Conditions: Malignant 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: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 674
Healthy volunteers: no

Brief summary:
The purpose of this study is to assess the safety and efficacy of pembrolizumab (MK-3475) combined with lenvatinib (MK-7902/E7080) compared to pembrolizumab alone (with placebo for lenvatinib) as first-line treatment in adults with no prior systemic therapy for their advanced melanoma.

The primary study hypotheses are that: 1) The combination of pembrolizumab and lenvatinib is superior to pembrolizumab and placebo as assessed by Progression-free Survival (PFS) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), and 2) The combination of pembrolizumab and lenvatinib is superior to pembrolizumab and placebo as assessed by Overall Survival (OS). For this study, RECIST 1.1 has been modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ.

Detailed description:
As of 03-April-2023 active participants, investigator, and sponsor personnel or delegate(s) involved in the treatment administration or clinical evaluation of the participants will be unblinded.

Arms:
arm 1: Participants receive pembrolizumab 200 mg via intravenous (IV) infusion on Day 1 of each 3-week cycle for up to 35 administrations (up to approximately 2 years) PLUS lenvatinib 20 mg via oral capsule daily for up to at least 2 years. arm 2: Participants receive pembrolizumab 200 mg via IV infusion on Day 1 of each 3-week cycle for up to 35 administrations (up to approximately 2 years) PLUS placebo for lenvatinib via oral capsule daily for up to at least 2 years.

Interventions: intervention 1: Pembrolizumab intervention 2: Lenvatinib intervention 3: Placebo for lenvatinib
Intervention descriptions: intervention 1: IV infusion intervention 2: Oral capsule intervention 3: Oral capsule

Protocol document:
Prot_SAP_000.pdf: 
Official Protocol Title:
NCT number:
Document Date:
A Phase 3 Randomized, Placebo-controlled Trial to 
Evaluate the Safety and Efficacy of Pembrolizumab 
(MK-3475) and Lenvatinib (E7080/MK-7902) Versus 
Pembrolizumab Alone as First-line Intervention in 
Participants with Advanced Melanoma (LEAP-003)
NCT03820986
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TITLE PAGE
THIS PROTOCOL AND ALL OF THE INFORMATION RELATING TO IT ARE 
CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK SHARP & 
DOHME LLC, RAHWAY, NJ, USA (MSD).
Protocol Title: A Phase 3 Randomized, Placebo-controlled Trial to Evaluate the Safety and 
Efficacy of Pembrolizumab (MK-3475) and Lenvatinib (E7080/MK-7902) Versus 
Pembrolizumab Alone as First-line Intervention in Participants with Advanced Melanoma 
(LEAP-003)
Protocol Number: 003-07 (E7080-G000-312)
Compound Number: MK-7902
Sponsor Name: Merck Sharp & Dohme LLC (hereafter called the Sponsor or MSD)
This 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):
NCT
03820986
EU CT
Not applicable
EudraCT
2018-002520-16
JRCT
Not applicable
WHO
Not applicable
UTN
Not applicable
IND
140155
Approval Date: 26 June 2023
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study 
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 7
26-JUN-2023
Protocol amended consistent with 
recommendations of the eDMC after an interim 
review of the data; specifically, to discontinue the 
study due to lack of efficacy.
Amendment 6
08-SEP-2022
Merck Sharp & Dohme Corp. underwent an 
entity name and address change to Merck Sharp 
& Dohme LLC, Rahway, NJ, USA. This 
conversion resulted only in an entity name change 
and update to the address.
Amendment 5 
UK specific
21-OCT-2021
To address feedback from UK regulatory 
authority.
Amendment 4
18-AUG-2021
Due to slower than expected Overall Survival 
event rate, a third IA for Overall Survival was 
added. IA strategies were adjusted to achieve 
optimal timing for IAs.
Amendment 3
10-MAY-2021
To update the Dose Modification and Toxicity 
Management Guidelines for irAEs and table for 
alignment with the USPI as requested by the 
FDA.
Amendment 2
26-MAR-2020
To clarify AE safety follow-up timelines, to 
clarify allowed concomitant medications, and to 
add MK-7902 program level updates.
Amendment 1
10-JAN-2019
To address feedback from regulatory authority 
and add MK-7902 program level updates.
Original Protocol
26-SEP-2018
Not applicable
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 07
Overall Rationale for the Amendment:
Protocol amended consistent with recommendations of the eDMC after an interim review of 
the data; specifically, to discontinue the study due to lack of efficacy.
Summary of Changes Table
Section Number and 
Name
Description of Change
Brief Rationale
Primary Reason for Amendment
Section 1.1, Synopsis
The changes specify which analyses 
and procedures will or will not 
continue to be conducted.
The changes were made to address new data.
They are consistent with recommendations of the 
eDMC after an interim review of the data; 
specifically, to discontinue the study due to lack 
of efficacy.
Section Number and 
Name
Description of Change
Brief Rationale
Other Changes in Amendment
Throughout
The structure of the protocol has been 
updated.
To comply with current industry 
regulations and guidelines. This 
restructuring does not affect the clinical or 
regulatory integrity of the protocol. All 
other relevant changes and their primary 
reasons are included for completeness.
Section 1.1, Synopsis, 
Duration of Participation
Lenvatinib to be discontinued if progression 
of disease.
Refer to the rationale for Section 1.1.
Section 1.1, Synopsis, 
Study Governance 
Committees
Executive Oversight Committee and eDMC 
are no longer applicable.
Refer to the rationale for Section 1.1.
Section 1.1, Synopsis, 
Hypotheses, Objectives, 
and Endpoints
Clarify which activities will or will not be 
performed during the study for participants 
who are still on study treatment.
Refer to the rationale for Section 1.1.
Section 1.2, Schema
New schema.
Refer to the rationale for Section 1.1.
Section 1.3, Schedule of 
Activities
Clarify which activities will or will not be 
performed during the study for participants 
who are still on study treatment. .
Refer to the rationale for Section 1.1.
Section 2.3, Risk/Benefit 
Assessment
Treatment of participants with study 
interventions is clarified.
Refer to the rationale for Section 1.1.
Section 3, Hypotheses, 
Objectives, and Endpoints
Clarify which activities will or will not be 
performed during the study for participants 
who are still on study treatment.
Refer to the rationale for Section 1.1.
Section 4.1, Overall Design
Overall study design changed.
Refer to the rationale for Section 1.1.
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Section Number and 
Name
Description of Change
Brief Rationale
Section 4.3.3, Maximum 
Dose Exposure for the 
Study
Treatment of participants with study 
interventions is clarified.
Refer to the rationale for Section 1.1.
Section 4.4, Beginning and 
End of Study Definition
Participants may be enrolled in an 
extension study.
Refer to the rationale for Section 1.1.
Section 6.1, Study 
Intervention(s) 
Administered
Treatment of participants with study 
interventions is clarified including 
discontinuation of placebo.
Refer to the rationale for Section 1.1.
Section 6.3.3, Blinding
Study unblinded due to result of IA3.
Refer to the rationale for Section 1.1.
Section 6.5.2, Prohibited 
Concomitant Medication(s)
Updated language to allow palliative 
surgery and palliative radiotherapy.
To clarify that participants may receive 
these treatments as no future efficacy 
analysis is planned.
Section 6.6, Dose 
Modification
Treatment of participants with study 
interventions is clarified.
Refer to the rationale for Section 1.1.1
Section 7.1,
Discontinuation of Study 
Intervention
Central tumor response assessments will be 
discontinued and performed locally in 
participants continuing to receive study 
intervention.
Refer to the rationale for Section 1.1.
Section 8.1.10, Participant 
Blinding/Unblinding
Study unblinded due to result of IA3.
Refer to the rationale for Section 1.1.
Section 8.1.13, Subsequent 
Antineoplastic Treatment
Participants on study intervention should be 
monitored through the AE reporting period.
Refer to the rationale for Section 1.1.
Section 8.2.1, Tumor 
Imaging and Assessment of 
Disease
Participants on study intervention will have 
local tumor imaging assessments.
Refer to the rationale for Section 1.1.
Section 8.2.1.3, End of
treatment and Follow up 
Tumor Scans
Tumor scans are discontinued.
Refer to the rationale for Section 1.1.
Section 8.2.1.5, iRECIST 
Assessment of Disease
Section retained.
Refer to the rationale for Section 1.1.
Section 8.2.2, Patient
reported Outcomes
Assessments will be discontinued.
Refer to the rationale for Section 1.1.
Section 8.8, Biomarkers
Sample collections will be discontinued. 
Refer to the rationale for Section 1.1.
Section 8.10, Medical 
Resource Utilization and 
Health Economics
Data collection will be discontinued.
Refer to the rationale for Section 1.1.
Section 8.11.3.2, Efficacy 
Follow up Visits
Efficacy Follow up Visits will be 
discontinued.
Refer to the rationale for Section 1.1.
Section 8.11.5, Survival 
Follow up
Survival Follow up Visits will be 
discontinued.
Refer to the rationale for Section 1.1.
Section 9, Statistical 
Analysis Plan
Clarifying analyses to be performed.
Refer to the rationale for Section 1.1.
Section 9.1, Statistical 
Analysis Plan Summary
Clarifying analyses to be performed.
Refer to the rationale for Section 1.1.
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Section Number and 
Name
Description of Change
Brief Rationale
Section 9.6, Statistical 
Methods
Clarifying analyses to be performed.
Refer to the rationale for Section 1.1.
Section 9.7, Interim 
Analyses
Clarifying analyses to be performed.
Refer to the rationale for Section 1.1.
Section 9.7.2, Safety 
Interim Analyses
Clarifying analyses to be performed.
Refer to the rationale for Section 1.1.
Section 9.8, Multiplicity
Clarifying analyses to be performed.
Refer to the rationale for Section 1.1.
Section 9.9, Sample Size 
and Power Calculations
Clarifying analyses to be performed.
Refer to the rationale for Section 1.1.
Section 10.7.3, Germany
Participant informed consent and MUGA 
scan information clarified.
Adherence to Health Authority 
requirements.
Throughout
Minor administrative, formatting, 
grammatical, and/or typographical changes 
were made throughout the document.
To ensure clarity and accurate 
interpretation of the intent of the protocol.
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TABLE OF CONTENTS
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................16
1.1
Synopsis.................................................................................................................16
1.2
Schema ..................................................................................................................22
1.3
Schedule of Activities...........................................................................................24
2
INTRODUCTION..........................................................................................................41
2.1
Study Rationale....................................................................................................41
2.2
Background ..........................................................................................................41
2.2.1
Pharmaceutical and Therapeutic Background .............................................41
2.2.1.1
Pembrolizumab ..................................................................................41
2.2.1.2
Lenvatinib ..........................................................................................42
2.2.1.3
Pembrolizumab Plus Lenvatinib........................................................43
2.2.1.4
Melanoma: Epidemiology and Current Therapeutic Options............43
2.2.1.5
Scientific Rationale for the Combination of Lenvatinib With 
Pembrolizumab ..................................................................................45
2.2.1.6
Clinical Data on Lenvatinib in Combination With Pembrolizumab 
for the Treatment of Melanoma.........................................................45
2.2.2
Preclinical and Clinical Studies ...................................................................46
2.2.3
Information on Other Study-related Therapy ..............................................46
2.3
Benefit/Risk Assessment......................................................................................46
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................48
4
STUDY DESIGN............................................................................................................51
4.1
Overall Design......................................................................................................51
4.2
Scientific Rationale for Study Design.................................................................53
4.2.1
Rationale for Endpoints ...............................................................................53
4.2.1.1
Efficacy Endpoints.............................................................................53
4.2.1.1.1
RECIST 1.1..............................................................................54
4.2.1.1.2
RECIST 1.1 for Immune-based Therapeutics (iRECIST) .......54
4.2.1.2
Safety Endpoints................................................................................54
4.2.1.3
Patient-reported Outcomes.................................................................55
4.2.1.3.1
EORTC QLQ-C30 ...................................................................55
4.2.1.3.2
EQ-5D-5L ................................................................................55
4.2.1.4
Pharmacokinetic Endpoints ...............................................................55
4.2.1.5
Pharmacodynamic Endpoints.............................................................56
4.2.1.6
Planned Exploratory Biomarker Research.........................................56
4.2.2
Rationale for the Use of Comparator/Placebo .............................................57
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4.3
Justification for Dose...........................................................................................58
4.3.1
Pembrolizumab ............................................................................................58
4.3.2
Lenvatinib ....................................................................................................59
4.3.3
Maximum Dose Exposure for This Study ...................................................59
4.4
Beginning and End-of-Study Definition ............................................................60
4.4.1
Clinical Criteria for Early Study Termination .............................................60
5
STUDY POPULATION ................................................................................................61
5.1
Inclusion Criteria.................................................................................................61
5.2
Exclusion Criteria................................................................................................65
5.3
Lifestyle Considerations......................................................................................68
5.3.1
Meals and Dietary Restrictions....................................................................68
5.3.2
Pregnancy.....................................................................................................68
5.3.3
Use in Nursing Women................................................................................69
5.4
Screen Failures.....................................................................................................69
5.5
Participant Replacement Strategy......................................................................69
6
STUDY INTERVENTION............................................................................................70
6.1
Study Intervention(s) Administered...................................................................70
6.1.1
Medical Devices...........................................................................................72
6.2
Preparation/Handling/Storage/Accountability .................................................72
6.2.1
Dose Preparation..........................................................................................72
6.2.2
Handling, Storage, and Accountability........................................................72
6.3
Measures to Minimize Bias: Randomization and Blinding..............................73
6.3.1
Intervention Assignment..............................................................................73
6.3.2
Stratification.................................................................................................73
6.3.3
Blinding........................................................................................................73
6.4
Study Intervention Compliance..........................................................................74
6.5
Concomitant Therapy..........................................................................................74
6.5.1
Allowed Concomitant Medication(s)...........................................................74
6.5.2
Prohibited Concomitant Medication(s)........................................................75
6.5.3
Drug Interactions .........................................................................................76
6.5.4
Rescue Medications and Supportive Care ...................................................76
6.6
Dose Modification ................................................................................................76
6.6.1
Dose Modification (Escalation/Titration/Other)..........................................77
6.6.1.1
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue).......................................................................................77
6.6.1.2
Dose Modification and Toxicity Management of Infusion 
Reactions Related to Pembrolizumab................................................80
6.6.2
Dose Modification With Lenvatinib/Placebo ..............................................82
6.6.2.1
Management of Hypertension............................................................84
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6.6.2.2
Management of Proteinuria................................................................86
6.6.2.3
Management of Diarrhea ...................................................................86
6.6.2.4
Management of Hepatotoxicity..........................................................87
6.6.2.5
Management of Thromboembolic Events..........................................87
6.6.2.6
Management of Posterior Reversible Encephalopathy 
Syndrome/Reversible Encephalopathy Syndrome/Reversible 
Posterior Leukoencephalopathy Syndrome .......................................87
6.6.2.7
Management of Hypocalcemia ..........................................................87
6.6.2.8
Management of Hemorrhage .............................................................88
6.6.2.9
Management of Gastrointestinal Perforation or Fistula.....................88
6.6.2.10
Management of QT Prolongation ......................................................88
6.6.2.11
Management of Osteonecrosis of the Jaw .........................................88
6.6.3
Dose Modifications for Overlapping Toxicities ..........................................88
6.6.4
Other Allowed Dose Interruptions for Lenvatinib/Placebo and 
Pembrolizumab ............................................................................................90
6.7
Intervention After the End of the Study............................................................90
6.8
Clinical Supplies Disclosure................................................................................90
6.9
Standard Policies..................................................................................................91
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................92
7.1
Discontinuation of Study Intervention...............................................................92
7.2
Participant Withdrawal From the Study...........................................................93
7.3
Lost to Follow-up .................................................................................................94
8
STUDY ASSESSMENTS AND PROCEDURES........................................................95
8.1
Administrative and General Procedures ...........................................................95
8.1.1
Informed Consent.........................................................................................95
8.1.1.1
General Informed Consent.................................................................95
8.1.2
Inclusion/Exclusion Criteria ........................................................................96
8.1.3
Participant Identification Card.....................................................................96
8.1.4
Medical History ...........................................................................................96
8.1.5
Prior and Concomitant Medications Review...............................................97
8.1.5.1
Prior Medications...............................................................................97
8.1.5.2
Concomitant Medications..................................................................97
8.1.6
Assignment of Screening Number...............................................................97
8.1.7
Assignment of Treatment/Randomization Number.....................................97
8.1.8
Study Intervention Administration ..............................................................97
8.1.8.1
Compliance ........................................................................................98
8.1.8.2
Timing of Dose Administration.........................................................98
8.1.8.2.1
Lenvatinib/Placebo ..................................................................98
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8.1.8.2.2
Pembrolizumab ........................................................................98
8.1.9
Discontinuation and Withdrawal .................................................................98
8.1.10
Participant Blinding/Unblinding..................................................................99
8.1.11
Calibration of Equipment.............................................................................99
8.1.12
Demography...............................................................................................100
8.1.13
Subsequent Antineoplastic Treatment .......................................................100
8.2
Efficacy/Immunogenicity Assessments ............................................................100
8.2.1
Tumor Imaging and Assessment of Disease..............................................100
8.2.1.1
Initial Tumor Scans..........................................................................101
8.2.1.2
Tumor Scans During the Study........................................................101
8.2.1.3
End-of-treatment and Follow-up Tumor Scans ...............................102
8.2.1.4
RECIST 1.1 Assessment of Disease................................................103
8.2.1.5
iRECIST Assessment of Disease.....................................................105
8.2.2
Patient-reported Outcomes.........................................................................106
8.3
Safety Assessments.............................................................................................107
8.3.1
Physical Examinations...............................................................................107
8.3.2
Vital Signs..................................................................................................108
8.3.3
Electrocardiograms ....................................................................................108
8.3.4
Echocardiogram or Multiple Gated Acquisition Scan...............................109
8.3.5
Clinical Safety Laboratory Assessments ...................................................109
8.3.5.1
Laboratory Safety Evaluations (Hematology, Chemistry and 
Urinalysis)........................................................................................109
8.3.5.2
Urine Dipstick..................................................................................109
8.3.6
Eastern Cooperative Oncology Group Performance Status.......................110
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events..................................................................................................................110
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ........................................................110
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events....113
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information.113
8.4.4
Regulatory Reporting Requirements for SAE ...........................................113
8.4.5
Pregnancy and Exposure During Breastfeeding ........................................114
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs..........................................................................................114
8.4.7
Events of Clinical Interest..........................................................................114
8.5
Treatment of Overdose......................................................................................115
8.6
Pharmacokinetics...............................................................................................116
8.6.1
Blood Collection for Serum Pembrolizumab.............................................116
8.6.2
Blood Collection for Plasma Lenvatinib....................................................116
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8.7
Pharmacodynamics............................................................................................117
8.8
Biomarkers .........................................................................................................117
8.8.1
Planned Genetic Analysis Sample Collection............................................117
8.9
Future Biomedical Research Sample Collection.............................................118
8.10
Medical Resource Utilization and Health Economics.....................................118
8.11
Visit Requirements.............................................................................................118
8.11.1
Screening....................................................................................................118
8.11.1.1
Rescreening......................................................................................119
8.11.2
Treatment Period........................................................................................119
8.11.2.1
Phone Contact Visit .........................................................................119
8.11.3
Posttreatment Visit.....................................................................................119
8.11.3.1
Safety Follow-up Visit.....................................................................119
8.11.3.2
Efficacy Follow-up Visits................................................................119
8.11.3.3
Survival Follow-up Contacts ...........................................................120
8.11.4
Survival Status ...........................................................................................120
8.11.5
Vital Status.................................................................................................120
9
STATISTICAL ANALYSIS PLAN ...........................................................................121
9.1
Statistical Analysis Plan Summary...................................................................121
9.2
Responsibility for Analyses/In-house Blinding ...............................................123
9.3
Hypotheses/Estimation ......................................................................................123
9.4
Analysis Endpoints.............................................................................................123
9.4.1
Efficacy Endpoints.....................................................................................123
9.4.2
Safety Endpoints........................................................................................124
9.4.3
Patient-reported Outcome Endpoints.........................................................124
9.5
Analysis Populations..........................................................................................124
9.5.1
Efficacy Analysis Population.....................................................................124
9.5.2
Safety Analysis Population........................................................................124
9.5.3
Patient-reported Outcome Analysis Populations .......................................125
9.5.4
Pharmacokinetic Analysis Population .......................................................125
9.6
Statistical Methods.............................................................................................125
9.6.1
Statistical Methods for Efficacy Analyses.................................................125
9.6.1.1
Progression-free Survival.................................................................125
9.6.1.2
Overall Survival...............................................................................127
9.6.1.3
Objective Response Rate .................................................................127
9.6.1.4
Analysis Strategy for Key Efficacy Endpoints................................128
9.6.2
Statistical Methods for Safety Analyses ....................................................129
9.6.3
Analysis Methods for Patient-reported Outcome Endpoints .....................131
9.6.4
Summaries of Demographic and Baseline Characteristics ........................131
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9.7
Interim Analyses ................................................................................................131
9.7.1
Efficacy Interim Analyses..........................................................................132
9.7.2
Safety Interim Analyses.............................................................................133
9.8
Multiplicity .........................................................................................................133
9.8.1
Progression-free Survival...........................................................................134
9.8.2
Overall Survival.........................................................................................136
9.8.3
Objective Response Rate ...........................................................................137
9.8.4
Safety Analyses..........................................................................................138
9.9
Sample Size and Power Calculations ...............................................................138
9.9.1
Progression-free Survival...........................................................................139
9.9.2
Overall Survival.........................................................................................139
9.9.3
Objective Response Rate ...........................................................................139
9.10
Subgroup Analyses.............................................................................................139
9.11
Compliance (Medication Adherence)...............................................................140
9.12
Extent of Exposure.............................................................................................140
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...................................................................................................141
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations......141
10.1.1
Code of Conduct for Interventional Clinical Trials ...................................141
10.1.2
Financial Disclosure...................................................................................144
10.1.3
Data Protection...........................................................................................145
10.1.3.1
Confidentiality of Data ....................................................................145
10.1.3.2
Confidentiality of Participant Records.............................................145
10.1.3.3
Confidentiality of IRB/IEC Information..........................................146
10.1.4
Committees Structure.................................................................................146
10.1.4.1
Scientific Advisory Committee (SAC)............................................146
10.1.4.2
Executive Oversight Committee......................................................146
10.1.4.3
External Data Monitoring Committee .............................................146
10.1.5
Publication Policy......................................................................................147
10.1.6
Compliance with Study Registration and Results Posting Requirements .147
10.1.7
Compliance with Law, Audit, and Debarment ..........................................147
10.1.8
Data Quality Assurance .............................................................................148
10.1.9
Source Documents .....................................................................................149
10.1.10
Study and Site Closure...............................................................................149
10.2
Appendix 2: Clinical Laboratory Tests............................................................150
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................152
10.3.1
Definitions of Medication Error, Misuse, and Abuse................................152
10.3.2
Definition of AE ........................................................................................152
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10.3.3
Definition of SAE ......................................................................................153
10.3.4
Additional Events Reported.......................................................................154
10.3.5
Recording AE and SAE .............................................................................154
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................157
10.4
Appendix 4: Medical Device and Drug–Device Combination Products: 
Product Quality Complaints/Malfunctions: Definitions, Recording, and 
Follow-up ............................................................................................................159
10.5
Appendix 5: Contraceptive Guidance..............................................................160
10.5.1
Definitions..................................................................................................160
10.5.2
Contraceptive Requirements......................................................................161
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................163
10.7
Appendix 7: Country-specific Requirements..................................................164
10.7.1
China..........................................................................................................164
10.7.2
France.........................................................................................................164
10.7.3
Germany.....................................................................................................165
10.7.4
United Kingdom.........................................................................................165
10.7.5
Italy ............................................................................................................166
10.7.6
Canada........................................................................................................166
10.8
Appendix 8: Description of the iRECIST Process for Assessment of 
Disease Progression............................................................................................167
10.9
Appendix 9: ECOG Performance Status.........................................................171
10.10 Appendix 10: Technical Note for the Poisson Mixture Model.......................172
10.11 Appendix 11: Abbreviations .............................................................................173
11
REFERENCES.............................................................................................................177
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LIST OF TABLES
Table 1
Adequate Organ Function Laboratory Values .............................................65
Table 2
Study Interventions......................................................................................71
Table 3
Dose Modification and Toxicity Management Guidelines for 
Nonhepatic Immune-related Adverse Events Associated With 
Pembrolizumab ............................................................................................78
Table 4
Pembrolizumab Infusion Reaction Dose Modification and 
Treatment Guidelines...................................................................................81
Table 5
Dose Modification Guidelines for Lenvatinib/Placebo-related Adverse 
Events...........................................................................................................83
Table 6
Imaging and Treatment After First Radiologic Evidence of Progressive 
Disease.......................................................................................................106
Table 7
Reporting Time Periods and Time Frames for Adverse Events and 
Other Reportable Safety Events.................................................................112
Table 8
Censoring Rules for Primary and Sensitivity Analyses of PFS.................126
Table 9
Analysis Strategy for Key Efficacy Endpoints..........................................128
Table 10
Analysis Strategy for Safety Parameters....................................................130
Table 11
Summary of Interim and Final Analyses Strategy.....................................132
Table 12
One-sided Alpha Allocation Scenarios......................................................134
Table 13
Efficacy Boundaries and Properties for Progression-free Survival 
Analyses.....................................................................................................135
Table 14
Efficacy Boundaries and Properties for Overall Survival Analyses..........136
Table 15
Potential Alpha-levels and Approximate Minimum Objective Response 
Rate Difference Required to Demonstrate Efficacy for ORR at Interim 
Analysis 1...................................................................................................138
Table 16
Protocol-required Clinical Laboratory Assessments .................................150
Table 17
Highly Effective Contraception Methods..................................................162
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LIST OF FIGURES
Figure 1
Original Study Design..................................................................................22
Figure 2
New Study Design .......................................................................................23
Figure 3
Imaging and Treatment for Clinically Stable Participants Treated With 
Pembrolizumab After First Radiologic Evidence of PD Assessed by the 
Investigator ................................................................................................104
Figure 4
One-sided Alpha Reallocation Strategy.....................................................134
Figure 5
PFS Curves Using the Poisson Mixture Model and Exponential Model...172
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 3 Randomized, Placebo-controlled Trial to Evaluate the Safety and 
Efficacy of Pembrolizumab (MK-3475) and Lenvatinib (E7080/MK-7902) Versus 
Pembrolizumab Alone as First-line Intervention in Participants with Advanced Melanoma 
(LEAP-003)
Short Title: Pembrolizumab plus Lenvatinib as First-line Intervention for Advanced 
Melanoma
Acronym: Protocol 003 (E7080-G000-312)
Hypotheses, Objectives, and Endpoints:
Throughout this protocol, the term Response Evaluation Criteria in Solid Tumors 
(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.
In all participants with unresectable advanced melanoma following administration of 
pembrolizumab in combination with lenvatinib versus pembrolizumab in combination with 
placebo:
NOTE: Based on the data from an interim safety and efficacy analysis for LEAP-003 (data 
cutoff 18-JAN-2023), eDMC recommended stopping the study due to lack of efficacy
because pembrolizumab in combination with lenvatinib did not demonstrate an improvement 
in OS, one of the trial’s dual primary endpoints, compared to pembrolizumab plus placebo
and appears unlikely to do so in a future analysis. Based upon these data and the 
recommendation of the eDMC, the study was unblinded as of 27-MAR-2023. The 
prespecified final analysis of the study described in the SAP will not be performed. Safety 
analysis will be performed at the end of the study; there will be no further analyses for
efficacy and ePRO endpoints.
NOTE: In alignment with the study-specific investigator letter sent to investigators on 
3-APR-2023, all study participants still receiving pembrolizumab should continue to receive 
pembrolizumab monotherapy on study and undergo modified protocol study procedures as 
specified in this amendment. Study participation should end after the 30-day Safety 
Follow-up Visit (last scheduled visit). All participants should stop ongoing treatment with 
lenvatinib/placebo. Exceptions may be requested for lenvatinib for study participants who, in 
the assessment of their study physician, are benefiting from ongoing lenvatinib after 
consulting with the Sponsor. This applies to participants currently on pembrolizumab and 
lenvatinib and participants who have completed 35 cycles of pembrolizumab and are 
currently continuing lenvatinib monotherapy. Participants who are considered by the 
investigator as candidates for continued monotherapy with lenvatinib after unblinding and 
completion of 35 cycles of pembrolizumab and lenvatinib require a separate communication 
with the Sponsor. Participants who discontinue pembrolizumab prior to completion of 
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Cycle 35 (eg, due to an AE) must discontinue lenvatinib at the same time. All participants 
beyond the 30-day Safety Follow-up Visit should be discontinued from study; however, 
standard safety reporting should continue, as applicable. As of Amendment 07, participants 
who are still on study treatment will no longer require ePRO assessments or tumor response 
assessments by BICR to be performed. Scans will no longer be submitted to the iCRO. 
Participants who are still on study medication should continue tumor imaging assessment per 
protocol. For participants no longer on study medication, local tumor imaging assessments 
should continue per SOC schedule. Biomarker specimen collection is discontinued. The 
30-day Safety Follow-up is the last required visit. Updated analyses are described in 
Section 9.
Primary Objective
Primary Endpoint
Objective: To compare progression-free 
survival (PFS) as assessed by blinded 
independent central review (BICR) per 
Response Evaluation Criteria in Solid 
Tumors (RECIST) 1.1.
Hypothesis (H1): The combination of 
pembrolizumab and lenvatinib is superior to 
pembrolizumab and placebo assessed by 
PFS per RECIST 1.1 by BICR.
PFS: The time from randomization to the 
first documented disease progression or 
death due to any cause, whichever occurs 
first
Objective: To compare the combination of 
pembrolizumab and lenvatinib to
pembrolizumab and placebo with respect to 
overall survival.
Hypothesis (H2): The combination of 
pembrolizumab and lenvatinib is superior to
pembrolizumab and placebo assessed by 
OS.
Overall survival: The time from 
randomization to death due to any cause
Secondary Objectives
Secondary Endpoints
Objective: To compare objective response 
rate (ORR) per RECIST 1.1 by BICR.
Hypothesis (H3): The combination of 
pembrolizumab and lenvatinib is superior to 
pembrolizumab and placebo as assessed by 
ORR per RECIST 1.1 by BICR.
Objective response, defined as best overall 
response of either complete response or 
partial response.
Objective: To assess duration of response 
(DOR) per RECIST 1.1 by BICR.
DOR, determined by disease assessment 
defined as the time from the earliest date of 
qualifying response until earliest date of 
disease progression or death from any 
cause, whichever comes first.
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Objective: To assess safety and tolerability.
Adverse events (AEs) 
Discontinuations due to AEs.
Objective: To compare the mean change 
from baseline in PRO scores in global 
health status/quality of life (QoL) and 
physical functioning.
European Organization for Research and 
Treatment of Cancer [EORTC] Quality of 
Life Questionnaire-Core 30 [QLQ-C30]:
- Global health status/QoL scale (items 
29 and 30)
- Physical functioning scale (items 1 to 
5).
Objective: To compare the time to true 
deterioration (TTD) in global health 
status/QoL and physical functioning.
TTD is the time from baseline to first onset 
of 10 points or more decrease from baseline 
with confirmation by the subsequent visit of 
10 points or more deterioration from 
baseline for EORTC QLQ-C30: 
- Global health status/QoL scale (items 
29 and 30)
- Physical functioning scale (items 1 to 
5)
Overall Design:
Study Phase
Phase 3
Primary Purpose
Treatment
Indication
Melanoma
Population
Participants with no prior systemic therapy for their 
advanced melanoma (prior adjuvant therapy is permitted)
Study Type
Interventional
Intervention Model
Parallel
This is a multi site study.
Type of Control
Placebo
Study Blinding
Double-blind with in-house blinding
Blinding Roles
Investigator
Participant
Sponsor
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 69 months from the time the first participant 
(or their legally acceptable representative) provides 
documented informed consent until the last participant’s 
last study-related contact.
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Extension portion of the study in China: The Sponsor 
estimates that the trial will require approximately 2 
additional years from the time the first participant provide 
documented informed consent until the last participant’s 
last visit.
Number of Participants:
Approximately 600 participants will be randomized as described in Section 9.1.
Extension portion of the study in China:  China will enroll participants in the global study. 
Once the sample size for the global study has been achieved (n ~660); the study will 
continue to enroll participants from China in the extension portion of the study until the 
overall sample size for China reaches ~130 (up to 137) participants in the global study and 
the extension portion of the study combined.
Intervention Groups and Duration:
Arm Name
Intervention 
Name
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen/
Treatment 
Period/
Vaccination 
Regimen
Use
Arm A
Pembrolizumab
25 mg/mL
200 mg
IV Infusion
Q3W
Test 
Product
Arm A
Lenvatinib
10 mg,
4 mg
20 mg
Oral
QD
Test 
Product
Arm B
Pembrolizumab
25 mg/mL
200 mg
IV Infusion
Q3W
Comparator
Arm B
Placebo
0 mg
0 mg
Oral
QD
Placebo
Abbreviations: EEA European Economic Area; IMP investigational medicinal product; NIMP/AxMP noninvestigational/
auxiliary medicinal product; Q3W every 3 weeks; QD once daily.
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Total 
Number of 
Intervention 
Groups/Arms
2 arms
Duration of 
Participation
After a Screening phase of up to 28 days, each participant will be 
randomized to receive intervention with pembrolizumab + lenvatinib or 
pembrolizumab + placebo until disease progression is radiographically 
documented and verified by BICR per RECIST 1.1, unacceptable adverse 
event(s) (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. 
Pembrolizumab treatment will be discontinued once the participant has 
received 35 administrations (approximately 2 years). Participants may 
continue treatment with lenvatinib or placebo beyond approximately 
2 years if they experience clinical benefit until unacceptable toxicity or 
disease progression upon Sponsor consultation and approval. All 
participants who continue on lenvatinib or placebo monotherapy will be 
monitored per the SoA. Participants who attain an investigator-determined 
confirmed complete response (CR) may consider stopping study 
intervention with pembrolizumab + lenvatinib or pembrolizumab + 
placebo, after at least 24 weeks of study intervention has been 
administered. In addition, if a confirmed CR per RECIST 1.1 is attained, at 
least 2 additional doses of pembrolizumab must be received after CR is 
first documented.
Note: Participants receiving lenvatinib who experience disease progression 
per RECIST 1.1 must be discontinued from lenvatinib. If they are 
concurrently receiving pembrolizumab, they may continue receiving 
pembrolizumab per iRECIST as outlined in the protocol.
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, and the participant is tolerating study 
intervention as per iRECIST. Treatment beyond disease progression per 
iRECIST may be permitted upon Sponsor consultation and approval and 
per criteria in Section 8.2.1.5.
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 
and verified by BICR, initiating a nonstudy cancer treatment, withdrawing 
consent, or becoming lost to follow-up. Participants who discontinue due 
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to radiographic disease progression will move to posttreatment Survival 
Follow-up.
All participants will be followed for OS until death, withdrawal of consent, 
or the end of the study.
The study will be considered positive if either one of the primary endpoints 
(PFS or OS) meets the criteria for statistical significance per Section 9.
Extension portion of the study:
After the enrollment of the global study is completed, participants from 
China will continue to be enrolled in an extension portion of the study 
designed to meet local regulatory requirements. Additional details are in 
Section 4.1 and Section 9.
Study Governance Committees:
Executive Oversight Committee
Yes
Data Monitoring Committee
Yes
Clinical Adjudication Committee
No
Steering Committee
No
Study governance considerations are outlined in Appendix 1.
As of Amendment 07, the Executive Oversight Committee and Data Monitoring Committee 
are no longer applicable.
Study Accepts Healthy Participants: No
A list of abbreviations is in Appendix 11.
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1.2
Schema
The original study design is depicted in Figure 1.
Figure 1
Original Study Design
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The new study design per Amendment 07 is depicted in Figure 2.
Figure 2
New Study Design
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1.3
Schedule of Activities
As of Amendment 07, participants who are still on study treatment will no longer require ePRO assessments or tumor 
response assessments by BICR to be performed. Scans will no longer be sent to the iCRO. Participants who are still on study 
medication should continue tumor imaging assessment per protocol. For participants no longer on study medication, local 
tumor imaging assessments should continue per SOC schedule. In addition, Efficacy Follow-up, 90-day Follow-up and 
Survival Follow-up Visits will no longer be conducted. Biomarker samples (blood for genetic analysis, RNA analysis, 
plasma/serum biomarker analysis, and ctDNA analysis) are discontinued. The following parameters will be assessed as 
follows:
Summary of changes in SoA:
•
Imaging: while still on treatment per protocol (both pembrolizumab and lenvatinib) (not submitted to iCRO), then 
SOC
•
PE, Vital signs: while still on treatment, then 30-day Safety FU, then SOC
•
ECG, MUGA: while still on lenvatinib treatment then 30-day Safety FU, then SOC
•
Urinary laboratory tests, including 24-hour urine collection as specified per protocol: while still on lenvatinib
treatment, then 30-day Safety FU, then SOC
•
Hematology/Chemistry: while still on treatment, then 30-day Safety FU, then SOC
•
T3, FT4, TSH: while still on treatment, then 30-day Safety FU, then SOC
•
HIV, HBV, HCV: while still on treatment, then 30-day Safety FU, then SOC
•
ECOG: while still on treatment, then 30-day Safety FU, then SOC
The full SoA table below is retained for reference.
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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
3 Onwardsa
At D/C
30 Days 
and 
90 Days 
After 
Last 
Dose
Q12W 
(± 7 d)
Q12W 
(± 7 d)
All procedures and assessments 
are to be performed prior to 
administration of study 
intervention unless otherwise 
indicated. Refer to Section 8.11 
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
Informed consent must be 
documented prior to any 
protocol specific procedures are 
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 last 
10 years.
Demographics
X
Staging 
X
At initial diagnosis and at study 
entry.
BRAF status
X
At study entry. 
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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
3 Onwardsa
At D/C
30 Days 
and 
90 Days 
After 
Last 
Dose
Q12W 
(± 7 d)
Q12W 
(± 7 d)
All procedures and assessments 
are to be performed prior to 
administration of study 
intervention unless otherwise 
indicated. Refer to Section 8.11 
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
Prior/Concomitant 
Medication Review
X
X
X
X
X
X
X
X
X
X
Concomitant medications taken 
during the study and for 30 days 
after the last dose of study 
intervention will be recorded. 
Randomization
X
Participants may be randomized 
up to 3 days prior to C1D1 and 
after confirmation of eligibility. 
All procedures and assessments on 
C1D1 should be performed after 
randomization.
Pembrolizumab 
plus lenvatinib or 
placebo 
Administration/
Dispensing
X
X
X
Pembrolizumab 200 mg Q3W; 
lenvatinib or placebo 20 mg QD. 
Lenvatinib/placebo will be taken 
in the clinic on C1D1, C1D15, and 
C2D1. On C1D1 and C2D1, 
lenvatinib/placebo will be taken 0 
to 4 hours after completion of 
pembrolizumab administration. 
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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
3 Onwardsa
At D/C
30 Days 
and 
90 Days 
After 
Last 
Dose
Q12W 
(± 7 d)
Q12W 
(± 7 d)
All procedures and assessments 
are to be performed prior to 
administration of study 
intervention unless otherwise 
indicated. Refer to Section 8.11 
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 Follow up. 
If a clinic visit is not feasible, 
follow up information may be 
obtained via telephone or email.
Phone contact visit
X
A phone visit will be scheduled to 
report blood pressure and record 
AEs. Blood pressure will be taken, 
for example, at home or at a local 
pharmacy, and will be reviewed 
with the investigator or designee 
during phone contact.
Participants will be contacted by 
telephone on C1D8 to assess for 
development of early toxicity. If 
early toxicity is suspected, an 
unscheduled visit can occur prior 
to C1D15 if deemed necessary by 
the investigator.
Survival status
Participants may be contacted for 
survival status at any time during 
the course of the study.
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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
3 Onwardsa
At D/C
30 Days 
and 
90 Days 
After 
Last 
Dose
Q12W 
(± 7 d)
Q12W 
(± 7 d)
All procedures and assessments 
are to be performed prior to 
administration of study 
intervention unless otherwise 
indicated. Refer to Section 8.11 
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
Tumor assessment 
chest, abdomen and 
pelvis (CT/MRI) 
X
X
X
Prior scans performed within the 
Screening period but before 
signing informed consent may be 
used if consistent with protocol 
requirements per SIM. 
All imaging visits have a 
scheduling window of ±7 days. 
Imaging to be performed Q9W or 
sooner if clinically indicated from 
the date of randomization until 
Week 54 of study intervention, 
Q12W or sooner if clinically 
indicated thereafter until Week 
102 until BICR verification of 
disease progression per 
RECIST 1.1. Progression will be 
verified by BICR prior to DC of 
study intervention. 
For participants who DC for 
reasons other than BICR verified 
progressive disease, imaging 
should be performed Q12W until 
BICR verified progressive 
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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
3 Onwardsa
At D/C
30 Days 
and 
90 Days 
After 
Last 
Dose
Q12W 
(± 7 d)
Q12W 
(± 7 d)
All procedures and assessments 
are to be performed prior to 
administration of study 
intervention unless otherwise 
indicated. Refer to Section 8.11 
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
disease. After Week 102 of FU, 
imaging should be performed 
Q24W or sooner if clinically 
indicated. 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.
Required at Screening and at all 
subsequent tumor assessment time 
points only if brain disease was 
present 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.
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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
3 Onwardsa
At D/C
30 Days 
and 
90 Days 
After 
Last 
Dose
Q12W 
(± 7 d)
Q12W 
(± 7 d)
All procedures and assessments 
are to be performed prior to 
administration of study 
intervention unless otherwise 
indicated. Refer to Section 8.11 
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
Report nonserious AEs occurring 
within 90 days after the last dose 
of study intervention or 30 days 
following cessation of study 
intervention if the participant 
initiates new anticancer therapy, 
whichever is earlier. 
Report SAEs occurring within 
120 days after the last dose of 
study intervention, or 30 days after 
the last dose of study intervention 
if a new anticancer therapy is 
initiated, whichever is earlier.
Full physical 
examination
X
At Screening, perform within 
7 days prior to C1D1.
Directed Physical 
Examination
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.
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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
3 Onwardsa
At D/C
30 Days 
and 
90 Days 
After 
Last 
Dose
Q12W 
(± 7 d)
Q12W 
(± 7 d)
All procedures and assessments 
are to be performed prior to 
administration of study 
intervention unless otherwise 
indicated. Refer to Section 8.11 
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), weight 
and height
X
X
X
X
X
X
X
X
BP and heart rate 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 is 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. 
ECG at C1D1 and C2D1 should 
be performed approximately 
2 hours post lenvatinib/placebo 
dose.
For high risk participants 
(Section 8.3.3), conduct ECG 
monitoring every cycle.
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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
3 Onwardsa
At D/C
30 Days 
and 
90 Days 
After 
Last 
Dose
Q12W 
(± 7 d)
Q12W 
(± 7 d)
All procedures and assessments 
are to be performed prior to 
administration of study 
intervention unless otherwise 
indicated. Refer to Section 8.11 
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
If lenvatinib/placebo is 
discontinued, ECGs are only 
required at the EOT and Safety 
Follow up Visits. 
Additional assessments may be 
performed if clinically indicated.
MUGA or ECHO 
for LVEF 
assessment
X
X
Additional assessments may be 
performed as clinically indicated. 
Assessments should use the same 
method (MUGA or ECHO) 
throughout the study.
Hematology and 
chemistry 
laboratory 
assessment 
X
X
X
X
X
X
X
To be assessed within 7 days prior 
to first dose of study intervention. 
Every effort should be made to 
collect samples at the same time of 
day. LDH is only required at 
Screening. 
Refer to Appendix 7 for country
specific Requirements.
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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
3 Onwardsa
At D/C
30 Days 
and 
90 Days 
After 
Last 
Dose
Q12W 
(± 7 d)
Q12W 
(± 7 d)
All procedures and assessments 
are to be performed prior to 
administration of study 
intervention unless otherwise 
indicated. Refer to Section 8.11 
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
Urine dipstick 
testing 
X
X
X
X
X
X
X
Performed locally within 7 days 
prior to start of intervention. 
After Screening, urine dipstick 
testing for protein will be 
performed within 3 days before 
Day 1 of every cycle while 
participants are taking 
lenvatinib/placebo.
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. 
PT/INR and 
aPTT/PTT
X
Perform eligibility labs within 
7 days prior to C1D1. Additional 
testing to be conducted as 
clinically indicated for participants 
taking anticoagulant therapy.
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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
3 Onwardsa
At D/C
30 Days 
and 
90 Days 
After 
Last 
Dose
Q12W 
(± 7 d)
Q12W 
(± 7 d)
All procedures and assessments 
are to be performed prior to 
administration of study 
intervention unless otherwise 
indicated. Refer to Section 8.11 
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
T3, FT4, TSH
X
X
X
X
X
Screening samples to be collected 
within 7 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.
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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
3 Onwardsa
At D/C
30 Days 
and 
90 Days 
After 
Last 
Dose
Q12W 
(± 7 d)
Q12W 
(± 7 d)
All procedures and assessments 
are to be performed prior to 
administration of study 
intervention unless otherwise 
indicated. Refer to Section 8.11 
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 
(POCBP only)
X
X
X
X
X
X
POCBP require negative test prior 
to randomization. If more than 24 
hours have elapsed prior to first 
dose of study intervention, another 
pregnancy test is required prior to 
starting study intervention A 
serum or urine pregnancy test will 
be performed per Appendix 2.
To be assessed prior to all 
subsequent scheduled visits. A 
serum or urine pregnancy test will 
be performed as indicated, prior to 
every cycle, and up to 120 days 
post 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 during 
Screening. See Appendix 7 for 
country specific guidelines.
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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
3 Onwardsa
At D/C
30 Days 
and 
90 Days 
After 
Last 
Dose
Q12W 
(± 7 d)
Q12W 
(± 7 d)
All procedures and assessments 
are to be performed prior to 
administration of study 
intervention unless otherwise 
indicated. Refer to Section 8.11 
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
HIV, HBV, HCV
X
Not required unless mandated by 
local health authorities. See 
Appendix 7 for country specific 
guidelines.
ECOG performance 
status
X
X
X
X
To be assessed within 7 days of 
C1D1 and prior to dosing during 
all subsequent scheduled visits. 
CCI
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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
3 Onwardsa
At D/C
30 Days 
and 
90 Days 
After 
Last 
Dose
Q12W 
(± 7 d)
Q12W 
(± 7 d)
All procedures and assessments 
are to be performed prior to 
administration of study 
intervention unless otherwise 
indicated. Refer to Section 8.11 
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
CCI
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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
3 Onwardsa
At D/C
30 Days 
and 
90 Days 
After 
Last 
Dose
Q12W 
(± 7 d)
Q12W 
(± 7 d)
All procedures and assessments 
are to be performed prior to 
administration of study 
intervention unless otherwise 
indicated. Refer to Section 8.11 
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
CCI
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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
3 Onwardsa
At D/C
30 Days 
and 
90 Days 
After 
Last 
Dose
Q12W 
(± 7 d)
Q12W 
(± 7 d)
All procedures and assessments 
are to be performed prior to 
administration of study 
intervention unless otherwise 
indicated. Refer to Section 8.11 
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
Patient-reported Outcomes (HRQoL Measures)
EORTC QLQ C30
X
X
X
X
X
Patient reported outcomes will be 
assessed on Day 1 (prior to first 
dose of study intervention) of 
every cycle during Year 1 
(Cycles 1 to 17), every other cycle 
during Year 2 (Cycles 19, 21, 23, 
25, 27, 29, 31, 33, and 35), and at 
treatment discontinuation visit and 
the 30 day and 90 day Safety 
Follow up Visits. If the EOT visit 
occurs 30 days from the last dose 
of study intervention, a 30 day 
Safety Follow up Visit is not 
required, ePROs do not need to be 
repeated. See additional details in 
Section 8.2.2.
EuroQoL (EQ) 5D
5L 
X
X
X
X
X
Abbreviations: AE adverse event; BICR blinded independent central review; BP blood pressure; C1 Cycle 1; C2 Cycle 2; C3 Cycle 3; C5 Cycle 5; CIV central imaging vendor; CT computed 
tomography; ctDNA circulating tumor DNA; ctRNA circulating tumor RNA; D1 Day 1; D15 Day 15; D8 Day 8; DC discontinue/discontinuing; ECG electrocardiogram; 
ECHO echocardiogram; ECOG Eastern Cooperative Oncology Group; EOT end of treatment; ePRO electronic patient reported outcome; FT4 free thyroxine; FU follow up; HBV hepatitis B 
virus; HCV hepatitis C virus; HIV human immunodeficiency virus; HRQoL health related quality of life; INR international normalized ratio; LDH lactate dehydrogenase; 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; Q24W every 24 weeks; QD once daily; RECIST Response Evaluation Criteria in Solid Tumors; RR respiratory rate; SAE serious adverse 
event; SIM site imaging manual; T3 triiodothyronine; TSH thyroid stimulating hormone; UPCR urine protein to creatinine; POCBP participant of childbearing potential;
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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
3 Onwardsa
At D/C
30 Days 
and 
90 Days 
After 
Last 
Dose
Q12W 
(± 7 d)
Q12W 
(± 7 d)
All procedures and assessments 
are to be performed prior to 
administration of study 
intervention unless otherwise 
indicated. Refer to Section 8.11 
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
a.
Participants who continue treatment with lenvatinib or placebo beyond approximately 2 years (only if they experience clinical benefit until unacceptable toxicity or disease progression and 
upon Sponsor consultation and approval) will follow the same SoA except for the following: 1) thyroid labs beyond approximately 2 years will be performed per SOC or as clinically indicated 
2) circulating tumor nucleic acid will no longer be collected. Participants who attain an investigator determined complete response (CR) and stop study intervention with pembrolizumab + 
lenvatinib or pembrolizumab + placebo will have 30 day and 90 day Safety Follow up Visits and move to the follow up visits per SoA. 
b.
If EOT visit occurs ~30 days from last dose of study intervention a 30 day Safety Follow up Visit is not required. In this situation, all procedures required at the 30 day Safety Visit and EOT 
are performed once and entered into the EOT visit only. End of treatment 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 an 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 DC study intervention for reasons other than BICR verified progressive disease, follow up visits to monitor disease status continue until BICR verified progressive disease 
or initiation of a new anticancer therapy. Participants who D/C study intervention with BICR verified 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 of study intervention or sooner if clinically indicated and Q12W thereafter until Week 
102; following Week 102, imaging should be performed every Q24W, or sooner if clinically indicated only if participants had 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 study to optimize the visualization of 
existing and new tumor burden.
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2
INTRODUCTION
2.1
Study Rationale
Pembrolizumab (MK-3475/KEYTRUDA®) is approved by the US Food and Drug 
Administration (FDA) and the European Commission for the treatment of both first-line and 
previously treated patients with advanced melanoma. However, there is a large population 
(~60%) of patients who do not respond to therapy with anti-PD-1 agents. Thus, combination 
strategies as first-line intervention are needed. 
The current study is designed to evaluate the safety and efficacy of combination therapy of 
lenvatinib (also known as E7080 or MK-7902; hereafter referred to as lenvatinib) and 
pembrolizumab in adult participants with advanced melanoma.
2.2
Background
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 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 Investigator’s Brochure (IB)/approved labeling for detailed 
background information on pembrolizumab and lenvatinib.
Pembrolizumab is a potent humanized IgG4 mAb with high specificity of binding to the 
PD-1 receptor, thus inhibiting its interaction with PD-L1 and PD-L2. Based on preclinical in 
vitro data, pembrolizumab has high affinity and potent receptor blocking activity for PD-1. 
Pembrolizumab has an acceptable preclinical safety profile and is in clinical development as 
an IV immunotherapy for advanced malignancies. Keytruda® (pembrolizumab) is indicated 
for the treatment of patients across several indications. For more details on specific 
indications refer to the IB.
2.2.1
Pharmaceutical and Therapeutic Background
2.2.1.1
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 CTLA-4 that has been shown to negatively 
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regulate antigen receptor signaling on engagement of its ligands (PD-L1 and/or PD-L2) 
[Greenwald, R. J., et al 2005] [Okazaki, T., et al 2001].
The structure of murine PD-1 has been resolved [Zhang, X., et al 2004]. PD-1 and its family 
members are type I transmembrane glycoproteins containing an IgV 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. After 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 CD3ζ, PKCθ, and ZAP70, 
which are involved in the CD3 T-cell signaling cascade [Okazaki, T., et al 2001] [Chemnitz, 
J. M., et al 2004] [Sheppard, K-A, et al 2004] [Riley, J. L. 2009]. The mechanism by which 
PD-1 down-modulates T-cell responses is similar to, but distinct from, that of CTLA-4, 
because both molecules regulate an overlapping set of signaling proteins [Parry, R. V., et al 
2005] [Francisco, L. M., et al 2010]. As a consequence, the PD-1/PD-L1 pathway is an 
attractive target for therapeutic intervention in melanoma.
2.2.1.2
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. and Hicklin, D. 
J. 2008] [Tammela, T. and Alitalo, K. 2010]. Accumulated evidence suggests that FGF and 
its receptor tyrosine kinase, FGFR also play important roles for tumor angiogenesis [Cross, 
M. J. and Claesson-Welsh L. 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 8-22 nmol/L, respectively. In cell-based assays, lenvatinib inhibited 
VEGF-derived and FGF-derived tube formation of 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 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), RCC, 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.
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In summary, lenvatinib inhibited VEGF-driven VEGFR2 phosphorylation and suppressed 
proliferation and tube formation in human umbilical vein endothelial cell (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.
2.2.1.3
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 CD8+ T-cells and the ratio 
of CD8+ effector T-cells/FoxP3+ regulatory T-cells (T-regs) correlates with improved 
prognosis and long-term survival in solid malignancies, such as ovarian, colorectal, and 
pancreatic cancer; hepatocellular carcinoma; malignant melanoma; and renal cell carcinoma. 
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 
to 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 to that of the respective 
monotherapy groups [Kato, Y., et al 2019]. All treatments were well tolerated and severe 
body weight loss was not observed.
2.2.1.4
Melanoma: Epidemiology and Current Therapeutic Options
Melanoma is the most serious form of skin cancer and affects adults of all ages. The 5-year 
prevalence of melanoma in the European Union (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 United States (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 prior to the use of anti-PD-1 agents was 17% 
once patients had Stage IV disease [American Cancer Society 2016].
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High-dose interleukin-2 was the first 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 limited 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, and the anti-CTLA-4 antibody (ipilimumab) and to targeted 
therapy such as BRAF and/or MEK inhibition (dabrafenib and/or trametinib, respectively). 
Both of these approaches prolong progression-free survival (PFS) and overall survival (OS) 
compared with chemotherapy [UpToDate, Inc. 2015], thus, they are standard therapeutic 
options for patients with melanoma.
Ipilimumab, an anti-CTLA-4 blocking antibody, and vemurafenib, a BRAF inhibitor, were 
the initial agents to demonstrate OS benefit in randomized, comparative Phase 3 registration 
studies. In the Phase 3 study MDX010-20, ipilimumab monotherapy demonstrated a hazard 
ratio of 0.66 and a 4-month median OS benefit compared to gp100 in pretreated advanced 
melanoma subjects [Hodi, F. S., et al 2010]. Grade 3 to 4 immune-related adverse events 
(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 the EU, ipilimumab is currently 
approved for the treatment of advanced melanoma in adults who have received prior therapy.
Approximately 50% of cutaneous melanoma cases are BRAF V600E mutation-positive 
[Larkin, J., et al 2014]. Vemurafenib was initially approved in the US and in the EU for the 
treatment of BRAF V600E mutation-positive advanced melanoma subjects 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 to dacarbazine with 
a hazard ratio (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 to BRAF inhibition alone as first-line therapy in patients with 
advanced melanoma. Both the combination of dabrafenib and trametinib or vemurafenib and 
cobimetinib are approved as first-line therapy in BRAF V600E mutation-positive melanoma 
patients [Robert, C., et al 2014] [Larkin, J., et al 2014].
KEYNOTE-006 Phase 3 study demonstrated superior efficacy of pembrolizumab compared 
to ipilimumab in PFS, OS and objective response rate (ORR). The ORR was 32.9% for 
pembrolizumab versus 11.9% for ipilimumab. Median PFS were 4.1 months for 
pembrolizumab versus 2.8 months for ipilimumab. The HR for the disease progression for 
pembrolizumab every 3 weeks (Q3W) versus ipilimumab was 0.58 (95% confidence interval 
[CI], 0.46 to 0.72; p<0.001). One-year estimates of survival for subjects receiving 
pembrolizumab Q3W were 68.4% as compared with ipilimumab at 58.2% (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 Data Monitor Committee (DMC) 
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 subjects with previously untreated advanced melanoma 
compared to dacarbazine and reported a 5.1-month median PFS compared to 2.2 months for 
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the dacarbazine. The ORR was 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 to 
42.1% in the dacarbazine group. Nivolumab showed significant improvements in PFS and 
OS 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 for the treatment of patients 
with unresectable or metastatic melanoma and disease progression following ipilimumab 
and, if BRAF V600E mutation-positive, a BRAF inhibitor. 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 advanced (unresectable or metastatic) melanoma 
regardless of BRAF status. The European Commission has also approved pembrolizumab 
and nivolumab, for both first-line and previously treated patients with advanced melanoma.
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 
mAbs has been investigated in the CT26 colorectal cancer syngeneic model (anti-PD-L1 
mAb) as well as the LL/2 lung cancer syngeneic model (anti-PD-1 mAb). Combination 
treatment with lenvatinib and either an anti-PD-1 or anti-PD-L1 mAb showed significant and 
superior antitumor effects compared with either compound alone in these 2 syngeneic models 
[Kato, Y., et al 2015].
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 plus pembrolizumab in participants with selected solid tumors is currently 
ongoing. Phase 1b of this study determined the maximum tolerated dose (MTD) and 
recommended Phase 2 dose (RP2D) as 20 mg lenvatinib once daily (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, endometrial cancer, 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 multicohort 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 
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are no standard effective therapies available. The study is ongoing but is no longer enrolling 
melanoma patients.
Eligible patients were aged 18 years or older and had histologically confirmed nonuveal 
melanoma, 0 to 2 prior systemic anticancer regimens and ECOG 0 or 1. The primary 
endpoint is ORR at Week 24 based on RECIST 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, duration of response (DOR), PFS, OS, and safety and tolerability of the 
combination. All patients received lenvatinib 20 mg daily in combination with 200 mg 
pembrolizumab IV Q3W. At data cutoff (01-MAR-2018), 21 metastatic melanoma patients 
were enrolled, and 38% of patients had 1 or more prior anticancer therapy. 
For all enrolled subjects (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 partial 
response (PR), and 1 (4.8%) was complete response (CR). Stable disease was observed in 7 
(33.3%) patients, and 3 (14.3%) experienced progressive disease (PD). One patient had an 
unknown response. Median duration of objective response was 12.5 months (95% CI, 
2.7 months, not estimable [NE]). Median PFS observed was 7.6 months (95% CI: 
2.6 months, 15.8 months).
All patients experienced ≥1 treatment-related adverse event (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%) patients, 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.
2.2.3
Information on Other Study-related Therapy
Not applicable.
2.3
Benefit/Risk Assessment
Beneficial effects of pembrolizumab have been seen in several melanoma studies 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 
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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 
alanine aminotransferase (ALT) and aspartate aminotransferase (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 informed consent documents.
NOTE: Based on the data from an interim safety and efficacy analysis for LEAP-003 (data 
cutoff 18-JAN-2023), eDMC recommended stopping the study due to lack of efficacy
because pembrolizumab in combination with lenvatinib did not demonstrate an improvement 
in OS, one of the trial’s dual primary endpoints, compared to pembrolizumab plus placebo
and appears unlikely to do so in a future analysis. Based upon these data and the 
recommendation of the eDMC, the study was unblinded as of 27-MAR-2023. The 
prespecified final analysis of the study described in the SAP will not be performed. Safety 
analysis will be performed at the end of the study; there will be no further analyses for
efficacy and ePRO endpoints. Biomarker specimen collection is discontinued.
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3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
Throughout this protocol, the term Response Evaluation Criteria in Solid Tumors 
(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.
In all participants with unresectable advanced melanoma following administration of 
pembrolizumab in combination with lenvatinib versus pembrolizumab in combination with 
placebo:
NOTE: Based on the data from an interim safety and efficacy analysis for LEAP-003 (data 
cutoff 18-JAN-2023), eDMC recommended stopping the study due to lack of efficacy
because pembrolizumab in combination with lenvatinib did not demonstrate an improvement 
in OS, one of the trial’s dual primary endpoints, compared to pembrolizumab plus placebo
and appears unlikely to do so in a future analysis. Based upon these data and the 
recommendation of the eDMC, the study was unblinded as of 27-MAR-2023. The 
prespecified final analysis of the study described in the SAP will not be performed. Safety 
analysis will be performed at the end of the study; there will be no further analyses for
efficacy and ePRO endpoints.
NOTE: In alignment with the study-specific investigator letter sent to investigators on 
3-APR-2023, all study participants still receiving pembrolizumab should continue to receive 
pembrolizumab monotherapy on study and undergo modified protocol study procedures as 
specified in this amendment. Study participation should end after the 30-day Safety 
Follow-up Visit (last scheduled visit). All participants should stop ongoing treatment with 
lenvatinib/placebo. Exceptions may be requested for lenvatinib for study participants who, in 
the assessment of their study physician, are benefiting from ongoing lenvatinib after 
consulting with the Sponsor. This applies to participants currently on pembrolizumab and 
lenvatinib and participants who have completed 35 cycles of pembrolizumab and are 
currently continuing lenvatinib monotherapy. Participants who are considered by the 
investigator as candidates for continued monotherapy with lenvatinib after unblinding and 
completion of 35 cycles of pembrolizumab and lenvatinib require a separate communication 
with the Sponsor. Participants who discontinue pembrolizumab prior to completion of 
Cycle 35 (eg, due to an AE) must discontinue lenvatinib at the same time. All participants 
beyond the 30-day Safety Follow-up Visit should be discontinued from study; however, 
standard safety reporting should continue, as applicable. As of Amendment 07, participants 
who are still on study treatment will no longer require ePRO assessments or tumor response 
assessments by BICR to be performed. Scans will no longer be submitted to the iCRO. 
Participants who are still on study medication should continue tumor imaging assessment per 
protocol. For participants no longer on study medication, local tumor imaging assessments 
should continue per SOC schedule. Biomarker specimen collection is discontinued. The 
30-day Safety Follow-up is the last required visit. Updated analyses are described in 
Section 9.
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Primary Objective
Primary Endpoint
Objective: To compare progression-free 
survival (PFS) as assessed by blinded 
independent central review (BICR) per 
Response Evaluation Criteria in Solid 
Tumors (RECIST) 1.1.
Hypothesis (H1): The combination of 
pembrolizumab and lenvatinib is superior to 
pembrolizumab and placebo assessed by 
PFS per RECIST 1.1 by BICR.
PFS: The time from randomization to the 
first documented disease progression or 
death due to any cause, whichever occurs 
first
Objective: To compare the combination of 
pembrolizumab and lenvatinib to
pembrolizumab and placebo with respect to 
overall survival.
Hypothesis (H2): The combination of 
pembrolizumab and lenvatinib is superior to
pembrolizumab and placebo assessed by 
OS.
Overall survival: The time from 
randomization to death due to any cause
Secondary Objectives
Secondary Endpoints
Objective: To compare objective response 
rate (ORR) per RECIST 1.1 by BICR.
Hypothesis (H3): The combination of 
pembrolizumab and lenvatinib is superior to 
pembrolizumab and placebo as assessed by 
ORR per RECIST 1.1 by BICR.
Objective response, defined as best overall 
response of either complete response or 
partial response.
Objective: To assess duration of response 
(DOR) per RECIST 1.1 by BICR.
DOR, determined by disease assessment 
defined as the time from the earliest date of 
qualifying response until earliest date of 
disease progression or death from any 
cause, whichever comes first.
Objective: To assess safety and tolerability.
Adverse events (AEs) 
Discontinuations due to AEs.
Objective: To compare the mean change 
from baseline in PRO scores in global 
health status/quality of life (QoL) and 
physical functioning.
European Organization for Research and 
Treatment of Cancer [EORTC] Quality of 
Life Questionnaire-Core 30 [QLQ-C30]:
- Global health status/QoL scale (items 
29 and 30)
- Physical functioning scale (items 1 to 
5).
o
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Objective: To compare the time to true 
deterioration (TTD) in global health 
status/QoL and physical functioning.
TTD is the time from baseline to first onset 
of 10 points or more decrease from baseline 
with confirmation by the subsequent visit of 
10 points or more deterioration from 
baseline for EORTC QLQ-C30: 
- Global health status/QoL scale (items 
29 and 30)
- Physical functioning scale (items 1 to 
5)
CCI
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4
STUDY DESIGN
4.1
Overall Design
Original protocol text that is contained in this section has been retained for reference.
NOTE: Based on the data from an interim safety and efficacy analysis for LEAP-003 (data 
cutoff 18-JAN-2023), eDMC recommended stopping the study due to lack of efficacy
because pembrolizumab in combination with lenvatinib did not demonstrate an improvement 
in OS, one of the trial’s dual primary endpoints, compared to pembrolizumab plus placebo
and appears unlikely to do so in a future analysis. Based upon these data and the 
recommendation of the eDMC, the study was unblinded as of 27-MAR-2023. The 
prespecified final analysis of the study described in the SAP will not be performed. Safety 
analysis will be performed at the end of the study; there will be no further analyses for
efficacy and ePRO endpoints.
NOTE: In alignment with the study-specific investigator letter sent to investigators on 
3-APR-2023, all study participants still receiving pembrolizumab should continue to receive 
pembrolizumab monotherapy on study and undergo modified protocol study procedures as 
specified in this amendment. Study participation should end after the 30-day Safety
Follow-up Visit (last scheduled visit). All participants should stop ongoing treatment with 
lenvatinib/placebo. Exceptions may be requested for lenvatinib for study participants who, in 
the assessment of their study physician, are benefiting from ongoing lenvatinib after 
consulting with the Sponsor. This applies to participants currently on pembrolizumab and 
lenvatinib and participants who have completed 35 cycles of pembrolizumab and are 
currently continuing lenvatinib monotherapy. Participants who are considered by the 
investigator as candidates for continued monotherapy with lenvatinib after unblinding and 
completion of 35 cycles of pembrolizumab and lenvatinib require a separate communication 
with the Sponsor. Participants who discontinue pembrolizumab prior to completion of 
Cycle 35 (eg, due to an AE) must discontinue lenvatinib at the same time. All participants 
beyond the 30-day Safety Follow-up Visit should be discontinued from study; however,
standard safety reporting should continue, as applicable. As of Amendment 07, participants 
who are still on study treatment will no longer require ePRO assessments or tumor response 
assessments by BICR to be performed. Scans will no longer be submitted to the iCRO. 
Participants who are still on study medication should continue tumor imaging assessment per 
protocol. For participants no longer on study medication, local tumor imaging assessments 
should continue per SOC schedule. Biomarker specimen collection is discontinued. The 
30-day Safety Follow-up is the last required visit. Updated analyses are described in 
Section 9.
This is a randomized, placebo-controlled, parallel-group, multisite, double-blinded, efficacy, 
and safety study of pembrolizumab in combination with lenvatinib or pembrolizumab in 
combination with placebo in participants with advanced melanoma.
Approximately 660 participants will be enrolled into the study. The design also includes the 
option for an extension. The study will continue to enroll participants from China in the 
extension portion of the study until the overall sample size for China reaches approximately 
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130 (up to 137) participants in the global study and the extension portion of the study 
combined. Participants will be stratified by BRAF mutation status (BRAF mutation-positive 
vs BRAF wild-type or unknown), prior adjuvant therapy with a PD-1 inhibitor (no prior 
adjuvant therapy with a PD-1 inhibitor vs. prior adjuvant therapy with a PD-1 inhibitor), and 
geographic region (participants from China vs. non-China countries) prior to randomization. 
Note: At the time of writing Amendment 07, enrollment in the China extension was 
complete. 
Participants will be treated with the combination of pembrolizumab + lenvatinib or 
pembrolizumab + placebo for approximately 2 years or until disease progression verified by 
BICR per RECIST 1.1, 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. Pembrolizumab treatment will be 
discontinued once the participant has received 35 administrations (approximately 2 years). 
Participants may continue treatment with lenvatinib or placebo beyond approximately 2 years 
if they experience clinical benefit until unacceptable toxicity or disease progression upon 
Sponsor consultation and approval. Participants who attain an investigator-determined 
confirmed CR may consider stopping study intervention with pembrolizumab + lenvatinib or 
pembrolizumab + placebo, after at least 24 weeks of study intervention has been 
administered. In addition, if a confirmed CR per RECIST 1.1 is attained, at least 2 additional 
doses of pembrolizumab must be received after CR is first documented.
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 is 
experiencing clinical benefit with continued treatment, and the participant is tolerating study 
intervention as per iRECIST. Treatment beyond disease progression per iRECIST may be 
permitted upon Sponsor consultation and approval.
After the enrollment of the global study is completed, participants from China will continue 
to be enrolled in an extension portion of the study designed to meet local regulatory 
requirements. The extension portion of the study will be identical to the global study (eg, 
inclusion and exclusion criteria, study endpoints, primary and secondary objectives, study 
procedures) and participants enrolled in China after completion of the global enrollment will 
not be included in the analyses for the global study. The purpose of the extension portion of 
the study is to assess the consistency of safety and efficacy in the participants enrolled in 
China. Participants in China will continue to be enrolled in a 1:1 ratio until the cumulative 
total sample size for participants enrolled in China reaches approximately 130 (up to 137) 
participants in the global study and the extension portion of the study combined. The efficacy 
and safety data from participants enrolled in China (including participants enrolled prior to 
and after completion of enrollment in the global study) will be analyzed separately. 
Additional detail regarding the analysis associated with these participants will be described in 
the supplemental SAP (sSAP).
The primary endpoint of PFS will be assessed by BICR per RECIST 1.1 criteria (modified to 
follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ) by 
BICR. Safety and tolerability will be assessed by clinical review of all relevant parameters 
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including AEs, laboratory tests, vital signs, and electrocardiogram (ECG) measurements, as 
appropriate. 
Three IAs are planned for this study. Results from the IAs will be reviewed by an external 
DMC (eDMC). Further details on the IAs are provided in Section 9.7.
Specific procedures to be performed during the study, including prescribed times and 
associated visit windows, are outlined in Section 1.3 of the SoA. 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 is shown to improve PFS and/or OS, 
this study could support the regulatory approval of the combination of pembrolizumab and 
lenvatinib in participants with advanced unresectable or metastatic melanoma.
4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
The dual primary endpoints are PFS and OS.
This study will use PFS, defined as the time from date of randomization until the earliest date 
of disease progression or death from any cause, whichever comes first, based on RECIST 1.1 
criteria as assessed by BICR as the primary endpoint. 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. OS is defined as 
the time from date of randomization to date of death due to any cause.
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.
ORR and DOR are secondary endpoints.
ORR is defined as the proportion of subjects who have best response as CR or PR. Responses 
are based on BICR using RECIST 1.1.
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DOR is defined as the time from the earliest date of qualifying response until earliest date of 
disease progression or death from any cause, whichever comes first.
4.2.1.1.1
RECIST 1.1
RECIST 1.1 will be used by the BICR when assessing images for efficacy measures. 
Although original RECIST 1.1 publication recommends a maximum of 5 target lesions in 
total and 2 per organ, this protocol has implemented an adjustment to RECIST 1.1 to allow a 
maximum of 10 target lesions in total and 5 per organ, if a larger number of target lesions is 
needed to adequately represent the tumor burden. Eligibility will also be prospectively 
assessed by BICR based on RECIST 1.1. Refer to Section 8.2.1.4 for additional detail.
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 
after 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 provide an accurate 
response assessment of 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 pseudoprogression. Of note, 
participants who had disease progression by RECIST 1.1, but not by the immune-related 
response criteria [Wolchok, J. D., et al 2009], had longer overall survival than participants 
with 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.
Modified RECIST 1.1 for immune-based therapeutics (iRECIST) assessment has been 
developed and published by the RECIST Working Group, with input from leading experts 
from industry and academia, along with participation from the US FDA and the EMA 
[Seymour, L., et al 2017]. The unidimensional measurement of target lesions, qualitative 
assessment of nontarget lesions, and response categories are identical to RECIST 1.1, until 
progression is seen by RECIST 1.1. However, if a participant is clinically stable, additional 
imaging may be performed to confirm radiographic progression. iRECIST will be used by 
investigators to assess tumor response and progression and make treatment decisions.
4.2.1.2
Safety Endpoints
Safety parameters frequently used for evaluating investigational-systemic anticancer 
treatments are included as safety endpoints including, but not limited to, the incidence of, 
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causality, and outcome of AEs/SAEs, and changes in vital signs and laboratory values. AEs 
will be assessed as defined by CTCAE, Version 4.0.
4.2.1.3
Patient-reported Outcomes
Symptomatic improvement is considered a clinical benefit and accepted by health authorities 
as additional evidence of the risk-benefit profile of any new study intervention. In this study, 
HRQoL and disease-related symptoms will be investigated via the following assessment 
tools: European Organisation for the Research and Treatment of Cancer (EORTC) QoL 
Questionnaire-Core 30 (QLQ-C30) and European QoL 5-dimension 5-level (EQ-5D-5L)
questionnaires. Health utilities will be evaluated using the EQ-5D-5L PRO instrument. These 
measures are not pure efficacy or safety endpoints because they are affected by both disease 
progression and treatment tolerability.
4.2.1.3.1
EORTC QLQ-C30
EORTC QLQ-C30 is a psychometrically and clinically validated instrument appropriate for 
assessing HRQoL in oncology studies [Aaronson, N. K., et al 1993]. The EORTC QLQ-C30 
is the most widely used cancer-specific HRQoL instrument, which contains 30 items and 
measures 5 functional dimensions (physical, role, emotional, cognitive, and social), 3 
symptom items (fatigue, nausea/vomiting, and pain), 6 single items (dyspnea, sleep 
disturbance, appetite loss, constipation, diarrhea, and financial impact), and a global health 
and QoL scale [Aaronson, N. K., et al 1993]. For the global health status or QoL and function 
scales, a higher value indicates a better level of function; for symptom scales and items, a 
higher value indicates increased severity of symptoms. TTD and mean change from baseline 
in global health status or QoL scale of the EORTC QLQ-C30, will be evaluated.
4.2.1.3.2
EQ-5D-5L
The EQ-5D-5L is a standardized instrument for use as a measure of health outcome and will 
provide data to develop health utilities for use in health economic analyses [Rabin, R. and de 
Charro, F. 2001]. The 5 health state dimensions in the EQ-5D-5L include the following: 
Mobility, Self-Care, Usual Activities, Pain/Discomfort, and Anxiety/Depression. Each 
dimension is rated on a 5-point scale from 1 (no problem) to 5 (unable to/extreme problems). 
The EQ-5D-5L also includes a graded (0 to 100) vertical visual analog scale on which the 
participant rates his or her general state of health at the time of the assessment. This 
instrument has been used extensively in cancer studies and published results from these 
studies support its validity and reliability [Pickard, A. S., et al 2007].
4.2.1.4
Pharmacokinetic Endpoints
Based on lenvatinib PK data obtained in this study and from other studies, a population PK 
analysis will be performed to characterize PK parameters to support the proposed dosing 
regimen.
The serum concentrations of pembrolizumab collected will be compared to historical data to 
ensure the consistency of exposure levels at 200 mg Q3W.
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4.2.1.5
Pharmacodynamic Endpoints
No pharmacodynamic endpoints are planned for this study.
CCI
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4.2.2
Rationale for the Use of Comparator/Placebo
Programmed cell death 1 inhibition is the standard of care first-line therapy in patients with 
advanced melanoma. Therefore, pembrolizumab will be offered to all participants in this 
study. Participants will be randomized to the combination of pembrolizumab + lenvatinib or 
CCI
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pembrolizumab + placebo. Placebo will be administered in the same manner as the 
investigational product. Placebo is being utilized to allow for a blinded study, thereby 
limiting bias and providing a comparator arm that is consistent with standard of care for 
patients with advanced melanoma. Placebo is a capsule for oral administration and does not 
require preparation.
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 KEYTRUDA® development program, 200 mg Q3W is the appropriate 
dose of pembrolizumab for adults across all indications and regardless of tumor type. As 
outlined below, this dose is justified by:
•
Clinical data from 8 randomized studies demonstrating flat dose- and exposure efficacy 
relationships from 2 mg/kg Q3W to 10 mg/kg 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 
from pharmacokinetic [PK] data) and tumor (inferred from physiologically based PK 
[PBPK] analysis) at 200 mg Q3W.
Among the 8 randomized dose-comparison studies, 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 
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 
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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 endometrial cancer, and 1 had melanoma. 
There were 2 dose-limiting toxicities (DLTs) at the lenvatinib 24 mg/day + pembrolizumab 
200 mg dose 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 plus 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
NOTE: In alignment with the study-specific investigator letter sent to investigators on 
3-APR-2023, all study participants still receiving pembrolizumab should continue to receive 
pembrolizumab monotherapy on study and undergo modified protocol study procedures as 
specified in this amendment. Study participation should end after the 30-day Safety 
Follow-up Visit (last scheduled visit). All participants should stop ongoing treatment with 
lenvatinib/placebo. Exceptions may be requested for lenvatinib for study participants who, in 
the assessment of their study physician, are benefiting from ongoing lenvatinib after 
consulting with the Sponsor. This applies to participants currently on pembrolizumab and 
lenvatinib and participants who have completed 35 cycles of pembrolizumab and are 
currently continuing lenvatinib monotherapy. Participants who are considered by the 
investigator as candidates for continued monotherapy with lenvatinib after unblinding and 
completion of 35 cycles of pembrolizumab and lenvatinib require a separate communication 
with the Sponsor. Participants who discontinue pembrolizumab prior to completion of 
Cycle 35 (eg, due to an AE) must discontinue lenvatinib at the same time. All participants 
beyond the 30-day Safety Follow-up Visit should be discontinued from study; however,
standard safety reporting should continue, as applicable. As of Amendment 07, participants 
who are still on study treatment will no longer require ePRO assessments or tumor response 
assessments by BICR to be performed. Scans will no longer be submitted to the iCRO. 
Participants who are still on study medication should continue tumor imaging assessment per 
protocol. For participants no longer on study medication, local tumor imaging assessments 
should continue per SOC schedule. Biomarker specimen collection is discontinued. The 
30-day Safety Follow-up is the last required visit. Updated analyses are described in 
Section 9.
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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 for approximately 2 years. Participants may continue treatment with 
lenvatinib/placebo beyond approximately 2 years if they experience clinical benefit until 
unacceptable toxicity or disease progression upon Sponsor consultation and approval.
4.4
Beginning and End-of-Study Definition
When the study is terminated, participants receiving study intervention may be enrolled in an
extension study to continue to receive study intervention.
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 (Section 
7.3). For purposes of analysis and reporting, the overall study ends when the Sponsor 
receives the last laboratory test result or at the time of final contact with the last participant, 
whichever comes last.
If the study includes countries in the European Economic Area (EEA), the local start of the 
study in the EEA is defined as First Site Ready (FSR) in any Member State.
4.4.1
Clinical Criteria for Early Study Termination
The clinical study may be terminated early if the extent (incidence and/or severity) of 
emerging effects 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 as described in Appendix 1.10.
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5
STUDY POPULATION
As stated in the Code of Conduct for Clinical Trials (Appendix 1.1), this study includes 
participants of varying age (as applicable), race, ethnicity, and sex (as applicable). The 
collection and use of these demographic data will follow all local laws and participant 
confidentiality guidelines while supporting the study of the disease, its related factors, and 
the IMP under investigation.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
An individual is eligible for inclusion in the study if the individual meets all of the following 
criteria:
Type of Participant and Disease Characteristics
1. The participant must have a histologically or cytologically confirmed diagnosis of
melanoma.
Note: Mucosal melanoma is limited to ≤20% of all study participants.
2. Have unresectable Stage III or Stage IV melanoma, as per American Joint Committee on 
Cancer 8th edition guidelines, not amenable to local therapy.
3. Have been untreated for advanced or metastatic disease except as follows:
a.
BRAF V600 mutation-positive melanoma may have received standard of care 
targeted therapy as first-line therapy for advanced or metastatic disease (eg, 
BRAF/MEK inhibitor, alone or in combination); participants that do not have a 
BRAF V600 mutation but did receive BRAF or BRAF/MEKi therapy are eligible to 
participate in this study after discussion with the medical monitor.
Note:  Prior first-line therapy for advanced or metastatic disease with targeted therapy 
is permitted if it was completed at least 4 weeks before randomization and all related 
AEs have either returned to baseline or stabilized (resolution of toxic effect(s) to 
Grade 1 or less [except alopecia and Grade 2 neuropathy]).
b.
Prior adjuvant or neoadjuvant therapy with targeted therapy or immunotherapy (such 
as anti-CTLA-4, anti-PD-1 therapy or interferon). Immunotherapy will only be 
permitted if relapse did not occur during active treatment or within 6 months of 
treatment discontinuation. No other prior adjuvant or neoadjuvant therapy will be 
allowed.
Note: Prior adjuvant or neoadjuvant therapy with anti-CTLA-4 in combination with anti-
PD-1 therapy will not be allowed.
4. Have documentation of BRAF V600-activating mutation status or consent to BRAF 
V600 mutation testing during the Screening period (participants with BRAF mutation-
positive melanoma as well as BRAF wild-type or unknown are eligible). 
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5. Have an Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1 
(Appendix 9).
6. Have the presence of at least 1 measurable lesion by CT or MRI per RECIST 1.1 criteria 
as determined by the local site investigator/radiology assessment. Measurable disease 
will be verified by central imaging vendor (CIV) prior to randomization. Cutaneous 
lesions and other superficial lesions are not considered measurable lesions for the 
purposes of this protocol but may be considered as nontarget lesions. Photographs of 
cutaneous lesions do not need to be submitted to the CIV.
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.
c.
If a participant does not have measurable disease by CIV, they will not be allowed to 
participate in the study.
7. Provide a tumor biopsy.
a.
Participants must submit tumor sample during Screening for assessment of adequacy 
of tumor tissue at a central pathology laboratory; central confirmation of presence of 
tumor tissue is not required prior to randomization. Participants who do not submit a 
tumor tissue sample will not be randomized. The tumor biopsy may not be obtained 
from a lone target lesion. 
b.
Newly obtained tissue is preferred (no intervening treatment [local or systemic] 
involving the site of tissue biopsy once tissue biopsy is obtained at time of study 
enrollment). 
Note: In cases where newly obtained tissue with no intervening local or systemic therapy 
is not possible to provide, an archival sample will be acceptable. If participants were 
treated with BRAF ± MEK targeted treatment, the archival sample could have been 
collected prior to BRAF ± MEK targeted treatment.
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
Is an individual of any sex/gender, from at least 18 years Choose an item. of age 
inclusive, at the time of providing the informed consent.
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Male Participants
9. If capable of producing sperm, the participant agrees to the following during the 
intervention period and for at least the time needed to eliminate the study intervention 
after the last dose of study intervention. The length of time required to continue 
contraception for the study intervention is:
o
Lenvatinib/Placebo: 7 days
o
Please note that 7 days after lenvatinib/placebo is stopped, if the participant is on 
pembrolizumab only, no male contraception measures are needed.
•
Abstains from penile-vaginal intercourse as their preferred and usual lifestyle (abstinent 
on a long-term and persistent basis) and agrees to remain abstinent
OR
•
Uses contraception as detailed below unless confirmed to be azoospermic (vasectomized 
or secondary to medical cause, documented from the site personnel’s review of the 
participant’s medical records, medical examination, or medical history interview) as 
detailed below:
o
Uses a penile/external condom plus nonparticipant of childbearing potential who 
is not currently pregnant and should also be advised of the benefit for that partner 
to use an additional method of contraception, as a condom may break or leak.
Note: Participants capable of producing ejaculate whose partner is pregnant or 
breastfeeding must agree to use penile/external condom during each episode of sexual 
activity in which the partner is at risk of drug exposure via ejaculate.
o
Contraceptive use by participants capable of producing sperm should be 
consistent with local regulations regarding the methods of contraception for those 
participating in clinical studies. If the contraception requirements in the local label 
for any of the study interventions are more stringent than the requirements above, 
the local label requirements are to be followed.
Female Participants
10. A participant assigned female sex at birth is eligible to participate if not pregnant or 
breastfeeding, and at least one of the following conditions applies:
•
Is not a POCBP
OR
•
Is a POCBP and:
o
Uses an acceptable contraceptive method, or is abstinent from penile-vaginal 
intercourse as their preferred and usual lifestyle (abstinent on a long-term and 
persistent basis), as described in Appendix 5 during the intervention period and 
for at least 120 days post pembrolizumab or 30 days post lenvatinib/placebo, 
whichever occurs last, 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. 
Contraceptive use by POCBPs should be consistent with local regulations 
regarding the methods of contraception for those participating in clinical studies.
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If the contraception requirements in the local label for any of the study 
interventions are more stringent than the requirements above, the local label 
requirements are to be followed.
o
Has a negative highly sensitive pregnancy test (urine or serum) as required by 
local regulations within 24 hours (for a urine test) or 72 hours (for a serum test) 
before the first dose of study intervention. If a urine test cannot be confirmed as 
negative (eg, an ambiguous result), a serum pregnancy test is required. In such 
cases, the participant must be excluded from participation if the serum pregnancy 
result is positive. Additional requirements for pregnancy testing during and after 
study intervention are in Section 8.3.5 and Appendix 2.
o
Medical history, menstrual history, and recent sexual activity has been reviewed 
by the investigator to decrease the risk for inclusion of a POCBP with an early 
undetected pregnancy.
Informed Consent
11. The participant (or legally acceptable representative) has provided documented informed
consent for the study.
Additional Categories
12. Have adequately controlled BP with or without antihypertensive medications, defined as 
BP ≤150/90 mm Hg with no change in antihypertensive medications within 1 week prior 
to randomization.
13. Adequate organ function as defined in the following table (Table 1). Specimens must be 
collected within 7 days before the start of study intervention.
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Table 1
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 calculated creatinine clearance b
(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)
≤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)
≤1.5 × ULN unless participant is receiving anticoagulant 
therapy as long as PT or PTT is within therapeutic range 
of intended use of anticoagulants
ALT (SGPT) alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT) aspartate 
aminotransferase (serum glutamic oxaloacetic transaminase); GFR glomerular filtration rate; ULN upper limit of 
normal.
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.
5.2
Exclusion Criteria
The participant must be excluded from the study if the participant meets any of the following 
criteria:
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.
2. Has a known additional malignancy that is progressing or requires active treatment. 
Exceptions include early stage cancers (carcinoma in situ or stage 1, nonulcerated 
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.
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3. Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis. Participants with previously treated brain 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 scans 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 mAb. 
For a list of excipients, refer to the respective IBs.
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 human immunodeficiency virus (HIV) (HIV 1/2 antibodies). No 
testing of HIV is required unless mandated by local health authority. (See Appendix 7 for 
country-specific requirements.)
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. (See Appendix 7 for country-
specific requirements.)
10. Has a history of (noninfectious) pneumonitis/interstitial lung disease that required 
steroids or has current pneumonitis/interstitial lung disease.
11. Has a history of active tuberculosis (Bacillus tuberculosis). (See Appendix 7 for country-
specific requirements.)
12. Gastrointestinal malabsorption or any other condition that might affect the absorption of 
lenvatinib.
13. Has had a major surgery within 3 weeks prior to first dose of study intervention. Note: 
Adequate wound healing after major surgery must be assessed clinically, independent of 
time elapsed for eligibility. 
14. Has preexisting Grade ≥3 gastrointestinal or nongastrointestinal fistula.
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15. Has radiographic evidence of encasement or invasion of a major blood vessel, or of 
intratumoral cavitation. 
Note: The degree of proximity to major blood vessels should be considered because of 
the potential risk of severe hemorrhage associated with tumor shrinkage/necrosis 
following lenvatinib therapy.
16. Has active hemoptysis (bright red blood of at least 0.5 teaspoon) within 3 weeks prior to 
the first dose of study intervention.
17. Has clinically significant cardiovascular disease within 12 months from first dose of 
study intervention, 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 with ≥2+ (≥100 mg/dL) proteinuria on urine dipstick testing (or 
urinalysis) will undergo 24-hour urine collection for quantitative assessment of 
proteinuria. 
19. Prolongation of QTcF interval to >480 ms.
Note: If the QTcF is prolonged to >480 ms in the presence of a pacemaker, contact the 
Sponsor to determine eligibility. (See Appendix 7 for Country-specific requirements.)
20. Has left ventricular ejection fraction (LVEF) below the institutional (or local laboratory) 
normal range, as determined by multigated acquisition scan (MUGA) or echocardiogram.
Prior/Concomitant Therapy
21. Has received prior systemic treatment for unresectable or metastatic melanoma other than 
targeted therapy as noted in Inclusion Criteria #3.
22. Has received prior therapy in the adjuvant setting. Note: Targeted therapy, anti-CTLA-4, 
or anti-PD-1 may be allowed as noted in Inclusion Criteria #3.
23. Received prior systemic anticancer therapy including investigational agents within 
4 weeks or 5 half-lives (whichever is longer) before administration of study intervention 
or not recovered (≤Grade 1 or at baseline) from AEs due to previously administered 
agents. Exception to this rule would be use of denosumab, which is not excluded.
Note: Participants with alopecia and ≤Grade 2 neuropathy are an exception and may 
enroll.
24. 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.
25. Has received 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, Bacillus Calmette-Guérin (BCG), and typhoid 
vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and 
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are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated 
vaccines and are not allowed. (See Appendix 7 for country-specific requirements.)
Prior/Concurrent Clinical Study Experience
26. 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.
Other Exclusions
27. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the study, interfere with the participant's participation 
for the full duration of the study, or is not in the best interest of the participant to 
participate, in the opinion of the treating investigator. 
28. Had an allogeneic tissue/solid organ transplant.
29. 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
Participants should maintain a normal diet unless modifications are required to manage an 
AE such as diarrhea, nausea, or vomiting.
5.3.2
Pregnancy
If a participant inadvertently becomes pregnant while on any study intervention, 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 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 as described in Section 8.4. 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.
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5.3.3
Use in Nursing Women
It is unknown whether the study interventions are 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 randomized in the study. A minimal set of screen-failure information is 
required to ensure transparent reporting of screen-failure participants to meet the 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.
Original protocol text contained in this section has been retained for reference.
Clinical supplies (pembrolizumab, lenvatinib, and placebo) 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
NOTE: In alignment with the study-specific investigator letter sent to investigators on 
3-APR-2023, all study participants still receiving pembrolizumab should continue to receive 
pembrolizumab monotherapy on study and undergo modified protocol study procedures as 
specified in this amendment. Study participation should end after the 30-day Safety 
Follow-up Visit (last scheduled visit). All participants should stop ongoing treatment with 
lenvatinib/placebo. Exceptions may be requested for lenvatinib for study participants who, in 
the assessment of their study physician, are benefiting from ongoing lenvatinib after 
consulting with the Sponsor. This applies to participants currently on pembrolizumab and 
lenvatinib and participants who have completed 35 cycles of pembrolizumab and are 
currently continuing lenvatinib monotherapy. Participants who are considered by the 
investigator as candidates for continued monotherapy with lenvatinib after unblinding and 
completion of 35 cycles of pembrolizumab and lenvatinib require a separate communication 
with the Sponsor. Participants who discontinue pembrolizumab prior to completion of 
Cycle 35 (eg, due to an AE) must discontinue lenvatinib at the same time. All participants 
beyond the 30-day Safety Follow-up Visit should be discontinued from study; however,
standard safety reporting should continue, as applicable.
The study intervention(s) to be used in this study are outlined in Table 2.
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Table 2
Study Interventions
Arm 
Name
Arm Type
Intervention 
Name
Intervention 
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen/
Treatment 
Period/
Vaccination 
Regimen
Use
IMP or 
NIMP/
AxMP
Sourcing
Arm A Experimental Pembrolizumab Drug
Solution
25 mg/mL
200 mg
IV Infusion
Q3W
Test 
Product
IMP
Central
Arm A Experimental Lenvatinib
Drug
Capsule
10 mg,
4 mg
20 mg
Oral
QD
Test 
Product
IMP
Central
Arm B
Active 
Comparator
Pembrolizumab Drug
Solution
25 mg/mL
200 mg
IV Infusion
Q3W
Comparator IMP
Central
Arm B
Placebo 
Comparator
Placebo
Drug
Capsule
0 mg
0 mg
Oral
QD
Placebo
IMP
Central
Abbreviations: EEA European Economic Area; IMP investigational medicinal product; NIMP/AxMP noninvestigational/auxiliary medicinal product; Q3W every 3 weeks; 
QD once daily.
4 mg lenvatinib capsules provided for successive dose reduction of lenvatinib/placebo, if needed, as described in Section 6.6.2.
The classification of IMP and NIMP/AxMP in this table is based on guidance issued by the European Commission and applies to countries in the EEA. Country differences
with respect to the definition/classification of IMP and NIMP/AxMP may exist. In these circumstances, local legislation is followed.
Note: As of PA07, use of placebo is discontinued.
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All study interventions will be administered on an outpatient basis.
All products indicated in Table 2 will be provided centrally by the Sponsor or locally by the 
study site, subsidiary, or designee, depending on local country operational or regulatory 
requirements.
For any commercially available product that is provided by the study site, subsidiary, or 
designee, every attempt will be made to source these supplies from a single lot/batch number. 
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product as per local guidelines unless otherwise instructed by the 
Sponsor.
Refer to Section 8.1.8 for details regarding administration of the study intervention.
All placebos were created by the Sponsor to match the active product.
6.1.1
Medical Devices
Not applicable.
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/placebo is a capsule for oral administration and does not require preparation. If a 
dose of lenvatinib/placebo is missed and cannot be taken within 12 hours from the scheduled 
administration, the participant should skip this dose and take the next dose at the scheduled 
time the next day. See Pharmacy Manual for additional information.
6.2.2
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
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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.
6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Intervention randomization will occur centrally using an IRT system. There are 2 study 
intervention arms. Participants will be assigned randomly in a 1:1 ratio to either Arm A 
(pembrolizumab + lenvatinib) or Arm B (pembrolizumab + placebo).
6.3.2
Stratification
Intervention allocation/randomization will be stratified according to the following factors:
BRAF mutation status:
•
BRAF mutation-positive
•
BRAF wild-type or unknown
Prior adjuvant therapy with a PD-1 inhibitor:
•
No prior adjuvant therapy with a PD-1 inhibitor
•
Prior adjuvant therapy with a PD-1 inhibitor
Geographic region:
•
Participants from China 
•
Participants from non-China countries
6.3.3
Blinding
As of IA3, the study was unblinded. Original protocol text that is contained in this section 
has been retained for reference.
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A double-blinding technique with in-house blinding will be used. Lenvatinib and placebo 
will be packaged identically so that blind is maintained. The participant, the investigator, and 
Sponsor personnel or delegate(s) who are involved in the study intervention administration or 
clinical evaluation of the participants are unaware of the intervention assignments.
See Section 8.1.10 for the description of unblinding if a medical emergency occurs during the 
study.
6.4
Study Intervention Compliance
Interruptions from the protocol-specified treatment ≥28 days (lenvatinib/placebo) 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 case report form (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.
6.5.1
Allowed Concomitant Medication(s)
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 
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considered in accordance with institutional guidelines. Bisphosphonates (including 
denosumab) are also allowed.
6.5.2
Prohibited Concomitant Medication(s)
Participants are prohibited from receiving the following therapies during the Screening and 
Treatment Phase of this study:
•
Concurrent anticancer therapies such as chemotherapy, targeted therapies (eg, tyrosine 
kinase inhibitors), antitumor interventions (surgical resection, surgical debulking of 
tumor, etc.), or cancer immunotherapy not specified in this protocol.
Note:  Topical anticancer agents to treat skin lesions (eg, in situ melanoma or squamous 
cell carcinoma) are allowed.
•
Note: Palliative surgery will be 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 are permitted only for the following purposes:
-
To modulate symptoms of an AE that is suspected to have an immunologic etiology
-
As needed for the prevention of emesis
-
Premedication for IV contrast allergies
-
Short-term oral or IV use in doses <10 mg/day prednisone equivalent for COPD 
exacerbations
-
For chronic systemic replacement not to exceed 10 mg/day prednisone equivalent
•
In addition, the following glucocorticoid use is allowed:
-
For topical use or ocular use
-
Intraarticular joint use
-
For inhalation in the management of asthma or chronic obstructive pulmonary 
disease. 
•
Palliative radiotherapy will be allowed.
For participants who, in an assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management, continuation of the study medication 
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.
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6.5.3
Drug Interactions
There are no DDI-related concomitant medication prohibitions or restrictions.
Lenvatinib is not expected to clinically meaningfully alter exposure to CYP3A4/ 
P-glycoprotein (Pgp) substrates based on results from a lenvatinib drug-drug interaction 
(DDI) study with midazolam (a sensitive CYP3A and Pgp substrate). Clinical studies also 
showed that co-administration of lenvatinib with either inducers or inhibitors of 
CYP3A4/Pgp are 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 nonenzymatic processes (lenvatinib IB).
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/placebo, 
suggested supportive care measures for the management of AEs with potential immunologic 
etiology are outlined in Table 3 in Section 6.6.1 along with the dose modification guidelines 
in Table 4 and Table 5 in Section 6.6.1 and Section 6.6.2.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/placebo. 
Note: If after the evaluation of the event, it is determined not to be related to pembrolizumab, 
the investigator does not need to follow the treatment guidance. It may be necessary to 
perform conditional procedures such as bronchoscopy, endoscopy, or skin photography as 
part of evaluation of the event.
6.6
Dose Modification
NOTE: In alignment with the study-specific investigator letter sent to investigators on 
3-APR-2023, all study participants still receiving pembrolizumab should continue to receive 
pembrolizumab monotherapy on study and undergo modified protocol study procedures as 
specified in this amendment. Study participation should end after the 30-day Safety 
Follow-up Visit (last scheduled visit). All participants should stop ongoing treatment with 
lenvatinib/placebo. Exceptions may be requested for lenvatinib for study participants who, in 
the assessment of their study physician, are benefiting from ongoing lenvatinib after 
consulting with the Sponsor. This applies to participants currently on pembrolizumab and 
lenvatinib and participants who have completed 35 cycles of pembrolizumab and are 
currently continuing lenvatinib monotherapy. Participants who are considered by the 
investigator as candidates for continued monotherapy with lenvatinib after unblinding and 
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completion of 35 cycles of pembrolizumab and lenvatinib require a separate communication 
with the Sponsor. Participants who discontinue pembrolizumab prior to completion of 
Cycle 35 (eg, due to an AE) must discontinue lenvatinib at the same time. All participants 
beyond the 30-day Safety Follow-up Visit should be discontinued from study; however,
standard safety reporting should continue, as applicable. As of Amendment 07, participants 
who are still on study treatment will no longer require ePRO assessments or tumor response 
assessments by BICR to be performed. Scans will no longer be submitted to the iCRO. 
Participants who are still on study medication should continue tumor imaging assessment per 
protocol. For participants no longer on study medication, local tumor imaging assessments 
should continue per SOC schedule. Biomarker specimen collection is discontinued. The 
30-day Safety Follow-up is the last required visit. Updated analyses are described in 
Section 9.
Adverse events will be graded using NCI CTCAE version 4.0. Investigators will decide the 
probability of the event being related to one or both drugs as to whether dose modification of 
one or both drugs is required.
Participants who interrupt lenvatinib/placebo or pembrolizumab due to toxicity can continue 
with the other drug until criteria for treatment discontinuation are met (eg, unacceptable 
toxicity, disease progression).
Participants who discontinue lenvatinib/placebo due to untoward toxicities can continue on 
the study receiving pembrolizumab as monotherapy. Participants who discontinue 
pembrolizumab due to untoward toxicities cannot continue on the study receiving only 
lenvatinib/placebo.
Refer to Section 6.6.3 for dose modification guidance for overlapping toxicity for the 
pembrolizumab plus lenvatinib/placebo combination.
6.6.1
Dose Modification (Escalation/Titration/Other)
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.
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Dose modification and toxicity management guidelines for irAEs associated with 
pembrolizumab are provided in Table 3.
Table 3
Dose Modification and Toxicity Management Guidelines for Nonhepatic 
Immune-related Adverse Events Associated With Pembrolizumab
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 
(CTCAE 
v4.0)
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 
to 2 mg/kg 
prednisone or 
equivalent) 
followed by taper
Add prophylactic 
antibiotics for 
opportunistic 
infections
Monitor participants 
for signs and 
symptoms of 
pneumonitis
Evaluate participants 
with suspected 
pneumonitis with 
radiographic imaging 
and initiate 
corticosteroid 
treatment
Recurrent 
Grade 2, or 
Grade 3 or 4
Permanently 
discontinue
Diarrhea/Colitis
Grade 2 or 3
Withhold
Administer 
corticosteroids 
(initial dose of 1 
to 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 
Recurrent 
Grade 3 or 
Grade 4
Permanently 
discontinue
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irAEs
Toxicity 
Grade 
(CTCAE 
v4.0)
Action With 
Pembrolizumab
Monotherapy, 
Coformulations, 
or IO 
Combinations
Corticosteroid 
and/or Other 
Therapies
Monitoring and Follow-
up
clear fluids. If 
sufficient oral fluid 
intake is not feasible, 
fluid and electrolytes 
should be substituted 
via IV infusion
T1DM or 
Hyperglycemia
New onset 
T1DM or 
Grade 3 or 4 
hyperglycemia 
associated 
with evidence 
of -cell 
failure
Withholda
Initiate insulin 
replacement 
therapy for 
participants with 
T1DM
Administer 
antihyperglycemic 
in participants 
with 
hyperglycemia
Monitor participants 
for hyperglycemia or 
other signs and 
symptoms of diabetes
Hypophysitis
Grade 2
Withhold
Administer 
corticosteroids 
and initiate 
hormonal 
replacements as 
clinically 
indicated
Monitor for signs and 
symptoms of 
hypophysitis 
(including 
hypopituitarism and 
adrenal insufficiency)
Grade 3 or 4
Withhold or 
permanently 
discontinuea
Hyperthyroidism
Grade 2
Continue
Treat with 
nonselective beta-
blockers (eg, 
propranolol) or 
thionamides as 
appropriate
Monitor for signs and 
symptoms of thyroid 
disorders
Grade 3 or 4
Withhold or 
permanently 
discontinuea
Hypothyroidism
Grade 2
Continue
Initiate thyroid 
replacement 
hormones (eg, 
levothyroxine or 
liothyronine) per 
standard of care
Monitor for signs and 
symptoms of thyroid 
disorders
Grade 3 or 4
Withhold or 
permanently 
discontinuea
Nephritis:
grading 
according to 
increased 
creatinine or 
acute kidney 
injury
Grade 2
Withhold
Administer 
corticosteroids 
(prednisone 1 to 
2 mg/kg or 
equivalent) 
followed by taper
Monitor changes of 
renal function
Grade 3 or 4
Permanently 
discontinue
Neurological 
Toxicities
Grade 2
Withhold
Based on severity 
of AE administer 
corticosteroids
Ensure adequate 
evaluation to confirm 
etiology and/or 
exclude other causes
Grade 3 or 4
Permanently 
discontinue
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irAEs
Toxicity 
Grade 
(CTCAE 
v4.0)
Action With 
Pembrolizumab
Monotherapy, 
Coformulations, 
or IO 
Combinations
Corticosteroid 
and/or Other 
Therapies
Monitoring and Follow-
up
Myocarditis
Asymptomatic 
cardiac 
enzyme 
elevation with 
clinical 
suspicion of 
myocarditis 
(which was 
previously 
myocarditis 
Grade 1 using 
CTCAE v4.0)
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
Exfoliative 
Dermatologic 
Conditions
Suspected 
SJS, TEN, or 
DRESS
Withhold
Based on severity 
of AE administer 
corticosteroids
Ensure adequate 
evaluation to confirm 
etiology or exclude 
other causes
Confirmed 
SJS, TEN, or 
DRESS
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 
based on the 
eventb
Recurrent 
Grade 3 or 
Grade 4
Permanently 
discontinue
AE(s) adverse event(s); CTCAE Common Terminology Criteria for Adverse Events; DRESS Drug Rash with 
Eosinophilia and Systemic Symptom; GI gastrointestinal; IO immuno oncology; ir immune related; 
IV intravenous; SJS Stevens Johnson Syndrome; T1DM type 1 diabetes mellitus; TEN Toxic Epidermal 
Necrolysis; ULN upper limit of normal.
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations.
a
The decision to withhold or permanently discontinue pembrolizumab monotherapy, coformulations, or IO 
combinations is at the discretion of the investigator or treating physician. If control achieved or ≤Grade 2, 
pembrolizumab monotherapy, coformulations, or IO combinations may be resumed.
b
Events that require discontinuation include, but are not limited to encephalitis and other clinically important irAEs 
(eg, vasculitis and sclerosing cholangitis)
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. 
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Dose modification and toxicity management guidelines on pembrolizumab associated 
infusion reactions are provided in Table 4.
Table 4
Pembrolizumab Infusion Reaction Dose Modification and 
Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at Subsequent Dosing
Grade 1
Mild reaction; infusion 
interruption not 
indicated; intervention 
not indicated
Increase monitoring of vital signs as 
medically indicated until the 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 h
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/h to 
50 mL/h). 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 intervention.
Participant may be premedicated 1.5 h 
(±30 min) prior to infusion of study 
intervention with:
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine).
Acetaminophen 500 to 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 after 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 intervention.
No subsequent dosing
CTCAE Common Terminology Criteria for Adverse Events; h hour; IV intravenous; NCI National Cancer 
Institute; NSAIDs nonsteroidal anti inflammatory drugs.
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
Other Allowed Dose Interruptions for Pembrolizumab
See Section 6.6.4 for other allowed dose interruptions for pembrolizumab and 
lenvatinib/placebo and stop time and restart time of lenvatinib/placebo for minor/major 
procedures.
6.6.2
Dose Modification With Lenvatinib/Placebo
Lenvatinib/placebo dose reduction and interruption for participants who experience 
lenvatinib/placebo-pembrolizumab combination therapy-related toxicity will be in 
accordance with the dose modification guidelines described in Table 5. An interruption of 
study intervention for more than 28 days will require Sponsor consultation and approval 
before treatment can be resumed. Participants who discontinue lenvatinib/placebo due to 
untoward toxicities can continue on the study receiving pembrolizumab as monotherapy.
The starting dose of lenvatinib/placebo is 20 mg/day. Dose reductions of lenvatinib/placebo 
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, 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), 
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thromboembolic events (Section 6.6.2.5), posterior reversible encephalopathy syndrome/ 
reversible encephalopathy syndrome/reversible posterior leukoencephalopathy syndrome 
(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), QT prolongation (6.6.2.10), 
and osteonecrosis of the jaw (Section 6.6.2.11) as appropriate, before consulting the dose 
modification table (Table 5). For overlapping toxicities of pembrolizumab and 
lenvatinib/placebo, please refer to Section 6.6.3.
Table 5
Dose Modification Guidelines for Lenvatinib/Placebo-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,f
First occurrence
Interrupt lenvatinib/placebo 
until resolved to Grade 0-1, 
or tolerable Grade 2
Reduce lenvatinib/placebo 
dose to 14 mg once a day (1-
level reduction) 
Second occurrence (same 
toxicity or new toxicity)
Interrupt lenvatinib/placebo 
until resolved to Grade 0-1, 
or tolerable Grade 2
Reduce lenvatinib/placebo 
dose to 10 mg once a day (1-
level reduction)
Third occurrence (same 
toxicity or new toxicity)
Interrupt lenvatinib/placebo 
until resolved to Grade 0-1, 
or tolerable Grade 2
Reduce lenvatinib/placebo 
dose to 8 mg orally once a 
day (1-level reduction) 
Fourth occurrence (same 
toxicity or new toxicity)
Interrupt lenvatinib/placebo 
Discuss with Sponsor
Grade 4g: 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/placebo 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 
have a minimum BMI of 25. The new stable weight should be used as the new baseline for 
further dose reductions. 
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Treatment-related
Toxicitya,b
Management
Dose Adjustment
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.
For Grade 3 thromboembolic event, permanently discontinue lenvatinib/placebo, see Section 
6.6.2.5.
g.
Excluding laboratory abnormalities judged to be nonlife-threatening, in which case manage as 
Grade 3.
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/placebo 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 C1D1. Early detection and effective management of hypertension are important to 
minimize the need for lenvatinib/placebo 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 
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/placebo should be withheld in any instance where a participant is at imminent risk 
to develop a hypertensive crisis or has significant risk factors for severe complications of 
uncontrolled hypertension (eg, BP ≥160/100 mm Hg, significant risk factors for cardiac 
disease, intracerebral hemorrhage, or other significant comorbidities). Once the participant 
has been on the same antihypertensive medications for at least 48 hours and the BP is
controlled, lenvatinib/placebo should be resumed as described below.
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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.
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 intervention and institute antihypertensive therapy for participants not 
already receiving antihypertensive therapy.
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/placebo 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.
o
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/placebo 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.
o
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/placebo 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.
o
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 intervention
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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:
•
Perform urine dipstick testing per the SoA (Section 1.3). Urine dipstick testing is the 
preferred method for testing urinary protein, however, urinalysis may be used if the 
use of urine dipstick is not feasible.
•
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:
o
The first (initial) occurrence of ≥2+ (≥100 mg/dL) proteinuria on urine dipstick 
(or urinalysis) while the participants is receiving lenvatinib/placebo
o
A subsequent increase in severity of urine dipstick or urinalysis proteinuria 
occurring on the same lenvatinib/placebo dose level
o
When there has been a lenvatinib/placebo dose reduction and at the new dose 
level the urine protein dipstick result is ≥2+ (≥100 mg/dL)
•
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/placebo administration will 
be based on the grade of proteinuria according to Table 5.
Monitoring:
•
Urine dipstick or urinalysis testing for participants with proteinuria ≥2+ 
(≥100 mg/dL) should be performed on D15 (or more frequently as clinically 
indicated) until the results have been 1+ (30 mg/dL) 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.
•
In the event of nephrotic syndrome, lenvatinib/placebo must be discontinued.
6.6.2.3
Management of Diarrhea
An anti-diarrheal agent should be recommended to the participant at the start of study 
intervention and participants should be instructed and educated to initiate anti-diarrheal 
treatment at the first onset of soft bowel movements. The choice of anti-diarrheal agent 
should be individualized to the participant’s clinical circumstances and follow standard 
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medical practice. If signs/symptoms of diarrhea persist despite optimal medical management, 
instructions contained in Table 5 should be followed.
6.6.2.4
Management of Hepatotoxicity
Liver function tests (alanine transaminase [ALT], aspartate transaminase [AST], 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 5 should be 
followed. Appropriate supportive care should be provided together with close monitoring. If 
hepatic failure (any grade per CTCAE v4.0) occurs, lenvatinib/placebo 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, and DVT 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 5 should 
be followed. Appropriate supportive care should be provided together with close monitoring. 
If a participant experiences a Grade 3 or life-threatening (Grade 4) thromboembolic 
reactions, 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 5 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).
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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 5 should be followed for the management of hemorrhage. Either resume 
at a reduced dose or discontinue lenvatinib/placebo depending on the severity and persistence 
of hemorrhage.
6.6.2.9
Management of Gastrointestinal Perforation or Fistula
Lenvatinib/placebo should be discontinued in any participants who develop gastrointestinal 
perforation of any grade or Grade 4 fistula.
See Appendix 7 for country-specific requirements.
6.6.2.10
Management of QT Prolongation
Lenvatinib/placebo should be withheld in the event of development of QT interval 
prolongation greater than 500 msec. Lenvatinib/placebo should be resumed at a reduced dose 
when QTc prolongation is resolved to <480 msec or baseline. Monitor potassium, calcium 
and magnesium, and replenish as appropriate.
6.6.2.11
Management of Osteonecrosis of the Jaw
Perform an oral examination prior to treatment with lenvatinib/placebo and periodically 
during lenvatinib/placebo treatment. Advise participants regarding good oral hygiene 
practices. Avoid invasive dental procedures, if possible, while on lenvatinib/placebo 
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/placebo 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
Participants who experience an unacceptable toxicity that is attributed to lenvatinib/placebo 
in the opinion of the investigator and the Sponsor, may permanently discontinue 
lenvatinib/placebo, but may continue with pembrolizumab, upon resolution of toxicity to 
Grade 0 or 1 or baseline, until unacceptable toxicity or progression. Participants who 
discontinue pembrolizumab due to untoward toxicities cannot continue on the study 
receiving only lenvatinib/placebo.
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 
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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 intervention. Therefore, evaluation of 
attribution is important for determining the study intervention 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/placebo 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/placebo 
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/placebo dose interruption is needed. 
◦
If an AE is identified at the beginning of a treatment cycle, lenvatinib/placebo can 
be interrupted and dosing of pembrolizumab should be held.
If the participant recovers from an AE in response to lenvatinib/placebo interruption (ie, 
positive dechallenge), the event is more likely to be related to lenvatinib/placebo. 
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.
3. Participants receiving the combination therapy (pembrolizumab + lenvatinib/placebo) 
must discontinue study intervention if any of the following occur:
◦
ALT or AST >5 × ULN for more than 2 weeks
Pembrolizumab will have already been permanently discontinued per Table 3, but 
lenvatinib/placebo may be administered at a reduced dose by the time this 
criterion is met and must be permanently discontinued immediately.
◦
ALT or AST >3 × ULN and (TBL >2 × ULN or INR >1.5)
Although Table 3 advises pembrolizumab to be withheld (interrupted), and 
Table 5 advises lenvatinib/placebo to have no dose modification or a reduction, if 
this criterion is met, both drugs must be permanently discontinued immediately.
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6.6.4
Other Allowed Dose Interruptions for Lenvatinib/Placebo and 
Pembrolizumab
If the participant is receiving treatment with lenvatinib/placebo and requires surgery during 
the study, the stop time and restart time of lenvatinib/placebo should be as follows:
•
For minor procedures: stop lenvatinib/placebo 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/placebo at least 1 week (5 half-lives) prior 
to surgery and then restart it at least 2 weeks after, once there is evidence of 
adequate healing and no risk of bleeding.
•
For scheduled dental surgery or invasive dental procedures, stop lenvatinib for at 
least 1 week before the procedure, then restart lenvatinib when deemed clinically 
appropriate.
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 after the end of the study.
6.8
Clinical Supplies Disclosure
The emergency unblinding call center will use the intervention/randomization schedule for 
the study to unblind participants and to unmask study intervention identity. The emergency 
unblinding call center should only be used in cases of emergency (see Section 8.1.10). If the 
emergency unblinding call center is not available for a given site in this study, the central 
electronic intervention allocation/randomization system (IRT) should be used to unblind 
participants and to unmask study intervention identity. The Sponsor will not provide random 
code/disclosure envelopes or lists with the clinical supplies.
See Section 8.1.10 for a description of the method of unblinding a participant during the 
study, should such action be warranted.
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6.9
Standard Policies
At the close of the study after unblinding, a letter is to be sent by the investigator to those 
participants who received placebos in the image of the competitor’s product to provide the 
following advice:
“You have participated in a study conducted by the Sponsor. This letter is to advise you that 
you were among those who received a look-alike capsule created to resemble the drug
LENVIMA® (lenvatinib) as much as possible. You did not receive the active drug
LENVIMA (lenvatinib) as manufactured by Eisai.”
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7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
Discontinuation of study intervention does not represent withdrawal from the study.
As certain data on clinical events beyond study intervention discontinuation may be 
important to the study, they must be collected through the participant’s last scheduled follow-
up, even if the participant has discontinued study intervention. Therefore, all participants 
who discontinue study intervention before completion of the protocol-specified treatment 
period/vaccination regimen will still continue to participate in the study as specified in
Section 1.3 and Section 8.11.3.
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 Sponsor, placed the participant at unnecessary risk from continued 
administration of study intervention.
•
The participant has a confirmed positive serum pregnancy test.
•
Any progression or recurrence of any malignancy, or any occurrence of secondary 
malignancy that requires active treatment. Exceptions to secondary malignancy include 
basal cell carcinoma of the skin, squamous cell carcinoma of the skin, new nonulcerated 
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).
•
Completion of 35 treatments (approximately 2 years) with pembrolizumab and 
lenvatinib/placebo. Note: Participants experiencing a clinical benefit may continue on 
lenvatinib/placebo alone beyond this time point until unacceptable toxicity or disease 
progression upon Sponsor consultation and approval (see Section 4.3.3 for additional 
details).
•
Grade 3 thromboembolic events require permanent discontinuation of lenvatinib/placebo.
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•
Participants receiving the combination therapy (pembrolizumab + lenvatinib/placebo) 
must discontinue study therapy if any of the following occur:
◦
ALT or AST >5 × ULN for more than 2 weeks
Pembrolizumab will have already been permanently discontinued per Table 3, but 
lenvatinib/placebo may be administered at a reduced dose by the time this 
criterion is met and must be permanently discontinued immediately.
◦
ALT or AST >3 × ULN and (TBL >2 × ULN or INR >1.5)
Although Table 3 advises pembrolizumab to be withheld (interrupted), and
Table 5 advises lenvatinib/placebo 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 any of the following reasons:
•
Discontinuation of study intervention with pembrolizumab and lenvatinib/placebo 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.
•
Progressive disease as verified by BICR.
Note: Participants will be permitted to continue treatment beyond RECIST 1.1-defined 
progression as long as investigator-assessed clinical stability is observed, and the 
participant is tolerating study intervention (Section 8.2.1.5). Treatment beyond PD per 
iRECIST may be permitted upon Sponsor consultation and approval.
As of Amendment 07, central tumor response assessments will no longer be performed. 
Participants on study intervention who are deriving clinical benefit and are continuing to 
receive study intervention will be assessed locally by the investigator for disease progression 
per protocol schedule. Scans will not be sent to the iCRO.

Participants with RECIST 1.1 progression per local investigator assessment may 
continue pembrolizumab per iRECIST if criteria for clinical stability are met. 

Participants with RECIST 1.1 disease progression must discontinue lenvatinib. 

At investigator-determined iCPD, pembrolizumab should be discontinued (exceptions 
may be made if participant is clinically stable, derives benefit and if the Sponsor 
approves treatment continuation beyond iCPD).
Original protocol text that is contained in this section and the following sections has been 
retained for reference.
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.
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If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, are outlined in Section 8.1.9. The procedures to be performed should a participant 
repeatedly fail to return for scheduled visits and/or if the study site is unable to contact the 
participant are outlined in Section 7.3.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
•
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
•
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.
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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 (by education, training, and experience) 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 (or dentist when appropriate).
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of ICF may be used for screening or baseline purposes 
provided the procedures meet the protocol-specified criteria and were performed within 
the time frame defined in the SoA.
•
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, hepatitis C), and thus local regulations 
may require that additional informed consent be obtained from the participant. In these 
cases, such evaluations/testing will be performed in accordance with those regulations.
•
Repeat or unscheduled samples may be taken for safety reasons or for technical issues 
with the samples.
8.1
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented informed 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 documented 
informed 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 study protocol number, study 
protocol title, dated signature, and agreement of the participant (or his/her legally acceptable 
representative) and of the person conducting the consent discussion.
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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.
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 treatment/randomization number to the 
participant identification card.
The participant ID card also contains contact information for the emergency unblinding call 
center so that a health care provider can obtain information about study intervention in 
emergency situations where the investigator is not available.
8.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee. The medical 
history will collect all active conditions and any condition diagnosed within the prior 
10 years that the investigator considers to be clinically important. Details regarding the 
disease for which the participant has enrolled in this study will be recorded separately and 
not listed as medical history.
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If a medical condition is diagnosed at the time of screening due to the physical examination, 
laboratory tests, radiologic assessment, other assessment, and/or a combination of these 
evaluations, the medical condition is to be recorded as a baseline condition along with the 
participant’s other medical history unless due to any protocol-specified intervention (eg, 
procedure, washout, or run-in treatment including placebo run-in).
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 starting the study. Treatment for the disease for which the participant 
has enrolled in this study will be recorded separately and not listed as a prior medication.
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study through the Safety Follow-up Visit. Concomitant medications will be 
recorded for 30 days after the last dose of study intervention.
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 before randomization. Each participant 
will be assigned only 1 screening number. Screening numbers must not be reused for 
different participants.
8.1.7
Assignment of Treatment/Randomization Number
All eligible participants will be randomly allocated and will receive a randomization number. 
The randomization number identifies the participant for all procedures occurring after 
randomization. Once a randomization number is assigned to a participant, it can never be 
reassigned to another participant.
A single participant cannot be assigned more than 1 randomization number.
8.1.8
Study Intervention Administration
Study intervention should begin within 3 days of randomization.
Lenvatinib/Placebo: Lenvatinib/placebo may be administered at home except on C1D1, 
C1D15, and C2D1; on these days, lenvatinib/placebo will be taken in the clinic. Please refer 
to Section 8.1.8.1.1 for further details. 
Pembrolizumab: Pembrolizumab will be administered by the investigator and/or study staff 
according to the specifications within the Pharmacy Manual.
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8.1.8.1
Compliance
Lenvatinib compliance will be calculated by the Sponsor based on the 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.
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.
8.1.8.2
Timing of Dose Administration
8.1.8.2.1
Lenvatinib/Placebo
Lenvatinib/placebo 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. However, 
on C1D1, and C2D1, lenvatinib/placebo will be administered in the clinic 0 to 4 hours after 
completion of pembrolizumab administration. Participants should not take their study 
medication on C1D15 and on C2D1 before their appointment.
If a lenvatinib/placebo 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.
8.1.8.2.2
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 and +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.
8.1.9
Discontinuation and Withdrawal
Participants who discontinue study intervention before completion of the treatment period
should be encouraged to continue to be followed for all remaining study visits
Participants who withdraw from the study should be encouraged to complete all applicable 
activities scheduled for the discontinuation visit (EOT visit) 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. If discontinuation occurs approximately 30 days 
after the last dose of study intervention, the 30-day Safety Follow-up Visit (Section 8.11.3.1) 
is not required. In this situation, all procedures required at the 30-day Safety Visit and EOT 
are performed once and entered into the EOT visit only.
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8.1.10
Participant Blinding/Unblinding
As of IA3, the study was unblinded. Original protocol text that is contained in this section 
has been retained for reference.
STUDY INTERVENTION IDENTIFICATION INFORMATION IS TO BE UNMASKED 
ONLY IF NECESSARY FOR THE WELFARE OF THE PARTICIPANT. EVERY 
EFFORT SHOULD BE MADE NOT TO UNBLIND.
For emergency situations where the investigator or medically qualified designee (consistent 
with local requirements) needs to identify the intervention used by a participant and/or the 
dosage administered, he/she will contact the emergency unblinding call center by telephone 
and make a request for emergency unblinding. As requested by the investigator or medically 
qualified designee, the emergency unblinding call center will provide the information to 
him/her promptly and report unblinding to the Sponsor. Before contacting the emergency 
unblinding call center to request unblinding of a participant’s intervention assignment, the 
investigator who is a qualified physician should make reasonable attempts to enter the
intensity/toxicity grade of the AEs observed, the relation to study intervention, the reason 
thereof, etc, in the medical record. If it is not possible to record this assessment in the 
medical record before the unblinding, the unblinding should not be delayed.
If unblinding has occurred, the circumstances around the unblinding (eg, date, reason, and 
person performing the unblinding) must be documented promptly, and the Sponsor Clinical 
Director notified as soon as possible.
Once an emergency unblinding or a nonemergency unblinding that is part of the study design
has taken place, the investigator, site personnel, and Sponsor personnel may be unblinded so 
that the appropriate follow-up medical care can be provided to the participant.
Participants whose treatment assignment has been unblinded by the investigator or medically 
qualified designee and/or nonstudy treating physician must be discontinued from study 
intervention but should continue to be monitored in the study.
Additionally, the investigator or medically qualified designee must go into the IRT system 
and perform the unblind in the IRT system to update drug disposition. If the emergency 
unblinding call center is not available for a given site in this study, the IRT system should be 
used for emergency unblinding if this is required for participant safety.
At the end of the study, random code/disclosure envelopes or lists and unblinding logs are to 
be returned to the Sponsor or designee.
8.1.11
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained are reliable and/or reproducible. 
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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, race/ethnicity.
8.1.13
Subsequent Antineoplastic Treatment
NOTE: As of Amendment 07, Survival Follow-up is no longer required.
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
Throughout this section, the term ‘scan’ refers to any medical imaging data used to assess 
tumor burden and may include cross-sectional imaging (such as CT or MRI), medical 
photography, or other methods as specified in this protocol.
As of Amendment 07: Central tumor response assessments will be discontinued. 
Imaging scans will no longer be submitted to the iCRO nor read by BICR. Original protocol 
text that is contained in this section has been retained for reference.
Participants still on study treatment who are deriving clinical benefit may continue study 
intervention until criteria for discontinuation are met. Local tumor imaging should continue 
per protocol schedule while participants remain on study therapy.
In addition to survival, efficacy will be assessed based on evaluation of scan changes in 
tumor burden over time, until the participant is discontinued from the study or goes into 
survival follow-up. The process for scan collection and transmission to the iCRO can be 
found in the SIM. Tumor scans by CT are strongly preferred. For the abdomen and pelvis, 
contrast-enhanced MRI may be used when CT with iodinated contrast is contraindicated, or 
when mandated by local practice. The same scan technique 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 response assessment based on scans.
Note: For the purposes of assessing tumor scans, the term “investigator” refers to the local 
investigator at the site and/or the radiological reviewer at the site or at an offsite facility. 
If brain scans are performed, magnetic resonance imaging is preferred; however, CT imaging 
will be acceptable, if MRI is medically contraindicated.
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Bone scans may be performed to evaluate bone metastases. Any supplemental scans 
performed to support a positive or negative bone scan, such as plain x-rays acquired for 
correlation, should also be submitted to the iCRO.
Participant eligibility will be determined using investigator assessment. All scheduled scans 
for each participant will be submitted to the iCRO. In addition, unscheduled scans to 
determine disease progression and scans obtained for other reasons but demonstrate 
radiologic progression are to be submitted to the iCRO.
When the investigator identifies disease progression, the iCRO will verify this progression 
and email the results to the study site and Sponsor see Section 8.2.1.5 and Figure 3. In 
clinically stable participants, scans are to continue until disease progression has been verified 
by BICR. If investigator-assessed progression was not verified by BICR, each subsequent 
scan must be submitted to the iCRO. Once progression is verified by BICR, subsequent scans 
(if acquired) should not be submitted to the iCRO.
8.2.1.1
Initial Tumor Scans
The scans at screening must be submitted to the iCRO to verify that eligibility criteria 
(Section 5.0) have been met before randomization. The site study team must submit 
screening images to the iCRO to confirm the participant has measurable disease per 
RECIST 1.1 prior to randomization. Tumor imaging performed as part of routine clinical 
management is acceptable for use as Screening tumor imaging if it is of diagnostic quality 
and performed within 28 days prior to the date of randomization and can be assessed by the 
iCRO. Brain imaging must be performed at Screening. If MRI is medically contraindicated, 
CT is an acceptable alternative.
Tumor imaging at baseline includes the following:
•
CT (preferred) or MRI of the abdomen and pelvis, must include IV contrast
•
CT of the chest
•
Brain MRI (preferred) or CT of the brain, must include IV contrast
8.2.1.2
Tumor Scans During the Study
The first on-study imaging assessment should be performed at 9 weeks (63 days ±7 days) 
from the date of randomization. Subsequent tumor imaging should be performed Q9W 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 Q24W, or sooner if clinically indicated. Imaging 
timing should follow calendar days from randomization 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 and verified by the iCRO (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 
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first. Radiographic PD cannot be determined by worsening of cutaneous lesions or 
appearance of new cutaneous lesions that cannot be observed radiographically.
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 Q9W (±7 days) from the date of randomization, 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 of 
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. 
Note: Response does not typically need to be verified in real time by the iCRO.
Per iRECIST (Section 8.2.1.5), disease progression should be confirmed by the site 4 to 8 
weeks after central verification of site-assessed first radiologic evidence of PD in clinically 
stable participants. Participants who have unconfirmed disease progression may continue on 
treatment at the discretion of the investigator until progression is confirmed by the site, 
provided they have met the conditions detailed in Section 8.2.1.5. Participants who receive 
confirmatory imaging do not need to undergo the next scheduled tumor imaging if it is less 
than 4 weeks later; tumor imaging may resume at the subsequent scheduled imaging time 
point, if clinically stable. Participants who have confirmed disease progression by iRECIST, 
as assessed by the site, will discontinue study 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 Tumor Scans
As of Amendment 07, follow-up tumor scans are no longer required.
If participants discontinue study intervention, tumor scans should be performed at the time of 
discontinuation (±4-week window) unless previous scans were obtained within 4 weeks of 
discontinuation. If participants discontinue study intervention due to documented disease 
progression, this is the final required tumor scan.
If participants discontinue study intervention without documented disease progression, every 
effort is to be made to monitor disease status by acquiring tumor scans using the same 
schedule calculated from the date of randomization, refer to Section 8.2.1.2.
Scans are to be continued until one of the following conditions are met:
•
disease progression as defined by RECIST 1.1 verified by BICR
•
the start of a new anticancer treatment
•
pregnancy
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•
death
•
withdrawal of consent
•
the end of the study
Participants who are clinically stable and treated past radiographic progression may continue 
to be assessed until progression is confirmed according to the rules of iRECIST, when 
clinically appropriate.
8.2.1.4
RECIST 1.1 Assessment of Disease
RECIST 1.1 will be used as the primary measure for assessment of tumor response, date of 
disease progression, and as a basis for all protocol guidelines related to disease status (eg, 
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.
Upon investigator-assessed disease progression, the indicative scans are to be submitted 
immediately to iCRO for BICR verification of progression. After submission of scan(s), the 
iCRO will email the assessment to the site and Sponsor.
If disease progression is not verified, the process continues as follows:
•
If participant is clinically stable, continue study intervention per protocol
o
continue scans per protocol schedule (the next scheduled scan should be ≥4 weeks 
from most recent scan acquired)
o
send scans to iCRO
o
continue local assessment
o
do not change investigator assessment of progression
o
if subsequent scan(s) indicate progression, request verification from iCRO
•
If the participant is not clinically stable, best medical practice is to be applied
Before stopping study intervention or imaging or starting new anticancer therapy in a 
participant who is clinically stable, communication with the Sponsor is required.
If disease progression is verified, the process continues as follows:
•
investigator judgment will determine action
•
if the participant is clinically stable and study intervention is to continue, communication 
with the Sponsor is required and a reconsent addendum must be signed
•
obtain scans locally per original protocol schedule
•
do not send scans to iCRO
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Figure 3 illustrates the study intervention decision process involving verification of disease 
progression for participants.
•
For the purpose of this decision process, lack of clinical stability is defined as:
o
unacceptable toxicity
o
clinical signs or symptoms indicating clinically significant disease progression
o
decline in performance status
o
rapid disease progression or threat to vital organs or critical anatomical sites (eg, 
CNS metastasis, respiratory failure due to tumor compression, spinal cord 
compression) requiring urgent alternative medical intervention
Figure 3
Imaging and Treatment for Clinically Stable Participants Treated With 
Pembrolizumab After First Radiologic Evidence of PD Assessed by the Investigator
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8.2.1.5
iRECIST Assessment of Disease
Original protocol text that is contained in this section has been retained for reference.
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 [Seymour, L., et al 2017]. When 
clinically stable, participants may continue study intervention beyond RECIST 1.1 
progression with continued assessment of response according to the rules outlined in
Appendix 8. iRECIST reflects that some participants can have a transient tumor flare after 
the start of immunotherapy then experience subsequent disease response. This data will be 
captured in the clinical database.
•
If participant is clinically stable (refer to Section 8.2.1.5), continue study intervention per 
protocol
o
Perform scans 4 to 8 weeks after RECIST 1.1 progression
o
Continue investigator assessment per iRECIST
o
PFS endpoint: If progression is BICR-verified, stop sending scans to iCRO
•
If the participant is not clinically stable, best medical practice is to be applied
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 6 and illustrated as a flowchart in Figure 3.
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Table 6
Imaging and Treatment After First Radiologic Evidence of Progressive 
Disease
Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
First radiologic 
evidence of PD by 
RECIST 1.1 that 
has been verified 
by BICR
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.
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.
8.2.2
Patient-reported Outcomes
As of Amendment 07: PROs and Quality of Life assessments will be discontinued. Original 
protocol text that is contained in this section has been retained for reference.
The EQ-5D-5L and EORTC QLQ-C30 questionnaires will be administered by trained site 
personnel and completed electronically by participants in the following order: EORTC 
QLQ-C30 first, then EQ-5D-5L. The questionnaires should be administered before dosing of 
every cycle during Year 1 (Cycles 1 to 17), every other cycle during Year 2 (Cycles 19, 21, 
23, 25, 27, 29, 31, 33, and 35), at time of discontinuation (EOT visit), and the 30-day and 
90-day Safety Follow-up Visits. If the EOT visit occurs 30 days from the last dose of study 
intervention a Safety Follow-up Visit is not required, ePROs do not need to be repeated.
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Every effort should be made to administer HRQoL surveys before study intervention 
administration and before other assessments and procedures.
It is best practice and strongly recommended that ePROs are administered to randomized 
participants before drug administration, AE evaluation, and disease status notification. If the 
participant does not complete the ePROs at a scheduled time point, the MISS_MODE form 
must be completed to capture the reason the assessment was not performed.
8.3
Safety Assessments
Safety assessments will consist of monitoring and recording all AEs, including all NCI 
CTCAE v4.0 grades (for both increasing and decreasing severity), and SAEs; regular 
laboratory evaluation for hematology, blood chemistry, urinalysis and thyroid function; 
periodic measurement of vital signs, ECGs and MUGA or echocardiogram; and the 
performance of physical examinations as detailed in Section 1.3. In addition, coagulation 
factors will be monitored at Screening, and will be assessed throughout the study as clinically 
indicated for participants taking anticoagulant therapy.
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.
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) per 
institutional standard. Physical examinations (comprehensive/full or symptom-directed) will 
be performed as specified in the SoA (Section 1.3). A comprehensive/full 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. 
Height and weight will also be measured and recorded; height will only be measured and 
recorded at Screening.
A brief directed physical examination including oral examination will be conducted by an 
investigator or medically qualified designee (consistent with local requirements) per 
institutional standard.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
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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 BP. Height will be measured at Screening only.
•
BP 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 BR <90 mm Hg. 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 5 minutes apart. If the BP assessment (ie, the 
mean of the 2 BP measurements obtained at least 5 minutes apart) shows an elevated BP 
(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.
•
At the C1D8 telephone visit and if required between clinic visits, participants will have 
BP measured. If the participant does not return to the study site for this BP measurement, 
BP may be measured, for example, at home or at a local pharmacy, and the results will be 
reviewed with the investigator or designee. The investigator/site may provide a diary as a 
tool to aid the participant in collecting BP evaluations between clinic visits. The Sponsor 
will not provide diaries to the site. If BP result raises concerns, the investigator may 
require additional follow-up, including an on-site BP retest, or other clinically 
appropriate intervention(s).
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 electrocardiograms 
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 
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to prolong the QT interval, including Class Ia and III antiarrhythmics. 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 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 CRF. The laboratory 
reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless 
judged by the investigator to be more severe than expected for the participant’s condition.
•
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.
•
If laboratory values from nonprotocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).
•
For any laboratory tests with values considered clinically significantly abnormal during 
participation In the study or within 90 days after the last dose of study intervention, every 
attempt should be made to perform repeat assessments until the values return to normal or 
baseline or if a new baseline is established as determined by the investigator.
8.3.5.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
CBC with differential and clinical chemistry results must be reviewed before administration 
of study intervention. Electrolytes such as potassium, calcium, and magnesium should be 
monitored and abnormalities, when considered clinically significant, should be corrected in 
all participants before starting study intervention.
8.3.5.2
Urine Dipstick
Urine dipstick testing will be performed locally within 7 days prior to start of treatment. 
Participants with ≥2+ (≥100 mg/dL) proteinuria on urine dipstick testing (urinalysis) during 
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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 randomized, 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.
Laboratory tests for hematology, chemistry, and urinalysis are specified in Appendix 2.
8.3.6
Eastern Cooperative Oncology Group Performance Status
The investigator or qualified designee will assess ECOG status (see Appendix 9) 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).
8.4
Adverse Events, Serious Adverse Events, 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.
Progression of the cancer under study is not considered an AE as described in Section 8.4.6
and 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 need to document if an SAE was associated with a medication error, misuse, or 
abuse.
Investigators remain responsible for following up AEs, SAEs, and other reportable safety 
events for outcome according to Section 8.4.3. The investigator, who is a qualified physician, 
will assess events that meet the definition of an AE or SAE as well as other reportable safety 
events with respect to seriousness, intensity/toxicity, and causality.
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 participant provides 
documented informed consent, but before intervention randomization, must be reported by 
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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 after 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 intervention 
allocation/randomization through the time required to eliminate systemic exposure after 
cessation of study intervention as described in Sections 5.1 and 8.3.5, or 30 days after 
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 specified above must be reported immediately to the Sponsor if the event is 
considered related to study intervention.
Investigators are not obligated to actively seek AEs or SAEs 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 the investigator 
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 7.
Exception: A positive pregnancy test at the time of initial screening is not a reportable event 
unless the participant has received study intervention.
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Table 7
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Period:
Consent to 
Randomization/
Allocation
Reporting Period:
Randomization/
Allocation 
Through 
Protocol-specified 
Follow-up Period
Reporting 
Period:
After the 
Protocol-
specified Follow-
up Period
Time Frame 
to Report 
Event and 
Follow-up 
Information to 
Sponsor
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
SAE
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:
– participant has been 
exposed to any 
protocol-specified 
intervention (eg, 
procedure, washout,
or run-in treatment 
including placebo 
run-in)
Exception: A positive 
pregnancy test at the 
time of initial 
screening is not a 
reportable event.
Report all
Previously 
reported – Follow 
to completion/
termination; 
report outcome
Within 
24 hours of 
learning of 
event
ECI (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
ECI (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
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Type of Event
Reporting Period:
Consent to 
Randomization/
Allocation
Reporting Period:
Randomization/
Allocation 
Through 
Protocol-specified 
Follow-up Period
Reporting 
Period:
After the 
Protocol-
specified Follow-
up Period
Time Frame 
to Report 
Event and 
Follow-up 
Information to 
Sponsor
New Cancer (that is 
not the cancer under 
study)
Report if:
– due to intervention
– causes exclusion
Report all
Not required
Within 
5 calendar days 
of learning of 
event (unless 
SAE)
Overdose
Report if:
– receiving placebo 
run-in or other run-
in medication
Report all
Not required
Within 
5 calendar days 
of learning of 
event (unless 
SAE)
DILI drug induced liver injury; ECI event of clinical interest; NSAE nonserious adverse event; SAE serious 
adverse event.
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 AEs, SAEs, and other reportable safety events, 
including pregnancy and exposure during breastfeeding, ECIs, 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 toward 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. The 
Sponsor will comply with country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and Sponsor policy and forwarded to investigators as necessary.
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An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.4.5
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding (spontaneously reported to the 
investigator or their designee) that occurs in a participant during the study are reportable to 
the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy.
Any pregnancy complication will be reported as an AE or SAE.
The medical reason (example: maternal health or fetal disease) for an elective termination of 
a pregnancy will be reported as an AE or SAE. Prenatal testing showing fetus will be born 
with severe abnormalities/congenital anomalies that leads to an elective termination of a 
pregnancy will be reported as an SAE for the fetus.
Pregnancy outcomes of ectopic pregnancy, spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth 
must be reported as serious events (Important Medical Events). If the pregnancy continues to 
term, the outcome (health of infant) must also be reported.
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
Efficacy endpoints as outlined in this section will not be reported to the Sponsor as described 
in Section 8.4.1.
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study.
The Sponsor will ensure that unblinded aggregated efficacy endpoint events and safety data 
are monitored to safeguard the participants in the study.
Any suspected endpoint which 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
Selected serious and nonserious AEs are also known as ECIs and must be reported to the 
Sponsor.
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Events of clinical interest for this study include:
1. An overdose of Sponsor's product, as defined in Section 8.5, that is not associated with 
clinical symptoms or abnormal laboratory results. 
2. 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).
The investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as indicated to elucidate the nature and/or causality between the AE and the 
medical device or device constituent of combination product.
8.5
Treatment of Overdose
For this study, an overdose of pembrolizumab will be defined as any dose of 1000 mg or 
greater.
No specific information is available on the treatment of overdose of pembrolizumab. In the 
event of overdose, the participant should be observed closely for signs of toxicity. 
Appropriate supportive treatment should be provided if clinically indicated.
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 adverse 
event
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.
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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 
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 
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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
Pharmacodynamic parameters will not be evaluated in this study.
8.8
Biomarkers
8.8.1
Planned Genetic Analysis Sample Collection
CCI
CCI
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8.9
Future Biomedical Research Sample Collection
8.10
Medical Resource Utilization and Health Economics
As of Amendment 07: Medical Resource Utilization and Health Economics data collection
will be discontinued. Original protocol text that is contained in this section has been retained 
for reference.
Medical resource utilization and health economic data, associated with medical encounters, 
will be collected in the CRF by the investigator and study-site personnel for all participants 
throughout the study. Protocol-mandated procedures, tests, and encounters are excluded.
The data collected may be used to conduct exploratory economic analyses and will include:
All-cause hospitalizations and emergency department visits must be reported in the eCRF 
from the time of treatment allocation/randomization through 120 days after cessation of study 
intervention or 30 days after cessation of study intervention if the participant initiates new 
anticancer therapy, whichever is earlier.
8.11
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.11.1
Screening
Approximately 28 days before intervention 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 providing documented consent as part of 
routine clinical management are acceptable in lieu of a Screening test if performed within the 
specified time frame. Screening procedures are to be completed within 28 days prior to the 
first dose of study intervention except for the following:
•
Laboratory tests are to be performed within 7 days of Cycle 1 Day 1. An exception is 
hepatitis and HIV testing which may be done up to 28 days prior to the first dose of study 
intervention if mandated by local health authority. 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 7 days of Cycle 1 Day 1.
•
Full physical examination to be performed within 7 days of Cycle 1 Day 1.
•
For women of reproductive potential, a urine or serum pregnancy test will be performed 
within 24 hours prior to Cycle 1 Day 1. If more than 24 hours have elapsed prior to first 
dose of study intervention, another pregnancy test is required prior to starting study 
CCI
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intervention. If urine pregnancy results cannot be confirmed as negative, a serum 
pregnancy test will be required (performed by the local study site laboratory).
•
Tumor tissue must have been obtained prior to randomization.
8.11.1.1
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.
8.11.2
Treatment Period
Visit requirements are outlined in the SoA (Section 1.3). Specific procedure-related details 
are provided in Section 8.1.
8.11.2.1
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).
8.11.3
Posttreatment Visit
8.11.3.1
Safety Follow-up Visit
The mandatory Safety Follow-up Visit should be conducted approximately 30 days after the 
last dose of study intervention or before initiation of a new anticancer treatment, whichever 
comes first.
8.11.3.2
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 Efficacy 
Follow-up and should be assessed approximately Q12W (or more frequently as needed) by 
clinic visit to monitor disease status. Every effort should be made to collect information 
regarding disease status until the start of new anticancer therapy, disease progression, death, 
end of study. Information regarding poststudy anticancer treatment will be collected if new 
treatment is initiated. Participants who completed all efficacy assessments and/or will not 
have further efficacy assessments must enter Survival Follow-up.
Participants who attain an investigator-determined CR and stop study intervention with 
pembrolizumab + lenvatinib or pembrolizumab + placebo will have 30- and 90-day Safety 
Follow-up Visits and move to follow-up visits per SoA.
After Year 3, imaging should be performed Q24W. The Sponsor may request survival status 
to be assessed at additional time points during the course of the study (not to exceed 
approximately 12 weeks).
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NOTE: As of Amendment 07: Efficacy Follow-up Visits will be discontinued. The section is 
retained for reference.
8.11.3.3
Survival Follow-up Contacts
Participant survival follow-up status will be assessed approximately every 12 weeks 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 treatment intervention and who will not enter Efficacy 
Follow-up, 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 completed assessments in Efficacy Follow-up, the first survival 
follow-up contact will be scheduled 12 weeks after the last efficacy assessment follow-up 
visit has been performed.
8.11.4
Survival Status
As of Amendment 07: Survival Follow-up Visits will be discontinued. Those participants 
remaining on study treatment at the time of Amendment 07 should continue to be monitored 
in the study through the AE reporting period (Section 8.4). Original protocol text that is 
contained in this section has been retained for reference.
To ensure current and complete survival data is available at the time of database locks, 
updated survival status may be requested during the course of the study by the Sponsor. For 
example, updated survival status may be requested prior to but not limited to an external
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.
8.11.5
Vital Status
To ensure current and complete survival information (vital status) is available at the time of 
database locks, updated vital status may be requested during the study by the Sponsor. For 
example, updated vital status may be requested before but not limited to, an eDMC review, 
interim and/or final analysis. Upon Sponsor notification, all participants who do not/will not 
have a scheduled study visit or study contact during the Sponsor-defined period will be 
contacted for their vital status.
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9
STATISTICAL ANALYSIS PLAN
As of Amendment 07: The Statistical Analysis Plan is amended as follows.
NOTE: Based on the data from an interim safety and efficacy analysis for LEAP-003 (data 
cutoff 18-JAN-2023), eDMC recommended stopping the study due to lack of efficacy
because pembrolizumab in combination with lenvatinib did not demonstrate an improvement 
in OS, one of the trial’s dual primary endpoints, compared to pembrolizumab plus placebo
and appears unlikely to do so in a future analysis. Based upon these data and the 
recommendation of the eDMC, the study was unblinded as of 27-MAR-2023. The 
prespecified final analysis of the study described in the SAP will not be performed. Safety 
analysis will be performed at the end of the study; there will be no further analyses for
efficacy and ePRO endpoints.
This section outlines the statistical analysis strategy and procedures for the study. The study 
has been unblinded as of 27-MAR-2023. Changes made to primary and/or key secondary 
hypotheses, or the statistical methods related to those hypotheses that occurred prior to 
Amendment 07 were documented in previous protocol amendments(s) (consistent with 
International Conference on Harmonisation [ICH] Guideline E-9). Changes to exploratory or 
other nonconfirmatory analyses made after the protocol has been finalized will be 
documented in an sSAP and referenced in the Clinical Study Report for the study. Post hoc 
exploratory analyses will be clearly identified in the Clinical Study Report. Separate analysis 
plans (ie, separate documents from the sSAP) may be developed to detail other planned 
analyses.
The extension portion of the study, which includes the additional enrollment of Chinese 
participants, will not be included as part of the study population used to address the protocol 
objectives. Additional detail regarding the analysis associated with these participants will be 
described in the sSAP.
9.1
Statistical Analysis Plan Summary
Key elements of the SAP are summarized here. The comprehensive plan is provided in 
Sections 9.2 through 9.12. As of Amendment 07, the prespecified final analysis of the study 
described in the SAP will not be performed. Safety analysis will be performed at the end of 
the study; there will be no further analyses of efficacy and ePRO endpoints. The SAP 
summary has been updated accordingly.
Study Design Overview
A Phase 3 Randomized, Placebo-controlled Trial to Evaluate the Safety and 
Efficacy of Pembrolizumab (MK-3475) and Lenvatinib (E7080/MK-7902) 
Versus Pembrolizumab Alone as First-line Intervention in Participants with 
Advanced Melanoma (LEAP-003)
Treatment Assignment
Approximately 660 participants will be randomized in a 1:1 ratio between 2 
treatment groups (1) pembrolizumab + lenvatinib or (2) pembrolizumab + 
placebo. Stratification factors are in Section 6.3.2. This is a randomized 
double-blinded study with in-house blinding.
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Analysis Populations
Efficacy: Intention-to-Treat (ITT)
Safety: All Participants as Treated (APaT)
Primary Endpoints
1) PFS as assessed by BICR per RECIST 1.1
2) Overall survival (OS)
Key Secondary Endpoints
1) Objective response (OR) as assessed by BICR per RECIST 1.1 
2) DOR as assessed by BICR per RECIST 1.1
Statistical Methods for Key 
Efficacy Analyses
The dual primary hypotheses on PFS and OS will be evaluated by 
comparing pembrolizumab + lenvatinib to pembrolizumab + placebo using 
a stratified log-rank test. Estimation of the hazard ratio (HR) will be done 
using a Cox regression model. Event rates over time will be estimated 
within each treatment group using the Kaplan-Meier method. The stratified 
Miettinen and Nurminen method [Miettinen, O. and Nurminen, M. 1985]
with sample size weights will be used for the analysis of ORR.
Statistical Methods for Key 
Safety Analyses
For analyses in which 95% CIs will be provided for between-treatment 
differences in the percentage of participants with events, these analyses will 
be performed using the Miettinen and Nurminen method.
Interim Analyses
As of Amendment 07, the prespecified final analysis of the study described 
in the SAP will not be performed.
Three IAs will be performed in this study. Results will be reviewed by an 
Multiplicity
Sample Size and Power 
As of Amendment 07, the final analysis of the study described in the SAP 
will not be performed.
The planned sample size is approximately 660 participants.
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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.
The Sponsor will generate the randomized allocation schedule(s) for study intervention 
assignment for this protocol, and the randomization will be implemented in interactive voice 
response system.
This study will be conducted as a double-blind study under in-house blinding procedures. 
The official, final database will not be unblinded until medical/scientific review has been 
performed, protocol deviations have been identified, and data have been declared final and 
complete. 
Blinding procedures related to the planned IAs are described in Section 9.7.
9.3
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.
9.4
Analysis Endpoints
9.4.1
Efficacy Endpoints
Dual Primary
Progression-free Survival (PFS) per RECIST 1.1 Assessed by BICR
PFS is defined as the time from randomization to the first documented disease progression 
per RECIST 1.1 based on BICR or death due to any cause, whichever occurs first. See 
Section 9.6.1 for the censoring rules.
Overall Survival (OS)
Overall survival is defined as the time from randomization to death due to any cause. 
Participants without documented death at the time of analysis will be censored at the date of 
last known contact. 
Secondary
Objective Response Rate (ORR) per RECIST 1.1 Assessed by BICR
Objective response rate is defined as the proportion of participants who have a CR, or a PR. 
Responses are based on confirmed assessments by the BICR per RECIST 1.1.
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. Response duration for 
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participants who have not progressed or died at the time of analysis will be censored at the 
date of their last tumor assessment. Response duration will be calculated per RECIST 1.1 
based on BICR by the imaging vendor.
Additional details of the efficacy measurements are described in Section 4.2.1.1.
9.4.2
Safety Endpoints
Safety parameters are described in Section 4.2.1.2.
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, laboratory values and vital signs.
9.4.3
Patient-reported Outcome Endpoints
The following secondary PRO endpoints will be evaluated:
•
Global Health Status/QoL scale (EORTC QLQ-C30 items 29-30)
•
Physical functioning scale (EORTC QLQ-C30 items 1-5) 
The EQ-5D-5L will be evaluated as an exploratory endpoint. The EQ-5D-5L analyses will be 
described in the sSAP.
9.5
Analysis Populations
9.5.1
Efficacy Analysis Population
The ITT population will serve as the population for primary efficacy analysis (PFS and OS). 
All randomized participants will be included in this population. Participants will be included 
in the treatment group to which they are randomized. 
The global study will only contain approximately 660 randomized participants. The 
extension portion of the study enrolling additional China participants will not be included in 
the global study population used as the primary population to address protocol objectives but 
will be analyzed as specified in the sSAP.
9.5.2
Safety Analysis Population
The APaT population will be used for the analysis of safety data in this study. The APaT 
population consists of all randomized participants who received at least one dose of study 
intervention. Participants will be included in the treatment group corresponding to the study 
intervention they actually received for the analysis of safety data using the APaT population. 
For most participants this will be the treatment group to which they are randomized. 
Participants who take incorrect study intervention for the entire treatment period will be 
included in the treatment group corresponding to the study intervention actually received. 
Any participant who receives the incorrect study medication for 1 or more cycles but receives 
the correct treatment for the remaining cycles will be analyzed according to the participant’s 
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randomized treatment group and a narrative will be provided for any events that occur during 
the cycle for which the participant was incorrectly dosed.
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.
The global study will only contain approximately 660 randomized participants. The 
extension portion of the study enrolling additional China participants will not be included in 
the global study population used as the primary population to address protocol objectives but 
will be analyzed as specified in the sSAP.
9.5.3
Patient-reported Outcome Analysis Populations
The PRO analyses are based on the PRO Full Analysis Set population, defined as participants 
who have at least 1 PRO assessment available and have received at least 1 dose of study 
medication.
9.5.4
Pharmacokinetic Analysis Population
The Population PK Analysis Set includes all the participants who have received at least 1 
dose of study intervention with documented dosing history in the lenvatinib plus 
pembrolizumab arm and have measurable plasma levels of lenvatinib or serum levels of 
pembrolizumab.
9.6
Statistical Methods
NOTE: As of Amendment 07, the prespecified final analysis of the study described in the 
SAP will not be performed. Safety analysis will be performed at the end of the study; there 
will be no further analyses of efficacy and ePRO endpoints. Original protocol text that is 
contained in this section has been retained for reference.
This section describes the statistical methods that address the primary and secondary 
objectives. Methods related to the exploratory objectives will be described in the sSAP.
The stratification factors used for randomization (Section 6.3.2) will be applied to the models 
for efficacy described herein. If there are a small number of responses in one or more strata, 
for the purpose of analysis, strata will be combined to ensure a sufficient number of 
participants, responses, and events in each stratum. Details regarding the combining of strata 
will be specified in the sSAP prior to database lock based on a blinded review of response 
and event counts by stratum.
9.6.1
Statistical Methods for Efficacy Analyses
9.6.1.1
Progression-free Survival
The nonparametric Kaplan-Meier method will be used to estimate the PFS curve in each 
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 The stratification factors used for 
randomization (see Section 6.3) will be applied to both the stratified log-rank test and the 
stratified Cox model.
Since disease progression is assessed periodically, PD can occur any time in the time interval 
between the last assessment where PD was not documented and the assessment when PD is 
documented. The true date of disease progression will be approximated by the date of the 
first assessment at which PD is objectively documented per RECIST 1.1 by BICR. Death is 
always considered as a confirmed PD event. Participants who do not experience a PFS event 
will be censored at the last disease assessment. Sensitivity analyses will be performed for 
comparison of PFS based on investigator's assessment.
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If sample size permits, DOR will be summarized descriptively using Kaplan-Meier medians 
and quartiles. Only the subset of participants who show a confirmed CR or PR will be 
included in this analysis. The details of censoring rules for DOR analysis will be described in 
the sSAP.
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Endpoint
Statistical Methoda
Analysis 
Population
Missing Data Approach
a.
Statistical models are described in further detail in the text. For stratified analyses, the 
stratification factors used for randomization (Section 6.3.1.1) will be applied to the analysis. 
Small strata will be combined in a way specified by a blinded statistician prior to the analysis.
b.
Miettinen and Nurminen method.
9.6.2
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, laboratory tests and vital signs.
Adverse Events
Adverse events will be coded using the standard Medical Dictionary for Regulatory 
Activities (MedDRA) and grouped system organ class. AEs will be graded by the 
investigator according to the NCI CTCAE, v4.0.
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9.6.3
Analysis Methods for Patient-reported Outcome Endpoints
The change from baseline in the following secondary PRO endpoints from the EORTC QLQ 
C30 will be assessed:
•
Global health status/QoL score (QLQ-C30 items 29-30)
•
Physical functioning score (QLQ-C30 items 1-5)
9.6.4
Summaries of Demographic and Baseline Characteristics
The comparability of the treatment groups for each relevant demographic and baseline 
characteristic will be assessed by the use of tables and/or graphs. No statistical hypothesis 
tests will be performed on these characteristics. The number and percentage of participants 
screened and randomized and the primary reasons for Screening failure and discontinuation 
will be displayed. Demographic variables (eg, age), baseline characteristics, primary and 
secondary diagnoses, and prior and concomitant therapies will be summarized by treatment 
either by descriptive statistics or categorical tables.
9.7
Interim Analyses
NOTE: As of Amendment 07, the prespecified final analysis of the study described in the 
SAP will not be performed. This section is retained for reference.
An eDMC will be convened to review the unblinded efficacy results and accumulating safety 
at the planned IAs. An external unblinded statistician and programmer will be responsible for 
conducting and presenting the IAs results to the eDMC. The eDMC responsibilities and 
review schedules will be outlined in the eDMC charter. The recommendation of the eDMC 
will be communicated to an Executive Oversight Committee. In the event of a 
recommendation to halt the study early due to safety concerns, the Sponsor will communicate 
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9.7.2
Safety Interim Analyses
The eDMC conducted regular safety interim analyses. The timing of these safety interim 
analyses was specified in the eDMC charter. No further formal efficacy analysis will be 
conducted. Safety monitoring will continue as per protocol. 
9.8
Multiplicity
NOTE: As of Amendment 07, the prespecified final analysis of the study described in the 
SAP will not be performed. Original protocol text that is contained in this section has been 
retained for reference.
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9.8.1
Progression-free Survival 
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9.8.2
Overall Survival
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9.8.3
Objective Response Rate
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9.8.4
Safety Analyses
The eDMC has responsibility for assessment of overall risk/benefit. When prompted by 
safety concerns, the eDMC can request corresponding efficacy data. External DMC review of 
efficacy data to assess the overall risk/benefit to study participants will not require a 
multiplicity adjustment typically associated with a planned interim efficacy analysis; 
however, to account for any multiplicity concerns raised by the eDMC review of unplanned 
efficacy data prompted by safety concerns, a sensitivity analysis for PFS adopting a
conservative multiplicity adjustment will be prespecified in the sSAP. This analysis will be 
performed if efficacy data is requested by the eDMC during a safety evaluation to assess 
risk/benefit.
9.9
Sample Size and Power Calculations
NOTE: As of Amendment 07, the prespecified final analysis of the study described in the 
SAP will not be performed. This section is retained for reference.
A total of approximately 660 participants will be randomized in a 1:1 ratio in the global 
study.
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and OS of combination therapy versus pembrolizumab monotherapy will be presented in 
forest plots for the subgroups. Median PFS and 95% CIs will be presented for all subgroups. 
Similar plots will be provided for OS. For safety endpoints, all treatment-emergent AEs, 
treatment-emergent AEs of NCI CTCAE v4.0 Grades 3 and 4, and treatment-emergent SAEs 
may be summarized by the subgroups.
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. Dose interruption for each drug, dose reduction or dose increase for lenvatinib will be 
summarized. Summary statistics will be provided on extent of exposure for the APaT 
population.
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Code of Conduct for Interventional Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
I.
Introduction
A. Purpose
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD), through its subsidiaries, 
conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, planning, 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 MSD’s global standards, local and/or national 
regulations (including all applicable data protection laws and regulations), and 
International Council for Harmonisation Good Clinical Practice (ICH GCP) E6 and 
ICH General Considerations for Clinical Studies E8, and in accordance with the 
ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical 
interventional investigations sponsored by MSD irrespective of the party (parties) 
employed for their execution (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. Input may be considered from a broad range of stakeholders, including 
patient advocacy groups/patients representing the trial population, caregivers, and 
healthcare providers to ensure operational feasibility. Trial design also includes 
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proactive identification of critical to quality factors utilizing a risk-based 
approach. Plans are then developed to assess and mitigate risks to those factors as 
appropriate during the trial. 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. Individuals involved in trial conduct receive training commensurate with 
their role prior to their becoming involved in the trial.
Where appropriate, and in accordance with regulatory authority guidance, MSD 
will make concerted efforts to raise awareness of clinical trial opportunities in 
various communities. MSD will seek to engage underrepresented groups and 
those disproportionately impacted by the disease under study. MSD will support 
clinical trial investigators to enroll underrepresented groups and expand access to 
those who will ultimately use the products under investigation.
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.
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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 and ICH Guidelines. 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. Trial designs include procedures and systems for 
the identification, monitoring, and reporting of safety concerns. 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.
During trial planning, the need for an independent Data Monitoring Committee 
(DMC) is assessed. DMC review of data accumulated during the conduct of the trial 
is integral to the well-being of trial participants.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent 
possible, as well as all applicable data protection rights. Unless required by law, only 
the investigator, Sponsor (or individuals acting on behalf of MSD), ethics committee, 
and/or regulatory authorities will have access to confidential medical records that 
might identify the participant by name.
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D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed 
consent authorized by an ethics committee.
E. Trial Results
At the time of providing informed consent and in accordance with local laws and 
regulations, participants should be informed about the plans for availability of trial 
results.
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 medical record 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 
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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, frequently known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
10.1.3
Data Protection
The Sponsor will conduct this study in compliance with all applicable data protection 
regulations.
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 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 before transmission to the Sponsor.
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By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules,
and regulations.
10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
10.1.4
Committees Structure
10.1.4.1
Scientific Advisory Committee (SAC)
This study was developed in collaboration with an SAC. The SAC is comprised of both 
Sponsor and non-Sponsor scientific experts who provide scientific and strategic guidance on 
various aspects of the clinical trial and/or development, which may include study design, 
interpretation of study results, and subsequent peer-reviewed scientific publications.
10.1.4.2
Executive Oversight Committee
The EOC is comprised of members of Sponsor Senior Management. The EOC will receive 
and decide on any recommendations made by the DMC regarding the study.
Additional details regarding the EOC can be found in the DMC charter.
10.1.4.3
External Data Monitoring Committee
To supplement the routine study monitoring outlined in this protocol, an external DMC will 
monitor the interim data from this study. The voting members of the committee are external 
to the Sponsor. The members of the DMC must not be involved with the study in any other 
way (eg, they cannot be study investigators) and must have no competing interests that could 
affect their roles with respect to the study.
The DMC will make recommendations to the EOC regarding steps to ensure both participant 
safety and the continued ethical integrity of the study. Also, the DMC will review interim 
study results, consider the overall risk and benefit to study participants (Section 9.7) 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.
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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 ICMJE authorship 
requirements.
10.1.6
Compliance with Study Registration and Results Posting Requirements
Under the terms of the FDAAA of 2007 and the EMA clinical trial Directive 2001/20/EC, the 
Sponsor of the study is solely responsible for determining whether the study and its results 
are subject to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu, or other local registries. MSD, as Sponsor of this study, will 
review this protocol and submit the information necessary to fulfill these requirements. MSD 
entries are not limited to FDAAA or the EMA clinical trials 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, ICH GCP: Consolidated Guideline and other generally accepted standards of GCP), 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 Trials.
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.
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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.
For investigators located in countries with serious breach reporting requirements, investigator 
will promptly report to the Sponsor any serious breach or suspected serious breach that 
occurs in compliance with those requirements. Unless more specifically defined in the 
applicable requirements, a serious breach is any breach of the applicable clinical trial 
regulation or of the clinical trial protocol which is likely to affect to a significant degree: (i) 
the safety or rights of a trial participant, or (ii) the reliability and robustness of the data 
generated in the clinical trial.
10.1.8
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
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.
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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/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.
10.1.10
Study and Site Closure
The Sponsor or its designee may stop the study or study-site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor or 
designee will promptly notify that study site’s IRB/IEC as specified by applicable regulatory 
requirement(s).
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10.2
Appendix 2: Clinical Laboratory Tests
•
The tests detailed in Table 16 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 5.2 of the protocol.
•
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations.
Table 16
Protocol-required Clinical 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
Carbon Dioxide 
(CO2) or 
Bicarbonatec
Chloridec
Phosphorousc
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Laboratory 
Assessments
Parameters
Creatinined
Sodium
Alanine 
Aminotransferase
(ALT)/ Serum 
Glutamic Pyruvic 
Transaminase 
(SGPT)
Total Proteinc
Glucose 
Calcium
Alkaline 
phosphatase
Magnesium
Thyroid-
stimulating 
hormone
Free thyroxine 
(FT4)e
Lactate 
dehydrogenasec
Cholesterolc
Triglyceridesc
CPKf
Pregnancy test
Triiodothyronine 
(Total T3)e
Routine 
Urinalysisg
Specific gravity
Glucose, pH, 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 
antibodyj).
Serum or urine β human chorionic gonadotropin (β hCG) pregnancy test (as 
needed for POCBP).
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 with Cycle 2), at the time of discontinuation (End of Treatment), and at the 30 and 
90 day 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 (and 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/placebo 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.
Not required unless mandated by local health authorities.
The investigator (or medically qualified designee) must document their review of each 
laboratory safety report.
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definitions of Medication Error, Misuse, and Abuse
Medication Error
This is an unintended failure in the drug treatment process that leads to or has the potential to 
lead to harm to the patient.
Misuse
This refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the terms of the product information.
Abuse
This corresponds to the persistent or sporadic intentional, excessive use of a medicinal 
product for a perceived psychological or physiological reward or desired nontherapeutic 
effect.
10.3.2
Definition of AE
AE definition
•
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.
•
Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.
•
Note: For purposes of AE definition, study intervention includes any pharmaceutical 
product, biological product, vaccine, diagnostic agent, medical device, combination 
product, or protocol-specified procedure whether investigational or marketed (including 
placebo, active comparator product, or run-in intervention), 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 preexisting 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.
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•
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.” Lenvatinib 
overdose without an associated adverse event is not reportable as an AE. Refer to Section 
8.5 for the definition of overdose for lenvatinib.
Events NOT meeting the AE definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
•
Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
•
Surgical procedure(s) planned prior to informed consent to treat a preexisting condition 
that has not worsened.
•
Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.3
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b. Is life-threatening
o
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
o
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 preexisting condition 
that has not worsened is not an SAE.) A preexisting 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
o
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
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o
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
o
In offspring of participant taking the product regardless of time to diagnosis.
f.
Other important medical events
o
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.
o
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.
10.3.4
Additional Events Reported
Additional events that require reporting
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor.
•
Is a new cancer (that is not the cancer under study) as noted in Section 8.4.1.
•
Is associated with an overdose.
10.3.5
Recording AE and SAE
AE and SAE recording
•
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.
•
The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.
•
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
•
There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.
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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/toxicity
•
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.
•
The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) according to the NCI CTCAE, version 4.0. Any AE that changes 
CTCAE grade over the course of a given episode will have each change of grade 
recorded on the AE CRFs/worksheets.
o
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated.
o
Grade 2: Moderate; minimal, local, or noninvasive intervention indicated; limiting 
age-appropriate instrumental ADL.
o
Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care ADL.
o
Grade 4: Life-threatening consequences; urgent intervention indicated.
o
Grade 5: Death related to AE.
Assessment of causality
•
Did the study intervention cause the AE?
•
The determination of the likelihood that the study intervention caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form ensures that a medically qualified assessment of causality was done. This initialed 
document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test product and the AE based upon the available information.
•
The following components are to be used to assess the relationship between the 
study intervention and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the study 
intervention caused the AE:
o
Exposure: Is there evidence that the participant was actually exposed to the study 
intervention such as: reliable history, acceptable compliance assessment (pill 
count, diary, etc), expected pharmacologic effect, or measurement of 
drug/metabolite in bodily specimen?
o
Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the study intervention? Is the time of onset of the AE 
compatible with a drug-induced effect (applies to studies with IMP)?
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o
Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental 
factors.
o
Dechallenge: Was the study intervention discontinued or 
dose/exposure/frequency reduced?
◦
If yes, did the AE resolve or improve?
◦
If yes, this is a positive dechallenge.
◦
If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent 
disability; (2) the AE resolved/improved despite continuation of the study 
intervention; (3) the study is a single-dose drug study; or (4) study intervention (s) 
is/are only used 1 time.)
o
Rechallenge: Was the participant reexposed to the study intervention in this 
study?
◦
If yes, did the AE recur or worsen?
◦
If yes, this is a positive rechallenge.
◦
If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or 
permanent disability; (2) the study is a single-dose drug study; or (3) study 
intervention (s) is/are used only 1 time.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE STUDY INTERVENTION, OR IF REEXPOSURE 
TO THE STUDY INTERVENTION POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR AS PER DOSE 
MODIFICATION GUIDELINES IN THE PROTOCOL, AND IF REQUIRED, THE 
IRB/IEC.
•
Consistency with study intervention profile: Is the clinical/pathological presentation of 
the AE consistent with previous knowledge regarding the study intervention or drug class 
pharmacology or toxicology?
•
The assessment of relationship will be reported on the case report forms/worksheets by 
an investigator who is a qualified physician according to their best clinical judgment, 
including consideration of the above elements.
•
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a study intervention relationship).
o
Yes, there is a reasonable possibility of study intervention relationship:
◦
There is evidence of exposure to the study intervention. The temporal sequence of 
the AE onset relative to the administration of the study intervention is reasonable. 
The AE is more likely explained by the study intervention than by another cause.
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o
No, there is not a reasonable possibility of study intervention relationship:
◦
Participant did not receive the study intervention OR temporal sequence of the AE 
onset relative to administration of the study intervention is not reasonable OR the 
AE is more likely explained by another cause than the study intervention. (Also 
entered for a participant with overdose without an associated AE.)
•
The investigator must review and provide an assessment of causality for each AE/SAE 
and document this in the medical notes.
•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.
•
The investigator may change their opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment.
•
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.
•
For studies in which multiple agents are administered as part of a combination regimen, 
the investigator may attribute each AE causality to the combination regimen or to a single 
agent of the combination. In general, causality attribution should be assigned to the 
combination regimen (ie, to all agents in the regimen). However, causality attribution 
may be assigned to a single agent if in the investigator’s opinion, there is sufficient data 
to support full attribution of the AE to the single agent.
Follow-up of AE and SAE
•
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
•
New or updated information will be recorded in the CRF.
•
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
10.3.6
Reporting of AEs, SAEs, 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 EDC tool.
o
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
o
If the electronic system is unavailable for more than 24 hours, then the site will 
use the paper AE Reporting form.
o
Reference Section 8.4.1 for reporting time requirements.
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•
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
•
After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.
•
If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).
•
Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF
•
If the EDC tool is not operational, facsimile transmission or secure email 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 and Drug–Device Combination Products: Product 
Quality Complaints/Malfunctions: Definitions, Recording, and Follow-up
No applicable.
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10.5
Appendix 5: Contraceptive Guidance
10.5.1
Definitions
Participants of Childbearing Potential (POCBP)
A participant assigned female sex at birth is considered fertile following menarche and 
capable of becoming pregnant until becoming postmenopausal unless permanently sterile 
(see below):
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Participants assigned female sex at birth who are in the following categories are not capable 
of becoming pregnant and, therefore, not considered POCBP:
•
Premenarchal
•
Premenopausal with 1 of the following:
o
Documented hysterectomy
o
Documented bilateral salpingectomy
o
Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Müllerian 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
o
A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause.
◦
A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in participants assigned female sex at birth who are not 
using hormonal contraception or HRT. However, in the absence of 12 months of 
amenorrhea, confirmation with 2 FSH measurements in the postmenopausal range 
is required.
o
Participants assigned female sex at birth who are on HRT and whose menopausal 
status is in doubt will be required to use one 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
Contraceptive 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 POCBP who is not currently pregnant.
o
The following are not acceptable methods of contraception:
•
Periodic abstinence (calendar, symptothermal, postovulation methods), withdrawal 
(coitus interruptus), spermicides only, and lactational amenorrhea method (LAM).
•
Male condom with cap, diaphragm, or sponge with spermicide.
•
Male and female condom cannot be used together.
o
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.
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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 17 during the protocol-defined time frame in Section 5.1.
Table 17
Highly Effective Contraception Methods
Contraceptives allowed during the study include:
Highly Effective Contraceptive Methods That Have Low User Dependencya
Failure rate of <1% per year when used consistently and correctly.
Progestogen-only subdermal contraceptive implant a,b
IUSb,c
Nonhormonal IUD
Bilateral tubal occlusion
Azoospermic partner (vasectomized or secondary to medical cause) –
All sexual partner(s) of the POCBP must be azoospermic. The participant must provide verbal 
confirmation of partner azoospermia during Medical History. If not, an additional highly effective method 
of contraception should be used. A spermatogenesis cycle is approximately 90 days.
Sexual Abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining from penile-
vaginal intercourse with partner(s) capable of producing sperm 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.
a
If locally required, in accordance with CTFG guidelines, acceptable contraceptive implants are limited to those 
which inhibit ovulation.
b
If hormonal contraception efficacy for a participant assigned female sex at birth is potentially decreased due to 
interaction(s) with study intervention(s) (eg, CYP3A4 inducers), penile/external condoms must be used in addition 
to POCBP’s hormonal contraception.
c
IUS is a progestin releasing IUD.
Note:
Male and female condoms should not be used together (due to risk of failure with friction)
Tubal occlusion includes tubal ligation
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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
China
Section 8.8
Biomarkers
To identify novel biomarkers, the following biospecimens to support exploratory analyses of 
cellular components (eg, protein, RNA, DNA, metabolites) and other circulating molecules 
will be collected from participants as specified in the SoA (Note: If a documented law or 
regulation prohibits [or local IRB/IEC does not approve] sample collection for these 
purposes, then such samples should not be collected at the corresponding sites); in China, the 
below samples, including tumor tissue or slides for PD-L1, will be collected for the 
participants who enrolled after HGRAC approval of the biomarker testing:
•
Tumor tissue blocks or slides for PD-L1 analysis
•
Blood for serum biomarkers
•
Blood for RNA analysis
•
Blood for circulating tumor nucleic acids 
•
Blood for genetic analysis
•
Stool sample for microbiome analysis (optional) 
10.7.2
France
Section 6.6.1.2
Dose Modification and Toxicity Management for Immune-related 
AEs Associated With Pembrolizumab
Participants should be discontinued from study intervention if any of the following AEs 
occur:
•
Recurrent Grade 3 colitis
•
Grade 4 skin rash
•
Stevens-Johnson syndrome
•
Toxic epidermal necrolysis
Please refer to the current pembrolizumab SmPC for additional guidance on management of 
immune-related AEs associated with pembrolizumab.
Please refer to the current lenvatinib SmPC for additional guidance on management of AEs 
associated with lenvatinib administration and other contraindications.
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10.7.3
Germany
Participant’s legally acceptable representative in Germany
As per Sections 7.1 (Discontinuation of Study Intervention), 7.2 (Participant Withdrawal 
from the Study, 8.1.1 (Informed Consent) and 8.1.1.1 (General Informed Consent), a 
participant’s legally acceptable representative may sign the Informed Consent or request 
discontinuation of the study. This is to clarify that in Germany participants incapable of 
giving informed consent for their study participation will not be enrolled into the study. In 
the event a participant should become incapable of giving informed consent during the study, 
this participant will be withdrawn from the study. Thus the “legally acceptable 
representative” in the above mentioned protocol sections is not applicable for Germany.
Exclusion of MUGA (  multigated acquisition) scans at German sites
Sections 5.2 (Exclusion criteria) and 8.3 (Safety assessments) as well as other sections of the 
protocol refer to MUGA scans or ECHO scans for LVEF assessments. As per protocol, 
MUGA or echocardiogram scans should be performed locally in accordance with the 
institution's standard practice. This is to clarify that in Germany MUGA scans are not 
standard practice and that therefore only ECHO scans will be done at the German sites. No 
MUGA scans will be done in Germany.
Section 5.2
Exclusion Criteria
•
Exclusion criterion #8 - Has a known history of human immunodeficiency virus (HIV) 
infection. HIV testing is required at Screening.
•
Exclusion criterion #9 - Has a known history of hepatitis B (defined as hepatitis B surface 
antigen [HBsAg] reactive) or known active hepatitis C virus (defined as HCV RNA 
[qualitative] is detected) infection. Testing for hepatitis B or hepatitis C is required at 
Screening.
•
Exclusion criterion #11 - Has a known history of active tuberculosis (TB; Bacillus
tuberculosis). Testing for tuberculosis is required at Screening.
10.7.4
United Kingdom
Section 5.2
Exclusion Criteria
•
Exclusion criterion #19 - Has prolongation of QTc interval (calculated using Fridericia’s 
formula) to >480 msec.
•
Exclusion criterion #25 - Live vaccines within 30 days prior to the first dose of study 
intervention, while receiving study intervention, and for 90 days after the last dose of 
study intervention, are prohibited.
Section 5.1
Inclusion Criteria
•
Inclusion criterion #11 - A pregnancy test is required every cycle for POCBP, and if urine 
pregnancy test cannot be confirmed as negative, a serum pregnancy test is required.
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10.7.5
Italy
Section 6.6.1.2
Dose Modification and Toxicity Management for Immune-related 
AEs Associated With Pembrolizumab
Participants should be discontinued from study intervention if any of the following AEs 
occur:
•
Recurrent Grade 3 colitis
Please refer to the current lenvatinib SmPC for management and monitoring of participants 
with AEs associated with lenvatinib administration.
10.7.6
Canada
Section 6.6.2.9
Management of Gastrointestinal Perforation or Fistula Formation
•
Lenvatinib/placebo should be discontinued in any participant who develops 
gastrointestinal perforation of any grade or ≥Grade 3 fistula.
Please refer to the current lenvatinib product monograph for management of AEs associated 
with lenvatinib administration.
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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 6 and Figure 2]). This decision by the investigator should be based on the 
participant’s overall clinical condition.
Clinical stability is defined as the following: 

Absence of symptoms and signs indicating clinically significant progression of
disease

No decline in ECOG performance status 

No requirements for intensified management, including increased analgesia, 
radiation, or other palliative care.
Any participant deemed clinically unstable should be discontinued from study intervention
at central verification of site-assessed first radiologic evidence of PD and is not required to 
have repeat tumor imaging for confirmation of PD by iRECIST.
If the investigator decides to continue treatment, the participant may continue to receive 
study intervention and the tumor assessment should be repeated 4 to 8 weeks later to confirm 
PD by iRECIST, per investigator assessment. Images should continue to be sent to the CIV
for potential retrospective BICR.
Tumor flare may manifest as any factor causing radiographic progression per RECIST 1.1, 
including:

Increase in the sum of diameters of target lesion(s) identified at baseline to ≥20% and 
≥5 mm from nadir
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.

Unequivocal progression of nontarget lesion(s) identified at baseline

Development of new lesion(s)
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iRECIST defines new response categories, including iUPD (unconfirmed PD) and iCPD 
(confirmed PD). 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 to any prior iUPD time point
o
For nontarget lesions, worsening is any significant growth in lesions overall, 
compared to a prior iUPD time point; this does not have to meet the 
“unequivocal” standard of RECIST 1.1
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
•
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)
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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 pseudoprogression, 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, an exception to continue study 
intervention may be considered following consultation with the Sponsor. In this case, if study 
intervention is continued, tumor imaging should continue to be performed following the 
intervals as outlined in Section 1.3 and submitted to the CIV.
Detection of Progression at Visits After Pseudoprogression Resolves
After resolution of pseudoprogression (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 pseudoprogression. 
The nadir is always the smallest sum of diameters seen during the entire study, 
either before or after an instance of pseudoprogression.
•
Nontarget lesions
o
If nontarget lesions have never shown unequivocal progression, their doing so for 
the first time results in iUPD.
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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 predisease 
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 more than 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., et al 1982]
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10.10 Appendix 10: Technical Note for the Poisson Mixture Model
The Poisson mixture model is applied to account for the failure rates decreasing over time in 
the study, which is a mixture of patients suffering disease recurrence and others who have 
excellent long-term results. The survival function [de Castro, M., et al 2010] as a function of 
time t for a control group (c) is:
For the advanced melanoma setting, according to the published literature [Hurley, J., et al 
2013], investigator’s feedback, and study assumption, ~30% of subjects will be cured over a 
long-term period of time (ie, Cure_Rate  0.3) and it is more likely after 1 to 2 years of study 
initiation, with minimal progression-free survival (PFS) events accumulation. 
According to the published literature [Hurley, J., et al 2013], we assume PFS follows a 
Poisson mixture model distribution with ~40% PFS rate at 12 months in the pembrolizumab 
arm.  shows the PFS curves using the Poisson mixture model and exponential model. The 
curve from the Poisson mixture model looks similar to the curve in the published literature 
[Hurley, J., et al 2013].
Figure 5
PFS Curves Using the Poisson Mixture Model and Exponential Model
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10.11 Appendix 11: Abbreviations
Abbreviation
Expanded Term
ADA
antidrug antibodies
ADL
activities of daily living
AE
adverse event 
ALT
alanine aminotransferase
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
BICR
blinded independent central review
BP
blood pressure
BRAF
proto-oncogene B-Raf
C1D1
Cycle 1 Day 1
C1D15
Cycle 1 Day 15
C2D1
Cycle 2 Day 1
CI
confidence interval
CIV
central imaging vendor
CNS
central nervous system 
COPD
chronic obstructive pulmonary disease
CR
complete response
CRF
Case Report Form 
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
DMC
Data Monitoring Committee 
DNA
deoxyribonucleic acid 
DOR
duration of response
DVT
deep vein thrombosis
ECG
electrocardiogram 
ECHO
echocardiogram
ECI
event of clinical interest
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
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Abbreviation
Expanded Term
eCTA
exploratory Clinical Trial Application
EDC
electronic data collection 
eDMC
external Data Monitoring Committee
EFS
event-free survival
EMA
European Medicines Agency
EOC
Executive Oversight Committee 
EORTC
European Organisation for Research and Treatment of Cancer
EOT
end-of-treatment
ePRO
electronic Patient-reported Outcomes
EQ-5D-5L
European Quality of Life 5-dimension 5-level (questionnaire)
FA
Final analysis
FBR
Future biomedical research
FDA
US Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FSH
Follicle-stimulating hormone 
FU
Follow up
GCP
Good Clinical Practice 
HCC
Hepatocellular Carcinoma
HCV
hepatitis C virus
HGRAC
Human Genetic Regulatory Administration of China
HR
hazard ratio
HRQoL
Health-related Quality of Life
HRT
hormone replacement therapy
IA
interim analysis
IB
Investigator’s Brochure 
ICF
Informed Consent Form 
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
iCPD
iRECIST confirmed progressive disease
iCR
iRECIST complete response
iCRO
imaging Contract Research Organization
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Abbreviation
Expanded Term
IEC
Independent Ethics Committee
IHC
immunohistochemistry
INR
international normalized ratio
irAE
immune-related adverse event
iPR
iRECIST partial response
IRB
Institutional Review Board 
iRECIST
RECIST 1.1 for Immune-based Therapeutics
IRT
interactive response technology
iUPD
iRECIST unconfirmed progressive disease
iSD
iRECIST stable disease
MCV
MCV  mean corpuscular volume
MEK
mitogen-activated extracellular signal-regulated kinase
MEKi
MEK 1/2 inhibitor
MRI
magnetic resonance imaging
MTD
maximum tolerated dose 
NCI
National Cancer Institute
NE
not estimable
NSCLC
non-small cell lung cancer
ORR
objective response rate
ORRWeek24
objective response rate at Week 24
OS
overall survival
PBPK
physiologically based PK
PD
Progressive disease
PD-1
programmed cell death 1
PET
positron emission tomography 
PFS
progression-free survival
PK
Pharmacokinetic
POCBP
Participant of childbearing potential
PR
Partial response
PRO
Patient-reported outcome
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Abbreviation
Expanded Term
PT
prothrombin time
PTT
partial thromboplastin time
Q3W
every 3 weeks
Q9W
every 9 weeks
Q12W
every 12 weeks
Q24W
every 24 weeks
QD
once daily
QLQ-C30
Quality of Life Questionnaire-Core 30
QoL
quality of life
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
ribonucleic acid
RTK
Receptor tyrosine kinase
SAC
Scientific Advisory Committee
SAE
serious adverse event 
SAP
statistical analysis plan
SoA
schedule of activities
SOC
standard of care
TB
tuberculosis
TRAE
treatment-related adverse event
TTD
Time to true deterioration
ULN
upper limit of normal
USPI
United States Package Insert
VEGF
vascular endothelial growth factor
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11
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