection....................................................98
8.9
Biomarkers ...........................................................................................................98
8.10
Visit Requirements...............................................................................................99
8.10.1
Screening......................................................................................................99
8.10.1.1
Rescreening......................................................................................100
8.10.2
Treatment Period........................................................................................100
8.10.2.1
Phone Contact Visit .........................................................................100
8.10.3
Posttreatment Visit.....................................................................................100
8.10.3.1
Safety Follow-up..............................................................................100
8.10.3.2
Efficacy Follow-up Visits................................................................100
8.10.3.3
Survival Follow-up ..........................................................................101
8.10.4
Survival Status ...........................................................................................101
9
STATISTICAL ANALYSIS PLAN ...........................................................................101
9.1
Statistical Analysis Plan Summary...................................................................102
9.2
Responsibility for Analyses/In-house Blinding ...............................................102
9.3
Hypotheses/Estimation ......................................................................................103
9.4
Analysis Endpoints.............................................................................................103
9.4.1
Efficacy Endpoints.....................................................................................103
9.4.1.1
Primary.............................................................................................103
9.4.1.2
Secondary.........................................................................................103
9.4.2
Safety Endpoints........................................................................................103
9.5
Analysis Populations..........................................................................................103
9.5.1
Efficacy Analysis Populations...................................................................103
9.5.2
Safety Analysis Populations ......................................................................104
9.5.3
Population Pharmacokinetic Analysis Set .................................................104
9.6
Statistical Methods.............................................................................................104
9.6.1
Statistical Methods for Efficacy Analyses.................................................104
9.6.1.1
Objective Response Rate (ORR) .....................................................104
9.6.1.2
Progression-free Survival (PFS) ......................................................104
9.6.1.3
Overall Survival (OS) ......................................................................105
9.6.1.4
Duration of Response (DOR)...........................................................105
9.6.1.5
Analysis Strategy for Key Efficacy Endpoint..................................106
9.6.2
Statistical Methods for Safety Analyses ....................................................107
9.6.3
Demographics and Baseline Characteristics..............................................107
9.7
Interim Analyses ................................................................................................108
9.8
Multiplicity .........................................................................................................108
9.9
Sample Size and Power Calculations ...............................................................108
9.10
Subgroup Analyses.............................................................................................108
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9.11
Compliance (Medication Adherence)...............................................................109
9.12
Extent of Exposure.............................................................................................109
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...................................................................................................110
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations......110
10.1.1
Code of Conduct for Clinical Trials...........................................................110
10.1.2
Financial Disclosure...................................................................................112
10.1.3
Data Protection...........................................................................................113
10.1.3.1
Confidentiality of Data ....................................................................113
10.1.3.2
Confidentiality of Participant Records.............................................113
10.1.3.3
Confidentiality of IRB/IEC Information..........................................113
10.1.4
Committees Structure.................................................................................114
10.1.4.1
Executive Oversight Committee......................................................114
10.1.4.2
External Data Monitoring Committee .............................................114
10.1.5
Publication Policy......................................................................................114
10.1.6
Compliance with Study Registration and Results Posting 
Requirements .............................................................................................114
10.1.7
Compliance with Law, Audit, and Debarment ..........................................115
10.1.8
Data Quality Assurance .............................................................................115
10.1.9
Source Documents .....................................................................................116
10.1.10
Study and Site Closure...............................................................................117
10.2
Appendix 2: Clinical Laboratory Tests............................................................118
10.3
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting.........................................120
10.3.1
Definition of AE ........................................................................................120
10.3.2
Definition of SAE ......................................................................................121
10.3.3
Additional Events Reported in the Same Manner as SAE.........................122
10.3.4
Recording AE and SAE .............................................................................122
10.3.5
Reporting of AE, SAE, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................123
10.4
Appendix 4: Medical Device Incidents: Definition and Procedures for 
Recording, Evaluating, Follow-up, and Reporting.........................................125
10.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing......................126
10.5.1
Definitions..................................................................................................126
10.5.2
Contraception Requirements......................................................................127
10.5.3
Pregnancy Testing......................................................................................128
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................129
10.7
Appendix 7: Country-specific Requirements..................................................130
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10.7.1
Canada........................................................................................................130
10.8
Appendix 8: Description of the iRECIST Process for Assessment of 
Disease Progression............................................................................................131
10.9
Appendix 9: ECOG Performance Status.........................................................135
10.10 Appendix 10: Abbreviations .............................................................................136
11
REFERENCES.............................................................................................................139
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LIST OF TABLES
Table 1
Schedule of Activities................................................................................19
Table 2
Adequate Organ Function Laboratory Values ...........................................52
Table 3
Study Interventions....................................................................................58
Table 4
Dose Modification and Toxicity Management Guidelines for 
Immune-related Adverse Events Associated with Pembrolizumab 
Monotherapy, Coformulations or IO Combinations..................................64
Table 5
Pembrolizumab Infusion Reaction Dose Modification and 
Treatment Guidelines.................................................................................68
Table 6
Dose Modification Guidelines for Lenvatinib-related Adverse 
Events.........................................................................................................71
Table 7
Imaging and Treatment After First Radiologic Evidence of 
Progressive Disease ...................................................................................89
Table 8
Reporting Time Periods and Time Frames for Adverse Events and 
Other Reportable Safety Events.................................................................94
Table 9
Censoring Rules for Analysis of Progression-free Survival....................105
Table 10
Censoring Rules for Duration of Response .............................................106
Table 11
Analysis Strategy for Key Efficacy Endpoints........................................106
Table 12
Analysis Strategy for Safety Parameters..................................................107
Table 13
Two-sided 95% Confidence Interval of ORR with 100 Participants.......108
Table 14
Protocol-required Safety Laboratory Assessments..................................119
Table 15
Highly Effective Contraception Methods................................................128
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LIST OF FIGURES
Figure 1
Study Design..............................................................................................18
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Multicenter, Open-label, Phase 2 Trial to Assess the Efficacy and Safety of 
Lenvatinib (E7080/MK-7902) in Combination with Pembrolizumab (MK-3475) in 
Participants with Advanced Melanoma Previously Exposed to an Anti-PD-1/L1 Agent 
(LEAP-004)
Short Title: Phase 2 study of lenvatinib plus pembrolizumab for advanced melanoma in 
anti-PD-1/L1-exposed participants
Acronym: Protocol 004 (E7080-G000-225)
Hypotheses, Objectives, and Endpoints:
In all participants with advanced melanoma previously exposed to an anti-PD-1/L1 agent, 
and following administration of lenvatinib in combination with pembrolizumab:
Primary Objectives
Primary Endpoints
- Objective: To evaluate ORR as assessed by 
BICR per RECIST 1.1.
- Objective Response: CR or PR.
Secondary Objectives
Secondary Endpoints
- Objective: To evaluate PFS as assessed by 
BICR per RECIST 1.1.
- PFS: The time from first day of study 
intervention to the first documented disease 
progression or death due to any cause, 
whichever occurs first.
- Objective: To evaluate OS.
- OS: The time from first day of study 
intervention to death due to any cause.
- Objective: To evaluate the DOR as assessed 
by BICR per RECIST 1.1.
- DOR: For participants who demonstrate CR 
or PR, DOR is defined as the time from first 
documented evidence of CR or PR until 
disease progression or death due to any 
cause, whichever occurs first.
- Objective: To assess safety and tolerability 
of treatment with lenvatinib in combination 
with pembrolizumab.
- Adverse events.
- Study drug discontinuations due to AEs.
- Objective: To characterize the population 
PK of lenvatinib when co-administered with 
pembrolizumab.
- Plasma concentration of lenvatinib.
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Overall Design:
Study Phase
Phase 2
Primary Purpose
Treatment
Indication
Treatment of advanced melanoma
Population
Participants previously exposed to anti-PD-1/L1 agents 
for treatment of their advanced melanoma
Study Type
Interventional
Intervention Model
Single Group
This is a multi-site study.
Type of Control
No treatment control
Study Blinding
Unblinded Open-label
Masking
No Masking
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 36 months from the time the first 
participant (or their legally acceptable representative) 
provides documented informed consent until the last 
participant’s last study-related telephone call or visit.
Number of Participants:
Approximately 100 participants will be allocated.
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Intervention Groups and Duration:
Intervention 
Groups
Intervention 
Group 
Name
Drug
Dose
Dose 
Frequency
Route of 
Administration
Regimen/ 
Treatment 
Period
Use
Arm 1
Pembrolizumab
200 mg
Q3W
IV
~2 years
Experimental
Lenvatinib
20 mg
QD
orally
≥2 years 
Experimental
Abbreviations: IV = intravenous; Q3W = every 3 weeks; QD = once daily
Total 
Number
1 arm
Duration of 
Participation
After a Screening Phase of up to 28 days, each participant will receive lenvatinib
(also known as E7080 or MK-7902), hereafter referred to as lenvatinib, in 
combination with pembrolizumab for up to 35 pembrolizumab administrations 
(approximately 2 years) or until disease progression, unacceptable toxicity, 
investigator decision or participant decision, withdrawal of consent, or death 
whichever occurs first. After completion of approximately 2 years, participants 
may receive lenvatinib monotherapy until disease progression or unacceptable 
toxicity. All participants who continue lenvatinib monotherapy will be 
monitored per the SoA. Disease progression per RECIST 1.1 should be 
radiographically documented. Disease progression can be confirmed by the site 
per RECIST 1.1 for immune-based therapeutics (iRECIST) when clinically 
appropriate. Participants may also discontinue treatment due to unacceptable 
AEs, withdrawal of consent, 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. Participants may 
interrupt or discontinue pembrolizumab due to toxicity and continue with 
lenvatinib. Similarly, participants may interrupt or discontinue lenvatinib due to 
toxicity and continue with pembrolizumab. Participants who attain an 
investigator-determined confirmed CR may consider stopping study intervention
with pembrolizumab and/or lenvatinib after at least 24 weeks of lenvatinib in 
combination with pembrolizumab have been administered (Note: participants 
may continue to receive lenvatinib monotherapy until disease progression or 
unacceptable toxicity). In addition, if a confirmed CR per RECIST 1.1 is 
attained, at least 2 additional doses of pembrolizumab in combination with 
lenvatinib must be received after CR is first documented.
08MHJL


PRODUCT: MK-7902 
17
PROTOCOL/AMENDMENT NO.: MK-7902-004-05 (E7080-G000-225)
MK-7902-004-05/(E7080-G000-225) FINAL PROTOCOL
15-JUL-2022
Participants will be permitted to continue study intervention beyond 
RECIST 1.1-defined disease progression as long as the treating investigator 
considers that the participant may experience clinical benefit with continued 
treatment as per iRECIST, and the participant is tolerating study intervention.
All decisions to continue treatment beyond 2 consecutive scans (at least 4 weeks 
apart) showing progression must be approved by the Sponsor (Section 8.2.1).
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 posttreatment follow-up imaging for disease status until 
disease progression is documented radiographically per RECIST 1.1, initiating a 
nonstudy cancer treatment, withdrawing consent, or becoming lost to follow-up, 
whichever occurs first. Participants who discontinue due to radiographic disease 
progression will move to Survival Follow-up.
All participants will be followed for OS until death, withdrawal of consent, or 
the end of the study. The overall study ends when the last participant completes 
the last study-related telephone-call or visit, withdraws from the study, or is lost 
to follow-up (ie, the participant is unable to be contacted by the investigator).
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 10.
08MHJL


PRODUCT: MK-7902 
18
PROTOCOL/AMENDMENT NO.: MK-7902-004-05 (E7080-G000-225)
MK-7902-004-05/(E7080-G000-225) FINAL PROTOCOL
15-JUL-2022
1.2
Schema
The study design is depicted in Figure 1.
Figure 1
Study Design
Abbreviations: BICR: blinded independent central review; BRAF = proto-oncogene B-raf; CTLA-4 = cytotoxic 
T-lymphocyte-associated protein 4; mAb = monoclonal antibody; MEKi = mitogen-activated protein kinase inhibitor; 
PD = progressive disease; PD-1 = programmed cell death 1; Q3W = every 3 weeks; QD = once daily; Q12W = every 
12 weeks.
a
All-comers with regards to PD-L1 and BRAF status.
b
Prior BRAF/MEKi, anti-CTLA-4, and anti-CTLA-4+PD-1/L1 agents allowed; the proportion of participants who have 
received combination anti-CTLA-4+PD-1/L1 therapy will be capped at 25%. Disease progression on anti-PD-1/L1 mAb 
(alone or in combination) for treatment of advanced melanoma must be documented within 12 weeks following the 
participant’s last dose with an anti-PD-1/L1 mAb (RECIST 1.1) and confirmed by a second scan showing progression 
no less than 4 weeks after the first scan (in the absence of rapid clinical progression [iRECIST]).
c
Participants will receive lenvatinib in combination with pembrolizumab for up to 35 administrations of pembrolizumab 
(approximately 2 years) or until disease progression or unacceptable toxicity. After completion of approximately 2 years, 
participants may receive lenvatinib monotherapy until disease progression or unacceptable toxicity.
d
For participants discontinuing for reasons other than PD, tumor imaging should be performed Q12W or more frequently 
ids clinically indicated until PD.
e
For participants in Survival Follow-up, they will be contacted approximately Q12W or sooner to assess for survival 
status until death, withdrawal of consent, or the end of the study, whichever occurs first.
08MHJL


PRODUCT: MK-7902 
19
PROTOCOL/AMENDMENT NO.: MK-7902-004-05 (E7080-G000-225)
MK-7902-004-05/(E7080-G000-225) FINAL PROTOCOL
15-JUL-2022
1.3
Schedule of Activities (SoA)
Table 1
Schedule of Activities
Study Period
Screening
Treatment
Cycle = 21 days
EOTb
Posttreatment Visits
Notes
Safetyb,c
Efficacy 
Follow-up
Visitsd
Survival
Visit Timing/Cycle 
Number
-28 to -1
1
2
Cycle 3 
Onwardsa
At DC
30 Days 
and 
90 Days 
After Last 
Dose
Q12W
Q12W
All procedures and assessments 
are to be performed prior to 
administration of study 
intervention unless otherwise 
indicated. Refer to Section 8 for 
visit details.
Cycle Day
1
8
15
1
15
1
Scheduling Window 
(Days)
-28 to -1
±3
±3
±3
±3
±3
+7
±7
±7
Administrative Procedures
Informed consent
X
Documented informed consent can 
be provided at any time prior to 
any protocol-specific screening 
procedures being performed.
Additional consent is required at 
disease progression.
Inclusion/exclusion 
criteria
X
Participant identification 
card
X
Medical/surgical history
X
Significant medical/surgical 
history will be captured for the last 
10 years.
Demographics
X
Staging 
X
At initial diagnosis and study 
entry.
08MHJL


PRODUCT: MK-7902 
20
PROTOCOL/AMENDMENT NO.: MK-7902-004-05 (E7080-G000-225)
MK-7902-004-05/(E7080-G000-225) FINAL PROTOCOL
15-JUL-2022
Study Period
Screening
Treatment
Cycle = 21 days
EOTb
Posttreatment Visits
Notes
Safetyb,c
Efficacy 
Follow-up
Visitsd
Survival
Visit Timing/Cycle 
Number
-28 to -1
1
2
Cycle 3 
Onwardsa
At DC
30 Days 
and 
90 Days 
After Last 
Dose
Q12W
Q12W
All procedures and assessments 
are to be performed prior to 
administration of study 
intervention unless otherwise 
indicated. Refer to Section 8 for 
visit details.
Cycle Day
1
8
15
1
15
1
Scheduling Window 
(Days)
-28 to -1
±3
±3
±3
±3
±3
+7
±7
±7
BRAF testing
X
BRAF V600 mutation analysis 
should be performed locally by the 
sites during Screening in 
participants without documented 
BRAF status. If the local 
laboratory is unable to perform 
BRAF testing, the site should 
submit the sample to the central 
laboratory for testing.
Prior/concomitant 
medication review
X
X
X
X
X
X
X
X
X
X
Concomitant medications will be 
recorded for 30 days after last 
dose.
Pembrolizumab +
lenvatinib 
administration/ 
dispensing
X
X
X
Pembrolizumab 200 mg Q3W; 
lenvatinib 20 mg QD; 21-day
cycle.
On C1D1 and C2D1, lenvatinib 
will be taken 0-4 hours after 
completion of pembrolizumab 
administration.
Lenvatinib will be taken in the 
clinic on C1D1, C1D15, and 
C2D1.
08MHJL


PRODUCT: MK-7902 
21
PROTOCOL/AMENDMENT NO.: MK-7902-004-05 (E7080-G000-225)
MK-7902-004-05/(E7080-G000-225) FINAL PROTOCOL
15-JUL-2022
Study Period
Screening
Treatment
Cycle = 21 days
EOTb
Posttreatment Visits
Notes
Safetyb,c
Efficacy 
Follow-up
Visitsd
Survival
Visit Timing/Cycle 
Number
-28 to -1
1
2
Cycle 3 
Onwardsa
At DC
30 Days 
and 
90 Days 
After Last 
Dose
Q12W
Q12W
All procedures and assessments 
are to be performed prior to 
administration of study 
intervention unless otherwise 
indicated. Refer to Section 8 for 
visit details.
Cycle Day
1
8
15
1
15
1
Scheduling Window 
(Days)
-28 to -1
±3
±3
±3
±3
±3
+7
±7
±7
Subsequent 
antineoplastic
treatment
X
X
X
All anticancer therapy will be 
recorded until time of death or 
termination of survival FU. If a 
clinic visit is not feasible, follow-
up information may be obtained 
via telephone or email.
Phone Contact
Visit
X
Telephone contact or visit on 
C1D8 will assess participants for 
development of early toxicity. An 
unscheduled phone call or visit 
can occur prior to C1D15 or at any 
time if deemed necessary by the 
investigator.
Survival status
Participants may be contacted for 
survival status at any time during
the study.
08MHJL


PRODUCT: MK-7902 
22
PROTOCOL/AMENDMENT NO.: MK-7902-004-05 (E7080-G000-225)
MK-7902-004-05/(E7080-G000-225) FINAL PROTOCOL
15-JUL-2022
Study Period
Screening
Treatment
Cycle = 21 days
EOTb
Posttreatment Visits
Notes
Safetyb,c
Efficacy 
Follow-up
Visitsd
Survival
Visit Timing/Cycle 
Number
-28 to -1
1
2
Cycle 3 
Onwardsa
At DC
30 Days 
and 
90 Days 
After Last 
Dose
Q12W
Q12W
All procedures and assessments 
are to be performed prior to 
administration of study 
intervention unless otherwise 
indicated. Refer to Section 8 for 
visit details.
Cycle Day
1
8
15
1
15
1
Scheduling Window 
(Days)
-28 to -1
±3
±3
±3
±3
±3
+7
±7
±7
Efficacy/Immunogenicity Procedures
Submission of initial
imaging
X
The site’s study team must have 
reviewed initial images that are of 
diagnostic quality from at least 
3 dates to determine that 
radiographic progression has 
occurred per RECIST 1.1 and 
confirmed per iRECIST no less 
than 4 weeks from the date of the 
first documented PD in the 
absence of rapid clinical 
progression. The CIV must have 
received these scans and have 
confirmed that they are of 
acceptable diagnostic quality prior 
to allocation in this study for a 
retrospective analysis of the 
eligibility criterion that 
participants must be refractory to 
anti-PD-1/L1 agents. The CIV will 
not be confirming this eligibility 
prior to allocation.
08MHJL


PRODUCT: MK-7902 
23
PROTOCOL/AMENDMENT NO.: MK-7902-004-05 (E7080-G000-225)
MK-7902-004-05/(E7080-G000-225) FINAL PROTOCOL
15-JUL-2022
Study Period
Screening
Treatment
Cycle = 21 days
EOTb
Posttreatment Visits
Notes
Safetyb,c
Efficacy 
Follow-up
Visitsd
Survival
Visit Timing/Cycle 
Number
-28 to -1
1
2
Cycle 3 
Onwardsa
At DC
30 Days 
and 
90 Days 
After Last 
Dose
Q12W
Q12W
All procedures and assessments 
are to be performed prior to 
administration of study 
intervention unless otherwise 
indicated. Refer to Section 8 for 
visit details.
Cycle Day
1
8
15
1
15
1
Scheduling Window 
(Days)
-28 to -1
±3
±3
±3
±3
±3
+7
±7
±7
Tumor assessment 
chest, abdomen and 
pelvis (CT/MRI)
X
X
Scans performed within the 
screening period but before 
providing documented informed 
consent may be used if consistent 
with protocol requirements per 
SIM. Investigators must receive 
confirmation of measurable 
disease by BICR prior to 
allocation. All imaging visits have 
a scheduling window of ±7 days. 
Imaging to be performed Q9W 
from the date of allocation until 
Week 54 of study intervention; 
Q12W thereafter or sooner if 
clinically indicated until Week 
102; and Q24W thereafter or 
sooner if clinically indicated until
disease progression per 
RECIST 1.1. 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.
08MHJL


PRODUCT: MK-7902 
24
PROTOCOL/AMENDMENT NO.: MK-7902-004-05 (E7080-G000-225)
MK-7902-004-05/(E7080-G000-225) FINAL PROTOCOL
15-JUL-2022
Study Period
Screening
Treatment
Cycle = 21 days
EOTb
Posttreatment Visits
Notes
Safetyb,c
Efficacy 
Follow-up
Visitsd
Survival
Visit Timing/Cycle 
Number
-28 to -1
1
2
Cycle 3 
Onwardsa
At DC
30 Days 
and 
90 Days 
After Last 
Dose
Q12W
Q12W
All procedures and assessments 
are to be performed prior to 
administration of study 
intervention unless otherwise 
indicated. Refer to Section 8 for 
visit details.
Cycle Day
1
8
15
1
15
1
Scheduling Window 
(Days)
-28 to -1
±3
±3
±3
±3
±3
+7
±7
±7
Imaging at EOT is not required if 
the previous tumor imaging 
assessment was within 4 weeks 
prior to the EOT visit.
Imaging of any anatomy that 
shows disease either at screening 
or in subsequent evaluations will 
be required and should be 
submitted to the CIV. 
Brain MRIe
X
X
X
All imaging visits have a 
scheduling window of ±7 days.
A brain MRI will be required at 
screening and at all subsequent 
tumor assessment time points only 
if brain disease was observed at 
screening or if clinically indicated.
Imaging at EOT is not required if 
the previous tumor imaging 
assessment was within 4 weeks 
prior to the EOT visit.
08MHJL


PRODUCT: MK-7902 
25
PROTOCOL/AMENDMENT NO.: MK-7902-004-05 (E7080-G000-225)
MK-7902-004-05/(E7080-G000-225) FINAL PROTOCOL
15-JUL-2022
Study Period
Screening
Treatment
Cycle = 21 days
EOTb
Posttreatment Visits
Notes
Safetyb,c
Efficacy 
Follow-up
Visitsd
Survival
Visit Timing/Cycle 
Number
-28 to -1
1
2
Cycle 3 
Onwardsa
At DC
30 Days 
and 
90 Days 
After Last 
Dose
Q12W
Q12W
All procedures and assessments 
are to be performed prior to 
administration of study 
intervention unless otherwise 
indicated. Refer to Section 8 for 
visit details.
Cycle Day
1
8
15
1
15
1
Scheduling Window 
(Days)
-28 to -1
±3
±3
±3
±3
±3
+7
±7
±7
Safety Procedures
AE monitoring
X
X
X
X
X
X
X
X
X
X
AEs: monitored up to 90 days
after last dose or 30 days 
following cessation of study 
intervention if the participant 
initiates new anticancer therapy, 
whichever is earlier.
SAEs and pregnancy: monitored 
up to 120 days after last dose, or 
30 days after last dose if 
participant starts a new anticancer 
therapy, whichever is sooner.
Full physical 
examination
X
To be performed within 7 days
prior to start of study intervention.
Directed physical 
examination
X
X
X
X
X
X
X
In addition to the directed PEs in 
the flowchart, a symptom-directed 
PE may be performed at any time 
during the study, as clinically 
indicated.
08MHJL


PRODUCT: MK-7902 
26
PROTOCOL/AMENDMENT NO.: MK-7902-004-05 (E7080-G000-225)
MK-7902-004-05/(E7080-G000-225) FINAL PROTOCOL
15-JUL-2022
Study Period
Screening
Treatment
Cycle = 21 days
EOTb
Posttreatment Visits
Notes
Safetyb,c
Efficacy 
Follow-up
Visitsd
Survival
Visit Timing/Cycle 
Number
-28 to -1
1
2
Cycle 3 
Onwardsa
At DC
30 Days 
and 
90 Days 
After Last 
Dose
Q12W
Q12W
All procedures and assessments 
are to be performed prior to 
administration of study 
intervention unless otherwise 
indicated. Refer to Section 8 for 
visit details.
Cycle Day
1
8
15
1
15
1
Scheduling Window 
(Days)
-28 to -1
±3
±3
±3
±3
±3
+7
±7
±7
Vital signs (resting BP, 
heart rate,
RR, and temp) and 
weight
X
X
X
X
X
X
X
X
Blood pressure and pulse will be 
measured after the participant has 
been resting for 5 minutes. See 
Section 6.6.2.1 for management of 
hypertension and Section 8.3.2 for 
vital signs. Height measured at 
Screening only. 
12-lead ECG
X
X
X
X
X
X
Single 12-lead ECG. Participants 
must be in the recumbent position 
for a period of 5 minutes prior to the 
ECG.
ECG at Screening, C1D1, C2D1, D1 
of every 4th cycle (12 weeks) 
thereafter (eg, C6, C10, C14, etc.), 
EOT, and Safety Follow-up. 
For high-risk participants 
(Section 8.8.3), conduct ECG 
monitoring every cycle.
If lenvatinib is discontinued, ECGs 
are only required at the EOT and 
Safety Follow-up visits.  
Additional assessments may be 
performed if clinically indicated.
At C1D1 only, an additional 2-hour 
post-lenvatinib dose ECG is 
required. 
08MHJL


PRODUCT: MK-7902 
27
PROTOCOL/AMENDMENT NO.: MK-7902-004-05 (E7080-G000-225)
MK-7902-004-05/(E7080-G000-225) FINAL PROTOCOL
15-JUL-2022
Study Period
Screening
Treatment
Cycle = 21 days
EOTb
Posttreatment Visits
Notes
Safetyb,c
Efficacy 
Follow-up
Visitsd
Survival
Visit Timing/Cycle 
Number
-28 to -1
1
2
Cycle 3 
Onwardsa
At DC
30 Days 
and 
90 Days 
After Last 
Dose
Q12W
Q12W
All procedures and assessments 
are to be performed prior to 
administration of study 
intervention unless otherwise 
indicated. Refer to Section 8 for 
visit details.
Cycle Day
1
8
15
1
15
1
Scheduling Window 
(Days)
-28 to -1
±3
±3
±3
±3
±3
+7
±7
±7
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.
Hematology and clinical 
chemistry laboratory 
assessment
X
X
X
X
X
X
X
Procedures/assessments should be 
performed within 3 days prior to 
administration of first dose of study 
intervention and prior to all 
subsequent scheduled visits. Every 
effort should be made to collect 
samples at the same time of day. 
LDH is only required at Screening.
Urine dipstick testing
X
X
X
X
X
X
X
Performed locally within 3 days
prior to administration of first dose 
of study intervention and prior to 
all subsequent scheduled visits. 
Participants with >1+ proteinuria 
on urine dipstick during Screening 
will undergo 24-hour urine 
collection for quantitative 
assessment of proteinuria.
See Sections 6.6.2.2 for 
management of proteinuria and 
Section 8.3.5.2 for dipstick testing.
08MHJL


PRODUCT: MK-7902 
28
PROTOCOL/AMENDMENT NO.: MK-7902-004-05 (E7080-G000-225)
MK-7902-004-05/(E7080-G000-225) FINAL PROTOCOL
15-JUL-2022
Study Period
Screening
Treatment
Cycle = 21 days
EOTb
Posttreatment Visits
Notes
Safetyb,c
Efficacy 
Follow-up
Visitsd
Survival
Visit Timing/Cycle 
Number
-28 to -1
1
2
Cycle 3 
Onwardsa
At DC
30 Days 
and 
90 Days 
After Last 
Dose
Q12W
Q12W
All procedures and assessments 
are to be performed prior to 
administration of study 
intervention unless otherwise 
indicated. Refer to Section 8 for 
visit details.
Cycle Day
1
8
15
1
15
1
Scheduling Window 
(Days)
-28 to -1
±3
±3
±3
±3
±3
+7
±7
±7
PT/INR and aPTT/PTT
X
Screening samples collected 
within 3 days of administration of 
first dose of study intervention. 
Additional testing to be conducted 
as clinically indicated for 
participants taking anticoagulant 
therapy.
Total T3, FT4, TSH
X
X
X
X
X
Screening samples to be collected 
within 3 days of C1D1. 
Subsequently, thyroid function 
tests will be performed at Cycle 2 
and every other cycle thereafter 
(eg, C4, C6, etc.), at the time of 
discontinuation (EOT), and at the 
30-and 90-day Safety Follow-up 
visits. 
Free T3 is acceptable where Total 
T3 cannot be determined. After 
C1, retrospective review of thyroid 
function testing results is allowed 
when the results are not available 
prior to dosing.
08MHJL


PRODUCT: MK-7902 
29
PROTOCOL/AMENDMENT NO.: MK-7902-004-05 (E7080-G000-225)
MK-7902-004-05/(E7080-G000-225) FINAL PROTOCOL
15-JUL-2022
Study Period
Screening
Treatment
Cycle = 21 days
EOTb
Posttreatment Visits
Notes
Safetyb,c
Efficacy 
Follow-up
Visitsd
Survival
Visit Timing/Cycle 
Number
-28 to -1
1
2
Cycle 3 
Onwardsa
At DC
30 Days 
and 
90 Days 
After Last 
Dose
Q12W
Q12W
All procedures and assessments 
are to be performed prior to 
administration of study 
intervention unless otherwise 
indicated. Refer to Section 8 for 
visit details.
Cycle Day
1
8
15
1
15
1
Scheduling Window 
(Days)
-28 to -1
±3
±3
±3
±3
±3
+7
±7
±7
Pregnancy test 
(WOCBP only)
X
X
X
X
X
X
To be assessed prior to all 
subsequent scheduled visits. A 
serum or urine pregnancy test will 
be performed as indicated, prior to 
every cycle, up to 120 days after 
last dose of study intervention or 
30 days after last dose if 
participant starts a new anticancer 
therapy, whichever comes first. 
Postmenopausal women who have 
not had menses for >12 months 
must have 2 FSH tests.
HIV, HBV, HCV
X
Testing is not required unless 
mandated by the local health 
authority.
ECOG performance 
status
X
X
X
X
To be assessed within 3 days of 
administration of first dose of 
study intervention and prior to 
dosing during all subsequent 
scheduled visits. 
Pharmacokinetics/Pharmacodynamics/Biomarkers
Pembrolizumab 
pharmacokinetics
X
X
X
Predose C1D1, C2D1, and C8D1
Pembrolizumab antidrug 
antibodies
X
X
X
Predose C1D1, C2D1, and C8D1
08MHJL


PRODUCT: MK-7902 
30
PROTOCOL/AMENDMENT NO.: MK-7902-004-05 (E7080-G000-225)
MK-7902-004-05/(E7080-G000-225) FINAL PROTOCOL
15-JUL-2022
Study Period
Screening
Treatment
Cycle = 21 days
EOTb
Posttreatment Visits
Notes
Safetyb,c
Efficacy 
Follow-up
Visitsd
Survival
Visit Timing/Cycle 
Number
-28 to -1
1
2
Cycle 3 
Onwardsa
At DC
30 Days 
and 
90 Days 
After Last 
Dose
Q12W
Q12W
All procedures and assessments 
are to be performed prior to 
administration of study 
intervention unless otherwise 
indicated. Refer to Section 8 for 
visit details.
Cycle Day
1
8
15
1
15
1
Scheduling Window 
(Days)
-28 to -1
±3
±3
±3
±3
±3
+7
±7
±7
Lenvatinib PK
blood sample
X
X
X
C1D1: 0.5-4 hours and 6-10 hours
postdose (Note: no predose 
sampling on C1D1).
C1D15: predose, and 2-12 hours
postdose. 
C2D1: predose, 0.5-4 hours and 
6-10 hours postdose.
Note: postdose samples not 
needed if lenvatinib administration 
is skipped. 
Note: all predose samples should 
be collected within 2 hours of 
lenvatinib dosing.
Blood for serum 
biomarker
X
X
X
X
X
Collect predose on C1D1, C1D15, 
C2D1, C3D1, C5D1, and at EOT. 
Blood for RNA analysis
X
X
X
X
Collect predose on C1D1, C2D1, 
C3D1, C5D1, and at EOT.
Blood for circulating 
tumor nucleic acids
X
X
X
X
Collect predose. C1D1, C2D1, 
C3D1, C5D1, and then D1 every 
3 cycles, and at EOT.
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Study Period
Screening
Treatment
Cycle = 21 days
EOTb
Posttreatment Visits
Notes
Safetyb,c
Efficacy 
Follow-up
Visitsd
Survival
Visit Timing/Cycle 
Number
-28 to -1
1
2
Cycle 3 
Onwardsa
At DC
30 Days 
and 
90 Days 
After Last 
Dose
Q12W
Q12W
All procedures and assessments 
are to be performed prior to 
administration of study 
intervention unless otherwise 
indicated. Refer to Section 8 for 
visit details.
Cycle Day
1
8
15
1
15
1
Scheduling Window 
(Days)
-28 to -1
±3
±3
±3
±3
±3
+7
±7
±7
Blood for plasma 
biomarker
X
X
X
X
Collect predose. C1D1, C2D1, 
C3D1, C5D1, and then D1 every 
3 cycles, and at EOT
Blood for genetic 
analysis
X
Collect predose. See Sections 8.8 
and 8.9 for additional information.
Tumor blocks or slides
X
Collected during Screening for 
confirmation of adequacy of tumor 
tissue at a central pathology 
laboratory and for other tumor 
biomarker assessments.
Stool analysis (optional)
X
Predose (at home within 1 week 
before infusion) on C1D1.
Abbreviations: AE = adverse event; aPTT = activated partial thromboplastin time; BICR = blinded independent central review; BP = blood pressure; C = Cycle; CIV = central 
imaging vendor; CR = complete response; CT = computed tomography; D1 = Day 1; D15 = Day 15; D8 = Day 8; DC = discontinuation; ECG = electrocardiogram; 
ECHO = echocardiogram; ECOG = Eastern Cooperative Oncology Group; EOT = end of treatment; FT4 = free thyroxine; FSH = follicle-stimulating hormone; FU = follow-up; 
HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = human immunodeficiency virus; INR = international normalized ratio; LVEF = left ventricular ejection fraction; 
MRI = magnetic resonance imaging; MUGA = multigated acquisition; PD = progressive disease; PE = physical examination; PK = pharmacokinetics; PT = prothrombin time; 
Q3W = every 3 weeks; Q9W = every 9 weeks; Q12W = every 12 weeks; QD = once daily; RECIST = Response Evaluation Criteria in Solid Tumors; RR = respiratory rate; 
SAE = serious adverse event; SIM = Site Imaging Manual; SoA = Schedule of Activities; SOC = standard of care; T3 = triiodothyronine; TSH = thyroid-stimulating hormone; 
WOCBP = women of childbearing potential.
a
Participants who continue treatment with lenvatinib beyond ~2 years will follow the same SoA except for the following: 1) thyroid labs beyond ~2 years will be performed 
per SOC or as clinically indicated 2) Circulating tumor nucleic acids will no longer be collected. Participants who attain an investigator-determined CR and stop study 
intervention with pembrolizumab + lenvatinib will have Safety Follow-up visits and move to follow-up per SoA.
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b
If EOT visit occurs ~30 days from last dose of study intervention, a Safety FU visit at 30 days is not required. In this situation, all procedures required at both the EOT visit 
and the Safety FU visit at 30 days should be performed. EOT will be defined as the date when the participant discontinues all study interventions.
c
Safety FU will occur during 2 separate visits: 30 days AND 90 days after last dose. If the 90-day Safety FU visit falls within the same window as the 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. 
d
For participants who discontinue study intervention for reasons other than progressive disease, follow-up visits to monitor disease status continue until progressive disease
or initiation of a new anticancer therapy. Participants who discontinue study intervention with progressive disease proceed directly to Survival Follow-up.
e
Brain MRI must be performed at Screening. Brain MRI should then be performed Q9W until Week 54 or sooner if clinically indicated; Q12W thereafter until Week 102; 
following Week 102, imaging should be performed every Q24W, or sooner if clinically indicated only for participants with brain disease present at Screening. Brain CT 
scan should only be used when MRI is contraindicated. The same imaging technique regarding modality and the use of contrast should be used in a participant throughout 
the trial to optimize the visualization of existing and new tumor burden.
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2
INTRODUCTION
2.1
Study Rationale
Pembrolizumab (MK-3475/Keytruda) was approved by the US Food and Drug 
Administration (FDA) as the first anti- programmed cell death 1 (anti-PD-1) agent for the 
treatment of unresectable or metastatic melanoma in all lines of therapy. The European 
Commission has also approved pembrolizumab for both first-line and previously treated 
patients with advanced melanoma. However, there remains a large population (~60%) of 
patients who do not respond to anti-PD-1 therapy, and data suggest that the combination or 
sequencing of immune checkpoint inhibitors may be used to restore activity in participants
who have progressed on a particular inhibitor. This strategy may also offer a more powerful 
tool to induce immune activity in tumors that respond poorly, (ie, those that may have a 
greater level of immune suppression) [Pennock, G. K. 2015]. The response rates in anti-PD-1 
agent-exposed patients to other available checkpoint inhibitors (CTLA4, CTLA4+PD-1 
combination) remain unsatisfactory, 16% and 21% respectively [Zimmer, L., et al 2017].
Therefore, there is a large unmet medical need for novel therapies or combinations in anti-
PD-1 agent-exposed patients.
The current study is designed to further evaluate the safety and efficacy of combination 
therapy of lenvatinib and pembrolizumab following approximately 2 years of pembrolizumab 
therapy and approximately 2 years or more lenvatinib therapy in adult participants with 
unresectable or advanced melanoma who have been exposed to anti-PD-1/L1 agents
approved for unresectable or metastatic melanoma.
2.2
Background
Pembrolizumab is a potent humanized immunoglobulin (Ig) G4 monoclonal antibody (mAb)
with high specificity of binding to the programmed cell death 1 (PD-1) receptor, thus 
inhibiting its interaction with programmed cell death ligand 1 (PD-L1) and programmed cell 
death ligand 2 (PD-L2).
Lenvatinib (also known as E7080 or MK-7902) inhibits the kinase activities of vascular 
endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and 
VEGFR3 (FLT4). Lenvatinib inhibits other kinases that have been implicated in pathogenic 
angiogenesis, tumor growth, and cancer progression in addition to their normal cellular 
functions, including fibroblast growth factor (FGF) receptors FGFR1, 2, 3, and 4; 
platelet-derived growth factor receptor alpha (PDGFRα), KIT, and RET. Lenvatinib also 
exhibited antiproliferative activity in cell lines dependent on activated fibroblast growth 
factor receptor (FGFR) signaling with a concurrent inhibition of FGF-receptor substrate 2α 
phosphorylation. Once daily (QD) dosing of lenvatinib combined with pembrolizumab is 
currently being developed for the treatment of melanoma.
Refer to the respective IB/approved labeling for detailed background information on 
pembrolizumab and lenvatinib.
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2.2.1
Pharmaceutical and Therapeutic Background
2.2.1.1
Lenvatinib
Angiogenesis, the formation of new blood vessels from a pre-existing vascular network, is 
essential for tumor growth and metastasis. VEGF and its family of receptors (VEGRs 1-3) 
play a major role in tumor angiogenesis [Ferrara, N., et al 2003] [Ellis, L. M. 2008] 
[Tammela, T. 2010]. Accumulated evidence suggests that FGF and its receptor tyrosine 
kinase, FGFR also play important roles for tumor angiogenesis [Cross, M. J. 2001] [Lieu, C., 
et al 2011] [Limaverde-Sousa, G., et al 2014]. 
Lenvatinib is a potent multiple RTK inhibitor that selectively inhibits VEGF receptors, 
VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4), FGFR1-4, PDGFRα, KIT, and 
RET. 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 
FGFRs, both of which are currently believed to be very important for tumor angiogenesis. 
Lenvatinib inhibited cell free kinase activities for VEGFR1-3 and FGFR1-3 with Ki values 
around 1 nmol/L, and 8 to 22 nmol/L, respectively[Yamamoto, Y., et al 2014]. In cell-based 
assays, lenvatinib inhibited VEGF-derived and FGF-derived tube formation of human 
umbilical vein endothelial cell (HUVEC) with IC50 values of 2.1 and 7.3 nmol/L, 
respectively. Analysis of the signal transduction molecules revealed that lenvatinib inhibited 
both the mitogen-activated protein kinase (MAPK) pathway and the mTOR-S6K-S6 pathway 
in HUVECs triggered by activated VEGFR and FGFR. Furthermore, lenvatinib (10, 
30 mg/kg) significantly inhibited both VEGF- and FGF-driven angiogenesis in a murine in 
vivo model [Yamamoto, Y., et al 2014]. In vivo, lenvatinib exhibited antitumor activity 
against various human tumor xenografts in athymic mice including 5 types of thyroid 
carcinomas (differentiated [papillary and follicular], anaplastic, squamous, and medullary 
thyroid carcinomas), renal cell carcinoma (RCC), hepatocellular carcinoma (HCC), 
melanoma, gastric cancer, NSCLC, ovarian cancer, Ewing’s sarcoma, and osteosarcoma. In 
addition, the antitumor activity of lenvatinib in combination with other anticancer agents in 
several xenograft models was greater than that of lenvatinib or the other agents alone.
In summary, lenvatinib inhibited VEGF-driven VEGFR2 phosphorylation and suppressed 
proliferation and tube formation in HUVEC models. Antitumor activity of lenvatinib in vivo 
has been shown in numerous xenograft animals. These results suggest that lenvatinib may be 
a novel anticancer therapy through inhibition of angiogenesis and may be useful as either 
monotherapy or in combination with other anticancer drugs.
2.2.1.2
Pembrolizumab
The PD-1 receptor ligand interaction is a major pathway hijacked by tumors to suppress 
immune control. The normal function of PD-1, expressed on the cell surface of activated 
T cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an Ig 
superfamily member related to CD28 and cytotoxic T-lymphocyte-associated protein 4 
(CTLA-4) that has been shown to negatively regulate antigen receptor signaling upon 
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engagement of its ligands (PD L1 and/or PD-L2) [Dudley, M. E., et al 2005] [Hunder, N. N., 
et al 2008]. 
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, protein kinase C-
theta, and zeta-chain-associated protein kinase, 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 melanoma.
2.2.1.3
Pembrolizumab Plus Lenvatinib
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades [Disis, M. L. 2010]. Accumulating evidence 
shows a correlation between tumor-infiltrating lymphocytes in cancer tissue and favorable 
prognosis in various malignancies. In particular, the presence of cluster of differentiation 
(CD)8+ T cells and the ratio of CD8+ effector T-cells/FoxP3+ regulatory T-cells (Tregs) 
correlates with improved prognosis and long-term survival in solid malignancies, such as 
ovarian, colorectal, and pancreatic cancer; hepatocellular carcinoma; malignant melanoma; 
and RCC. Tumor-infiltrating lymphocytes can be expanded ex vivo and reinfused, inducing 
durable objective tumor responses in cancers such as melanoma [Dudley, M. E., et al 2005] 
[Hunder, N. N., et al 2008].
In preclinical models, lenvatinib decreased the tumor-associated macrophage (TAM)
population, which is known as an immune-regulator in the tumor microenvironment. The 
decrease in TAM population was accompanied by increases in activated cytotoxic T-cell 
populations through stimulation of interferon-gamma signaling, resulting in increased 
immune activation [Kimura, T., et al 2018]. The immune-modulating effect of lenvatinib 
may result in a potent combination effect with PD-1/L1 signal inhibitors. The effect of 
combining lenvatinib with an anti-human PD-1 humanized mAb was investigated in 4 
murine tumor isograft models, which showed significant tumor growth inhibition compared 
with control. In the RAG murine tumor isograft tumor model, survival in the group treated 
with the combination was significantly longer than that of the respective monotherapy 
groups. In the CT26 murine tumor isograft model, treatment with the combination 
significantly increased the population of activated cytotoxic T cells compared with that of the 
respective monotherapy groups [Kato, Y., et al 2019]. All treatments were well tolerated and 
severe body weight loss was not observed.
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2.2.1.4
Melanoma: Epidemiology and Current Therapeutic Options
Melanoma is the most serious form of skin cancer and impacts adults of all ages. The 5-year 
prevalence of melanoma in the EU is approximately 326,000 patients with an incidence of 
approximately 83,000 per year and approximately 16,000 deaths annually [WHO Health 
Organization 2012]. Melanoma accounts for approximately 5% of all new cases of cancer in 
the US. The incidence of melanoma continues to rise by almost 3% per year in the US. This 
translates to 76,000 new cases a year with 9,000 associated deaths. The male-to-female
incidence ratio of melanoma is 1.4:1, respectively [Siegel, R., et al 2012]. The 5-year 
survival rate is 17% for distant-stage disease [American Cancer Society 2016].
High-dose interleukin-2 was the first immune-modulating treatment to modify the natural 
history of patients with metastatic melanoma and may be curative for a small fraction of 
patients. However, its severe toxicity limits its application to carefully selected patients 
treated at centers with experience in managing the side effects of treatment. More recent 
research led to the development of immunotherapy using checkpoint inhibitors such as 
anti-PD-1 antibodies (pembrolizumab and nivolumab), the anti-CTLA-4 antibody 
ipilimumab, and to MAPK pathway targeted therapy with BRAF and/or MEK inhibition
(dabrafenib and/or trametinib, respectively). Both of these approaches prolong PFS and OS
compared with chemotherapy [UpToDate, Inc. 2015] [Ugurel, S., et al 2017]; thus, they are 
standard therapeutic options for patients with melanoma refractory to anti-PD-1/L1 agents.
Ipilimumab, an anti-CTLA-4 antibody, was the first checkpoint inhibitor to demonstrate OS
benefit in a randomized, comparative Phase 3 registration study. In the Phase 3 study 
MDX010-20, ipilimumab monotherapy demonstrated a hazard ratio (HR) of 0.66 and a 
4-month median OS benefit compared with gp100 in pretreated advanced melanoma 
participants [Hodi, F. S., et al 2010]. Grade 3 to 4 immune-related AEs included colitis 
(3.2%), diarrhea (4.5%), endocrinopathies (1.1%), and rash (1.3%). In the US, 3 mg/kg of 
ipilimumab was approved for advanced melanoma based on data from MDX010-20 and 
without restriction to line of therapy, in part because of the results of an additional Phase 3
randomized ipilimumab clinical study, CA184024. In the CA184024 study, treatment-naïve 
advanced melanoma participants treated with 10 mg/kg ipilimumab in combination with 
dacarbazine demonstrated an HR of 0.72 and a 2-month median OS benefit compared with 
monotherapy dacarbazine [Robert, C., et al 2011]. In the EU, ipilimumab is currently 
approved for the treatment of advanced (unresectable and metastatic) melanoma in adults 
who have received prior therapy. 
Approximately 50% of cutaneous melanoma cases are BRAF V600E mutation positive. 
Vemurafenib was initially approved in the US and in the EU for the treatment of BRAF 
V600E mutation-positive advanced melanoma participants regardless of line of therapy [U.S. 
Prescribing Information 2015]. In the BRIM-3 Phase 3 study, vemurafenib demonstrated a 
48% response rate and an increased OS benefit compared with dacarbazine with an HR of 
0.37, but with inadequate follow-up. More recently, the combination of a BRAF inhibitor 
plus a MEK inhibitor demonstrated an increased efficacy and a better safety profile 
compared with BRAF inhibition alone as first-line therapy in patients with advanced 
melanoma. Both the combination of dabrafenib and trametinib or vemurafenib and 
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cobimetinib are approved as first-line therapy in BRAF V600E mutation-positive melanoma 
patients [Robert, C., et al 2014] [Robert, C., et al 2015] [Larkin, J., et al 2014].
Pembrolizumab has shown in a randomized Phase 3 study (KEYNOTE-006) a significant 
benefit in OS, PFS, and response rate in patients with unresectable or metastatic melanoma 
compared with ipilimumab. The estimated PFS rate was 46.4% at 6 months for 
pembrolizumab 10 mg/kg every 3 weeks versus 26.5% for ipilimumab. The ORR was 32.9% 
for pembrolizumab 2 mg/kg Q3W versus 11.9% for ipilimumab. Responses were ongoing in 
96.7% of participants after a median follow-up of 7.9 months. Median PFS were 4.1 months 
for pembrolizumab versus 2.8 months for ipilimumab. The HR for disease progression for 
pembrolizumab Q3W versus ipilimumab was 0.58 (95% CI, 0.46 to 0.72; p<0.001). The 
1-year estimate of survival for participants receiving pembrolizumab Q3W was 68.4% 
compared with 58.2% for ipilimumab (HR for death as compared with ipilimumab group 
0.69; 95% CI, 0.52 to 0.90; p=0.0036). Because the OS results were superior to those for the 
ipilimumab group the IDMC recommended stopping the study early to allow patients in the 
ipilimumab group the option of receiving pembrolizumab [Robert, C., et al 2015].
Similarly, nivolumab was studied in participants with previously untreated advanced 
melanoma compared with dacarbazine. The median PFS was 5.1 months compared with 
2.2 months for the dacarbazine group. The ORR were 40% in the nivolumab group and 
13.9% in the dacarbazine group. At 1 year, the overall rate of survival was 72.9% for the 
nivolumab group compared with 42.1% in the dacarbazine group. Nivolumab significantly
improved OS and PFS compared with dacarbazine among previously untreated patients who 
had metastatic melanoma without BRAF mutation [Robert, C., et al 2014].
In 2014, the FDA approved both nivolumab and pembrolizumab, PD-1 blocking antibodies, 
for the treatment of patients with unresectable or metastatic melanoma and disease 
progression following ipilimumab and, if BRAF V600E mutation-positive, a BRAF inhibitor. 
Both approvals were under the accelerated approval process and were based on tumor 
response rates and durability of response. Both pembrolizumab and nivolumab received 
National Comprehensive Cancer Network (NCCN) compendia listing recommendations for 
use in the first-line metastatic melanoma setting based on these data. In November 2015, 
nivolumab received approval for first-line treatment of patients with BRAF V600 wild-type 
unresectable or metastatic melanoma. In December 2015, the pembrolizumab label was 
expanded to include first-line treatment of patients with unresectable or metastatic melanoma 
regardless of BRAF status. The European Commission also approved pembrolizumab and 
nivolumab for both first-line and previously treated patients with advanced melanoma.
There remains a high unmet medical need for efficacious combination therapies in patients 
not responding or refractory to anti-PD-1 agents. A retrospective analysis in advanced 
melanoma patients after anti-PD-1 treatment failure showed objective response rates for 
ipilumab alone and in combination with nivolumab as 16% and 21%, respectively. One-year 
OS rates for the ipilimumab and the combination-group were 54% and 55%, respectively
[Zimmer, L., et al 2017]. Thus, although ipilimumab should be considered as a viable 
treatment option for patients with failure to prior anti-PD-1 therapy, the combination of 
ipilimumab and nivolumab appears significantly less effective in this setting compared with 
treatment-naïve patients.
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2.2.1.5
Scientific Rationale for the Combination of Lenvatinib with Pembrolizumab
In preclinical models, lenvatinib decreased the 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 agents 
has been investigated in the CT26 colorectal cancer syngeneic model (anti-PD-L1 agent) as 
well as the LL/2 lung cancer syngeneic model (anti-PD-1 agent). Combination treatment with 
lenvatinib and either an anti-PD-1 or anti-PD-L1 agent showed significant and superior 
antitumor effects compared with either compound alone in these 2 syngeneic models [Kato, 
Y., et al 2015].
Based on these results, an open-label, Phase 1b/2 study (Study E7080-A001-111 
[Study 111]) to assess the safety and preliminary antitumor activity of the combination of 
lenvatinib + pembrolizumab in participants with selected solid tumors is currently ongoing. 
Phase 1b of this study determined the MTD and recommended Phase 2 dose (RP2D) as 
20 mg lenvatinib QD in combination with 200 mg of pembrolizumab given IV Q3W. The 
safety and efficacy of the combination at the lenvatinib RP2D is being assessed in the Phase 
2 portion of the study that includes 6 cohorts (ie, NSCLC, RCC, EC, urothelial carcinoma, 
melanoma, and squamous cell carcinoma of the head and neck).
2.2.1.6
Clinical Data on Lenvatinib in Combination with Pembrolizumab for the 
Treatment of Melanoma
E7080-A001-111/KEYNOTE-146 is an ongoing multi-cohort Phase 2 study to assess the 
efficacy and safety of lenvatinib in combination with pembrolizumab in 6 types of 
biomarker-unselected metastatic solid tumors, including melanoma (excluding uveal 
melanoma), that have progressed after treatment with approved therapies or for which there 
are no standard effective therapies available. The study is ongoing but is no longer enrolling 
melanoma patients.
Eligible participants were aged 18 years or older and had histologically confirmed non-uveal 
melanoma, 0 to 2 prior systemic anticancer regimens and ECOG 0 or 1. The primary 
endpoint is ORR at Week 24 based on Response Evaluation Criteria in Solid Tumors 1.1 for 
Immune-based Therapeutics (iRECIST), as determined by investigator-read tumor 
assessments performed at baseline, every 6 weeks until Week 24, and then every 9 weeks 
thereafter. Secondary endpoints include ORR, DOR, PFS, OS, and safety and tolerability of 
the combination. All participants received lenvatinib 20 mg daily in combination with 
200 mg pembrolizumab IV Q3W. At data cutoff (01-MAR-2018), 21 metastatic melanoma 
participants were enrolled, and 38% of participants had 1 or more prior anticancer therapy. 
For all enrolled participants (N=21), the ORRWeek24 was 47.6% (95% CI: 25.7%, 70.2%) 
using iRECIST by investigator review. Of the 10 confirmed responses, 9 (42.9%) were PR, 
and 1 (4.8%) was CR. Stable disease was observed in 7 (33.3%) participants, and 3 (14.3%) 
experienced PD. One participant (4.8%) had an unknown response. Median duration of 
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objective response was 12.5 months (95% CI: 2.7 months, NE). Median PFS observed was 
7.6 months (95% CI: 2.6 months, 15.8 months).
All participants experienced ≥1 TRAE. There were no fatal TRAEs. The most common any-
grade TRAEs were fatigue (52%), decreased appetite (48%), diarrhea (48%), hypertension 
(48%), dysphonia (43%), and nausea (43%). Dose reduction and interruption due to TRAEs 
occurred in 13 (62%) and 10 (47.6%) participants, respectively.
The safety profile of lenvatinib in combination with pembrolizumab appears manageable in 
patients with malignant melanoma and other tumor types and is consistent with each agent’s 
safety profile when administered as monotherapy.
2.2.2
Preclinical and Clinical Studies
Refer to the respective IBs for preclinical and clinical study data for pembrolizumab and 
lenvatinib.
2.3
Benefit/Risk Assessment
Beneficial effects of pembrolizumab have been seen in several melanoma trials to date. 
Publications of a significantly positive benefit/risk ratio have been reported for melanoma in 
single-arm and randomized studies as monotherapy (KEYNOTE-001, KEYNOTE-002, 
KEYNOTE-006). 
As discussed in Sections 2.2.1.3 and 2.2.1.4, both lenvatinib and pembrolizumab in 
combination have shown promising efficacy in participants with melanoma and preliminary 
safety data of the combination of lenvatinib and pembrolizumab suggest toxicity is 
manageable. Given the relevance of improving and expanding treatment options for patients 
with advanced melanoma, there is an unmet medical need for novel combinations 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 melanoma with other immune check point inhibitors other than transient elevations in 
ALT and AST. 
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.
Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the accompanying IB and ICF documents.
3
HYPOTHESIS, OBJECTIVES, AND ENDPOINTS
Throughout this protocol, the term RECIST 1.1 refers to the modification of RECIST 1.1 to 
include a maximum of 10 target lesions and a maximum of 5 target lesions per organ. Refer 
to Section 4.2.1.1.1 for further details.
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In all participants with advanced melanoma previously exposed to an anti-PD-1/L1 agent, 
and following administration of lenvatinib in combination with pembrolizumab:
Objectives
Endpoints
Primary
•
Objective: To evaluate ORR as assessed 
by BICR per RECIST 1.1.
•
Objective Response: CR or PR.
Secondary
•
Objective: To evaluate PFS as assessed 
by BICR per RECIST 1.1.
•
PFS: The time from first day of study 
intervention to the first documented 
disease progression or death due to any 
cause, whichever occurs first.
•
Objective: To evaluate OS.
•
OS: The time from first day of study 
intervention to death due to any cause.
•
Objective: To evaluate the DOR as 
assessed by BICR per RECIST 1.1.
•
DOR: For participants who demonstrate 
CR or PR, DOR is defined as the time 
from first documented evidence of CR or 
PR until disease progression or death due 
to any cause, whichever occurs first.
•
Objective: To assess safety and 
tolerability of treatment with lenvatinib in 
combination with pembrolizumab.
•
Adverse events.
•
Study drug discontinuations due to AEs.
•
Objective: To characterize the population 
PK of lenvatinib when co-administered 
with pembrolizumab.
•
Plasma concentration of lenvatinib.
Tertiary/Exploratory
•
Objective: To evaluate ORR, PFS, and 
DOR per iRECIST as assessed by 
investigator review.
•
Objective Response: CR or PR.
•
PFS: The time from first day of study 
intervention to the first documented 
disease progression or death due to any 
cause, whichever occurs first.
•
DOR: For participants who demonstrate 
CR or PR, DOR is defined as the time 
from first documented evidence of CR or 
PR until disease progression or death due 
to any cause (whichever occurs first).
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Objectives
Endpoints
•
Objective: To identify molecular 
(genomic, metabolic, and/or proteomic) 
biomarkers that may be indicative of 
clinical response/resistance, safety, 
and/or the mechanism of action of 
lenvatinib and pembrolizumab.
•
Molecular (genomic, metabolic, and/or 
proteomic) determinants of response or
resistance to treatments, using blood 
and/or tumor tissue.
4
STUDY DESIGN
4.1
Overall Design
This is an open-label study to evaluate the efficacy and safety of lenvatinib in combination 
with pembrolizumab in participants with advanced melanoma previously exposed to an 
anti-PD-1/L1 agent. All-comers with regards to PD-L1 and BRAF status are eligible for 
enrollment if they meet all of the inclusion and none of the exclusion criteria. Disease 
progression on an anti-PD-1/L1 mAb (alone or in combination) for the treatment of advanced 
melanoma must be documented within 12 weeks following the participant’s last dose with an 
anti-PD-1/L1 mAb (RECIST 1.1) and confirmed by a second scan showing progression no 
less than 4 weeks after the first scan (in the absence of rapid clinical progression) (iRECIST). 
The proportion of participants who have received combination anti-CTLA-4+PD-1/L1 
therapy will be capped at 25%.
Approximately 100 participants will be enrolled into the study. After a Screening Phase of up 
to 28 days, participants will be treated with the combination of lenvatinib and 
pembrolizumab for up to 35 administrations of pembrolizumab (approximately 2 years) or 
until disease progression, unacceptable toxicity, investigator decision or participant decision,
withdrawal of consent, or death, whichever occurs first. After completion of approximately 
2 years of combination treatment, participants may receive lenvatinib monotherapy until 
disease progression or unacceptable toxicity. Participants may interrupt or discontinue 
pembrolizumab due to toxicity and continue with lenvatinib. Similarly, participants may 
interrupt or discontinue lenvatinib due to toxicity and continue with pembrolizumab. 
Participants may also discontinue study intervention due to unacceptable AEs, withdrawal of 
consent, 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.
The primary endpoint of OR will be assessed by BICR per RECIST 1.1 criteria. The 
secondary endpoints are PFS, OS, and DOR. Safety and tolerability will be assessed by 
clinical review of all relevant parameters including AEs, laboratory tests, vital signs, and 
ECG measurements, as appropriate. 
After the end of treatment, each participant will be followed for the occurrence of AEs and 
spontaneously reported pregnancy as described in Section 8.4.
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Participants who discontinue for reasons other than radiographic disease progression will 
have posttreatment follow-up imaging for disease status until disease progression is 
documented radiographically per RECIST 1.1, initiating a nonstudy cancer treatment, 
withdrawing consent, or becoming lost to follow-up, whichever occurs first.
Participants will be permitted to continue study intervention beyond RECIST 1.1-defined 
disease progression if the treating investigator considers that the participant may experience 
clinical benefit with continued treatment as per iRECIST, and the participant is tolerating 
study intervention. Treatment beyond progressive disease per iRECIST may be permitted 
following Sponsor consultation and approval.
All participants will be followed for OS until death, withdrawal of consent, or the end of the 
study.
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.
4.2
Scientific Rationale for Study Design
If the safety profile is acceptable and this combination improves ORR, this study could 
support the regulatory approval of the combination of pembrolizumab and lenvatinib in 
participants with unresectable or advanced melanoma previously exposed to an anti-PD-1/L1
mAb.
4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
This study will use OR, defined as a best overall response of CR or PR, as assessed by BICR 
per RECIST 1.1 criteria as the primary endpoint.
Progression-free survival (PSF), OS, and DOR are secondary endpoints.
Progression-free survival (PFS) 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 radiologic 
progression as determined by central review will be communicated to the site. Overall 
survival (OS) has been recognized as the gold standard for the demonstration of superiority 
of a new antineoplastic therapy in randomized clinical studies. Duration of response as 
assessed by BICR per RECIST 1.1 will serve as an additional measure of efficacy and is a 
commonly accepted endpoint by both regulatory authorities and the oncology community.
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iRECIST will also be used by the local site to make treatment decisions once PD has been 
documented per RECIST 1.1 and verified by BICR.
OS is defined as the time from the first day of study intervention to death due to any cause.
For participants who demonstrate CR or PR, DOR is defined as the time from first 
documented evidence of CR or PR until disease progression or death due to any cause, 
whichever occurs first.
4.2.1.1.1
RECIST 1.1
RECIST 1.1 will be used by the BICR when assessing images for efficacy measures and 
when determining eligibility (Section 8.2.1.5). 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
RECIST 1.1 for Immune-based Therapeutics (iRECIST)
RECIST 1.1 will be adapted to account for the unique tumor response characteristics seen 
following treatment with pembrolizumab (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 fully capture the 
treatment benefits from immunotherapeutic agents such as pembrolizumab. Based on an 
analysis of participants with melanoma enrolled in KEYNOTE-001 (KN001), 7% of 
evaluable participants experienced delayed or early tumor pseudo-progression. Of note, 
participants who had progressive disease by RECIST 1.1 but not by the immune-related 
response criteria [Wolchok, J. D., et al 2009] had longer OS than participants with disease 
progression 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. 
iRECIST assessment has been developed and published by the RECIST Working Group, 
with input from leading experts from industry and academia, along with participation from 
the US Food and Drug Administration and the European Medicines Agency [Seymour, L., et 
al 2017]. The unidimensional measurement of target lesions, qualitative assessment of 
nontarget lesions, and response categories are identical to RECIST 1.1, until progression is 
seen by RECIST 1.1. However, if a participant is clinically stable, additional imaging may be 
performed to confirm radiographic progression. iRECIST will be used by investigators to 
assess tumor response and progression and make treatment decisions as well as for 
exploratory efficacy analyses, where specified.
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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 AEs/SAEs; and changes in vital signs and laboratory values. 
Adverse events will be assessed as defined by the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE), Version 4.0.
4.2.1.3
Pharmacokinetic Endpoints
Based on PK data obtained in this study and from other studies, a population PK analysis will
be performed to characterize PK parameters of lenvatinib when co-administered with 
pembrolizumab to support the proposed dosing regimen.
4.2.1.4
Pharmacodynamic Endpoints
No pharmacodynamic endpoints are planned for this study. 
4.2.1.5
Planned Exploratory Biomarker Research
Cancer immunotherapies represent an important and novel class of antitumor agents. 
However, the mechanism of action of these exciting new therapies, including novel 
combinations with antiangiogenesis therapy, is not completely understood and much remains 
to be learned regarding how best to leverage these new drugs in treating patients. Thus, to aid 
future patients, it is important to investigate the determinants of response or resistance to 
cancer immunotherapy and other treatments administered, as well as determinants of AEs in 
the course of our clinical studies. These efforts may identify novel predictive/PD biomarkers 
and generate information that may better guide single-agent and combination therapy with 
immuno-oncology 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 toward the development/progression of cancer 
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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 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 blood RNA analyses
Both genome-wide and targeted messenger RNA (mRNA) expression profiling and 
sequencing in tumor tissue and in blood may be performed to define gene signatures that 
correlate to clinical response to treatment with pembrolizumab or other immunotherapies. 
Pembrolizumab induces a response in tumors that likely reflects an inflamed/immune 
phenotype. Specific immune-related gene sets (ie, those capturing interferon-gamma 
transcriptional pathways) may be evaluated and new signatures may be identified. Individual 
genes related to the immune system and growth factor signaling pathways (eg, VEGF and 
FGF) may also be evaluated. 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). 
PD-L1 protein level in tumor sections, assessed by IHC, has been shown to correlate with 
response to pembrolizumab in patients with NSCLC, and an in vitro diagnostic (IVD) device 
has been developed for use with pembrolizumab in NSCLC. Preliminary data indicates that 
this association may also be true in additional cancer types (ie, triple negative breast cancer, 
head and neck, and gastric). Additional tumor or blood-derived proteins may also correlate 
with response to pembrolizumab and lenvatinib combination therapy. 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 spectrometry. This 
approach could identify novel protein biomarkers that could aid in patient selection for 
pembrolizumab (MK-3475) and lenvatinib combination therapy.
Other blood-derived biomarkers
In addition to expression on the tumor tissue, PD-L1, circulating cytokines and angiogenic 
factors, and other tumor derived proteins can be shed from tumor and released into the blood. 
Assays such as enzyme-linked immunosorbent assay (ELISA) measure such proteins in 
serum. Correlation of expression with response to pembrolizumab and lenvatinib 
combination 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.
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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.
Biomarker Research using Stool
Landmark studies have demonstrated that the gut microbiome can shape anti-tumor 
immunity and responses to immune checkpoint blockade in mouse models, and that 
modulation of the gut microbiome may enhance responses to immune checkpoint blockade. 
This has also been studied in patients on immune checkpoint blockade (anti-CTLA-4 and 
anti-PD-1), with evidence that differential bacterial signatures exist in responders versus non-
responders to therapy (with responders having higher diversity of the gut microbiome and 
differential composition compared with non-responders). Importantly, these differences in 
the gut microbiome are associated with differential immune signatures in the tumor 
microenvironment [Lynch, S. V. 2016].
4.3
Justification for Dose
4.3.1
Pembrolizumab
The planned dose of pembrolizumab for this study is 200 mg Q3W. Based on the totality of 
data generated in the pembrolizumab 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 Q2W,

Clinical data showing meaningful improvement in benefit-risk including OS at 200 mg
Q3W across multiple indications, and

Pharmacology data showing full target saturation in both systemic circulation (inferred 
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 NSCLC, covering different disease settings (treatment naïve, previously 
treated, PD-L1 enriched, and all-comers) and different treatment settings (monotherapy and 
in combination with chemotherapy). Five studies compared 2 mg/kg Q3W versus 10 mg/kg 
Q3W (KN001 Cohort B2, KN001 Cohort D, KN002, KN010, and KN021), and 3 studies 
compared 10 mg/kg Q3W versus 10 mg/kg Q2W (KN001 Cohort B3, KN001 Cohort F2 and 
KN006). All of these studies demonstrated flat dose- and exposure-response relationships 
across the doses studied representing an approximate 5- to 7.5-fold difference in exposure. 
The 2 mg/kg (or 200 mg fixed-dose) Q3W provided similar responses to the highest doses 
studied. Subsequently, flat dose-exposure-response relationships were also observed in other 
tumor types including head and neck cancer, bladder cancer, gastric cancer, and classical 
Hodgkin Lymphoma, confirming 200 mg Q3W as the appropriate dose independent of the 
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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 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.
4.3.2
Lenvatinib
The dosing regimen of lenvatinib was selected based on the results of the Phase 1b portion of 
Study 111, the primary endpoint of which was to determine the MTD and RP2D for 
lenvatinib in combination with pembrolizumab 200 mg Q3W. Thirteen participants 
(lenvatinib 24 mg/day + pembrolizumab 200 mg IV Q3W: n=3; lenvatinib 20 mg/day + 
pembrolizumab 200 mg: n=10) were enrolled in the Phase 1b portion of the study. Eight of 
the participants had RCC, 2 had NSCLC, 2 had EC, and 1 had melanoma. There were 
2 DLTs at the dose of lenvatinib 24 mg/day + pembrolizumab 200 mg IV Q3W (1 participant 
had Grade 3 arthralgia, and another had Grade 3 fatigue); hence, this was defined as the toxic 
dose. Neither of these participants had melanoma. No DLTs were reported in the next 
10 participants (expansion part), all of whom received the lenvatinib 20 mg/day + 
pembrolizumab 200 mg Q3W dose. Based on review of all of the clinical data from these 
23 participants, the MTD and RP2D were determined to be 20 mg lenvatinib daily in 
combination with a fixed dose of 200 mg pembrolizumab given Q3W.
4.3.3
Maximum Dose/Exposure for This Study
The maximum dose/exposure of pembrolizumab allowed in this study is 200 mg Q3W for 
approximately 2 years. The maximum dose/exposure of lenvatinib allowed in this study is 
20 mg QD until disease progression or unacceptable toxicity.
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).
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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
Male/female participants with advanced melanoma who are at least 18 years of age will be 
enrolled in this study.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
1. Have histologically or cytologically confirmed melanoma.
2. Have unresectable Stage III or Stage IV melanoma, per American Joint Committee on 
Cancer (AJCC) staging system version 8, not amenable to local therapy.
3. Have the presence of at least 1 measurable lesion by CT or MRI per RECIST 1.1 as 
confirmed by BICR. Cutaneous lesions and other superficial lesions are not 
considered measurable lesions for the purposes of this protocol but may be considered
as nontarget lesions.
a.
If participants have only 1 measurable lesion per RECIST 1.1, the biopsy 
specimen should be obtained from the nontarget lesion or archival tissue.
b. Lesions that are in an area that has been previously irradiated should not be 
considered measurable unless there has been documented growth of the lesions 
since the completion of radiation.
4. Participants must have progressed on treatment with an anti-PD-1/L1 mAb
administered either as monotherapy, or in combination with other checkpoint 
inhibitors or other therapies. PD-1 treatment progression is defined by meeting all of 
the following criteria:
a.
Received at least 2 doses of an anti-PD-1/L1 mAb.
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b. Has demonstrated disease progression after PD-1/L1 as defined by RECIST 1.1. 
The initial evidence of RECIST 1.1 disease progression is to be confirmed using 
iRECIST by a second assessment no less than 4 weeks from the date of the first 
documented progressive disease, in the absence of rapid clinical progressioni,ii.
i
Seymour et al, iRECIST: Guidelines for response criteria for use in trials 
testing immunotherapeutics. Lancet Oncol (2017): 18: e143-52.
ii
This determination is made by the investigator. Once progressive disease is 
confirmed, the initial date of RECIST 1.1 progressive disease documentation 
will be considered the date of disease progression.
c.
Progressive disease has been documented within 12 weeks from the last dose of 
anti-PD-1/L1 mAb.
Note: the proportion of participants who have received combination 
anti-CTLA-4+PD-1/L1 therapy will be capped at 25%.
5. Have submitted initial imaging.
Note: The site’s study team must have reviewed initial images that are of diagnostic 
quality from at least 3 dates to determine that radiographic progression has occurred 
per RECIST 1.1 and confirmed per iRECIST no less than 4 weeks from the date of 
the first documented progressive disease in the absence of rapid clinical progression 
(see Section 8.2.1.1 for further details). The CIV must have received these scans and 
have confirmed that they are of acceptable diagnostic quality prior to treatment
allocation in this study for a retrospective analysis of inclusion criterion #4: 
participants must be refractory to anti-PD-1/L1 agents. The CIV will not be 
confirming this eligibility criterion prior to treatment allocation.
6. Have an ECOG performance status 0 to 1 (Appendix 9).
7. Have provided a baseline tumor biopsy.
a.
Must submit the tumor sample during Screening for confirmation of adequacy of 
tumor tissue at a central pathology laboratory. Participants who do not submit a 
tumor tissue sample will not be allocated to treatment. The biopsy may not be 
obtained from a lone target lesion. This condition can be waived if collecting a 
tumor sample is not feasible or not in the best interest of the participant, following 
Sponsor’s approval. 
b. Newly obtained tissue is preferred and must be collected after progression on 
prior anti-PD-1/L1 agent. 
Note: Following collection of tissue at study enrollment, participants may not
receive intervening treatment (local or systemic) involving the site of the tissue 
biopsy. 
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8. Have resolution of toxic effect(s) of the most recent prior therapy to Grade 1 or less 
(except alopecia). If participant received major surgery or radiation therapy of 
>30 Gy, they must have recovered from the toxicity and/or complications from the 
intervention.
Demographics
9. Be Male or Female and is at least 18 years of age at the time of providing 
documented informed consent.
Male Participants
10. Male participants are eligible to participate if they agree to the following during the 
intervention period and for at least 95 days, corresponding to time needed to eliminate 
study interventions (eg, 5 terminal half-lives) after the last dose of study intervention:
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.
Male participants must also agree to use a male condom when engaging in any 
activity that allows for passage of ejaculate to another person of any sex.
Female Participants
11. A female participant is eligible to participate if she is not pregnant or breastfeeding, 
and at least 1 of the following conditions applies:
- Not a woman of childbearing potential (WOCBP).
OR
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Is a WOCBP and using a contraceptive method that is highly effective (with a 
failure rate of <1% per year), with lower 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 95 days, corresponding to the time needed to 
eliminate any study interventions (eg, 5 terminal half-lives) after the last dose of 
study intervention. 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 test result is positive.
Additional requirements for pregnancy testing during and after study intervention 
are in Appendix 5.
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 undetectable pregnancy.
Informed Consent
12. Have provided documented informed consent for the study.
Additional Categories
13. Have adequately controlled BP, with or without antihypertensive medications, 
defined as BP ≤150/90 mmHg at Screening and no change in antihypertensive 
medications within 1 week before Cycle 1, Day 1.
Note: Eligibility of a participant that is receiving >3 antihypertensive medications 
prior to study entry will require Sponsor approval
14. Have adequate organ function as defined in Table 2. Specimens must be collected
within 3 days prior to the start of study intervention.
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Table 2
Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
≥1500/µL
Platelets
≥100 000/µL
Hemoglobin
≥9.0 g/dL or ≥5.6 mmol/La
Renal
Creatinine OR
Measured or calculatedb creatinine clearance
(GFR can also be used in place of creatinine or 
CrCl)
≤1.5 × ULN OR
≥30 mL/min for participant with creatinine levels 
>1.5 × institutional ULN
Hepatic
Total bilirubin
≤1.5 ×ULN OR direct bilirubin ≤ULN for participants 
with total bilirubin levels >1.5 × ULN except for 
unconjugated hyperbilirubinemia of
Gilbert’s syndrome.
AST (SGOT) and ALT (SGPT), and ALP
≤2.5× ULN (≤5 × ULN for participants with liver 
metastases)c
Coagulation
International normalized ratio (INR) OR 
prothrombin time (PT)
Activated partial thromboplastin time 
(aPTT)/PTT
≤1.5 × ULN unless participant is receiving anticoagulant 
therapy as long as PT or PTT is within therapeutic range 
of intended use of anticoagulants
Abbreviations: ALT (SGPT) = alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT) = aspartate 
aminotransferase (serum glutamic oxaloacetic transaminase); ALP = alkaline phosphatase; CrCl = creatinine clearance; GFR
= glomerular filtration rate; ULN = upper limit of normal.
a Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within 
last 2 weeks.
b Creatinine clearance (CrCl) should be calculated per institutional standard.
c Participants with ALP values >3 times the ULN and known to have bone metastases can be included. 
Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value requirements 
should be adapted according to local regulations and guidelines for the administration of specific chemotherapies.
5.2
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. 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 before the first dose of study intervention.
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2. Has a known additional malignancy that is progressing or has required active 
treatment within the past 3 years. Exceptions include early stage cancers (carcinoma in 
situ or Stage 1, non-ulcerated primary melanoma <1 mm in depth with no nodal 
involvement) treated with curative intent, basal cell carcinoma of the skin, squamous 
cell carcinoma of the skin, in situ cervical cancer, or in situ breast cancer that has 
undergone potentially curative therapy.
3. Has known active CNS metastases and/or carcinomatous meningitis. Participants with 
previously treated CNS metastases may participate provided they are stable (without 
evidence of progression by imaging for at least 4 weeks before the first dose of study 
intervention and any neurologic symptoms have returned to baseline), have no 
evidence of new or enlarging brain metastases confirmed by repeat imaging, and have 
not required steroids for at least 14 days before study intervention.
Note: Participants with asymptomatic previously untreated brain metastases may 
participate provided there are ≤3 total lesions in the brain and their longest diameter is 
<1 cm. Stability of these lesions does not need to be confirmed by repeat imaging. 
Baseline MRI brain scan will be obtained for all participants. Brain CT scan should 
only be used when MRI is contraindicated.
4. Has ocular melanoma.
5. Has known hypersensitivity to active substances or any of their excipients including 
previous clinically significant hypersensitivity reaction to treatment with another 
monoclonal antibody. For a list of excipients, refer to the respective IB.
6. 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, etc.) is not considered a 
form of systemic treatment.
7. Has an active infection requiring systemic therapy.
8. Has known history of HIV (HIV 1/2 antibodies). No testing of HIV is required unless 
mandated by local health authority.
9. Has known history of or is positive for hepatitis B (hepatitis B surface antigen 
[HBsAg] reactive) or hepatitis C (HCV RNA [qualitative] is detected). No testing of 
hepatitis B or C is required unless mandated by local health authority.
10. Has a history of (noninfectious) pneumonitis/interstitial lung disease that required 
steroids or current pneumonitis/interstitial lung disease.
11. Has a history of active tuberculosis (Bacillus tuberculosis).
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12. Has presence of a gastrointestinal condition including malabsorption, gastrointestinal 
anastomosis, or any other condition that might affect the absorption of lenvatinib.
13. Has had major surgery within 3 weeks prior to first dose of study interventions. Note: 
Adequate wound healing after major surgery must be assessed clinically, independent 
of time elapsed for eligibility.
14. Has a pre-existing Grade ≥3 gastrointestinal or nongastrointestinal fistula. 
15. Has radiographic evidence of major blood vessel invasion/infiltration. The degree of 
tumor invasion/infiltration of major blood vessels should be considered because of the 
potential risk of severe hemorrhage associated with tumor shrinkage/necrosis 
following lenvatinib therapy.
16. Has clinically significant hemoptysis or tumor bleeding within 2 weeks prior to the 
first dose of study drug.
17. Has clinically significant cardiovascular disease within 12 months from first dose of 
study drug, including New York Heart Association Class III or IV congestive heart 
failure, unstable angina, myocardial infarction, cerebral vascular accident, or cardiac
arrhythmia associated with hemodynamic instability.
Note:  Medically controlled arrhythmia would be permitted.
18. Has urine protein ≥1 g/24-hour. 
Note: Participants having >1+ proteinuria on urinalysis will undergo 24-hour urine 
collection for quantitative assessment of proteinuria.
19. Has a prolongation of QTc interval (calculated using Fridericia’s formula) of
>480 msec.
20. Has LVEF below the institutional normal range as determined by MUGA or 
echocardiogram.
Prior/Concomitant Therapy
21. Has received prior radiotherapy within 2 weeks of Cycle 1 Day 1. Participants must 
have recovered from all radiation-related toxicities, not require corticosteroids, and not 
have had radiation pneumonitis.
22. Has received a live vaccine within 30 days before the first dose of study intervention.
Examples of live vaccines include, but are not limited to, the following: measles,
mumps, rubella, chicken pox, 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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Prior/Concurrent Clinical Study Experience
23. 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
Other Exclusions 
24. Had a history or has current evidence of any condition, therapy, or laboratory 
abnormality that might confound the results of the study, interfere with the
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.
25. Has had an allogeneic tissue/solid organ transplant.
26. Has a known psychiatric or substance abuse disorder that would interfere with 
cooperation with the requirements of the study.
5.3
Lifestyle Considerations
5.3.1
Meals and Dietary Restrictions
Participant should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea, or vomiting.
5.3.2
Contraception
Lenvatinib and pembrolizumab may have adverse effects on a fetus in utero. 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 embryo toxicity and 
teratogenicity in rats and rabbits.
Participants should be informed that taking the study medication may involve unknown risks 
to the fetus (unborn baby) if pregnancy were to occur during the study. To participate in the 
study, participants of childbearing potential must adhere to the contraception requirement 
(Appendix 5) from the day of study medication initiation (or 14 days prior to the initiation of 
study medication for oral contraception) throughout the study period up to 120 days after the 
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last dose of study medication. If there is any question that a participant of childbearing 
potential will not reliably comply with the requirements for contraception, that participant 
should not be entered into the study.
5.3.3
Pregnancy
If a participant inadvertently becomes pregnant while on treatment with pembrolizumab
and/or lenvatinib, the participant will be immediately discontinued from study intervention. 
The site will contact the participant at least monthly and document the participant’s status 
until the pregnancy has been completed or terminated. The outcome of the pregnancy will be 
reported to the Sponsor without delay and within 24 hours if the outcome is a serious adverse 
experience (eg, death, abortion, congenital anomaly, or other disabling or life-threatening 
complication to the mother or newborn). The study investigator will make every effort to 
obtain permission to follow the outcome of the pregnancy and report the condition of the 
fetus or newborn to the Sponsor. If a male participant impregnates his female partner, the 
study personnel at the site must be informed immediately and the pregnancy must be reported 
to the Sponsor and followed as described in Section 8.4.
5.3.4
Use in Nursing Women
It is unknown whether pembrolizumab and/or lenvatinib is excreted in human milk. Since 
many drugs are excreted in human milk, and because of the potential for serious adverse 
reactions in the nursing infant, participants who are breastfeeding are not eligible for 
enrollment.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study, but 
are not subsequently entered in the study. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any AEs or SAEs meeting reporting 
requirements as outlined in the data entry guidelines.
5.5
Participant Replacement Strategy
A participant who discontinues from study intervention OR withdraws from the study will 
not be replaced.
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6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
Clinical supplies (pembrolizumab and lenvatinib) will be packaged to support enrollment  
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
6.1
Study Intervention(s) Administered
The study interventions to be used in this study are outlined in Table 3.
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Table 3
Study Interventions
Arm 
Name
Arm 
Type
Intervention 
Name
Type
Dose 
Formulation
Unit Dose
Dosage 
Level(s)
Route of 
Administration
Regimen/
Treatment 
Period/
Vaccination 
Regimen
Use
IMP/
NIMP
Sourcing
Arm 1
Experi-
mental
Pembrolizumab Drug
Solution for 
Infusion
25 mg/mL
200 mg
IV Infusion
Q3W
Experimental
IMP
Central
Experi-
mental
Lenvatinib
Drug
Capsule
10 mg, 
4 mga
20 mg
Oral
Once daily
Experimental
IMP
Central
Abbreviations: IMP = Investigational Medicinal Product; IV = intravenous; Q3W = every 3 weeks.
a
4 mg capsules provided for successive dose reduction of lenvatinib, if needed, as described in Section 6.6.2.
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All supplies indicated in Table 3 will be provided per the "Sourcing" row depending upon 
local country operational requirements. Every attempt should 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 per local guidelines 
unless otherwise instructed by the Sponsor.
Refer to Section 8.1.8 for details regarding administration of the study intervention.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
Details on preparation and administration of pembrolizumab are provided in the Pharmacy 
Manual. 
Lenvatinib is a capsule for oral administration and does not require preparation. See the 
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 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
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6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Intervention allocation will occur centrally using an interactive response technology (IRT) 
system. There is one study intervention arm. Participants in this study will be allocated by 
nonrandom assignment.
6.3.2
Stratification
No stratification based on age, sex, or other characteristics will be used in this study.
6.3.3
Blinding
This is an open-label study; therefore, the Sponsor, investigator, and participant will know 
the intervention administered.
6.4
Study Intervention Compliance
Interruptions from the protocol specified treatment: >28 days (lenvatinib) or >12 weeks 
(pembrolizumab) require consultation between the investigator and the Sponsor and written 
documentation of the collaborative decision on participant management.
6.5
Concomitant Therapy
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the treatment period. If there is a clinical indication for any medication or vaccination 
specifically prohibited, discontinuation from study intervention may be required. The 
investigator should discuss any questions regarding this with the Sponsor. 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.
Any medication (including over-the-counter medications) or therapy administered to the 
participant during the study (starting at the date of informed consent) will be recorded on the 
appropriate CRF. The investigator will record the AE for which the concomitant 
medication/therapy was administered on the appropriate CRF. If the concomitant 
medication/therapy is being administered for a medical condition present at the time of entry 
into the study, the investigator will record the medical condition on the appropriate CRF.
All prior medications (including over-the-counter medications) administered 30 days before 
the first dose of study intervention and any concomitant therapy administered to the 
participant during the course of the study (starting at the date of informed consent) until 
30 days after the final dose of study intervention will be recorded. Additionally, all 
diagnostic, therapeutic, or surgical procedures relating to malignancy should be recorded. 
Any medication that is considered necessary for the participant’s health, and that is not 
expected to interfere with the evaluation of or interact with the study medication, may be 
continued during the study.
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6.5.1
Allowed Concomitant Medications
Treatment of complications or AEs, or therapy to ameliorate symptoms (including blood 
products, blood transfusions, fluid transfusions, antibiotics, and antidiarrheal drugs), may be 
given at the discretion of the investigator, unless it is expected to interfere with the evaluation 
of (or to interact with) the study medication. Anti-emetic or any other prophylaxis should be 
considered in accordance with institutional guidelines.
Any additional procedural or participant-specific particularities should be discussed with the 
investigator and the Sponsor.
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, antitumor 
interventions (surgical resection, surgical debulking of tumor, etc.), or cancer 
immunotherapy not specified in this protocol.
Note: Topical anticancer agents to treat skin lesions (eg, in situ melanoma or squamous 
cell carcinoma) are allowed, excluding skin metastasis of melanoma.
Note: Palliative surgery to treat a nontarget symptomatic solitary lesion or to the brain 
will be allowed after confirmed progressive disease. Palliative surgery to treat nontarget 
lesions without documentation of progressive disease will need Sponsor consultation and 
approval. Palliative surgery of target lesions is not allowed.
•
Other concurrent investigational drugs.
•
Live vaccines within 30 days and while participating in the study. Examples of live 
vaccines include, but are not limited to, the following: measles, mumps, rubella, chicken 
pox, yellow fever, rabies, BCG, and typhoid (oral) 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.
•
Systemic glucocorticoids for any purpose other than to modulate symptoms from an AE 
that is suspected to have immunologic etiology. Physiologic doses of corticosteroids not 
exceeding 10 mg daily of prednisone equivalent may be used during the study. 
Note: Inhaled steroids are allowed for management of asthma or seasonal allergies.
•
Palliative radiotherapy other than to treat a symptomatic solitary lesion or to the brain, 
and only after initial documentation of progressive disease. Palliative radiotherapy to 
treat nontarget lesions without documentation of progressive disease will need Sponsor 
consultation and approval. Palliative radiotherapy of target lesions without 
documentation of progressive disease is not allowed.
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For participants who, in an assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management, continuation of study intervention and 
further participation in the study must be discussed and agreed upon with the Sponsor.
If participants receive additional anticancer therapies, this will be judged to represent 
evidence of disease progression, and study medication will be discontinued. These 
participants should complete all end of treatment assessments and continue to be followed for 
survival in the Follow-up Period.
6.5.3
Drug Interactions
There are no DDI-related concomitant medication prohibitions or restrictions.
Lenvatinib is not expected to clinically alter exposure to CYP3A4/ P-glycoprotein (Pgp) 
substrates based on results from a lenvatinib DDI study with midazolam (a sensitive CYP3A 
and Pgp substrate). Clinical studies also showed that coadministration of lenvatinib with 
either inducers or inhibitors of CYP3A4/Pgp is not of clinical concern.
No drug interaction is expected between pembrolizumab and lenvatinib because of divergent 
metabolic pathways. Pembrolizumab is a monoclonal antibody and is primarily catabolized 
like other proteins, while lenvatinib is metabolized by enzymatic (CYP3A and aldehyde 
oxidase) and non-enzymatic 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. For participants receiving pembrolizumab + lenvatinib, suggested 
supportive care measures for the management of AEs with potential immunologic etiology 
are outlined in Table 4 in Section 6.6.1 along with the dose modification guidelines in Table 
5 and Table 6 in Section 6.6.1 and Section 6.6.2, respectively. 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 or lenvatinib. 
Note: If after the evaluation of an event, it is determined not to be related to pembrolizumab
or lenvatinib, the investigator does not need to follow the treatment guidance. It may be 
necessary to perform conditional procedures such as bronchoscopy, endoscopy, or skin 
photography as part of evaluation of an event.
6.5.5
Hematopoietic Growth Factors
Primary prophylactic use of granulocyte colony stimulating factors (G-CSF) may be used per 
the discretion of the treating physician and in line with local guidelines.
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6.6
Dose Modification (Escalation/Titration/Other)
6.6.1
Pembrolizumab
Pembrolizumab dose reductions are not permitted. Pembrolizumab treatment may be 
interrupted or discontinued due to toxicity. Pembrolizumab may be interrupted for a 
maximum of 12 weeks. An interruption of study intervention for more than 12 weeks will 
require Sponsor approval before treatment can be resumed (see Section 6.4). 
6.6.1.1
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue)
Dose Modification and Toxicity Management for 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 irAEs associated with 
pembrolizumab monotherapy, coformulations, or IO combinations are provided in Table 4.
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Table 4
Dose Modification and Toxicity Management Guidelines for 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
AST / ALT 
Elevation or 
Increased 
Bilirubin
Grade 2
Withhold
   Administer corticosteroids 
(initial dose of 0.5-1 mg/kg 
prednisone or equivalent) 
followed by taper
   Monitor with liver function tests (consider weekly or 
more frequently until liver enzyme value returned to 
baseline or is stable)
Grade 3 or 4 
Permanently 
discontinue
   Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper
T1DM or 
Hyperglycemia
New onset T1DM 
or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of β-cell 
failure
Withhold a
   Initiate insulin replacement 
therapy for participants with 
T1DM
   Administer anti-
hyperglycemic in participants 
with hyperglycemia
   Monitor participants for hyperglycemia or other signs 
and symptoms of diabetes
Hypophysitis
Grade 2
Withhold
   Administer corticosteroids 
and initiate hormonal 
replacements as clinically 
indicated
   Monitor for signs and symptoms of hypophysitis 
(including hypopituitarism and adrenal insufficiency)
Grade 3 or 4
Withhold or 
permanently 
discontinue a
Hyperthyroidism 
Grade 2
Continue
   Treat with non-selective 
beta-blockers (eg, 
propranolol) or thionamides 
as appropriate
   Monitor for signs and symptoms of thyroid disorders
Grade 3 or 4
Withhold or 
Permanently 
discontinue a
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irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Hypothyroidism
Grade 2-4
Continue
   Initiate thyroid replacement 
hormones (eg, levothyroxine 
or liothyronine) per standard 
of care
   Monitor for signs and symptoms of thyroid disorders
Nephritis and 
renal dysfunction
Grade 2
Withhold
   Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by taper
   Monitor changes of renal function
Grade 3 or 4
Permanently 
discontinue
Myocarditis
Grade 1 
Withhold
   Based on severity of AE 
administer corticosteroids
   Ensure adequate evaluation to confirm etiology 
and/or exclude other causes
Grade 2, 3 or 4
Permanently 
discontinue
All Other irAEs
Persistent Grade 2
Withhold
   Based on severity of AE 
administer corticosteroids
   Ensure adequate evaluation to confirm etiology or 
exclude other causes
Grade 3
Withhold or 
discontinue b
Recurrent Grade 3 
or Grade 4 
Permanently 
discontinue
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; 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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6.6.1.2
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 5.
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Table 5
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 study drug treatment
Participant may be premedicated 1.5 h 
(± 30 minutes) prior to infusion of 
pembrolizumab with:
-
Diphenhydramine 50 mg PO (or 
equivalent dose of antihistamine).
-
Acetaminophen 500-1000 mg PO 
(or equivalent dose of 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 study drug treatment.
No subsequent dosing
Abbreviations: CTCAE = Common Terminology Criteria for Adverse Events; IV = intravenous; NCI = National Cancer Institute; NSAIDs = nonsteroidal anti-inflammatory drugs; 
PO = by mouth.
Note:  Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of drug administration.
For further information, please refer to the CTCAE v4.0 at http://ctep.cancer.gov
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Other allowed dose interruptions for pembrolizumab 
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as 
medical/surgical events or logistical reasons not related to study therapy. Participants should 
be placed back on study therapy within 3 weeks of the scheduled interruption, unless 
otherwise discussed with the Sponsor. The reason for interruption should be documented in 
the participant's study record. Imaging should not be delayed for delays in cycle treatment.
Participants may interrupt or discontinue pembrolizumab and continue in the study with 
lenvatinib (see Section 4.1). 
6.6.2
Lenvatinib
Lenvatinib dose reduction and interruption for participants who experience lenvatinib-related 
or lenvatinib-pembrolizumab combination therapy-related toxicity will be in accordance with 
the dose modification guidelines described in Table 6. 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 v4.0. 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 20 mg/day. Dose reductions of lenvatinib occur in 
succession based on the previous dose level (14, 10, and 8 mg/day). Any dose reduction 
below 8 mg/day must be discussed with the Sponsor. Once the study intervention dose has 
been reduced, it may not 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.
Refer to the subsections below for management of hypertension (Section 6.6.2.1), proteinuria 
(Section 6.6.2.2), diarrhea (Section 6.6.2.3), hepatotoxicity (Section 6.6.2.4), 
thromboembolic events (Section 6.6.2.5), posterior reversible encephalopathy syndrome/ 
reversible posterior leukoencephalopathy syndrome (PRES/RPLS; Section 6.6.2.6), 
hypocalcemia (Section 6.6.2.7), hemorrhage (Section 6.6.2.8), gastrointestinal perforation or 
fistula formation (Section 6.6.2.9), and osteonecrosis of the jaw (Section 6.6.2.10) as 
appropriate, before consulting the dose modification table (Table 6). For overlapping 
toxicities of pembrolizumab and lenvatinib, please refer to Section 6.6.3.
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Table 6
Dose Modification Guidelines for Lenvatinib-related Adverse Events
Treatment-Related Toxicitya,b
Management
Dose Adjustment
Grade 1 or Tolerable Grade 2
Continue treatment
No change
Intolerable Grade 2c,d or Grade 3e,g
First occurrence
Interrupt lenvatinib until resolved to 
Grade 0-1, or tolerable Grade 2
Reduce lenvatinib dose to 14 mg 
once a day (1-level reduction) 
Second occurrence (same toxicity 
or new toxicity)
Interrupt lenvatinib until resolved to 
Grade 0-1, or tolerable Grade 2
Reduce lenvatinib dose to 10 mg 
once a day (1-level reduction)
Third occurrence (same toxicity 
or new toxicity)
Interrupt lenvatinib until resolved to 
Grade 0-1, or tolerable Grade 2
Reduce lenvatinib dose to 8 mg 
orally once a day (1-level 
reduction)
Fourth occurrence (same toxicity 
or new toxicity)
Interrupt lenvatinib 
Discuss with Sponsor
Grade 4f,g: Discontinue Study Intervention
Abbreviations: AE = adverse event; BMI = body mass index; CTCAE = Common Terminology Criteria for Adverse Events.
Note: For grading see CTCAE version 4.0. Collect all AE grades (ie, decreasing and increasing CTCAE grade).
a
An interruption of study intervention for more than 28 days will require Sponsor’s approval before treatment can be 
resumed.
b
Initiate optimal medical management for nausea, vomiting, hypertension, hypothyroidism, and/or diarrhea prior to any 
lenvatinib interruption or dose reduction. 
c
Applicable only to Grade 2 toxicities judged by the participant and/or physician to be intolerable.
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 intervention at a lower dose once their 
weight remains stable for at least 1 week and they reach at least a BMI of 25. The new stable weight should be used as 
the new baseline for further dose reductions. 
e
For asymptomatic laboratory abnormalities, such as Grade ≥3 elevations of amylase and lipase that are not considered 
clinically relevant by the investigator, continuation of treatment should be discussed with Sponsor.
f
Excluding laboratory abnormalities judged to be nonlife-threatening, in which case manage as Grade 3.
g
For Grade 3 thromboembolic event, permanently discontinue lenvatinib. See Section 6.6.2.5.
6.6.2.1
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.
Regular assessment of BP should be as detailed in the SoA (Section 1.3). 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 first BP measurement of the current assessment 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 
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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 co-morbidities). 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 the Day 15 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 to the participant to capture the 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 intervention can be continued without dose 
modification.
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.
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- 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 Sponsor.
The following guidelines should be followed for the management of Grade 4 hypertension 
(life-threatening consequences):
1. Institute appropriate medical management
2. Discontinue study drug
6.6.2.2
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).
2. A 24-hour urine collection initiated as soon as possible and at least within 72 hours 
(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 study 
drug
- 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+.
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3. A 24-hour urine collection (initiated as soon as possible and at least within 72 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 lenvatinib administration will be 
based on the grade of proteinuria according to Table 6.
-
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.
- Proteinuria monitoring can be performed at the local laboratory or investigator site 
but must be managed by the site physician.
6.6.2.3
Management of Diarrhea
An antidiarrheal agent should be recommended to the participant at the start of study 
intervention, 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 6 should be followed.
6.6.2.4
Management of Hepatotoxicity
Liver function tests (ALT, AST, and bilirubin levels) should be conducted as detailed in the 
SoA (Section 1.3) and as clinically indicated. If signs/symptoms indicating liver injury occur, 
instructions contained in Table 6 should be followed. Appropriate supportive care should be 
provided together with close monitoring. If hepatic failure occurs, the study drug must be 
discontinued.
6.6.2.5
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 
treating physician. If a thromboembolic event is confirmed, instructions contained in Table 6
should be followed. Appropriate supportive care should be provided together with close 
monitoring. Lenvatinib must be discontinued for a Grade 3 thromboembolic event that 
requires urgent intervention. If a participant experiences a Grade 3 or a life-threatening 
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(Grade 4) thromboembolic reaction, including pulmonary embolism, lenvatinib/placebo 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 study 
intervention discontinuation.
6.6.2.6
Management of Posterior Reversible Encephalopathy Syndrome/Reversible
Encephalopathy Syndrome/Reversible Posterior Leukoencephalopathy 
Syndrome
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 6 should be followed.
6.6.2.7
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.
6.6.2.8
Management of Hemorrhage
Instructions in Table 6 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.
6.6.2.9
Management of Gastrointestinal Perforation or Fistula Formation
Lenvatinib should be discontinued in any participants who develop gastrointestinal 
perforation of any grade or ≥Grade 4 fistula.
6.6.2.10
Management of Osteonecrosis
Perform an oral examination prior to treatment with lenvatinib and periodically during 
lenvatinib treatment. Advise participants regarding good oral hygiene practices. Avoid 
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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 6.6.4).
6.6.3
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.
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.
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3. Participants receiving the combination therapy (pembrolizumab + lenvatinib) must 
discontinue study intervention if any of the following occur:
o
ALT or AST >5 × ULN for more than 2 weeks
Pembrolizumab will have already been permanently discontinued per Table 4, but 
lenvatinib may be administered at a reduced dose by the time this criterion is met 
and must be permanently discontinued immediately.
o
ALT or AST >3 × ULN and (TBL >2 × ULN or INR >1.5)
Although Table 4 advises pembrolizumab to be withheld (interrupted), and Table 
6 advises lenvatinib to have no dose modification or a reduction, if this criterion is 
met, both drugs must be permanently discontinued immediately.
6.6.4
Other Allowed Dose Interruptions for Lenvatinib and Pembrolizumab
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.
Pembrolizumab 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 study therapy 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.
6.7
Intervention After the End of the Study
There is no study-specified intervention following the end of the study.
6.8
Clinical Supplies Disclosure
This study is open-label; therefore, the participant, the study site personnel, the Sponsor, 
and/or designee are not blinded. Study intervention is included in the label text; random 
code/disclosure envelopes or lists are not provided.
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.
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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 discontinued 
from the study intervention at the discretion of the investigator should any untoward effect 
occur. In addition, a participant may be discontinued from study intervention by the 
investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or 
for administrative and/or other safety reasons. Specific details regarding procedures to be 
performed at study intervention discontinuation are provided in Section 8.1.9.
A participant must be discontinued from study intervention but continue to be monitored in 
the study for any of the following reasons:
•
The participant or participant’s legally acceptable representative requests to discontinue 
study intervention.
•
The participant has a medical condition or personal circumstance, which, in the opinion 
of the investigator and/or Sponsor, placed the participant at unnecessary risk from 
continued administration of study intervention.
•
The participant has a confirmed positive serum pregnancy test.
•
Progressive disease as verified by investigator.
Note: Participants will be permitted to continue treatment beyond confirmed 
RECIST 1.1-defined progression if investigator-assessed clinical stability is observed,
and the participant is tolerating study intervention (Section 8). Treatment beyond 
progressive disease per iRECIST may be permitted following Sponsor consultation and 
approval.
•
Any progression or recurrence of any malignancy, or any occurrence of another 
malignancy that requires active treatment. Exceptions to secondary malignancy include 
basal cell carcinoma of the skin, squamous cell carcinoma of the skin, new non-ulcerated 
primary melanoma <1 mm in depth with no nodal involvement, or carcinoma in situ (eg, 
breast carcinoma, cervical cancer in situ) that have undergone potentially curative 
therapy. Exceptions should be discussed with the Sponsor prior to continuing therapy or 
remaining in follow-up.
•
Recurrent Grade 2 pneumonitis and other AEs that may require treatment discontinuation
per Section 6.6 (Dose Modification).
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•
Completion of 35 treatments (approximately 2 years) with pembrolizumab. 
Note: Participants may receive lenvatinib monotherapy until disease progression or 
unacceptable toxicity.
•
Grade 3 thromboembolic events require permanent discontinuation of lenvatinib.
•
Participants receiving the combination therapy (pembrolizumab + lenvatinib) must 
discontinue study intervention if any of the following occur:
o
ALT or AST >5 × ULN for more than 2 weeks
Pembrolizumab will have already been permanently discontinued per Table 4, but 
lenvatinib may be administered at a reduced dose by the time this criterion is met and 
must be permanently discontinued immediately.
o
ALT or AST >3 × ULN and (TBL >2 × ULN or INR >1.5)
Although Table 4 advises pembrolizumab to be withheld (interrupted), and Table 6
advises lenvatinib to have no dose modification or a reduction, if this criterion is met, 
both drugs must be permanently discontinued immediately.
A participant may be discontinued from study intervention but continue to be monitored in 
the study for the following reason:
•
Discontinuation of study intervention with pembrolizumab and lenvatinib may be 
considered for participants who have attained a confirmed CR and have been treated for 
at least 24 weeks, receiving at least 2 doses of pembrolizumab beyond the date when the 
initial CR was declared.
Note: The number of treatments is calculated starting with the first dose of 
pembrolizumab.
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.
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7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
•
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
•
The investigator or designee must make every effort to regain contact with the participant 
at each missed visit (eg, telephone calls and/or a certified letter to the participant’s last 
known mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
•
Note: A participant is not considered lost to follow-up until the last scheduled visit for the 
individual participant. The missing data for the participant will be managed via the 
prespecified statistical data handling and analysis guidelines.
8
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and their timing are summarized in the SoA.
•
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
•
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified or trained staff. Delegation of study site personnel responsibilities 
will be documented in the Investigator Trial File Binder (or equivalent).
•
All study-related medical or dental decisions must be made by an investigator who is a 
qualified physician.
•
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.
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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 their legally acceptable 
representative) prior to participating in this clinical study. If there are changes to the 
participant’s status during the study (eg, health or age of majority requirements), the 
investigator or medically qualified designee must ensure the appropriate consent is in place.
8.1.1.1
General Informed Consent
    Informed consent given by the participant or their legally acceptable representative must 
be documented on a consent form. The form must include the trial protocol number, trial 
protocol title, dated signature, and /agreement of the participant (or his/her legally 
acceptable representative) and of the person conducting the consent discussion..
    A copy of the signed and dated informed consent form should be given to the participant 
(or their legally acceptable representative) before participation in the study.
    The initial ICF, any subsequent revised ICF, and any written information provided to the 
participant must receive the IRB/IEC’s approval/favorable opinion in advance of use. The 
participant or his/her legally acceptable representative should be informed in a timely 
manner if new information becomes available that may be relevant to the participant’s 
willingness to continue participation in the study. The communication of this information 
will be provided and documented via a revised consent form or addendum to the original 
consent form that captures the participant’s or the participant’s legally acceptable 
representative’s dated signature.
    If the investigator recommends continuation of study intervention beyond disease 
progression, the participant or their legally acceptable representative will be asked to 
provide documented informed consent.
    Specifics about the study and the study population are to be included in the study 
informed consent form.
    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.
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8.1.3
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant provides documented informed consent. At the time of intervention 
allocation/randomization, site personnel will add the intervention/randomization number to 
the participant identification card.
The participant identification card also contains contact information for the emergency 
unblinding call center so that a healthcare provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
8.1.4
Medical History
A medical/surgical history and staging will be obtained by the investigator or qualified 
designee. The medical and surgical history will collect all active conditions and any 
condition diagnosed within the prior 10 years that the investigator considers to be clinically 
significant. This will include disease staging at initial diagnosis and at study entry.
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 30 days before first dose of study medication.
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study. Concomitant medications will be recorded for 30 days after the last dose.
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 intervention allocation.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.
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8.1.7
Assignment of Treatment/Randomization Number
All eligible participants will be allocated, by nonrandom assignment, 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.
A single participant cannot be assigned more than 1 treatment/randomization number.
8.1.8
Study Intervention Administration
Lenvatinib: Lenvatinib may be taken at home except on C1D1, C1D15, and C2D1; on these 
days lenvatinib will be taken in the clinic. Please refer to Section 8.1.8.1 for further details. 
Pembrolizumab: Pembrolizumab will be administered by the investigator and/or study staff 
according to the specifications within the Pharmacy Manual. 
8.1.8.1
Timing of Dose Administration
8.1.8.1.1
Lenvatinib
Lenvatinib 20 mg (two 10-mg capsules) once daily will be taken orally with water (with or 
without food) at approximately the same time each day in 21-day cycles. Participants should 
not take lenvatinib on C1D1, C1D15, or C2D1 before their appointment; on C1D15 and 
C2D1, participants should be instructed to bring their lenvatinib to the clinic. On C1D1 and 
C2D1, lenvatinib will be administered in the clinic 0-4 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 will be administered as a 30-minute IV infusion on Day 1 of each 21-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 to +10 minutes is permitted (ie, infusion time is 30 minutes: –5 min/+10 min).
After Cycle 1 Day 1, pembrolizumab may be administered up to 3 days before or after the 
scheduled Day 1 of each subsequent cycle due to administrative reasons.
8.1.8.2
Compliance 
Lenvatinib: Lenvatinib compliance will be calculated by the Sponsor based on the study 
drug accountability documented by the site staff and monitored by the Sponsor/designee. The 
objective is 100% compliance and investigators and their staff should evaluate compliance at
each visit and take appropriate steps to optimize compliance.
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Pembrolizumab: Administration of pembrolizumab will be administered by the investigator 
and/or qualified designee. The total volume of study intervention infused will be compared 
with the total volume prepared to determine compliance with each dose administered.
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 End-of-treatment visit should be performed (at the time of withdrawal). 
Any AEs that are present at the time of withdrawal should be followed in accordance with 
the safety requirements outlined in Section 8.4 .
8.1.10 Participant Blinding/Unblinding
This is an open-label study; there is no blinding for this study.
8.1.11 Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained is reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
8.1.12 Demography
Participant demography information will be collected at the Screening visit. Demography 
information includes date of birth (or age), sex, and race/ethnicity.
8.1.13 Subsequent Antineoplastic Treatment 
The investigator or qualified designee will review all new antineoplastic treatment initiated 
after the last dose of study intervention. Once new antineoplastic treatment has been initiated, 
the participant will move into Survival Follow-up. All antineoplastic treatment 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. 
8.2
Efficacy/Immunogenicity Assessments
8.2.1
Tumor Imaging and Assessment of Disease
The process for image collection and transmission to the CIV can be found in the SIM. In 
general, imaging should include the chest, abdomen, and pelvis. Tumor imaging of the chest 
is to be acquired by CT scan. For the abdomen and pelvis, contrast-MRI may be used when 
CT with iodinated contrast is contraindicated, or when mandated by local practice. MRI is 
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the strongly preferred modality for imaging the brain. Imaging of any anatomy that shows 
disease either at screening or in subsequent evaluations will be required and should be 
submitted to the CIV. The same imaging technique regarding modality 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 located at the site or at an offsite facility. Participant eligibility will be 
determined using prospective BICR assessment of measurable disease based on RECIST 1.1.
All scheduled images for all study participants from the sites will be submitted to the CIV. 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 that 
demonstrate radiologic progression, should also be submitted to the CIV.
8.2.1.1
Initial Tumor Imaging
The site’s study team must have reviewed images from at least 3 dates to confirm that 
radiographic progression has occurred per RECIST 1.1 and confirmed per iRECIST no less 
than 4 weeks from the date of the first documented PD in the absence of rapid clinical 
progression. These images should include:
1. Baseline image for prior anti-PD-1/L1 or an image showing nadir during prior anti-PD-
1/L1 agent treatment
2. An image showing progression on prior anti-PD-1/L1 treatment
3. An image confirming progression on prior anti-PD-1/L1 agent treatment, no less than 4 
weeks from the date of the first documented PD (Note: in rapidly progressing 
participants, confirmation of PD by a second scan may be waived after consultation with 
the Sponsor).
These images may have been collected prescreening, and the final image confirming 
progression may also be the baseline tumor image on trial, if collected during the 28-day 
screening window. The CIV must have received these scans prior to treatment allocation in 
this study for a retrospective analysis of the eligibility criterion of progression on prior 
PD-1/L1 agent. The CIV must also confirm that the images are of diagnostic quality prior to 
treatment allocation.
The baseline tumor image collected during the screening period must be also submitted to the 
CIV for confirmation of measurable disease per RECIST 1.1 for eligibility prior to treatment 
allocation.
Tumor imaging performed as part of routine clinical management is acceptable for use as 
baseline tumor imaging if it is of diagnostic quality and performed within 28 days prior to the 
date of treatment allocation, and can be assessed by the CIV. 
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A brain MRI at screening will be performed in all participants. When brain imaging is 
performed, MRI should be used if possible. If MRI is medically contraindicated, then CT 
with contrast is an acceptable alternative.
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 treatment allocation. Subsequent tumor imaging should be performed every 
9 weeks (63 days ±7 days) or more frequently if clinically indicated. Following Week 54, 
imaging should be performed Q12W, or sooner if clinically indicated until Week 102. 
Following Week 102, imaging should be performed every Q24W, or sooner if clinically 
indicated. Imaging timing should follow calendar days from treatment allocation and should 
not be adjusted for delays in cycle starts. Imaging should continue to be performed until 
disease progression per RECIST 1.1 is identified by the investigator (unless the investigator
is able continue treatment and follow iRECIST), the start of new anticancer treatment, 
withdrawal of consent, or death, or notification by the Sponsor, whichever occurs first. 
Following initial brain imaging, subsequent brain imaging will be performed on all 
participants with brain disease present at screening, or as clinically indicated. This imaging 
will be performed every Q9W (±7 days) after treatment allocation, or sooner if clinically 
indicated, until Week 54. Following Week 54, imaging should be performed Q12W, or 
sooner if clinically indicated, until Week 102. Following Week 102, imaging should be 
performed every Q24W, or sooner if clinically indicated.
Objective response should be confirmed by a repeat imaging assessment. Tumor imaging to 
confirm PR or CR should be performed at the next scheduled scan or at least 4 weeks after 
the first indication of a response is observed. If participants confirmed PR or CR outside their 
regular scheduled imaging, they 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. 
Per iRECIST (Section 8.2.1.5), disease progression should be confirmed by the site 4 to 
8 weeks after site-assessed first radiologic evidence of progressive disease in clinically stable 
participants. Participants who have unconfirmed disease progression may continue on study 
intervention 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 intervention. Treatment beyond disease 
progression per iRECIST may be permitted upon Sponsor consultation and approval.
8.2.1.3
End-of-treatment and Follow-up 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 
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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. All images should be submitted to the CIV.
For participants who discontinue study intervention without documented disease progression, 
every effort should be made to continue monitoring disease status by tumor imaging using 
the same imaging schedule used while on treatment calculated from the date of allocation 
(see Section 8.2.1.2) until the start of a new anticancer treatment, disease progression, 
pregnancy, death, withdrawal of consent, or the end of the study, or notification by the 
Sponsor, whichever occurs first.
8.2.1.4
RECIST 1.1
RECIST 1.1 will be used by BICR as the primary measure for assessment of tumor response, 
date of disease progression, and as a basis for all protocol guidelines related to disease status 
(eg, discontinuation of study intervention). Although RECIST 1.1 references a maximum of 
5 target lesions in total and 2 per organ, this protocol allows a maximum of 10 target lesions 
in total and 5 per organ, if clinically relevant, to enable a broader sampling of tumor burden. 
8.2.1.5
RECIST 1.1 for Immune-based Therapeutics (iRECIST)
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 8. This allowance to continue 
study intervention 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. These data will be 
captured in the clinical database.
Clinical stability is defined as the following: 

Absence of symptoms and signs (including worsening of laboratory values) indicating 
progression of disease

Absence of rapid progression of disease or of progressive tumor at critical anatomical 
sites (eg, cord compression) requiring urgent alternative medical intervention

No decline in ECOG performance status 

No requirements for intensified management, including increased analgesia, radiation, or 
other palliative care
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Any participant deemed clinically unstable should be discontinued from study intervention at 
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 
CIV for 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 8, 
study intervention should be discontinued; however, if the participant is achieving a 
clinically meaningful benefit, an exception to continue study intervention may be considered 
following consultation with Sponsor and after the following criteria have been met: 
(1) absence of symptoms and signs (including worsening of laboratory values) indicating 
disease progression, and (2) absence of rapid progression of disease or of progressive tumor 
at critical anatomical sites (eg, cord compression) requiring urgent alternative medical 
intervention.  
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 CIV. A 
description of the adaptations and iRECIST process is provided in Appendix 8, 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 7.
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Table 7
Imaging and Treatment After First Radiologic Evidence of Progressive Disease
Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
First radiologic 
evidence of PD 
by RECIST 1.1 
Repeat imaging at 
4 to 8 weeks to 
confirm PD.
May continue study 
intervention 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; iRECIST = 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; VOP = verification of progression.
8.3
Safety Assessments
Progression of melanoma and signs and symptoms clearly related to the progression of 
melanoma should not be captured as an AE. Disease progression is a study endpoint and 
should be captured in the CRF as per the guidelines for reporting disease progression.
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 the laboratory 
manual.
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Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
A complete physical examination including oral examination will be conducted by an 
investigator or medically qualified designee (consistent with local requirements) as per 
institutional standard. Physical examinations (comprehensive or symptom-directed) will be 
performed as specified in the SoA (Section 1.3). A comprehensive physical examination will 
include evaluations of the head, eyes, ears, nose, throat, neck, chest (including heart and 
lungs), abdomen, limbs, skin, and a complete neurological examination.
Documentation of the physical examination will be included in the source documentation at 
the investigational site. Significant findings prior to participant treatment allocation will be 
recorded on the appropriate CRF. Changes from screening physical examination findings that 
meet the definition of an AE will be recorded on the appropriate CRF. Weight will also be 
measured and recorded. Height will only be measured and recorded at screening.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.3.2
Vital Signs
The investigator or qualified designee will take vital signs at Screening, before the 
administration of each dose of study intervention and during the Follow-up Period, as 
specified in the SoA (Section 1.3). Vital signs include temperature, heart rate, respiratory 
rate, weight, and blood pressure. Height will be measured at Screening only.
•
Blood pressure and heart rate 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 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.
•
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.
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8.3.3
Electrocardiograms
•
Electrocardiograms 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.
•
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. 
•
QTc prolongation has been seen in some lenvatinib studies. Monitor ECGs every cycle 
(as specified in the Schedule of Assessments) in patients with congenital long QT 
syndrome, congestive heart failure, bradyarrhythmias, or those who are taking drugs 
known to prolong the QT interval, including Class Ia and III antiarrhythmics. Please refer 
to the lenvatinib IB.
8.3.4
Echocardiogram or Multiple Gated Acquisition Scan

A MUGA scan (using technetium-based tracer) or an echocardiogram will be performed
to assess left ventricular ejection fraction (LVEF) as designated in the SoA (Section 1.3). 
MUGA or echocardiogram 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 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
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.
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•
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.
8.3.5.1
Hematology and Clinical Chemistry
Hematology and clinical chemistry assessments will be performed within 3 days prior to 
administration of first dose of study intervention and prior to all subsequent scheduled visits.
The results must be reviewed prior to administration of study therapy. Electrolytes such as 
potassium, calcium, and magnesium should be monitored and abnormalities, when 
considered clinically significant, should be corrected in all participants before starting 
treatment.
8.3.5.2
Urine Dipstick 
Urine dipstick testing will be performed locally within 3 days prior to start of treatment. At 
baseline, participants with >1+ proteinuria on urine dipstick during screening will undergo 
24-hour urine collection for quantitative assessment of proteinuria. Participants with urine 
protein ≥1 g/24-hour will not be eligible.
Once participants are allocated to treatment, 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. Urine dipstick 
testing should be performed at the investigational site. If a new event of proteinuria ≥2+ 
occurs, the participant must resume the Day 15 urine dipstick testing for evaluation of 
proteinuria until results are 1+ or negative for 2 consecutive treatment cycles.
For participants with proteinuria ≥2+, see Section 6.6.2.2 for management of proteinuria.
8.3.5.3
Pregnancy Test
All women who are being considered for participation in the study, and who are not 
surgically sterilized or postmenopausal, must be tested for pregnancy within 24 hours of the 
first dose of study intervention.
8.3.6
Eastern Cooperative Oncology Group Performance Status
The investigator or qualified designee will assess ECOG performance status at Screening and 
before the administration of each cycle of study intervention and as specified in the SoA 
(Section 1.3).
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8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Reportable 
Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3.
Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant's legally authorized 
representative).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators remain responsible for following up AE, 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.
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 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 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 cessation of study intervention, or 
30 days following cessation of study intervention if the participant initiates new 
anticancer therapy must be reported by the investigator.
•
Additionally, any SAE brought to the attention of an investigator at any time outside the 
time period specified above must be reported immediately to the Sponsor if the event is 
considered drug-related.
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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 8.
Table 8
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:
Nonserious Adverse 
Event (NSAE) 
Report if:
- due to protocol-
specified 
intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other 
run-in treatment
Report all
Not required
Per data entry 
guidelines
Serious Adverse 
Event (SAE) 
including Cancer 
and Overdose
Report if:
- due to protocol-
specified 
intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other 
run-in treatment
Report all
Report if:
- drug/vaccine related.
(Follow ongoing to 
outcome)
Within 24 hours 
of learning of 
event
Pregnancy/Lactation 
Exposure
Report if:
- due to 
intervention
- causes exclusion
Report all
Previously reported –
Follow to 
completion/termination; 
report outcome
Within 24 hours 
of learning of 
event
Event of Clinical 
Interest (require 
regulatory reporting)
Report if:
- due to 
intervention
- causes exclusion
Report
- Potential DILI
- Require regulatory 
reporting
Not required
Within 24 hours 
of learning of 
event
Event of Clinical 
Interest (Do not 
require regulatory 
reporting)
Report if:
- due to 
intervention
- causes exclusion
Report
- non-DILI ECIs 
and those not 
requiring regulatory 
reporting
Not required
Within 5 
calendar days of 
learning of event
Abbreviations: DILI = drug-induced liver injury; ECI = event of clinical interest; SAE = serious adverse event.
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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.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.4.5
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to 
the investigator or their designee) that occurs during the study are reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy. 
Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, 
blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth must be reported as 
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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 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 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.
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: 
•
An overdose of Sponsor's product, as defined in Section 8.5, that is not associated with 
clinical symptoms or abnormal laboratory results.
•
An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less 
than 2X the upper limit of normal, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.* 
*Note: These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that must trigger 
an additional evaluation for an underlying etiology. The study site guidance for 
assessment and follow up of these criteria can be found in the Investigator Study File 
Binder (or equivalent).
8.5
Treatment of Overdose
For purposes of this study, an overdose will be defined as any dose exceeding the prescribed 
dose for:

Pembrolizumab: ≥5 times the protocol-specified dose

Lenvatinib: any dose above the protocol-prescribed dose if associated with an AE
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There is no specific antidote for an overdose of lenvatinib. Due to its high degree of plasma 
protein binding, lenvatinib is not expected to be dialyzable. Adverse reactions in patients 
receiving single doses of lenvatinib as high as 40 mg were similar to those in clinical studies 
at the recommended dose for differentiated thyroid cancer, RCC, and HCC.
No specific information is available on the treatment of overdose of pembrolizumab or 
lenvatinib.
All reports of pembrolizumab overdose with and without an AE and all reports of lenvatinib 
overdose with an AE must be reported by the investigator within 24 hours to the Sponsor 
either by electronic media or paper.
Reports of pembrolizumab overdose without any associated clinical symptoms or abnormal 
laboratory results should be reported using the terminology “accidental or intentional 
overdose without adverse effect.”
8.6
Pharmacokinetics
Blood samples will be collected as specified in the SoA (Section 1.3). 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.
To evaluate the immunogenicity and exposure of pembrolizumab in this indication, blood 
samples for PK and ADA will be collected and may be stored only at this time. Further 
analysis may be performed if required and reported separately if conducted. 
Blood samples will be collected from all participants. Plasma concentrations of lenvatinib 
when co-administered with pembrolizumab will be measured. Lenvatinib will be analyzed 
using a population PK approach.
Lenvatinib will be quantified by use of validated High-Performance Liquid Chromatography 
-tandem mass spectroscopy method.
8.6.1
Blood Collection for Serum Pembrolizumab
Sample collection, storage, and shipment instructions for plasma samples will be provided in 
the laboratory manual.
To evaluate pembrolizumab immunogenicity and pembrolizumab exposure in this 
combination with lenvatinib, sample collections for analysis of ADA and PK are currently 
planned as shown in the SoA (Section 1.3). Blood samples will be obtained to measure PK 
and ADA of serum pembrolizumab. These samples collected may be stored at this time. 
Analysis may be performed if required. If ongoing ADA and/or PK results are deemed to be 
unnecessary by the Sponsor, it may be decided to discontinue or reduce further sample 
collection in this study. Should this occur, it will be communicated by an administrative 
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memo. If PK and/or ADA analyses are performed, the results of these analyses will be 
reported separately.
8.6.2
Blood Collection for Plasma Lenvatinib
Blood samples will be collected as specified in the SoA (Section 1.3). 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. 
Plasma concentrations of lenvatinib and serum concentrations of pembrolizumab will be 
measured. Lenvatinib will be analyzed using a population PK approach. Lenvatinib will be 
quantified by use of validated High-Performance Liquid Chromatography-tandem mass 
spectroscopy methods. If at some point prospective PK blood sample collection is no longer 
required, it will be notified to the sites.
8.7
Pharmacodynamics
No pharmacodynamic endpoints are planned for this study.
8.8
Planned Genetic Analysis Sample Collection
The planned genetic analysis sample should be drawn for planned analysis of the association 
between genetic variants in DNA and drug response. This sample will not be collected at the 
site if there is either a local law or regulation prohibiting collection or if the IRB/IEC does 
not approve the collection of the sample for these purposes.
8.9
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 serum biomarkers
•
Blood for genetic analysis
•
Blood for RNA analysis
•
Blood for circulating tumor nucleic acid analysis
•
Blood for plasma biomarkers
•
Tumor blocks or slides
Note: Participants with a newly obtained biopsy considered not adequate may undergo 
re-biopsy at the discretion of the investigator. Please refer to the laboratory manual for 
additional details.
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•
Stool analysis (optional)
Sample collection, storage, and shipment instructions for the exploratory biomarker 
specimens will be provided in the operations/laboratory manual.
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 allocation/randomization, potential participants 
will be evaluated to determine that they fulfill the entry requirements as set forth in 
Section 5. Screening procedures may be repeated after consultation with the Sponsor.
Documented 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 3 days prior to the first dose of study 
intervention. An exception is hepatitis and HIV testing, which may be done up to 28 days 
prior to the first dose of study intervention. Repeated laboratory evaluation to establish 
eligibility is not allowed unless discussed and agreed upon with the Sponsor.
•
Evaluation of ECOG is to be performed within 3 days prior to the date of first dose of 
study intervention.
•
Full physical examination to be performed within 7 days prior to start of study 
intervention.
•
For women of reproductive potential, a urine or serum pregnancy test will be performed 
within 24 hours prior to the first dose of study intervention. If more than 24 hours have 
elapsed prior to first dose of study intervention, another pregnancy test is required prior 
to starting study intervention. If urine pregnancy results cannot be confirmed as negative, 
a serum pregnancy test will be required (performed by the local trial site laboratory).
•
Newly or recently obtained tumor tissue must have been obtained prior to treatment 
allocation and after the latest systemic treatment for melanoma.
•
If additional time is needed for initial image submission and CIV diagnostic quality 
review, an extension of the screening window of up to 7 days may be approved following 
mandatory Sponsor consultation. 
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8.10.1.1
Rescreening
Participants may be rescreened after initially failing to meet the inclusion/exclusion criteria. 
Results from assessments during the initial screening period are acceptable in lieu of a repeat 
screening test if performed within the specified time frame and the corresponding 
inclusion/exclusion criteria is met. 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). Assessments/procedures are to be 
performed prior to the administration of study intervention.
8.10.2.1
Phone Contact Visit
Telephone contact or visit on Cycle 1 Day 8 will be conducted to assess participants for 
development of early toxicity as outlined in the SoA (Section 1.3). 
8.10.3 Posttreatment Visit 
8.10.3.1
Safety Follow-up
Mandatory Safety Follow-up visits should be conducted approximately 30 days and 90 days 
after the last dose of study intervention or before the initiation of a new anticancer treatment, 
whichever comes first. If the EOT visit occurs approximately 30 days from last dose of study 
intervention, the 30-day Safety Follow-up visit is not required. In this situation, all 
procedures required at both the EOT visit and the 30-day Safety Follow-up visit should be 
performed at the EOT visit. End of treatment is defined as the date when the participant 
discontinues all study interventions.
If the 90-day Safety Follow-up visit falls within the same window as the 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 visit.
Participants who attain an investigator-determined confirmed complete response (CR) and 
stop study intervention with pembrolizumab + lenvatinib will have Safety Follow-up visits
and move to follow-up per SoA (Section 1.3).
All AEs that occur prior to the Safety Follow-up visits should be recorded. Participants with 
an AE of Grade >1 will be followed until the resolution of the AE to Grade 0-1 or until the 
beginning of a new anticancer therapy, whichever occurs first. Serious AEs that occur within 
120 days of the end of treatment or before initiation of a new anticancer treatment should 
also be followed and recorded. 
8.10.3.2
Efficacy Follow-up Visits 
Participants who complete the protocol-required cycles of study intervention or who 
discontinue study intervention for a reason other than disease progression will begin the 
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Efficacy Follow-up Phase and should be assessed approximately Q12W (or more frequently 
as needed) by clinic visit to monitor disease status; if a clinic visit is not feasible, the 
participant may be contacted by telephone or email. After Week 102, imaging should be 
performed Q24W. The Sponsor may request survival status to be assessed at additional time 
points during the study (not to exceed approximately 12 weeks). Every effort should be made 
to collect information regarding disease status until the start of new anticancer therapy, 
disease progression, death, end of study or if the participant begins retreatment with 
pembrolizumab as detailed in Section 6.6.4. Information regarding poststudy anticancer 
treatment will be collected if new treatment is initiated. Participants who complete all 
efficacy assessments and/or will not have further efficacy assessments must enter the 
Survival Follow-up Phase.
Participants who attain an investigator-determined confirmed CR and stop study intervention
with pembrolizumab and lenvatinib will have Safety Follow-up visits and move to follow-up 
per SoA. 
8.10.3.3
Survival Follow-up
Participant survival follow-up status will be assessed approximately Q12W to assess for 
survival status until death, withdrawal of consent, or the end of the study, whichever occurs 
first.
The first Survival Follow-up assessment should be scheduled as described below:

For participants who discontinue study intervention and who will not enter the Efficacy 
Follow-up Phase, the first Survival Follow-up contact will be scheduled 12 weeks after 
the Discontinuation Visit and/or Safety Follow-up Visit (whichever is last).

For participants who complete assessments in the Efficacy Follow-up Phase, the first 
Survival Follow-up contact will be scheduled 12 weeks after the last assessment in the 
Efficacy Follow-up Visit has been performed.
8.10.4 Survival Status 
To ensure current and complete survival data are available at the time of database locks, 
updated survival status may be requested during the study by the Sponsor. For example, 
updated survival status may be requested prior to but not limited to an external DMC review, 
interim and/or final analysis. Upon Sponsor notification, all participants who do not/will not 
have a scheduled study visit or study contact during the Sponsor-defined time period will be 
contacted for their survival status.
9
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study. If, after the 
study has begun, changes are made to primary and/or key secondary objectives, or the 
statistical methods related to those objectives, then the protocol will be amended (consistent 
with ICH Guideline E-9). Changes to exploratory or other nonconfirmatory analyses made 
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after the protocol has been finalized, but prior to the conduct of any analysis, will be 
documented in a supplemental SAP (sSAP) and referenced in the Clinical Study Report for 
the study. A separate PK analysis plan as well as biomarker analysis plan may be provided. 
Post hoc exploratory analyses will be clearly identified in the Clinical Study Report.
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Section 9.2 through Section 9.12.
9.1
Statistical Analysis Plan Summary
Study Design 
Overview
A Multicenter, Open-label, Phase 2 Trial to Assess the Efficacy and Safety of Lenvatinib 
(E7080/MK-7902) in Combination with Pembrolizumab (MK-3475) in Participants with 
Advanced Melanoma Previously Exposed to an Anti-PD-1/L1 Agent (LEAP-004)
Treatment 
Assignment
Approximately 100 participants will be enrolled to treatment with the combination of 
pembrolizumab and lenvatinib. This is an open-label study.
Analysis 
Populations
Efficacy and Safety: All Participants as Treated set (APaT)
Primary 
Endpoint(s)
OR as assessed by BICR per RECIST 1.1
Key Secondary 
Endpoint(s)
1.
PFS as assessed by BICR per RECIST 1.1
2.
OS
3.
DOR as assessed by BICR per RECIST 1.1
Statistical Methods 
for Key Efficacy 
Analyses
Estimation of ORR; 
Estimation of PFS, OS, and DOR using the Kaplan-Meier method.
Statistical Methods 
for Key Safety 
Analyses
Counts and percentages of participants with AEs will be provided.
Interim Analyses
No efficacy interim analyses are planned. The external data monitoring committee 
(eDMC) will conduct regular safety monitoring.
Multiplicity
No multiplicity adjustment is planned.
Sample Size and 
Power 
A sample size of approximately 100 is planned. Section 9.9 provides the precision of the 
ORR estimates.
Abbreviations: BICR = blinded independent central review; DOR = duration of response; ORR = objective 
response rate; OS = overall survival; PD-1 = programmed cell death protein 1; PFS = progression-free survival; 
RECIST 1.1 = Response Evaluation Criteria in Solid Tumors 1.1
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 is being conducted as a 
nonrandomized, open-label study, ie, participants, investigators, and Sponsor personnel will 
be aware of participant treatment assignments after each participant is enrolled and treatment 
is assigned.
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9.3
Hypotheses/Estimation
There is no statistical hypothesis to be tested in this study. Objectives and endpoints of the 
study are stated in Section 3.
9.4
Analysis Endpoints
9.4.1
Efficacy Endpoints
9.4.1.1
Primary

Objective Response Rate (ORR) per RECIST 1.1 assessed by BICR
Objective Response is defined as a best overall response of CR or PR. The details of the 
ORR analysis plan can be found in Section 9.6.1.1.
9.4.1.2
Secondary

Progression-free Survival (PFS) per RECIST 1.1 assessed by BICR
PFS is defined as the time from the first day of study intervention to the first documented 
disease progression or death due to any cause, whichever occurs first. See Section 9.6.1.2 for 
definition of censoring.

Overall Survival (OS)
OS is defined as the time from the first day of study intervention to death due to any cause. 
Participants without documented death at the time of the final analysis will be censored at the 
date of the last follow-up.

Duration of Response (DOR) per RECIST 1.1 assessed by BICR
For participants who demonstrate CR or PR, DOR is defined as the time from first 
documented evidence of CR or PR until disease progression or death due to any cause, 
whichever occurs first. See Section 9.6.1.4 for definition of censoring.
9.4.2
Safety Endpoints
Safety measurements are described in Section 4.2.1.2.
9.5
Analysis Populations
9.5.1
Efficacy Analysis Populations
The APaT population will serve as the primary population for the analysis of efficacy data in 
this study. The APaT population consists of all allocated participants who receive at least one 
dose of study intervention.
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9.5.2
Safety Analysis Populations
Safety Analyses will be conducted in the APaT population as well. At least 1 laboratory or 
vital sign measurement obtained subsequent to at least 1 dose of study intervention is 
required for inclusion in the analysis of each specific parameter. To assess change from 
baseline, a baseline measurement is also required.
9.5.3
Population Pharmacokinetic Analysis Set
The Population Pharmacokinetic Analysis Set includes all the participants who have received 
at least 1 dose of study intervention with documented dosing history in the lenvatinib +
pembrolizumab arm and have measurable plasma levels of lenvatinib or serum levels of 
pembrolizumab.
9.6
Statistical Methods
9.6.1
Statistical Methods for Efficacy Analyses
This section describes the statistical methods that address the primary and secondary 
objectives. Methods related to exploratory objectives will be described in the supplemental 
SAP.
9.6.1.1
Objective Response Rate (ORR)
ORR will be calculated as the ratio of the number of participants reported to have achieved a 
confirmed CR or PR verified by BICR, divided by the number of participants included in 
APaT population. Participants in the APaT analysis population without ORR assessments
will be counted as nonresponders.
A 95% exact binomial CI (based on method Clopper and Pearson,1934) will be calculated for 
the true ORR. 
9.6.1.2
Progression-free Survival (PFS)  
The nonparametric Kaplan-Meier method will be used to estimate the PFS distribution. 
95% CIs for the median PFS and PFS point estimates at various follow-up times from first 
day of study intervention will be calculated.
Since disease progression is assessed periodically, progressive disease can occur any time in 
the time interval between the last assessment where progressive disease was not documented 
and the assessment when progressive disease is documented. The true date of progressive 
disease will be approximated by the date of the first assessment at which progressive disease
is objectively documented based on RECIST 1.1 by BICR. Death is always considered as a 
PFS event. Participants who do not experience a PFS event will be censored at the last 
disease assessment. 
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For the analysis of PFS, if the events (progressive disease or death) are immediately after 
more than one 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 censoring rule is
summarized in Table 9. If a participant meets multiple criteria for censoring, the censoring 
criterion that occurs earliest will be applied.
Table 9
Censoring Rules for Analysis of Progression-free Survival
Situation
Date of Progression or Censoring
PD or death documented after 
≤1 missed disease assessment, 
and before new anticancer 
therapy, if any
Progressed at date of documented PD or death
PD or death documented 
immediately after 
≥2 consecutive missed disease 
assessments or after new 
anticancer therapy, if any
Censored at last disease assessment prior to the earlier date of 
≥2 consecutive missed disease assessment and new anticancer therapy, if any
No PD and no death; and new 
anticancer treatment is not 
initiated
Censored at last disease assessment 
No PD and no death; new 
anticancer treatment is initiated
Censored at last disease assessment before new anticancer treatment 
Abbreviations: PD = progressive disease; PFS = progression-free survival
9.6.1.3
Overall Survival (OS)
The nonparametric Kaplan-Meier method will be used to estimate the OS distribution. 
95% CIs for the median OS and OS point estimates at various follow-up times from first day 
of study intervention will be calculated.
9.6.1.4
Duration of Response (DOR)
DOR will be summarized descriptively using the nonparametric Kaplan-Meier method. Only 
the subset of participants who show a CR or PR will be included in this analysis. Censoring 
rules for DOR are summarized in Table 10.
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Table 10
Censoring Rules for Duration of Response
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 immediately 
after ≥2 consecutive missed 
disease assessments or after new 
anticancer therapy, if any
Earlier date of last adequate disease 
assessment prior to ≥2 missed 
adequate disease assessments and 
new anticancer therapy, if any
Censor
(nonevent)
Death or progression after
≤1 missed disease assessments and 
before new anticancer therapy, if 
any
Progressive disease or death
End of response
(Event)
Abbreviations: DOR = duration of response
Note: A missed disease assessment includes any assessment that is not obtained or is considered inadequate for evaluation of 
response. 
9.6.1.5
Analysis Strategy for Key Efficacy Endpoint
Table 11 summarizes the primary analysis approach for key efficacy endpoints.
Table 11
Analysis Strategy for Key Efficacy Endpoints
Endpoint
Statistical Methoda
Analysis 
Population
Missing Data Approach
Primary Endpoints
ORR per RECIST 1.1 
by BICR 
Exact method based on binomial
distribution (Clopper-Pearson
method)
APaT
Participants without assessments 
are considered nonresponders.
Key Secondary Endpoint
PFS per RECIST 1.1 
by BICR
Summary statistics using Kaplan-
Meier method
APaT
Primary censoring rule.
(More details are provided in
Table 9.)
OS
Summary statistics using Kaplan-
Meier method
APaT
Censored at the last known alive 
date.
DOR per RECIST 1.1 
by BICR
Summary statistics using Kaplan-
Meier method
APaT
Nonresponders are excluded from 
analysis. Responders are censored 
according to the censoring rules
listed in Table 10.
Abbreviations: APaT=All Participants as Treated; BICR = blinded independent central review; DOR = duration of response; 
ORR = objective response rate; OS = overall survival; PFS = progression-free survival; RECIST = Response Evaluation 
Criteria in Solid Tumors.
a
Statistical models are described in further detail in the text.
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9.6.2
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
adverse experiences and laboratory parameters.
The broad AE categories consisting of the percentage of participants with any AE, any
drug-related AE, any Grade 3 to 5 AE, any serious AE, any AE that is both drug-related and 
Grade 3 to 5, any AE that is both drug-related and serious, any discontinuation due to an AE, 
and death will be summarized via point estimates with 95% CIs (Table 12).
Table 12
Analysis Strategy for Safety Parameters
Safety Endpoint
Within Group 95% CI
Descriptive Statistics
Any AE
X
X
Any Serious AE
X
X
Any Grade 3-5 AE
X
X
Any Drug-related AE
X
X
Any Serious and Drug-related AE
X
X
Any Grade 3-5 and Drug-related AE
X
X
Discontinuation due to AE
X
X
Death
X
X
Specific AEs, SOCs, or PDLCs
X
Change from Baseline Results (Labs, Vital 
Signs)
X
Abbreviations:  AE = adverse event; CI = confidence interval; PDLC = predefined Limit of Change; SOC = System Organ 
Class.
Note: 95% CIs will be calculated using the Clopper-Pearson method.
X  = results will be provided
For continuous measures such as changes from baseline in laboratory parameters, summary 
statistics for baseline, on-treatment, and change from baseline values will be provided in 
table format.
9.6.3
Demographics and Baseline Characteristics
The number and percentage of participants screened, allocated, the primary reasons for 
screening failure, and the primary reasons for discontinuation will be displayed. 
Demographic variables (eg, age, gender), baseline characteristics, primary and secondary 
diagnoses, and prior and concomitant therapies will be summarized either by descriptive 
statistics or categorical tables for all enrolled participants.
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9.7
Interim Analyses
No interim efficacy analyses are planned for this study. The external data monitoring 
committee (eDMC) will conduct regular safety monitoring as specified in the DMC charter.
However, unblinded efficacy endpoints will be made available to the DMC upon request to 
enable a benefit-risk assessment.
9.8
Multiplicity
No multiplicity adjustment is planned for this study.
9.9
Sample Size and Power Calculations
In this study, approximately 100 participants will be enrolled. Table 13 shows the 2-sided 
95% CI of ORR with 100 participants for different observed response rates based on the 
method of Clopper and Pearson (1934).
Table 13
Two-sided 95% Confidence Interval of ORR with 100 Participants
Number of Observed 
Responders
ORR Estimates
95% CI of ORR
20
20%
(12.7%, 29.2%)
25
25%
(16.9%, 34.7%)
30
30%
(21.2%, 40.0%)
35
35%
(25.7%, 45.2%)
40
40%
(30.3%, 50.3%)
45
45%
(35.3%, 55.3%)
50
50%
(39.8%, 60.2%)
55
55%
(44.7%, 65.0%)
Abbreviations: CI = confidence interval; ORR = objective response rate.
9.10
Subgroup Analyses
To determine whether the response rate is consistent across various subgroups, the estimate 
of the response rate (with a nominal 95% CI) for the primary endpoint will be estimated 
within each category of the following classification variables:
•
Age category (<65 vs. ≥65 years)
•
Sex (female vs. male)
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•
Race (white vs. nonwhite)
•
Disease stage (III vs. IVM1a vs. IVM1b vs IVM1c)
•
Brain metastasis (yes vs. no)
•
ECOG status (0 vs. 1)
•
PD-L1 status (positive vs. negative [includes indeterminate])
•
Geographic region of enrolling site (US vs. ex-US)
•
Prior adjuvant exposure to checkpoint inhibitor (yes vs. no)
•
BRAF wild type vs. BRAF mutant (no prior treatment) vs. BRAF mutant, prior adjuvant 
BRAFi/MEKi treatment, no BRAFi/MEKi treatment for metastatic disease vs. BRAF 
mutant, prior BRAFi/MEKi treatment for metastatic disease, no adjuvant BRAFi/MEKi 
treatment vs. BRAF mutant, prior adjuvant BRAFi/MEKi treatment and BRAFi/MEKi 
treatment for metastatic disease.
•
Lactate dehydrogenase (≤ULN vs. >ULN but <2 × ULN vs. ≥2 × ULN)
•
Participant progressed on prior treatment with CTLA-4+PD-1 combination therapy 
(nivolumab and ipilimumab) (yes vs. no)
A Forest plot will be produced, which provides the estimated point estimates and CIs for the 
treatment effect across the categories of subgroups listed above.
Any specified subgroups that have less than 10 participants will be excluded from analysis. 
9.11
Compliance (Medication Adherence)
Drug accountability data for study intervention will be collected during the study. Any 
deviation from protocol-directed administration will be reported.
9.12
Extent of Exposure
The extent of exposure for lenvatinib will be summarized as duration of treatment in days. 
The extent of exposure for pembrolizumab will be summarized as duration of treatment in 
cycles. Summary statistics will be provided on Extent of Exposure for APaT population.
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1 Code of Conduct for Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing, and reporting these trials 
in compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design and conduct of clinical trials. In all cases, MSD clinical trials will be conducted 
in compliance with local and/or national regulations (including all applicable data protection laws and 
regulations), and International Council for Harmonisation Good Clinical Practice (ICH-GCP), and also in 
accordance with the ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD irrespective of the party (parties) employed for their execution (e.g., contract research organizations, 
collaborative research efforts). This Code is not intended to apply to trials that are observational in nature, or 
which are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the 
full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of MSD or comparator products. Alternatively, MSD 
may conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to 
determine patient preferences, etc.
The design (i.e., participant population, duration, statistical power) must be adequate to address the specific 
purpose of the trial and shall respect the data protection rights of all participants, trial site staff and, where 
applicable, third parties. All trial protocols are and will be assessed for the need and capability to enroll 
underrepresented groups. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
MSD’s clinical trials are conducted globally in many different countries and in diverse populations, including 
people of varying age, race, ethnicity, gender, and accounting for other potential disease related factors. MSD 
selects investigative sites based on medical expertise, access to appropriate participants, adequacy of facilities 
and staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial initiation, 
sites are evaluated by MSD personnel (or individuals acting on behalf of MSD) to assess the ability to 
successfully conduct the trial.
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Where appropriate, and in accordance with regulatory authority guidance, MSD will make concerted efforts 
to raise awareness of clinical trial opportunities in various communities. MSD will seek to engage 
underrepresented groups and those disproportionately impacted by the disease under study. MSD will support 
clinical trial investigators to enroll underrepresented groups and expand access to those who will ultimately 
use the products under investigation.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and Good Clinical Practice 
(GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data are verified versus 
source documentation according to standard operating procedures. Per MSD policies and procedures, if 
potential fraud, scientific/research misconduct, privacy incidents/breaches or Clinical Trial-related 
Significant Quality Issues are reported, such matters are investigated. When necessary, appropriate corrective 
and/or preventative actions are defined and regulatory authorities and/or ethics review committees are 
notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the pre-specified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important 
to patients, physicians, and payers. Some early phase or pilot trials are intended to be hypothesis-generating rather 
than hypothesis testing; in such cases, publication of results may not be appropriate since the trial may be 
underpowered and the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). In summary, authorship should reflect significant contribution to the design and 
conduct of the trial, performance or interpretation of the analysis, and/or writing of the manuscript. All named 
authors must be able to defend the trial results and conclusions. MSD funding of a trial will be acknowledged in 
publications.
III. Participant Protection
A. Regulatory Authority and Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics 
Committee [IEC])
All protocols and protocol amendments will be submitted by MSD for regulatory authority 
acceptance/authorization prior to implementation of the trial or amendment, in compliance with local and/or 
national regulations.
The protocol, protocol amendment(s), informed consent form, investigator’s brochure, and other relevant trial 
documents must be reviewed and approved by an IRB/IEC before being implemented at each site, in compliance 
with local and/or national regulations. Changes to the protocol that are required urgently to eliminate an 
immediate hazard and to protect participant safety may be enacted in anticipation of ethics committee approval. 
MSD will inform regulatory authorities of such new measures to protect participant safety, in compliance with 
local and/or national regulations.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance. 
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At 
a minimum, trial designs will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Participants may withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
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C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible, as well as all 
applicable data protection rights. Unless required by law, only the investigator, Sponsor (or individuals acting on 
behalf of MSD), ethics committee, and/or regulatory authorities will have access to confidential medical records 
that might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD does not pay incentives to 
enroll participants in its trials. However, when enrollment is particularly challenging, additional payments may be 
made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent 
on chart review and medical evaluation to identify potentially eligible participants.
B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may 
wish to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
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 
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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.
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.
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10.1.4 Committees Structure
10.1.4.1
Executive Oversight Committee
The Executive Oversight Committee (EOC) will receive and decide upon any 
recommendations made by the DMC regarding the study. Additional details regarding the 
EOC can be found in the DMC charter.
10.1.4.2
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) 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 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, 
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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.
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 
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or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including participants’ documented informed consent, pertaining to 
the conduct of this study must be retained by the investigator for 15 years after study 
completion unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor.
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.
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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 14 will be performed by the local laboratory.
•
Pregnancy testing:
•
Pregnancy testing requirements for study inclusion are described in Section 5.1.
•
Pregnancy testing (urine or serum as required by local regulations) should be 
conducted at monthly intervals during intervention.
•
Pregnancy testing (urine or serum as required by local regulations) should be 
conducted at the end of relevant systemic exposure and correspond with the time 
frame for female participant contraception in Section 5.1.
•
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.
•
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5.1 and Section 5.2, respectively, 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.
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Table 14
Protocol-required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count 
RBC Indices:
MCVc
MCHc
%Reticulocytesc
WBC count with Differentiala:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Chemistry
Blood Urea Nitrogen 
(BUN)b
Potassium
Aspartate 
Aminotransferase
(AST)/ Serum 
Glutamic-Oxaloacetic 
Transaminase (SGOT)
Total bilirubin (and 
direct bilirubin, if 
total bilirubin is 
elevated above the 
upper limit of 
normal)
Albumin
Bicarbonatec
Chloridec
Phosphorousc
Creatinined
Sodium
Alanine 
Aminotransferase
(ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase (SGPT)
Total Proteinc
Glucose 
Calcium
Alkaline phosphatase
Magnesium
Thyroid-stimulating 
hormone
Free thyroxinee
Lactate dehydrogenasec
Amylase
Lipasej
Cholesterolc
Triglyceridesc
CPKf
Pregnancy test
Triiodothyronine (Total 
T3)e
Routine 
Urinalysisg
Specific gravity
pH, glucose, proteinh, hemoglobin or blood, ketones by dipstick
Microscopic examination (if blood or protein is abnormal)
Other Screening 
Tests
PT/INR and aPTT/PTTi
Serology (HIV RNA, hepatitis B surface antigen [HBsAg], and hepatitis C virus antibody).
Serum or urine β human chorionic gonadotropin (β hCG) pregnancy test (as needed for WOCBP).
a Absolute or % acceptable per institutional standard.
b Urea is acceptable if BUN is not available as per institutional standard.
c Performed only if considered local standard of care.
d GFR (measured or calculated) or creatinine clearance can be used in place of creatinine.
e Free T4, Total T3, and TSH levels will be performed during screening and then repeated on Day 1 of Cycle 2 and then 
every other cycle (starting Cycle 2), at the time of discontinuation (end of treatment), and at the Safety Follow-up visits. 
Free T3 is acceptable where Total T3 cannot be determined. There may be instances when sites are unable to obtain 
thyroid function testing results prior to the scheduled dosing. After C1, review of thyroid function test results after dosing 
is acceptable. 
f CPK isoenzymes (CK-MB) should be evaluated if CPK is greater than 3 × ULN.
g If urine dipstick testing suggests a urinary tract infection, or if clinically indicated, a urine microscopy, culture, and 
sensitivity should be performed at the institution’s laboratory.
h 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 or an immediate spot urine protein-to-creatinine (UPCR) test 
should be done to quantify the 24-hour urine protein excretion. A 24-hour urine collection (initiated as soon as possible 
and at least within 72 hours) to verify the grade of proteinuria is required when UPCR is ≥2.4
i Performed as part of the screening assessment and as clinically indicated for participants taking anticoagulation therapy.
j If amylase is not per institutional standards then lipase is sufficient.
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 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.
•
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.”
Events NOT meeting the AE definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
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•
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 8.4.7 for protocol-specific exceptions.
10.3.2 Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b. Is life-threatening
•
The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
•
Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not an SAE. A pre-existing condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
d. Results in persistent or significant disability/incapacity
•
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
•
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
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.
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f.
Other important medical events
•
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.3.3 Additional Events Reported in the Same Manner as SAE
Additional events that require reporting in the same manner as SAE
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor in the same 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
10.3.4 Recording AE and SAE
AE and SAE recording
•
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.
•
The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.
•
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
•
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.
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•
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.
Assessment of causality
Follow-up of AE and SAE
•
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
•
New or updated information will be recorded in the CRF.
•
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
10.3.5 Reporting of 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.
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•
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).
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
Male Participants
Male participants with female partners of childbearing potential are eligible to participate if 
they agree to 1 of the following during the protocol-defined time frame in Section 5.1:

Be abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long-term and persistent basis) and agree to remain abstinent.

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.
-
The following are not acceptable methods of contraception:
o
Periodic abstinence (calendar, symptothermal, postovulation methods), 
withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea 
method (LAM).
o
Male condom with cap, diaphragm, or sponge with spermicide.
o
Male and female condom cannot be used together.
-
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 
penetration.
Female Participants
Female participants of childbearing potential are eligible to participate if they agree to 
consistent and correct use of a highly effective method of contraception that has a low user 
dependency as described in Table 15 during the protocol-defined time frame in Section 5.1.
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Table 15
Highly Effective Contraception Methods
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 contraceptive implant
•
Intrauterine hormone-releasing system (IUS)b
•
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.

Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for participants of clinical studies.

If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable 
contraceptive implants are limited to those which inhibit ovulation.
a
Male condoms must be used in addition to the hormonal contraception.
b
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).
10.5.3 Pregnancy Testing
Pregnancy testing is required for only WOCBP.
WOCBP should only be included after a negative highly sensitive urine or serum pregnancy 
test assessed within 24 hours of treatment initiation.
Following initiation of treatment pregnancy testing will be performed whenever an expected 
menstrual cycle is missed or when pregnancy is otherwise suspected; at the time points
specified in the SoA, and as required locally.
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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 Canada
Please refer to the current lenvatinib product monograph for management of AEs associated 
with lenvatinib administration.

Section 6.6.2.9 Management of Gastrointestinal Perforation or Fistula Formulation
Lenvatinib should be discontinued in any participant who develops gastrointestinal 
perforation of any grade or ≥Grade 3 fistula.
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10.8
Appendix 8: 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 7]). 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 (including worsening of laboratory values) indicating 
progression of disease

Absence of rapid progression of disease or of progressive tumor at critical anatomical 
sites (eg, cord compression) requiring urgent alternative medical intervention

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 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 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
o
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.
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
Unequivocal progression of nontarget lesion(s) identified at baseline

Development of new lesion(s)
iRECIST defines new response categories, including iUPD (unconfirmed progressive 
disease) and iCPD (confirmed progressive disease). For purposes of iRECIST assessment, 
the first visit showing progression according to RECIST 1.1 will be assigned a visit (overall) 
response of iUPD, regardless of which factors caused the progression.
At this visit, target and nontarget lesions identified at baseline by RECIST 1.1 will be 
assessed as usual.
New lesions will be classified as measurable or nonmeasurable, using the same size 
thresholds and rules as for baseline lesion assessment in RECIST 1.1. From measurable new 
lesions, up to 5 lesions total (up to 2 per organ), may be selected as New Lesions – Target. 
The sum of diameters of these lesions will be calculated and kept distinct from the sum of 
diameters for target lesions at baseline. All other new lesions will be followed qualitatively 
as New Lesions – Nontarget.
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
o
For target lesions, worsening is a further increase in the sum of diameters of 
≥5 mm, compared with any prior iUPD time point
o
For nontarget lesions, worsening is any significant growth in lesions overall, 
compared with a prior iUPD time point; this does not have to meet the 
“unequivocal” standard of RECIST 1.1
o
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
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
Any new factor appears that would have triggered PD by RECIST 1.1
Persistent iUPD
Progression is considered not confirmed, and the overall response remains iUPD, if:

None of the progression-confirming factors identified above occurs AND

The target lesion sum of diameters (initial target lesions) remains above the initial PD 
threshold (by RECIST 1.1)
Additional 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 intervention may continue and follow the 
regular imaging schedule. If PD is confirmed, participants will be discontinued from study 
intervention.
NOTE: If a participant has confirmed radiographic progression (iCPD) as defined above, but 
the participant is achieving a clinically meaningful benefit [For those studies in which PFS is 
the primary endpoint, add the following: 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 2 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
o
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 trial, 
either before or after an instance of pseudo-progression.

Nontarget lesions
o
If nontarget lesions have never shown unequivocal progression, their doing so for 
the first-time results in iUPD.
o
If nontarget lesions have shown previous unequivocal progression, and this 
progression has not resolved, iUPD results from any significant further growth of 
nontarget lesions, taken as a whole.

New lesions
o
New lesions appear for the first time
o
Additional new lesions appear
o
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
o
Previously identified nontarget 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 publications [Seymour, L., et 
al 2017].
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10.9
Appendix 9: ECOG Performance Status
Grade
Description
0
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction.
1
Symptoms, but ambulatory. Restricted in physically strenuous activity, 
but ambulatory and able to carry out work of a light or sedentary nature 
(eg, light housework, office work).
2
In bed <50% of the time. Ambulatory and capable of all self-care, but 
unable to carry out any work activities. Up and about >50% of waking 
hours.
3
In bed >50% of the time. Capable of only limited self-care, confined to 
bed or chair more than 50% of waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair.
5
Dead.
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity 
And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982. The 
Eastern Cooperative Oncology Group, Robert Comis M.D., Group Chair.
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10.10 Appendix 10: Abbreviations
Abbreviation
Expanded Term
ADA
antidrug antibody
AE
adverse event 
ALT
alanine aminotransferase
APaT
all participants as treated
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
BICR
blinded independent central review
BP
blood pressure
BRAF
proto-oncogene B-raf
C
cycle
CD
cluster of differentiation
CI
confidence interval
CIV
central imaging vendor
CNS
central nervous system 
CR
complete response
CRF
Case Report Form 
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTLA-4
cytotoxic T-lymphocyte-associated protein 4
DDI
drug-drug interaction
DMC
Data Monitoring Committee 
DNA
deoxyribonucleic acid 
DOR
duration of response
ECG
electrocardiogram 
ECHO
echocardiogram
ECI
event of clinical interest
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
EMA
European Medicines Agency
EOC
Executive Oversight Committee 
EOT
end of treatment
EU
European Union
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FGF
fibroblast growth factor
FGFR
fibroblast growth factor receptors
FU
follow-up
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Abbreviation
Expanded Term
GCP
Good Clinical Practice 
HBV
hepatitis B virus
HCC
hepatocellular carcinoma
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HR
hazard ratio
HRT
hormone replacement therapy
HUVECs
human umbilical vein endothelial cell
IB
Investigator’s Brochure 
ICF
Informed Consent Form 
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
Ig
immunoglobulin
IND
Investigational New Drug 
INR
international normalized ratio
IRB
Institutional Review Board 
iRECIST
modified Response Evaluation Criteria in Solid Tumors
IUD
intrauterine device
IV
intravenous
LVEF
left ventricular ejection fraction
mAb
monoclonal antibody
MAPK
mitogen-activated protein kinase
MEKi
mitogen-activated protein kinase inhibitor
MRI
magnetic resonance imaging
MTD
maximum tolerated dose 
MUGA
multigated acquisition
NCI
National Cancer Institute
NE
not estimable
NSCLC
non-small cell lung cancer
OR
objective response
ORR
objective response rate
OS
overall survival
PBPK
physiologically based PK
PD-1
programmed cell death 1
PD-L1
programmed cell death ligand 1
PDGF
platelet-derived growth factor
PE
physical examination
PET
positron emission tomography 
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Abbreviation
Expanded Term
PFS
progression-free survival
PK
pharmacokinetic
PR
partial response
PT
prothrombin time
Q3W
every 3 weeks
Q9W
every 9 weeks
Q12
every 12 weeks
QD
once daily
OS
overall survival
RCC
renal cell carcinoma
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
ribonucleic acid
RR
respiratory rate
RTK
receptor tyrosine kinase
SAE
serious adverse event 
SIM
Site Imaging Manual
SoA
schedule of activities
SOC
standard of care
TBL
total bilirubin lab
Tregs
regulatory T cells
ULN
upper limit of normal
US
United States
VEGF
vascular endothelial growth factor
WOCBP
woman/women of childbearing potential 
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11
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