A Phase 2, Single-arm, Open-label Clinical Trial of Pembrolizumab Plus Lenvatinib in Participants With First-line Advanced/Metastatic Non-clear Cell Renal Cell Carcinoma (nccRCC) (KEYNOTE-B61)
Phase: PHASE2
Conditions: Renal Cell Carcinoma
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
NCT04704219 
Document Date: 
31-Oct-2024
A Phase 2, Single-arm, Open-label Clinical Trial of Pembrolizumab 
Plus Lenvatinib in Participants with First-line Advanced/Metastatic 
Non-clear Cell Renal Cell Carcinoma (nccRCC) (KEYNOTE-B61)

PRODUCT: MK-3475  
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PROTOCOL/AMENDMENT NO.: B61-04
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Title Page
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME LLC, RAHWAY, NJ, USA (MSD).
Protocol Title: A Phase 2, Single-arm, Open-label Clinical Trial of Pembrolizumab Plus 
Lenvatinib in Participants with First-line Advanced/Metastatic Non-clear Cell Renal Cell 
Carcinoma (nccRCC) (KEYNOTE-B61)
Protocol Number: B61-04
Compound Number: MK-3475 (pembrolizumab) and MK-7902 (E7080/lenvatinib)
Sponsor Name:
Merck Sharp & Dohme LLC
(hereafter referred to as the Sponsor or MSD)
This study is part of a collaboration between MSD and Eisai.
Legal Registered Address:
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Regulatory Agency Identifying Number(s):
NCT
NCT04704219
IND
122,753
EU CT
2023-504944-32-00
EudraCT
2020-004087-26
Approval Date: 31 October 2024
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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 4
31-OCT-2024
To add the option of an extension study.
Amendment 3
04-AUG-2022
To clarify that treatment may continue beyond radiographic disease progression if the 
participant is deriving clinical benefit and after Sponsor consultation.
Amendment 2
25-AUG-2021
Administrative changes, clarifications to protocol language and interpretation, and country-
specific requirements were updated.
Amendment 1
15-APR-2021
Amendment implemented to update non-clear cell histology confirmation requirements. 
The revision is removing the prospective mandatory central review process during 
screening. This revision allows confirmation of non-clear cell RCC histology/diagnosis to 
be performed locally to confirm eligibility. 
Pembrolizumab dose modification table (DMT) updated.
Additional changes were also made to align with regional authority requirements and to 
comply with the lenvatinib label requirements for ONJ.
Original Protocol
22-SEP-2020
Not applicable
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 04
Overall Rationale for the Amendment:
To add the option of an extension study.
Summary of Changes Table
Section Number 
and Name
Description of Change
Brief Rationale
Primary Reason for Amendment
Section 6.7, 
Intervention After 
the End of the 
Study
Added extension study language for intervention 
after the end of the study.
To address a strategy change by providing an 
option for participants to roll over into an 
extension study.
Section Number 
and Name
Description of Change
Brief Rationale
Additional Changes
Title Page  
Added NCT number.
For completeness. 
Added EU CT number.
See rational above.
Section 4.4, 
Beginning and 
End of Study 
Definition
Added definition of when the overall study ends 
for purposes of analysis and reporting.
To align with the EU CTR.
Added definition of local start of the study for 
EEA countries.
See rationale above about the EU CTR.
Section 8.4.4, 
Regulatory 
Reporting 
Requirements for 
SAE
Added a statement describing how to report 
SUSARs.
Refer to Section 4.4 rationale about the 
EU CTR. 
Section 9.1, 
Statistical 
Analysis Plan 
Summary
Specified that no formal interim analysis is 
planned.
Interim analyses have been performed but were 
not formally planned. 
Section 9.5.2, 
Safety Analysis 
Population
Removed reference to Section 9.6 for details on 
handling missing data for safety analyses.
To correct an error.
Section 9.7,
Interim Analyses 
Specified that no formal interim analyses are 
planned.
Refer to Section 9.1 rationale. 
Section 9.7.1, 
Efficacy Interim 
Analysis
Specified that no formal interim analysis for 
efficacy is planned.
Refer to Section 9.1 rationale.
Updated timing of final analysis from 24 
months to approximately 36 months.
To align with the end of the study.
Section 10.1.3, 
Data Protection
Added text regarding Sponsor’s EU-approved 
Binding Corporate Rules.
Refer to Section 4.4 rationale about the 
EU CTR.
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Section Number 
and Name
Description of Change
Brief Rationale
Section 10.1.5, 
Compliance With 
Study 
Registration and 
Results Posting 
Requirements
Updated referenced EU regulation and added a 
submission website link.
Refer to Section 4.4 rationale about the 
EU CTR.
Section 10.1.6, 
Compliance with
Law, Audit, and 
Debarment
Added text for investigators located in countries 
with serious breach reporting requirements. 
Refer to Section 4.4 rationale about the 
EU CTR.
Section 10.1.7, 
Data Quality 
Assurance
Added the EU CTR requirement for a longer 
retention period for records and documents.
Refer to Section 4.4 rationale about the 
EU CTR.
Section 10.3.1, 
Definitions of 
Medication Error, 
Misuse, and 
Abuse
Added this section.
Refer to Section 4.4 rationale about the 
EU CTR.
Renumbered former Sections 10.3.1 through 
10.3.5 to current Sections 10.3.2 through 10.3.6.
Due to the addition of new Section 10.3.1. 
Throughout
document
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 ............................................................................................14
1.1
Synopsis.................................................................................................................14
1.2
Schema ..................................................................................................................17
1.3
Schedule of Activities...........................................................................................18
1.3.1
Initial Treatment Phase ................................................................................18
1.3.2
Translational Oncology Research................................................................28
1.3.3
Second Course Treatment Phase..................................................................29
2
INTRODUCTION..........................................................................................................33
2.1
Study Rationale....................................................................................................33
2.1.1
Non-clear Cell Renal Cell Carcinoma .........................................................33
2.1.2
Current Therapeutic Options for nccRCC ...................................................34
2.1.3
Rationale for the Use of Pembrolizumab and Lenvatinib in Patients with 
nccRCC........................................................................................................35
2.2
Background ..........................................................................................................35
2.2.1
Pharmaceutical and Therapeutic Background .............................................36
2.2.1.1
Pembrolizumab ..................................................................................36
2.2.1.2
Lenvatinib ..........................................................................................37
2.2.1.3
Pembrolizumab Plus Lenvatinib........................................................37
2.3
Benefit/Risk Assessment......................................................................................38
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................39
4
STUDY DESIGN............................................................................................................40
4.1
Overall Design......................................................................................................40
4.2
Scientific Rationale for Study Design.................................................................41
4.2.1
Rationale for Endpoints ...............................................................................41
4.2.1.1
Efficacy Endpoints.............................................................................41
4.2.1.2
Safety Endpoints................................................................................42
4.2.1.3
Planned Exploratory Biomarker Research.........................................42
4.3
Justification for Dose...........................................................................................44
4.3.1
Pembrolizumab ............................................................................................44
4.3.2
Lenvatinib ....................................................................................................44
4.4
Beginning and End of Study Definition .............................................................45
4.4.1
Clinical Criteria for Early Study Termination .............................................45
5
STUDY POPULATION ................................................................................................46
5.1
Inclusion Criteria.................................................................................................46
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5.2
Exclusion Criteria................................................................................................49
5.3
Lifestyle Considerations......................................................................................52
5.3.1
Meals and Dietary Restrictions....................................................................52
5.3.2
Contraception...............................................................................................52
5.4
Screen Failures.....................................................................................................52
5.5
Participant Replacement Strategy......................................................................53
6
STUDY INTERVENTION............................................................................................54
6.1
Study Intervention(s) Administered...................................................................54
6.2
Preparation/Handling/Storage/Accountability .................................................56
6.2.1
Dose Preparation..........................................................................................56
6.2.2
Handling, Storage, and Accountability........................................................56
6.3
Measures to Minimize Bias: Randomization and Blinding..............................57
6.3.1
Intervention Assignment..............................................................................57
6.3.2
Stratification.................................................................................................57
6.3.3
Blinding........................................................................................................57
6.4
Study Intervention Compliance..........................................................................57
6.5
Concomitant Therapy..........................................................................................57
6.5.1
Rescue Medications and Supportive Care ...................................................59
6.5.2
Drug Interactions .........................................................................................59
6.6
Dose Modification (Escalation/Titration/Other)...............................................60
6.6.1
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue).................................................................................................60
6.6.2
Dose Modification With Lenvatinib............................................................66
6.6.2.1
Management of Hypertension............................................................68
6.6.2.2
Management of Proteinuria................................................................70
6.6.2.3
Management of Diarrhea ...................................................................71
6.6.2.4
Management of Hepatotoxicity..........................................................71
6.6.2.5
Management of Thromboembolic Events..........................................71
6.6.2.6
Management of Posterior Reversible Encephalopathy 
Syndrome/Reversible Encephalopathy Syndrome/ Reversible 
Posterior Leukoencephalopathy Syndrome .......................................71
6.6.2.7
Management of Hypocalcemia ..........................................................72
6.6.2.8
Management of Hemorrhage .............................................................72
6.6.2.9
Management of Gastrointestinal Perforation or Fistula Formation...72
6.6.2.10
Management of QT Prolongation ......................................................72
6.6.2.11
Management of Osteonecrosis of the Jaw .........................................72
6.6.3
Dose Modifications for Overlapping Toxicities ..........................................73
6.6.4
Other Allowed Dose Interruptions...............................................................74
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6.6.5
Second Course Treatment Phase..................................................................74
6.7
Intervention After the End of the Study............................................................74
6.8
Clinical Supplies Disclosure................................................................................75
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................76
7.1
Discontinuation of Study Intervention...............................................................76
7.2
Participant Withdrawal From the Study...........................................................77
7.3
Lost to Follow-up .................................................................................................77
8
STUDY ASSESSMENTS AND PROCEDURES........................................................78
8.1
Administrative and General Procedures ...........................................................78
8.1.1
Informed Consent.........................................................................................78
8.1.1.1
General Informed Consent.................................................................79
8.1.2
Inclusion/Exclusion Criteria ........................................................................79
8.1.3
Participant Identification Card.....................................................................79
8.1.4
Medical History ...........................................................................................80
8.1.5
Prior and Concomitant Medications Review...............................................80
8.1.5.1
Prior Medications...............................................................................80
8.1.5.2
Concomitant Medications..................................................................80
8.1.6
Assignment of Screening Number...............................................................80
8.1.7
Assignment of Treatment/Randomization Number.....................................80
8.1.8
Study Intervention Administration ..............................................................81
8.1.8.1
Timing of Dose Administration.........................................................81
8.1.8.1.1
Lenvatinib ................................................................................81
8.1.8.1.2
Pembrolizumab ........................................................................81
8.1.9
Discontinuation and Withdrawal .................................................................81
8.1.10
Participant Blinding/Unblinding..................................................................82
8.1.11
Calibration of Equipment.............................................................................82
8.1.12
Tumor Tissue Collection..............................................................................82
8.2
Efficacy Assessments ...........................................................................................82
8.2.1
Tumor Imaging and Assessment of Disease................................................82
8.2.1.1
Initial Tumor Imaging........................................................................83
8.2.1.2
Tumor Imaging During the Study......................................................83
8.2.1.3
End-of-Treatment and Follow-up Tumor Imaging............................84
8.2.1.4
Second Course (Retreatment) Tumor Imaging..................................84
8.2.1.5
RECIST 1.1 Assessment of Disease..................................................85
8.3
Safety Assessments...............................................................................................86
8.3.1
Physical Examinations.................................................................................86
8.3.1.1
Full Physical Examination.................................................................86
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8.3.1.2
Directed Physical Examination..........................................................86
8.3.2
Vital Signs....................................................................................................87
8.3.3
Electrocardiograms ......................................................................................87
8.3.4
Echocardiogram or Multiple Gated Acquisition Scan.................................88
8.3.5
Clinical Safety Laboratory Assessments .....................................................88
8.3.5.1
Laboratory Safety Evaluations (Hematology, Chemistry, and 
Urinalysis)..........................................................................................89
8.3.5.2
Pregnancy Test...................................................................................89
8.3.6
Performance Assessments............................................................................89
8.3.6.1
Eastern Cooperative Oncology Group Performance Scale................89
8.3.6.2
Karnofsky Performance Status ..........................................................89
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events....................................................................................................................89
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................90
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......92
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...92
8.4.4
Regulatory Reporting Requirements for SAE .............................................92
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................92
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................93
8.4.7
Events of Clinical Interest............................................................................93
8.5
Treatment of Overdose........................................................................................93
8.6
Pharmacokinetics.................................................................................................94
8.7
Pharmacodynamics..............................................................................................94
8.8
Biomarkers ...........................................................................................................94
8.8.1
Planned Genetic Analysis Sample Collection..............................................94
8.9
Future Biomedical Research Sample Collection...............................................94
8.10
Visit Requirements...............................................................................................95
8.10.1
Screening......................................................................................................95
8.10.2
Treatment Period Visits ...............................................................................95
8.10.3
Discontinued Participants Continuing to be Monitored in the Study ..........95
8.10.4
Posttreatment Visits .....................................................................................96
8.10.4.1
Safety Follow-up Visit.......................................................................96
8.10.4.2
Efficacy Follow-up Visits..................................................................96
8.10.4.3
Survival Follow-up Contacts .............................................................96
8.10.5
Survival Status .............................................................................................97
9
STATISTICAL ANALYSIS PLAN .............................................................................98
9.1
Statistical Analysis Plan Summary.....................................................................98
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9.2
Responsibility for Analyses/In-house Blinding .................................................98
9.3
Hypotheses/Estimation ........................................................................................99
9.4
Analysis Endpoints...............................................................................................99
9.4.1
Efficacy Endpoints.......................................................................................99
9.4.2
Safety Endpoint............................................................................................99
9.5
Analysis Populations..........................................................................................100
9.5.1
Efficacy Analysis Populations...................................................................100
9.5.2
Safety Analysis Population........................................................................100
9.6
Statistical Methods.............................................................................................100
9.6.1
Statistical Methods for Efficacy Analysis..................................................100
9.6.1.1
Objective Response Rate, Clinical Benefit Rate, and Disease 
Control Rate.....................................................................................100
9.6.1.2
Duration of Response.......................................................................100
9.6.1.3
Progression-free Survival.................................................................101
9.6.1.4
Overall Survival...............................................................................102
9.6.1.5
Analysis Strategy for Key Efficacy Variables.................................103
9.6.2
Statistical Methods for Safety Analysis.....................................................103
9.6.3
Demographic and Baseline Characteristics ...............................................104
9.7
Interim Analyses ................................................................................................104
9.7.1
Efficacy Interim Analysis ..........................................................................104
9.7.2
Safety Interim Analysis..............................................................................104
9.8
Multiplicity .........................................................................................................104
9.9
Sample Size and Power Calculations ...............................................................104
9.10
Subgroup Analyses.............................................................................................105
9.11
Compliance (Medication Adherence)...............................................................105
9.12
Extent of Exposure.............................................................................................105
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...................................................................................................106
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations......106
10.1.1
Code of Conduct for Clinical Trials...........................................................106
10.1.2
Financial Disclosure...................................................................................108
10.1.3
Data Protection...........................................................................................109
10.1.3.1
Confidentiality of Data ....................................................................109
10.1.3.2
Confidentiality of Participant Records.............................................109
10.1.3.3
Confidentiality of IRB/IEC Information..........................................109
10.1.4
Publication Policy......................................................................................110
10.1.5
Compliance with Study Registration and Results Posting Requirements .110
10.1.6
Compliance with Law, Audit, and Debarment ..........................................110
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10.1.7
Data Quality Assurance .............................................................................111
10.1.8
Source Documents .....................................................................................112
10.1.9
Study and Site Closure...............................................................................112
10.2
Appendix 2: Clinical Laboratory Tests............................................................113
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................115
10.3.1
Definitions of Medication Error, Misuse, and Abuse................................115
10.3.2
Definition of AE ........................................................................................115
10.3.3
Definition of SAE ......................................................................................116
10.3.4
Additional Events Reported in the Same Manner as SAE.........................118
10.3.5
Recording AE and SAE .............................................................................118
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................122
10.4
Appendix 4: Medical Device and Drug-device Combination Products: 
Product Quality Complaints/Malfunctions: Definitions, Recording, and 
Follow-up ............................................................................................................124
10.5
Appendix 5: Contraceptive Guidance..............................................................125
10.5.1
Definitions..................................................................................................125
10.5.2
Contraception Requirements......................................................................126
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................127
10.7
Appendix 7: Country-specific Requirements..................................................128
10.7.1
UK-specific Requirements.........................................................................128
10.7.2
Canada-specific Requirements...................................................................128
10.8
Appendix 8: Description of the iRECIST Process for Assessment of 
Disease Progression............................................................................................129
10.9
Appendix 9: Abbreviations ...............................................................................130
11
REFERENCES.............................................................................................................133
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LIST OF TABLES
Table 1
Schedule of Activities – Initial Treatment Phase.............................................18
Table 2
Schedule of Activities – Additional Biomarker Collections From Select 
Sites..................................................................................................................28
Table 3
Schedule of Activities – Second Course Treatment Phase..............................29
Table 4
Adequate Organ Function Laboratory Values .................................................49
Table 5
Study Interventions..........................................................................................55
Table 6
Dose Modification and Toxicity Management Guidelines for Immune-
related Adverse Events Associated with Pembrolizumab Monotherapy, 
Coformulations or IO Combinations ...............................................................61
Table 7
Pembrolizumab Infusion Reaction Dose Modification and Treatment 
Guidelines ........................................................................................................65
Table 8
Dose Modification Guidelines for Lenvatinib-Related Adverse Events .........67
Table 9
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events.................................................................................91
Table 10
Censoring Rules for Duration of Response ...................................................101
Table 11
Censoring Rules for Primary and Sensitivity Analysis of PFS......................102
Table 12
Analysis Strategy for Key Efficacy Variables...............................................103
Table 13
Two-sided 95% Confidence Intervals for ORR with 152 Participants..........104
Table 14
Protocol-required Safety Laboratory Assessments........................................114
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LIST OF FIGURES
Figure 1
Study Schema...................................................................................................17
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 2, Single-arm, Open-label Clinical Trial of Pembrolizumab Plus 
Lenvatinib in Participants with First-line Advanced/Metastatic Non-clear Cell Renal Cell 
Carcinoma (nccRCC) (KEYNOTE-B61)
Short Title: Pembro + Lenva for 1L nccRCC
Acronym: KEYNOTE-B61
Hypotheses, Objectives, and Endpoints:
In male or female participants at least 18 years of age with previously untreated 
histologically confirmed advanced/metastatic nccRCC:
Primary Objectives
Primary Endpoints
- To evaluate the ORR of pembrolizumab + 
lenvatinib per RECIST 1.1 by blinded 
independent central review (BICR)
- Objective response (OR): a confirmed 
complete response (CR) or partial response 
(PR)
Secondary Objectives
Secondary Endpoints
- To evaluate the DOR of pembrolizumab + 
lenvatinib in participants with a confirmed 
CR or PR per RECIST 1.1 by BICR
- DOR: the time from first documented 
evidence of CR or PR until disease 
progression or death due to any cause, 
whichever occurs first
- To evaluate PFS per RECIST 1.1 by BICR 
in participants receiving pembrolizumab + 
lenvatinib
- PFS: the time from first dose to the first 
documented PD or death from any cause, 
whichever occurs first
- To evaluate the overall survival (OS) of 
participants receiving pembrolizumab + 
lenvatinib
- OS: the time from first dose until death 
from any cause
- To evaluate the CBR of pembrolizumab + 
lenvatinib per RECIST 1.1 by BICR
- Clinical benefit: a confirmed CR, PR, or 
stable disease (SD) for at least 6 months
- To evaluate the DCR of pembrolizumab + 
lenvatinib per RECIST 1.1 by BICR
- Disease control: a confirmed CR, PR or 
SD
- To evaluate the safety of pembrolizumab + 
lenvatinib
- Adverse events (AEs)
- Discontinuations due to AEs
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Overall Design:
Study Phase
Phase 2
Primary Purpose
Treatment
Indication
Previously untreated advanced or metastatic nccRCC
Population
Participants with previously untreated advanced or 
metastatic nccRCC
Study Type
Interventional
Intervention Model
Single Group
This is a multisite study.
Type of Control
No Treatment Control
Study Blinding
Unblinded Open-label
Blinding Roles
Outcomes Assessor
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 5 years from the time the first participant 
(or their legally acceptable representative) provides 
documented informed consent until the last participant’s 
last study-related contact.
Number of Participants:
Approximately 152 participants will be enrolled in the study.
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Intervention Groups and Duration:
Intervention 
Groups
Intervention 
Group Name
Drug
Dose 
Strength
Dose 
Frequency
Route of 
Adminis-
tration
Regimen/ 
Treatment 
Period
Use
Pembrolizumab 
+ Lenvatinib
Pembro-
lizumab
400 mg
Q6W
IV
Up to 18 
infusions, 
progressive 
disease or 
discontinuation
Experi-
mental
Lenvatinib
20 mg
QD
Oral
Until 
progressive 
disease or 
discontinuation
Experi-
mental
IV=intravenous; Q6W=every 6 weeks; QD=every day.
Other current or former names or aliases for study interventions are as 
follows: 
Pembrolizumab: KEYTRUDA®, MK-3475, lambrolizumab
Lenvatinib: LENVIMA®, Kisplyx, MK-7902, E7080
Total 
Number of 
Intervention 
Groups/ 
Arms
1
Duration of 
Participation
Each participant will participate in the study from the time the participant 
provides documented informed consent through the final protocol-
specified contact.
After a screening phase of up to 28 days, each participant will be assigned 
to receive study intervention. Study intervention with pembrolizumab will 
continue for up to 18 administrations (approximately 2 years) or until a 
discontinuation criterion is met. Study intervention with lenvatinib may 
continue beyond 2 years until a discontinuation criterion is met. 
Participants who stop study intervention after receiving 18 administrations 
of pembrolizumab for reasons other than disease progression or 
intolerability, or participants who attain a complete response and stop 
study intervention may be eligible for up to 9 additional administrations of 
pembrolizumab (approximately 1 year) upon experiencing disease 
progression (Section 8.10.3).
After the end of treatment, each participant will be followed for the 
occurrence of adverse events and spontaneously reported pregnancy as 
described under Section 8.4.
08Y0F5

PRODUCT: MK-3475  
17
PROTOCOL/AMENDMENT NO.: B61-04
MK-3475-B61-04 FINAL PROTOCOL
31-OCT-2024
Participants who discontinue for reasons other than radiographic disease 
progression will have post-treatment follow-up imaging for disease status 
until disease progression is documented radiographically per RECIST 1.1, 
the start of a new anti-cancer treatment, withdrawal of consent, pregnancy, 
death, or loss to follow-up. All participants will be followed by telephone 
for overall survival until death, withdrawal of consent, or the end of the 
study.
Study Governance Committees:
Steering Committee
No
Executive Oversight Committee
No
Data Monitoring Committee
No
Clinical Adjudication Committee
No
Study Accepts Healthy Volunteers: No
A list of abbreviations used in this document can be found in Appendix 9.
1.2
Schema
The study design is depicted in Figure 1.
Figure 1
Study Schema
1L=first-line; AJCC=American Joint Committee on Cancer; DC=discontinuation; IMDC=International Metastatic RCC 
Database Consortium; IV=intravenous; KPS=Karnofsky Performance Status; nccRCC=non-clear cell renal cell carcinoma; 
PO=per oral; PD=progressive disease; Q6W=every 6 weeks; QD=every day.
08Y0F5

PRODUCT: MK-3475  
18
PROTOCOL/AMENDMENT NO.: B61-04
MK-3475-B61-04 FINAL PROTOCOL
31-OCT-2024
1.3
Schedule of Activities
1.3.1
Initial Treatment Phase
Table 1
Schedule of Activities – Initial Treatment Phase
Trial Period
Screening
Initial Treatment Phase
Cycle = 42 Days
EOT
Posttreatment
Notes
Safety 
FU
Efficacy 
FU
Survival 
FU
Visit Timing/
Cycle 
Number
1
2
3
4
5 to 18
>18
At 
D/C
30 days 
after 
last 
dose
Per 
Imaging 
Schedule
Q12W
All procedures/ 
assessments are to be 
performed prior to 
dosing unless 
otherwise indicated.
Cycle Day
1
8
15
22
36
1
22
1
22
1
22
1
22
1
22
Scheduling 
Window 
(days)
-28 to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+7
±7
±14
Administrative Procedures
Informed 
Consent
X
Informed consent must 
be obtained prior to any 
protocol-specific 
procedures.
If the investigator plans 
to treat beyond disease 
progression, additional 
consent is required.
Inclusion/
Exclusion 
Criteria
X
Participant 
Identification 
Card
X
X*
*Update with allocation 
number from IRT.
nccRCC 
Disease 
History
X
Demographics 
and Medical 
History
X
Medical history includes 
substance usage (drugs, 
alcohol, tobacco and 
caffeine), family history 
of premature CV 
disease, and surgical 
history.
08Y0F5

PRODUCT: MK-3475  
19
PROTOCOL/AMENDMENT NO.: B61-04
MK-3475-B61-04 FINAL PROTOCOL
31-OCT-2024
Trial Period
Screening
Initial Treatment Phase
Cycle = 42 Days
EOT
Posttreatment
Notes
Safety 
FU
Efficacy 
FU
Survival 
FU
Visit Timing/
Cycle 
Number
1
2
3
4
5 to 18
>18
At 
D/C
30 days 
after 
last 
dose
Per 
Imaging 
Schedule
Q12W
All procedures/ 
assessments are to be 
performed prior to 
dosing unless 
otherwise indicated.
Cycle Day
1
8
15
22
36
1
22
1
22
1
22
1
22
1
22
Scheduling 
Window 
(days)
-28 to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+7
±7
±14
Prior/
Concomitant 
Medication 
Review
X
Record medications 
received within 28 days 
before the first dose of 
study intervention 
through 30 days after 
the last dose of study 
intervention, or >30
days for medications for 
SAEs and ECIs as 
outlined for AE 
monitoring timeframe 
below.
Treatment 
Allocation
X
First dose of study 
treatment must be 
administered within 3 
days of allocation.
Study Intervention Administration
Lenvatinib 
Dispensed
X
X
X
X
X
X
X
X
X
X
X
X
Lenvatinib 
Container 
Returned
X
X
X
X
X
X
X
X
X
X
X
X
Pembrolizumab 
Administration
X
X
X
X
X
08Y0F5

PRODUCT: MK-3475  
20
PROTOCOL/AMENDMENT NO.: B61-04
MK-3475-B61-04 FINAL PROTOCOL
31-OCT-2024
Trial Period
Screening
Initial Treatment Phase
Cycle = 42 Days
EOT
Posttreatment
Notes
Safety 
FU
Efficacy 
FU
Survival 
FU
Visit Timing/
Cycle 
Number
1
2
3
4
5 to 18
>18
At 
D/C
30 days 
after 
last 
dose
Per 
Imaging 
Schedule
Q12W
All procedures/ 
assessments are to be 
performed prior to 
dosing unless 
otherwise indicated.
Cycle Day
1
8
15
22
36
1
22
1
22
1
22
1
22
1
22
Scheduling 
Window 
(days)
-28 to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+7
±7
±14
Tumor Imaging and Efficacy Assessments
Imaging of 
chest/
abdomen/
pelvis and 
Response 
Assessment
X
The same modality 
should be used for all 
scans.
The first on-treatment 
assessment should occur 
at Week 12 (84 ± 7 
days) and be repeated 
Q6W (42 ± 7 days) until 
Week 54 and then 
Q12W (84 ± 7 days) 
thereafter. Schedule 
should follow calendar 
days and not be adjusted 
for delays in treatment.
08Y0F5

PRODUCT: MK-3475  
21
PROTOCOL/AMENDMENT NO.: B61-04
MK-3475-B61-04 FINAL PROTOCOL
31-OCT-2024
Trial Period
Screening
Initial Treatment Phase
Cycle = 42 Days
EOT
Posttreatment
Notes
Safety 
FU
Efficacy 
FU
Survival 
FU
Visit Timing/
Cycle 
Number
1
2
3
4
5 to 18
>18
At 
D/C
30 days 
after 
last 
dose
Per 
Imaging 
Schedule
Q12W
All procedures/ 
assessments are to be 
performed prior to 
dosing unless 
otherwise indicated.
Cycle Day
1
8
15
22
36
1
22
1
22
1
22
1
22
1
22
Scheduling 
Window 
(days)
-28 to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+7
±7
±14
Bone Scan
X
Perform a screening 
bone scan in all 
participants.
After allocation, only 
continue bone scans if 
participant’s scan at 
Screening was positive.
The schedule for bone 
scans is at Week 18 (126 
± 7 days); Q12W (84 ± 
7 days) until Week 54; 
then Q24W (168 ± 
7 days) thereafter.
Perform for participants 
at time of CR if positive 
at baseline.
Schedule should follow 
calendar days and not be 
adjusted for delays in 
treatment.
Brain Scan
X*
*Perform at Screening 
ONLY for participants 
with previously 
documented brain 
metastases (to confirm 
stability) or who are 
clinically symptomatic.
Brain scans will be 
performed as clinically 
indicated and to confirm 
a CR in participants 
with brain metastasis at 
baseline.
08Y0F5

PRODUCT: MK-3475  
22
PROTOCOL/AMENDMENT NO.: B61-04
MK-3475-B61-04 FINAL PROTOCOL
31-OCT-2024
Trial Period
Screening
Initial Treatment Phase
Cycle = 42 Days
EOT
Posttreatment
Notes
Safety 
FU
Efficacy 
FU
Survival 
FU
Visit Timing/
Cycle 
Number
1
2
3
4
5 to 18
>18
At 
D/C
30 days 
after 
last 
dose
Per 
Imaging 
Schedule
Q12W
All procedures/ 
assessments are to be 
performed prior to 
dosing unless 
otherwise indicated.
Cycle Day
1
8
15
22
36
1
22
1
22
1
22
1
22
1
22
Scheduling 
Window 
(days)
-28 to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+7
±7
±14
Subsequent 
Anticancer 
Therapy 
Status
X
X
X
X
Survival 
Status
X
Upon Sponsor request, 
participants may be 
contacted for survival 
status at any time during 
the course of the study.
Clinical Procedures/Assessments
Full Physical 
Examination
X
X
Directed 
Physical 
Examination
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Height
X
Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HR, DBP, SBP, RR, 
temperature.
ECHO/
MUGA
X
X
Additional assessments 
may be performed as 
clinically indicated.
08Y0F5

PRODUCT: MK-3475  
23
PROTOCOL/AMENDMENT NO.: B61-04
MK-3475-B61-04 FINAL PROTOCOL
31-OCT-2024
Trial Period
Screening
Initial Treatment Phase
Cycle = 42 Days
EOT
Posttreatment
Notes
Safety 
FU
Efficacy 
FU
Survival 
FU
Visit Timing/
Cycle 
Number
1
2
3
4
5 to 18
>18
At 
D/C
30 days 
after 
last 
dose
Per 
Imaging 
Schedule
Q12W
All procedures/ 
assessments are to be 
performed prior to 
dosing unless 
otherwise indicated.
Cycle Day
1
8
15
22
36
1
22
1
22
1
22
1
22
1
22
Scheduling 
Window 
(days)
-28 to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+7
±7
±14
12-lead ECG
X
X
X
X
X*
X*
X*
X
X
*After Cycle 2, repeat 
ECG every other cycle 
(eg,C4, C6, C8, C10, 
etc.). 
For high-risk 
participants
(Section 8.3.3), conduct 
ECG monitoring every 
cycle.
If lenvatinib is 
discontinued, ECGs are 
only required at the 
EOT and Safety Follow-
up visits.
KPS
X
At screening, perform 
within 10 days prior to 
first dose of study 
intervention.
ECOG 
Performance 
Status
X
X
X
X
X
X
X
X
X
At screening, perform 
within 10 days prior to 
first dose of study 
intervention.
08Y0F5

PRODUCT: MK-3475  
24
PROTOCOL/AMENDMENT NO.: B61-04
MK-3475-B61-04 FINAL PROTOCOL
31-OCT-2024
Trial Period
Screening
Initial Treatment Phase
Cycle = 42 Days
EOT
Posttreatment
Notes
Safety 
FU
Efficacy 
FU
Survival 
FU
Visit Timing/
Cycle 
Number
1
2
3
4
5 to 18
>18
At 
D/C
30 days 
after 
last 
dose
Per 
Imaging 
Schedule
Q12W
All procedures/ 
assessments are to be 
performed prior to 
dosing unless 
otherwise indicated.
Cycle Day
1
8
15
22
36
1
22
1
22
1
22
1
22
1
22
Scheduling 
Window 
(days)
-28 to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+7
±7
±14
AE/SAE 
Review
X
X*
*Report AEs occurring 
within 30 days after the 
last dose of study 
intervention treatment or 
before initiation of a 
new anticancer 
treatment. Report SAEs 
occurring within 90 days 
after the last dose of 
study intervention, or 
within 30 days after the 
last dose of study 
intervention if new 
anticancer therapy is 
initiated, whichever is 
earlier.
Laboratory Procedures/Assessments
Pregnancy 
Test – Urine 
or Serum hCG 
(WOCBP 
only)
X
X*
X
X
X
X
X
X
X
X
X
X
X
X
WOCBP require 
negative test prior to 
allocation. 
*If more than 24 hours 
have elapsed prior to 
first dose of study 
intervention, another 
negative pregnancy test 
is required prior to 
starting study 
intervention.
Ongoing pregnancy tests 
should be conducted as 
indicated in Appendix 2.
08Y0F5

PRODUCT: MK-3475  
25
PROTOCOL/AMENDMENT NO.: B61-04
MK-3475-B61-04 FINAL PROTOCOL
31-OCT-2024
Trial Period
Screening
Initial Treatment Phase
Cycle = 42 Days
EOT
Posttreatment
Notes
Safety 
FU
Efficacy 
FU
Survival 
FU
Visit Timing/
Cycle 
Number
1
2
3
4
5 to 18
>18
At 
D/C
30 days 
after 
last 
dose
Per 
Imaging 
Schedule
Q12W
All procedures/ 
assessments are to be 
performed prior to 
dosing unless 
otherwise indicated.
Cycle Day
1
8
15
22
36
1
22
1
22
1
22
1
22
1
22
Scheduling 
Window 
(days)
-28 to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+7
±7
±14
Urine Dipstick 
Testing (or 
Urinalysis) for 
Protein
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis as clinically 
indicated. See Section 
6.6.2.2 for guidance on 
testing frequency in 
cases of elevated 
protein.
Participants with 
proteinuria ≥2+ 
(≥100 mg/dL) at 
screening will undergo 
24-hour urine collection 
for quantitative 
assessment of 
proteinuria.
HIV, Hepatitis 
B, Hepatitis C
X*
*Only if mandated by 
local health authority.
Refer to Appendix 7 for 
country-specific 
requirements.
Hematology
X
X
X
X
X
X
X
X
X
X
At screening, perform 
within 10 days prior to 
first dose of study 
intervention.
Chemistry
X
X
X
X
X
X
X
X
X
X
Lipase and 
Amylase
X
X
X
X
X
X
X
X
X
X
08Y0F5

PRODUCT: MK-3475  
26
PROTOCOL/AMENDMENT NO.: B61-04
MK-3475-B61-04 FINAL PROTOCOL
31-OCT-2024
Trial Period
Screening
Initial Treatment Phase
Cycle = 42 Days
EOT
Posttreatment
Notes
Safety 
FU
Efficacy 
FU
Survival 
FU
Visit Timing/
Cycle 
Number
1
2
3
4
5 to 18
>18
At 
D/C
30 days 
after 
last 
dose
Per 
Imaging 
Schedule
Q12W
All procedures/ 
assessments are to be 
performed prior to 
dosing unless 
otherwise indicated.
Cycle Day
1
8
15
22
36
1
22
1
22
1
22
1
22
1
22
Scheduling 
Window 
(days)
-28 to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+7
±7
±14
PT/INR and 
aPTT or PTT
X
At screening, perform 
within 10 days prior to 
first dose of study 
intervention.
PTT is acceptable if 
aPTT cannot be 
determined.
Perform additional 
testing as clinically 
indicated for 
participants taking 
anticoagulants.
T3 or FT3, 
FT4, TSH
X
X
X
X
X
X
X
X
X
At screening, perform 
within 10 days prior to 
first dose of study 
intervention.
Biomarkers
Blood for 
Genetic 
Analysis
X
This sample should be 
drawn for planned 
analysis of the 
association between 
genetic variants in DNA 
and drug response. This 
sample will not be 
collected at that site if 
there is either a local 
law or regulation 
prohibiting collection, or 
if the IRB/IEC does not 
approve the collection of 
the sample for these 
purposes.
08Y0F5

PRODUCT: MK-3475  
27
PROTOCOL/AMENDMENT NO.: B61-04
MK-3475-B61-04 FINAL PROTOCOL
31-OCT-2024
Trial Period
Screening
Initial Treatment Phase
Cycle = 42 Days
EOT
Posttreatment
Notes
Safety 
FU
Efficacy 
FU
Survival 
FU
Visit Timing/
Cycle 
Number
1
2
3
4
5 to 18
>18
At 
D/C
30 days 
after 
last 
dose
Per 
Imaging 
Schedule
Q12W
All procedures/ 
assessments are to be 
performed prior to 
dosing unless 
otherwise indicated.
Cycle Day
1
8
15
22
36
1
22
1
22
1
22
1
22
1
22
Scheduling 
Window 
(days)
-28 to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+7
±7
±14
Blood for 
Serum 
Biomarkers
X
X
X
X
X
Blood for 
ctDNA 
Analysis
X
X
X
X*
X*
X*
X
* After C3D1, collect 
blood for ctDNA at D1 
of every cycle (C4, C5, 
C6, etc.) up until and at 
C10. After C10D1, 
collect D1 of every 
other cycle (C12, C14, 
C16, etc.). Collect at 
EOT. 
Archival or 
Newly 
Obtained 
Tumor Tissue 
Sample 
Collection
X
Tumor tissue (archival 
or newly acquired core 
or excisional biopsy)
will be obtained and 
submitted at screening. 
Tumor blocks are 
preferred over cut slides.
AE=adverse event; aPTT=activated PTT; C=Cycle; ctDNA=circulating tumor DNA; CR=complete response; CV=cardiovascular; D=Day; DBP=diastolic blood pressure; D/C=discontinuation; 
DNA=deoxyribonucleic acid; ECG=electrocardiogram; ECI=event of clinical interest; ECHO=echocardiogram; ECOG=Eastern Cooperative Oncology Group; EOT=end-of-treatment; FT3=free T3; 
FT4=free thyroxine; FU=follow-up; hCG=human chorionic gonadotropin; HIV=human immunodeficiency virus; HR=heart rate; IEC=independent ethics committee; INR=international normalized 
ratio; IRB=institutional review board; IRT=interactive response technology; KPS=Karnofsky performance status; MUGA=multiple gated acquisition scan; nccRCC=non-clear cell renal cell 
carcinoma; PT=prothrombin time; PTT=partial thromboplastin time; Q6W=every 6 weeks; Q12W=every 12 weeks; Q24W=every 24 weeks; RR=respiratory rate; SAE=serious adverse event; 
SBP=systolic blood pressure; T3=triiodothyronine; TSH=thyroid-stimulating hormone; WOCBP=woman of childbearing potential.
08Y0F5

PRODUCT: MK-3475  
28
PROTOCOL/AMENDMENT NO.: B61-04
MK-3475-B61-04 FINAL PROTOCOL
31-OCT-2024
1.3.2
Translational Oncology Research
Table 2
Schedule of Activities – Additional Biomarker Collections From Select Sites
Trial Period
Screen-
ing
Initial Treatment Phase
Cycle = 42 Days
EOT
Posttreatment
Notes
Safety 
FU
Efficacy 
FU
Survival 
FU
Visit Timing/
Cycle Number
1
2
3
4
5 to 18
>18
At 
D/C
30 days 
after 
last 
dose
Per 
Imaging 
Schedule
Q12W
At selected TOR sites, 
all samples will be 
collected as indicated in 
the Schedule of 
Activities from all 
participants at these 
sites. See Procedure 
Manual for details of 
selected sites. 
Cycle Day
1
8
15
22
36
1
22
1
22
1
22
1
22
1
22
Scheduling 
Window (days)
-28 to 
-1
+
3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+7
±7
±14
Biomarker Sample Collection
Blood for RNA 
Analysis
X
X
X
X
Blood for PBMC
X
X
X
X
D/C=discontinuation; EOT=end-of-treatment; FU=follow-up; PBMC=peripheral blood mononuclear cells; Q12W=every 12 weeks; RNA=ribonucleic acid; TOR=translational oncology research.
08Y0F5

PRODUCT: MK-3475  
29
PROTOCOL/AMENDMENT NO.: B61-04
MK-3475-B61-04 FINAL PROTOCOL
31-OCT-2024
1.3.3
Second Course Treatment Phase
Table 3
Schedule of Activities – Second Course Treatment Phase
Trial Period
Second Course Treatment Phase
Cycle = 42 days
EOT
Posttreatment
Notes
Visit Timing/
Cycle Number
1
2
3 to 9
Safety
FU
Efficacy 
FU
Survival 
FU
Cycle Day
1
22
1
22
1
22
At 
D/C
30 days 
after 
D/C
Per 
Imaging 
Schedule
Q12W
All procedures/ assessments are to be performed prior to 
dosing unless otherwise indicated.
Scheduling Window (days)
+3
±3
±3
±3
±3
±3
+7
±7
±7
±14
Administrative Procedures
Informed consent
X
Obtain prior to initiating Second Course treatment.
If the investigator plans to treat beyond disease 
progression, additional consent is required.
Second Course Eligibility 
Criteria
X
The Second Course eligibility criteria must be 
satisfied, and all safety parameters listed in the 
inclusion criteria and none listed in the exclusion 
criteria must be met.
Concomitant Medications
Record medications received within 28 days before 
the first dose of study intervention through 30 days 
after the last dose of study intervention, or >30 days 
for medications for SAEs and ECIs as outlined for AE 
monitoring timeframe below.
Study Intervention Administration
Lenvatinib Dispensed
X
X
X
X
X
X
Lenvatinib Container 
Returned
X
X
X
X
X
X
Pembrolizumab 
Administration
X
X
X
Tumor Imaging and Efficacy Assessments
Imaging of 
chest/abdomen/pelvis and 
Response Assessment
Baseline imaging should be performed within 28 days 
before C1. 
Perform subsequent imaging Q12W (84±7 days) from 
C1. This schedule will be followed regardless of 
delays in study intervention.
All imaging should be submitted for BICR.
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Trial Period
Second Course Treatment Phase
Cycle = 42 days
EOT
Posttreatment
Notes
Visit Timing/
Cycle Number
1
2
3 to 9
Safety
FU
Efficacy 
FU
Survival 
FU
Cycle Day
1
22
1
22
1
22
At 
D/C
30 days 
after 
D/C
Per 
Imaging 
Schedule
Q12W
All procedures/ assessments are to be performed prior to 
dosing unless otherwise indicated.
Scheduling Window (days)
+3
±3
±3
±3
±3
±3
+7
±7
±7
±14
Bone Scan
Perform a baseline bone scan within 28 days before 
C1. Only continue bone scans if participant has
positive baseline bone scan. The schedule for on-
study bone scans is Q24W (168 ± 7 days).
Perform for participants at time of CR if positive at 
baseline.
Schedule should follow calendar days and not be 
adjusted for delays in treatment.
Brain Scan
X*
*Perform within 28 days before C1 ONLY for 
participants with previously documented brain 
metastases (to confirm stability) or who are clinically 
symptomatic.
Brain scans will be performed as clinically indicated 
and to confirm a CR in participants with brain 
metastasis at baseline.
Subsequent Anticancer 
Therapy Status
X
X
X
X
Survival Status
X
Upon Sponsor request, participants may be contacted 
for survival status at any time during the course of the 
study.
Clinical Procedures/Assessments
Full Physical Examination
X
X
Directed Physical 
Examination
X
X
X
X
X
X
Weight
X
X
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
HR, DBP, SBP, RR, temperature.
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Trial Period
Second Course Treatment Phase
Cycle = 42 days
EOT
Posttreatment
Notes
Visit Timing/
Cycle Number
1
2
3 to 9
Safety
FU
Efficacy 
FU
Survival 
FU
Cycle Day
1
22
1
22
1
22
At 
D/C
30 days 
after 
D/C
Per 
Imaging 
Schedule
Q12W
All procedures/ assessments are to be performed prior to 
dosing unless otherwise indicated.
Scheduling Window (days)
+3
±3
±3
±3
±3
±3
+7
±7
±7
±14
ECHO/MUGA
X*
X
*If a previous ECHO/MUGA in the Initial Treatment 
Phase was performed within 24 weeks prior to C1D1 
of the Second Course Treatment Phase, this 
assessment does not need to be repeated.
Additional assessments may be performed as 
clinically indicated.
12-lead ECG
X
X*
X
X
*After Cycle 1, repeat ECG every other cycle (eg, C3, 
C5, C7, etc.).
For high-risk participants (Section 8.3.3), conduct 
ECG monitoring every cycle.
If lenvatinib is discontinued, ECGs are only required 
at the EOT and Safety Follow-up visits.
ECOG Performance Status
X
X
X
X
X
AE/SAE Review
X*
*Report AEs occurring within 30 days after the last 
dose of study intervention. Report SAEs occurring 
within 90 days after the last dose of study 
intervention, or within 30 days after the last dose of 
study intervention if new anticancer therapy is 
initiated, whichever is earlier.
Laboratory Procedures/Assessments
Pregnancy Test – Urine or 
Serum hCG (WOCBP only)
X
X
X
X
X
X
X
WOCBP require negative test within 24 hours prior to 
first dose of intervention in the Second Course 
Treatment Phase. Ongoing pregnancy tests should be 
conducted as indicated in Appendix 2. 
Urine Dipstick Testing (or 
Urinalysis) for Protein
X
X
X
X
X
X
Urinalysis as clinically indicated. See Section 6.6.2.2 
for guidance on testing frequency in cases of elevated 
protein.
Hematology
X
X
X
Chemistry
X
X
X
Lipase and Amylase
X
X
X
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Trial Period
Second Course Treatment Phase
Cycle = 42 days
EOT
Posttreatment
Notes
Visit Timing/
Cycle Number
1
2
3 to 9
Safety
FU
Efficacy 
FU
Survival 
FU
Cycle Day
1
22
1
22
1
22
At 
D/C
30 days 
after 
D/C
Per 
Imaging 
Schedule
Q12W
All procedures/ assessments are to be performed prior to 
dosing unless otherwise indicated.
Scheduling Window (days)
+3
±3
±3
±3
±3
±3
+7
±7
±7
±14
PT/INR and aPTT or PTT
X
PTT is acceptable if aPTT cannot be determined.
Perform testing as clinically indicated for participants 
taking anticoagulants.
T3 or FT3, FT4, TSH
X
X
X
X
X
AE=adverse event; aPTT=activated PTT; BICR=blinded independent central review; C=Cycle; CR=complete response; DBP=diastolic blood pressure; D/C=discontinuation; 
ECG=electrocardiogram; ECI=event of clinical interest; ECHO=echocardiogram; ECOG=Eastern Cooperative Oncology Group; EOT=end-of-treatment; FT3=free T3; FT4=free thyroxine; 
FU=follow-up; hCG=human chorionic gonadotropin; HR=heart rate; INR=international normalized ratio; MUGA=multiple gated acquisition scan; PT=prothrombin time; PTT=partial 
thromboplastin time; Q12W=every 12 weeks; Q24W=every 24 weeks; RR=respiratory rate; SAE=serious adverse event; SBP=systolic blood pressure; T3=triiodothyronine; TSH=thyroid-stimulating 
hormone; WOCBP=woman of childbearing potential.
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2
INTRODUCTION
This study will evaluate the efficacy and safety of pembrolizumab in combination with
lenvatinib for the first-line treatment of participants with advanced/metastatic nccRCC.
2.1
Study Rationale
2.1.1
Non-clear Cell Renal Cell Carcinoma
RCC accounts for 3% to 4% of all adult malignancies, representing the sixth most common 
cancer in men and the eighth most common cancer in women in the US [Siegel, R. L., et al 
2020]. Globally in 2018 there were an estimated 403,000 new cases of kidney cancer and 
175,000 deaths due to the disease reported [Bray, F., et al 2018].
RCC originates within the renal cortex and is the most common kidney cancer constituting 
up to approximately 85% of primary renal neoplasms, with a median age at diagnosis of 
64 years [National Comprehensive Cancer Network 2019]. Smoking, obesity, and 
hypertension are established risk factors for RCC development, and several hereditary 
conditions (eg, von Hippel-Lindau disease) also predispose patients to having an increased 
risk of developing RCC [National Comprehensive Cancer Network 2019]. The most 
important prognostic determinants of the 5-year survival rates in RCC are tumor stage, grade, 
local extent of the tumor, presence of regional nodal metastases, and evidence of metastatic 
disease at presentation [National Comprehensive Cancer Network 2019]. RCC primarily 
metastasizes to the lung, bone, liver, lymph nodes, adrenal gland, and brain [Bianchi, M., et 
al 2012]. 
At initial diagnosis, approximately two-thirds of patients with RCC present with localized 
disease and one-third present with unresectable or metastatic disease at diagnosis [Siegel, R. 
L., et al 2020]. And approximately 20% to 30% of patients with localized tumors will 
eventually relapse [National Comprehensive Cancer Network 2019].
Recent analyses of the SEER database indicate that the incidence of RCC has been rising on 
average 0.6% each year and death rates have been falling on average 0.7% each year from
2006 through 2015. [National Cancer Institute 2020]. However, although the 5-year survival 
for localized RCC is high at 92.6%, the 5-year survival rate for patients with distant 
metastasis remains dismal at 13.0% [National Comprehensive Cancer Network 2019].
The vast majority of RCC contain a clear cell histology (70% to 80%) with the remainder of 
cases being summarized as non-clear cell. This heterogeneous group is further subclassified 
into less common subtypes such as papillary (10% to 15% of all RCCs), chromophobe (5% 
to 7%), collecting duct (1% to 2%), renal medullary (<1%), and translocation RCC tumors
(<1%) [Leibovich, B. C., et al 2010] [Lipworth, L., et al 2016] [Moch, H., et al 2000]. 
In the advanced/metastatic setting, survival in all subtypes of nccRCC is uniformly worse 
compared to ccRCC, due to the inherent aggressiveness of these cancers and a lack of 
effective systemic treatment options [Leibovich, B. C., et al 2010]. Median survival 
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following a diagnosis of metastatic nccRCC remains poor, with 5-year OS rates ranging from
7% to 12%.
2.1.2
Current Therapeutic Options for nccRCC
Currently there is no globally accepted standard of care in nccRCC, and clinical trials of 
immune and targeted agents have predominantly focused on patients with clear cell histology 
due to the higher prevalence of ccRCC compared to nccRCC. Therefore, and due to limited 
data in nccRCC patients, the role of various agents in the treatment of nccRCC is poorly 
defined and there is no standard of care. As such, treatment guidelines from the NCCN, 
SITC, and EAU state that enrollment in clinical trials is a preferred strategy for patients with 
nccRCC [National Comprehensive Cancer Network 2019].
Several studies have compared treatment with sunitinib or everolimus specifically in patients 
with nccRCC. In the ASPEN trial, 108 patients with nccRCC were randomized to treatment 
with sunitinib or everolimus. The estimated ORR for sunitinib and everolimus were 18% and 
9%, respectively, with a median PFS of 8.3 months and 5.6 months, respectively (HR: 1.41; 
80% CI: 1.03 to 1.92; p=0.16) [Armstrong, A. J., et al 2016]. In the ESPN trial, 68 patients 
were randomized to sunitinib or everolimus and an interim analysis showed that first-line 
therapy with sunitinib resulted in an ORR of 9.5% and a median PFS of 6.1 months versus an 
ORR of 2.8% and a median PFS of 4.1 months with everolimus. However, no statistically 
significant difference in OS (16.2 versus 14.9 months) was observed between the 2 arms
[Tannir, N. M., et al 2016]. The RECORD-3 trial included a 66-patient cohort of nccRCC 
comparing sequential first-line everolimus and second-line sunitinib versus first-line 
sunitinib and second-line everolimus. The median first-line PFS was 7.2 months in the 
sunitinib arm and 5.1 months in the everolimus arm, but this difference was not statistically 
significant.
Based on all of these trials, both sunitinib and everolimus are included in NCCN treatment 
recommendations as Category 2A options for treatment-naïve patients with Stage IV 
nccRCC, with sunitinib as the preferred treatment option [National Comprehensive Cancer 
Network 2019].
A Phase 3 trial of temsirolimus demonstrated that participants with poor prognosis risk 
factors may benefit from treatment with temsirolimus compared to IFNα, and therefore the 
NCCN recommends the use of temsirolimus in these patients [National Comprehensive 
Cancer Network 2019]. An exploratory retrospective subgroup analysis of different tumor 
histologies demonstrated a median OS of 11.6 months (95% CI: 8.9 to 14.5, N=37) in the 
temsirolimus arm compared to a median OS of 4.3 months (95% CI: 3.2 to 7.3, N=36) in the 
IFNα arm [Dutcher, J. P., et al 2009].
Cabozantinib and bevacizumab are also included in treatment recommendations, but the 
clinical data supporting these recommendations are very limited [National Comprehensive 
Cancer Network 2019].
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2.1.3
Rationale for the Use of Pembrolizumab and Lenvatinib in Patients with 
nccRCC
KEYNOTE-427 Cohort B contains the largest cohort of participants with nccRCC in a 
clinical trial (n=165) providing proof of concept for clinical activity of pembrolizumab 
monotherapy in the first-line setting. At the 2-year follow-up, pembrolizumab demonstrated 
an ORR of 26.7% with a DCR of 43% and a median PFS and OS of 4.2 and 28.9 months,
respectively. Clinical activity was demonstrated across key patient subgroups, including 
IMDC risk groups, histologic subtype, PD-L1 status, and sarcomatoid differentiation.
A single-arm Phase 2 trial of lenvatinib plus everolimus (n =31) demonstrated an ORR of 
25.8% and a DCR of 71% with a median PFS of 9.2 months and median OS of 15.6 months. 
Given the observed ORR of everolimus as reported above, the improved ORR in this study is 
thought to be primarily due to the lenvatinib component. However, it is noted that in 
chromophobe subtypes, given the high rates of mTOR pathway alterations, the contribution 
of everolimus to the clinical activity might be larger.
An open-label, Phase 1b/2 study (E7080-A001-111) of the combination of lenvatinib plus 
pembrolizumab in participants with select metastatic tumor types, including metastatic 
ccRCC, is ongoing to assess the safety and efficacy of the combination of lenvatinib plus 
pembrolizumab. As of a data cutoff date of 12-JAN-2020, 46 of 91 evaluable participants 
with ccRCC had achieved a confirmed PR for an ORR of 51% with a median DOR of 
9.9 months. The safety of the combination was also assessed, with the most common TRAEs 
(≥30%) being fatigue (49%), diarrhea (44%), proteinuria (37%), hypertension (31%), and 
nausea (31%). No new safety signals were observed beyond what was already known for the 
combination of pembrolizumab and lenvatinib.
Given the observed efficacy of PD-1/PD-L1 targeted therapies and lenvatinib in the 
advanced/metastatic RCC population, along with the high unmet medical need in patients 
specifically with non-clear cell histologies, there is strong rationale to support the exploration 
of the combination of pembrolizumab and lenvatinib in patients with nccRCC.
2.2
Background
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 a number of indications.
Lenvatinib (also known as E7080 or MK-7902) inhibits the kinase activities of 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 FGF receptors 
FGFR1, 2, 3, and 4; platelet derived growth factor receptor alpha (PDGFRα), KIT, and RET. 
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Lenvatinib also exhibited antiproliferative activity in cell lines dependent on activated FGFR 
signaling with a concurrent inhibition of FGF-receptor substrate 2α phosphorylation.
Refer to the respective IB/approved labeling for detailed background information on 
pembrolizumab and lenvatinib.
2.2.1
Pharmaceutical and Therapeutic Background
2.2.1.1
Pembrolizumab
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].
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 
regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2) 
[Greenwald, R. J., et al 2005] [Okazaki, T., et al 2001].
The structure of murine PD-1 has been resolved [Zhang, X., et al 2004]. PD-1 and its family 
members are type I transmembrane glycoproteins containing an 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. Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases, SHP-1 
and SHP-2, to the immunoreceptor tyrosine-based switch motif within its cytoplasmic tail, 
leading to the dephosphorylation of effector molecules such as 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 nccRCC.
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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.
In summary, lenvatinib inhibited VEGF-driven VEGFR2 phosphorylation and suppressed 
proliferation and tube formation in HUVEC models. Antitumor activity of lenvatinib in vivo 
has been shown in numerous xenograft animals. These results suggest that lenvatinib may be 
a novel anticancer therapy through inhibition of angiogenesis and may be useful as either 
monotherapy or in combination with other anticancer drugs.
2.2.1.3
Pembrolizumab Plus Lenvatinib
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 
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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.
2.3
Benefit/Risk Assessment
It cannot be guaranteed that participants in clinical studies will directly benefit from 
treatment during participation, as clinical studies are designed to provide information about 
the safety and effectiveness of an investigational medicine.
Pembrolizumab in combination with axitinib has been approved for the first-line treatment of 
patients with advanced RCC. Additionally, the combination of lenvatinib plus everolimus has 
been approved for the treatment of patients with advanced RCC following one prior 
anti-angiogenic treatment. In this study, the activity in nccRCC is expected to be attributed 
primarily to the lenvatinib given the historical response rates of everolimus in nccRCC 
(Section 2.1.2). And early data from KEYNOTE-427B provided signs of clinical activity of 
pembrolizumab monotherapy in participants with nccRCC.
The safety profile of the combination of pembrolizumab and lenvatinib has been well 
characterized across many indications including RCC. In KEYNOTE-146, the most common 
TRAEs were fatigue, diarrhea, proteinuria, hypertension, and nausea. The safety profile of 
the combination treatment was generally consistent with the known safety profiles of 
pembrolizumab and lenvatinib. Taken together, the existing data suggest that exploring the 
combination of pembrolizumab + lenvatinib in participants with first-line nccRCC is a 
promising therapeutic strategy, and the benefit/risk assessment for participants in this study is 
considered to be favorable. 
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.
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3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
In male or female participants at least 18 years of age with previously untreated 
histologically confirmed advanced/metastatic nccRCC:
Objectives
Endpoints
Primary
•
To evaluate the ORR of pembrolizumab 
+ lenvatinib per RECIST 1.1 by blinded 
independent central review (BICR)
•
Objective response (OR): a confirmed 
complete response (CR) or partial 
response (PR)
Secondary
•
To evaluate the DOR of pembrolizumab 
+ lenvatinib in participants with a 
confirmed CR or PR per RECIST 1.1 by 
BICR
•
DOR: the time from first documented 
evidence of CR or PR until disease 
progression or death due to any cause, 
whichever occurs first
•
To evaluate PFS per RECIST 1.1 by 
BICR in participants receiving 
pembrolizumab + lenvatinib
•
PFS: the time from first dose to the first 
documented PD or death from any 
cause, whichever occurs first
•
To evaluate the overall survival (OS) of 
participants receiving pembrolizumab + 
lenvatinib
•
OS: the time from first dose until death 
from any cause
•
To evaluate the CBR of pembrolizumab 
+ lenvatinib per RECIST 1.1 by BICR
•
Clinical benefit: a confirmed CR, PR, or 
stable disease (SD) for at least 6 months
•
To evaluate the DCR of pembrolizumab 
+ lenvatinib per RECIST 1.1 by BICR
•
Disease control: a confirmed CR, PR or 
SD
•
To evaluate the safety of pembrolizumab 
+ lenvatinib
•
Adverse events (AEs)
•
Discontinuations due to AEs
Tertiary/Exploratory
•
To identify molecular (genomic, 
metabolic, and/or proteomic) biomarkers 
that may be indicative of clinical 
response/resistance, safety, 
pharmacodynamic activity, and/or the 
mechanism of action of pembrolizumab 
+ lenvatinib
•
Molecular (genomic, metabolic and/or 
proteomic) determinants of response or 
resistance to treatments, using blood 
and/or tumor tissue
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4
STUDY DESIGN
4.1
Overall Design
This is a Phase 2, nonrandomized, single-arm, multisite, open-label study of pembrolizumab 
+ lenvatinib in participants with previously untreated advanced/metastatic nccRCC including 
all IMDC risk groups. Participants must have histologically confirmed diagnosis of nccRCC 
pathology to participate. Collecting duct histology is excluded.
Approximately 152 participants will be enrolled and allocated to receive treatment with 
pembrolizumab 400 mg Q6W and lenvatinib 20 mg QD. Pembrolizumab treatment will 
continue for up to ~2 years or until a discontinuation criterion (Section 7.1) is met, and 
lenvatinib treatment may continue beyond 2 years until a discontinuation criterion 
(Section 7.1) is met.
During initial treatment, participants who have been receiving study intervention for 
≥24 weeks (at least 4 cycles) and who attain a CR may consider stopping pembrolizumab 
treatment. If a confirmed CR per RECIST 1.1 is attained after at least 24 weeks, participants 
must receive pembrolizumab for at least 1 additional cycle after CR is first documented.
Treatment may continue after radiographic progression of RCC per RECIST 1.1 as long as 
the investigator believes that the participant is still receiving clinical benefit from study 
intervention and that the potential benefit of continuing study intervention outweighs 
potential risks. Treatment beyond disease progression requires Sponsor consultation. 
Continued participation requires additional consent (Section 8.1.1). Participants who 
continue treatment beyond disease progression will continue with all protocol-required 
assessments and procedures, and will resume the existing imaging schedule.
Participants who stop pembrolizumab treatment after receiving 18 administrations (2 years)
of pembrolizumab with SD or better, or participants who have been receiving 
pembrolizumab for at least 24 weeks, attain a confirmed CR, and stop pembrolizumab may 
be eligible for up to 9 additional cycles (approximately 1 year) of pembrolizumab upon 
experiencing investigator-assessed PD. This retreatment is termed the Second Course 
Treatment Phase and is only available if the study remains open and the participant meets the 
criteria in Section 6.6.5. Participants may also continue lenvatinib treatment during the 
Second Course Treatment Phase. If lenvatinib is continued, participants will be treated at the 
same dose level and frequency of lenvatinib they were receiving when PD occurred.
Imaging assessments will include chest CT and abdomen and pelvis CT/MRI throughout the 
study. Bone scans will be performed at screening and will only be repeated throughout the 
study if a participant has a positive result at screening. Brain imaging at screening is only 
required for participants with previously documented brain metastases. On-study brain 
imaging will only be performed as clinically indicated or to confirm CR in a participant with 
brain lesions at baseline. All imaging obtained will be submitted to the iCRO for BICR, 
which will assess the images per RECIST 1.1, adjusted to allow for a maximum of 10 total 
target lesions and a maximum of 5 target lesions per organ. However, all decisions to 
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discontinue study intervention(s) due to disease progression are based solely on the site 
radiology’s assessment.
Adverse event monitoring will be ongoing throughout the study. AEs will be graded in 
severity according to the guidelines outlined in the NCI CTCAE Version 5.0.
During both Initial Treatment Phase and the Second Course Treatment Phase, if 
pembrolizumab is discontinued because of toxicity, lenvatinib alone may be continued based 
on physician discretion regarding the benefits of continuing VEGFR-based oral 
monotherapy. If lenvatinib is discontinued due to toxicity, pembrolizumab alone may be 
continued.
Specific procedures to be performed during the study, as well as their prescribed times and 
associated visit windows, are outlined in the SoA in Section 1.3. Details of each procedure 
are provided in Section 8.
4.2
Scientific Rationale for Study Design
This study is being performed as a single-arm open-label study in order to rapidly provide 
information on the potential benefits of the combination of pembrolizumab and lenvatinib in 
participants with nccRCC, a population with high unmet medical need where new treatments 
are sorely needed. The data from this study will provide additional information on the 
potential efficacy and safety of the combination treatment in participants specifically with 
non-clear cell histologies. A single-arm design was chosen as there is no globally accepted 
standard-of-care regimen for participants with previously untreated nccRCC.
4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
This study will use ORR based on RECIST 1.1 criteria as assessed by BICR as the primary 
endpoint. ORR is an acceptable measure of clinical benefit for a late stage study, 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 ORR is typically considered acceptable by regulatory 
authorities. Images will be submitted to an iCRO and read by an independent central review 
to minimize bias in the response assessments. 
Secondary efficacy endpoints for this study include CBR, DCR, DOR, PFS, and OS.
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. Refer to Section 8.2.1.5 for additional 
detail.
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4.2.1.2
Safety Endpoints
Safety parameters commonly used for evaluating investigational systemic anticancer 
treatments are included as safety endpoints including, but not limited to, the incidence of, 
causality, and outcome of AEs/SAEs; and changes in vital signs and laboratory values. AEs 
will be assessed as defined by CTCAE, Version 5.0.
4.2.1.3
Planned Exploratory Biomarker Research
Cancer immunotherapies represent an important and novel class of antitumor agents. 
However, the mechanism of action of these exciting new therapies is not completely 
understood and much remains to be learned regarding how best to leverage these new drugs 
in treating patients. Thus, to aid future patients, it is important to investigate the determinants 
of response or resistance to cancer immunotherapy and other treatments administered, as well 
as determinants of AEs in the course of our clinical studies. These efforts may identify novel 
predictive/PD biomarkers and generate information that may better guide single-agent and 
combination therapy with immuno-oncology drugs. To identify novel biomarkers, 
biospecimens (ie, blood components, tumor material) will be collected to support analyses of 
cellular components (eg, protein, DNA, RNA, metabolites) and other circulating molecules. 
Investigations may include but are not limited to:
Germline (blood) genetic analyses (eg, SNP analyses, whole exome sequencing, whole 
genome sequencing)
This research may evaluate whether genetic variation within a clinical study population 
correlates with response to the treatment(s) under evaluation. If genetic variation is found to 
predict efficacy or AEs, the data might inform optimal use of therapies in the patient 
population. Furthermore, it is important to evaluate germline DNA variation across the 
genome in order to interpret tumor-specific DNA mutations. Finally, MSI may be evaluated 
as this is an important biomarker for some cancers (ie, colorectal cancer).
Genetic (DNA) analyses from tumor
The application of new technologies, such as next generation sequencing, has provided 
scientists the opportunity to identify tumor-specific DNA changes (ie, mutations, methylation 
status, microsatellite instability). Key molecular changes of interest to immuno-oncology 
drug development include the mutational burden of tumors and the clonality of T-cells in the 
tumor microenvironment. Increased mutational burden (sometimes referred to as a ‘hyper-
mutated’ state) may generate neo-antigen presentation in the tumor microenvironment. To 
conduct this type of research, it is important to identify tumor-specific mutations that occur 
across all genes in the tumor genome. Thus, genome-wide approaches may be used for this 
effort. Note that in order to understand tumor-specific mutations, it is necessary to compare 
the tumor genome with the germline genome. Microsatellite instability may also be evaluated 
as this is an important biomarker for some cancers (ie, colorectal cancer). Circulating tumor 
DNA and/or RNA may also be evaluated from blood samples.
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Tumor and blood RNA analyses
Both genome-wide and targeted mRNA expression profiling and sequencing in tumor tissue 
and in blood may be performed to define gene signatures that correlate to clinical response to 
treatment with pembrolizumab or other immunotherapies. Pembrolizumab induces a response 
in tumors that likely reflects an inflamed/immune phenotype. Specific immune-related gene 
sets (ie, those capturing interferon-gamma transcriptional pathways) may be evaluated and 
new signatures may be identified. Individual genes related to the immune system may also be 
evaluated (eg, IL-10). MicroRNA profiling may also be pursued as well as exosomal 
profiling.
Proteomics and IHC using blood or tumor
Tumor and blood samples from this study may undergo proteomic analyses (eg, PD-L1 IHC). 
PD-L1 protein level in tumor sections, assessed by IHC, has been shown to correlate with 
response to pembrolizumab in patients with NSCLC, and an IVD device has been developed 
for use with pembrolizumab in NSCLC. Preliminary data indicates that this association may 
also be true in additional cancer types (ie, triple negative breast cancer, head and neck, and 
gastric). Additional tumor or blood-derived proteins may also correlate with response to 
pembrolizumab. Therefore, tumor tissue may be subjected to proteomic analyses using a 
variety of platforms that could include but are not limited to immunoassays and liquid 
chromatography/mass spectrometry. This approach could identify novel protein biomarkers 
that could aid in patient selection for pembrolizumab (MK-3475) therapy.
Other blood-derived biomarkers
In addition to expression on the tumor tissue, PD-L1 and other tumor derived proteins can be 
shed from tumor and released into the blood. Assays such as ELISA measure such proteins in 
serum. Correlation of expression with response to pembrolizumab therapy may identify new 
approaches for predictive biomarkers in blood, representing a major advance from today’s 
reliance on assessing tumor biomarkers. This research would serve to develop such assays for 
future clinical use.
Other molecular changes of interest include the subtype of T-cells in the tumor 
microenvironment. The T-cell repertoire from tumor tissue and blood components may be 
evaluated.
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4.3
Justification for Dose
4.3.1
Pembrolizumab
The planned dose of pembrolizumab is 400 mg Q6W. Based on the totality of data generated 
in the KEYTRUDA development program, 400 mg Q6W is an appropriate dose of 
pembrolizumab for adults across all indications and regardless of tumor type based on 
modeling and simulation analyses, given the following rationale:
•
PK simulations demonstrating that in terms of pembrolizumab exposures:
-
Average concentration over the dosing interval (Cavg) (or AUC) at 400 mg Q6W is 
similar to that at the approved 200 mg Q3W dose, thus bridging efficacy between 
dosing regimens.
-
Trough concentrations (Cmin) at 400 mg Q6W are generally within the range of those 
achieved with 2 mg/kg or 200 mg Q3W in the majority (>99%) of patients.
-
Peak concentrations (Cmax) at 400 mg Q6W are well below the Cmax for the highest 
clinically tested dose of 10 mg/kg Q2W, supporting that the safety profile for 400 mg 
Q6W should be comparable to the established safety profile of pembrolizumab.
•
Exposure-response analysis for pembrolizumab has been demonstrated to be flat across 
indications, and OS predictions demonstrate that efficacy at 400 mg Q6W is expected to 
be similar to that at 200 mg or 2 mg/kg Q3W, given the similar exposures; thus 400 mg 
Q6W is expected to be efficacious across indications.
•
Clinical safety profiles were similar between 2 mg/kg Q3W, 10 mg/kg Q3W, and 
10 mg/kg Q2W in multiple tumor types based on randomized dose comparisons; hence, 
the safety profile at 400 mg Q6W is also expected to be similar. 
Overall, a 400 mg Q6W dosing regimen for KEYTRUDA monotherapy is predicted to have 
a similar efficacy and safety profile compared to the currently approved 200 mg Q3W dosing 
regimen.
4.3.2
Lenvatinib
The dosing regimen of lenvatinib was selected based on the results of the Phase 1b portion of 
Phase 1b/2 Study 111/KEYNOTE-146, 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 carcinoma, and 1 
had melanoma. There were 2 DLTs at the dose of lenvatinib 24 mg/day + pembrolizumab 
200 mg IV Q3W (1 participant had Grade 3 arthralgia, and another had Grade 3 fatigue); 
hence, this was defined as the toxic dose. No DLTs were reported in the next 10 participants 
(expansion part), all of whom received the lenvatinib 20 mg/day + pembrolizumab 200 mg 
Q3W dose.
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Based on review of all of the clinical data from these 13 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. Based on the promising antitumor efficacy and tolerable safety 
profile seen in both the endometrial carcinoma and RCC expansion cohorts from 
Study 111/KEYNOTE-146 [Makker, V., et al 2018], 2 Phase 3 studies have been initiated for 
both of these tumor types, Study E7080-G000-309/KEYNOTE-775 and Study E7080-G000-
307/ KEYNOTE-581.
4.4
Beginning and End of Study Definition
The overall study begins when the first participant (or their legally acceptable representative) 
provides documented informed consent. The overall study ends when the last participant 
completes the last study-related contact, withdraws consent, or is lost to follow-up
(Section 7.3), or the last participant on active treatment is consented in the extension study.
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 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/clinical endpoints is such that the risk/benefit ratio to the study population 
as a whole is unacceptable. In addition, further recruitment in the study or at (a) particular 
study site(s) may be stopped due to insufficient compliance with the protocol, GCP, and/or 
other applicable regulatory requirements, procedure-related problems or the number of 
discontinuations for administrative reasons is too high.
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5
STUDY POPULATION
Male and female participants at least 18 years of age with previously untreated and 
histologically confirmed diagnosis of nccRCC will be enrolled in this study.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
A participant will be eligible for inclusion in the study if the participant:
Type of Participant and Disease Characteristics
1. Must have a histologically confirmed diagnosis of nccRCC.
2. Has locally advanced/metastatic disease (ie, Stage IV per the American Joint Committee 
on Cancer).
3. Has received no prior systemic therapy for advanced nccRCC.
Note: Prior neoadjuvant/adjuvant therapy for nccRCC is acceptable if completed 
>12 months prior to allocation.
Demographics
4. Is male or female, from 18 years to 120 years of age inclusive, at the time of providing
informed consent.
Male Participants
5. Male participants are eligible to participate if they agree to the following during the 
intervention period and for at least 7 days after the last dose of study intervention:
•
Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent 
on a long term and persistent basis) and agree to remain abstinent
OR
•
Must agree to use contraception unless confirmed to be azoospermic (vasectomized or 
secondary to medical cause [Appendix 5]) as detailed below:
-
Agree to use a male condom plus partner use of an additional contraceptive method 
when having penile-vaginal intercourse with a WOCBP who is not currently 
pregnant. Note: Men with a pregnant or breastfeeding partner must agree to remain 
abstinent from penile-vaginal intercourse or use a male condom during each episode 
of penile-vaginal penetration.
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•
Contraceptive use by men should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.
•
Please note that 7 days after lenvatinib is stopped, if the male participant is on 
pembrolizumab only, no male contraception measures are needed.
Female Participants
6. A female participant is eligible to participate if she is not pregnant or breastfeeding, and 
at least one of the following conditions applies: 
•
Is not a WOCBP
OR
•
Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate 
of <1% per year), with low user dependency, or be abstinent from heterosexual 
intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent 
basis), as described in Appendix 5 during the intervention period and for at least 120 days 
post pembrolizumab or 30 days post lenvatinib, whichever occurs last. The investigator 
should evaluate the potential for contraceptive method failure (ie, noncompliance, 
recently initiated) in relationship to the first dose of study intervention.
•
A WOCBP must have a negative highly sensitive pregnancy test ([urine or serum] as 
required by local regulations) within 24 hours before the first dose of study intervention.
•
If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum 
pregnancy test is required. In such cases, the participant must be excluded from 
participation if the serum pregnancy result is positive.
•
Additional requirements for pregnancy testing during and after study intervention are 
located in Appendix 2.
•
The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy.
•
Contraceptive use by women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.
Informed Consent
7. The participant (or legally acceptable representative) has provided documented informed 
consent/assent for the study.
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Additional Categories
8. Has measurable disease per RECIST 1.1 as assessed by BICR. Lesions situated in a 
previously irradiated area are considered measurable if progression has been 
demonstrated in such lesions.
9. Has submitted an archival tumor tissue sample or newly obtained core or incisional
biopsy of a tumor lesion not previously irradiated. FFPE tissue blocks are preferred to 
slides. Newly obtained biopsies are preferred to archived tissue. Details pertaining to 
tumor tissue submission can be found in the Procedures Manual.
10. Has KPS ≥70% as assessed within 10 days prior to the start of study intervention.
11. Has 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 allocation.
12. Have adequate organ function as defined in the following table (Table 4). Specimens 
must be collected within 10 days prior to the start of study intervention.
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Table 4
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 ANDb/OR
Measured or calculatedc creatinine clearance
(GFR can also be used in place of creatinine or 
CrCl)
≤1.5 × ULN ANDb /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
AST (SGOT) and ALT (SGPT)
≤2.5 × ULN (≤5 × ULN for participants with liver 
metastases)
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); CrCl=creatinine clearance; GFR=glomerular filtration rate; 
ULN=upper limit of normal.
a Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within 
last 2 weeks.
b Applicable only when local guidelines require both assessments.
c CrCl should be calculated per institutional standard.
Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value requirements 
should be adapted according to local regulations and guidelines for the administration of specific chemotherapies.
5.2
Exclusion Criteria
The participant must be excluded from the study if the participant:
Medical Conditions
1. Has collecting duct histology.
2. A WOCBP who has a positive urine pregnancy test within 24 hours before the first dose 
of study intervention (see Appendix 2 and Appendix 5). If the urine test cannot be 
confirmed as negative, a serum pregnancy test is required. In such cases, the participant 
must be excluded from participation if the serum pregnancy result is positive.
3. Has pre-existing ≥Grade 3 gastrointestinal or non-gastrointestinal fistula.
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4. Has urine protein ≥1 g/24 hours.
Note: Participants with proteinuria ≥2+ (≥100 mg/dL) on urine dipstick testing
(urinalysis) will undergo 24-hour urine collection for quantitative assessment of 
proteinuria.
5. Has a left ventricular ejection fraction below the institutional (or local laboratory) normal 
range, as determined by multigated acquisition or echocardiogram.
6. Has radiographic 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.
7. Has prolongation of QTcF interval to >480 msec.
8. 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.
9. Has gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition 
that might affect the absorption of lenvatinib.
10. Has active hemoptysis (bright red blood of at least 0.5 teaspoon) within 3 weeks prior to 
the first dose of study drug.
Prior/Concomitant Therapy
11. Has had 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.
12. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an 
agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, 
OX-40, CD137).
13. Has received prior systemic anticancer therapy including investigational agents within 
4 weeks prior to allocation.
Note: Participants must have recovered from all AEs due to previous therapies to 
≤Grade 1 or baseline. Participants with ≤Grade 2 neuropathy may be eligible.
14. Has received prior radiotherapy within 2 weeks of start of study intervention. Participants 
must have recovered from all radiation-related toxicities, not require corticosteroids, and 
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not have had radiation pneumonitis. A 1-week washout is permitted for palliative 
radiation (≤2 weeks of radiotherapy) to non-CNS disease.
15. Has received a live or attenuated vaccine within 30 days before the first dose of study 
intervention. Note: Killed vaccines are allowed. Refer to Section 6.5 for information on 
COVID-19 vaccines.
Prior/Concurrent Clinical Study Experience
16. Is currently participating in or has participated in a study of an investigational agent or 
has used an investigational device within 4 weeks prior to the first dose of study 
intervention.
Note: Participants who have entered the follow-up phase of an investigational study may 
participate as long as it has been 4 weeks after the last dose of the previous 
investigational agent.
Diagnostic Assessments
17. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in 
dosing exceeding 10 mg daily of prednisone equivalent) or any other form of 
immunosuppressive therapy within 7 days prior the first dose of study intervention.
18. Has a known additional malignancy that is progressing or has required active treatment 
within the past 3 years.
Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the 
skin, or carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) that have 
undergone potentially curative therapy are not excluded.
19. Has known active CNS metastases and/or carcinomatous meningitis. Participants with 
previously treated brain metastases may participate provided they are radiologically 
stable, (ie, without evidence of progression) for at least 4 weeks by repeat imaging (note 
that the repeat imaging should be performed during study screening), clinically stable and 
without requirement of steroid treatment for at least 14 days prior to first dose of study 
intervention.
20. Has severe hypersensitivity (≥Grade 3) to pembrolizumab, lenvatinib and/or any of their 
excipients.
21. Has an active autoimmune disease that has required systemic treatment in past 2 years 
(ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs). 
Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency) is not considered a form of systemic 
treatment and is allowed.
22. Has a history of (noninfectious) pneumonitis/interstitial lung disease that required 
steroids or has current pneumonitis/interstitial lung disease.
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23. Has an active infection, requiring systemic therapy.
24. Has a known history of HIV infection. No HIV testing is required unless mandated by 
local health authority.
Refer to Appendix 7 for country-specific requirements.
25. Has a known history of Hepatitis B (defined as HBsAg reactive) or known active 
Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection.
Note: No testing for Hepatitis B and Hepatitis C is required unless mandated by local 
health authority.
Refer to Appendix 7 for country-specific requirements.
26. Has a known history of active tuberculosis (TB; Bacillus tuberculosis).
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. Has a known psychiatric or substance abuse disorder that would interfere with the 
participant’s ability to cooperate with the requirements of the study.
Other Exclusions
29. Has had an allogenic tissue/solid organ transplant.
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
Contraception
Lenvatinib and pembrolizumab may have adverse effects on a fetus in utero. Refer to 
Appendix 5 for approved methods of contraception.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study, but 
are not subsequently entered in the study. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the CONSORT 
publishing requirements and to respond to queries from regulatory authorities. Minimal 
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information includes demography, screen failure details, eligibility criteria, and any AEs or 
SAEs meeting reporting requirements as outlined in the data entry guidelines.
Participants who fail screening may be rescreened for eligibility following consultation 
between the investigator and the Sponsor and written documentation of the collaborative 
decision on participant management.
5.5
Participant Replacement Strategy
A participant who discontinues from study intervention or withdraws from the study will not 
be replaced.
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6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
Clinical supplies (study interventions provided by the Sponsor) will be packaged to support 
enrollment. Clinical supplies will be affixed with a clinical label in accordance with 
regulatory requirements.
6.1
Study Intervention(s) Administered
The study interventions to be used in this study are outlined in Table 5.
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Table 5
Study Interventions
Arm Name
Arm 
Type
Intervention 
Name
Intervention 
Type
Dose 
Formu-
lation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Adminis-
tration
Regimen/
Treatment 
Period/
Vaccination 
Regimen
Use
IMP/
NIMP/
AxMP
Sourcing
Pembrolizumab 
+ Lenvatinib
Experi-
mental
Pembrolizumab
Biological/
Vaccine
Solution 
for 
Infusion
25 mg/mL
400 mg
IV 
Infusion
Q6W
Test 
product
IMP
Provided 
centrally 
by the 
Sponsor
Pembrolizumab 
+ Lenvatinib
Experi-
mental
Lenvatinib
Drug
Capsule
10 mg
20 mg
Oral
QD
Test 
product
IMP
Provided 
centrally 
by the 
Sponsor
Pembrolizumab 
+ Lenvatinib
Experi-
mental
Lenvatinib
Drug
Capsule
4 mg
14 mg 
to 8 mg
Oral
QD
Test 
product
IMP
Provided 
centrally 
by the 
Sponsor
AxMP=auxiliary medicinal product; EEA=European Economic Area; IMP=investigational medicinal product; IV=intravenous; NIMP=non-investigational medicinal product; 
Q6W=every 6 weeks; QD=every day.
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/NIMP/AxMP may exist. In these circumstances, local legislation is followed.
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All study interventions will be administered on an outpatient basis.
All products indicated in Table 5 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.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
Details on preparation and administration of pembrolizumab and lenvatinib are provided in 
the Pharmacy Manual.
There are no specific calculations or evaluations required to be performed in order to 
administer the proper dose to each participant. The rationale for selection of doses to be used 
in this study is provided in Section 4.3.
6.2.2
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
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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 allocation will occur centrally using an IRT system. There is 1 study 
intervention arm that participants will be allocated into.
6.3.2
Stratification
This is a single-arm study. No stratification based on age, sex, or other characteristics will be 
used in this study.
6.3.3
Blinding
This is an open-label study; therefore, the Sponsor, investigator, and participant will know 
the interventions administered.
6.4
Study Intervention Compliance
Interruptions from the protocol-specified treatment plan for more than 12 weeks between 
pembrolizumab doses for nondrug-related or administrative reasons require consultation 
between the investigator and the Sponsor and written documentation of the collaborative 
decision on participant management.
Interruptions from the protocol-specified treatment plan for >28 days for lenvatinib 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 time periods specified by this protocol for that medication or vaccination. If there is a 
clinical indication for any medication or vaccination specifically prohibited, discontinuation 
from study therapy or vaccination may be required. The investigator should discuss any 
questions regarding this with the Sponsor's Clinical Director. The final decision on any 
supportive therapy or vaccination rests with the investigator and/or the participant's primary 
physician. However, the decision to continue the participant on study intervention requires 
the mutual agreement of the investigator, the Sponsor, and the participant.
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Participants are prohibited from receiving the following therapies during the screening and 
treatment periods of the study: 
•
Antineoplastic systemic chemotherapy or biological therapy
•
Immunotherapy not specified in this protocol
•
Chemotherapy not specified in this protocol
•
Investigational agents other than pembrolizumab and lenvatinib
•
Radiation therapy
Note: Radiation therapy to a symptomatic solitary lesion or to the brain may be allowed 
at the investigator’s discretion.
•
Live vaccines within 30 days prior to the first dose of study intervention and while 
participating in the study. Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and 
typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live 
attenuated vaccines and are not allowed.
Note: Any licensed COVID-19 vaccine (including for Emergency Use) in a particular 
country is allowed in the study as long as they are mRNA vaccines, adenoviral vaccines, 
or inactivated vaccines. These vaccines will be treated just as any other concomitant 
therapy.
Investigational vaccines (ie, those not licensed or approved for Emergency Use) are not 
allowed.
Refer to Appendix 7 for country-specific requirements.
•
Systemic glucocorticoids for any purpose other than to modulate symptoms from an AE
that is suspected to have an immunologic etiology. The use of physiologic doses of 
corticosteroids may be approved after consultation with the Sponsor.
Participants who, in the assessment of the Investigator, require the use of any of the 
aforementioned treatments for clinical management should be discontinued from study 
intervention.
All treatments that the investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care. All concomitant medication will be recorded on the eCRF including all 
prescription, OTC products, herbal supplements, and IV medications and fluids. If changes 
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occur during the study period, documentation of drug dosage, frequency, route, and date 
should also be included on the eCRF.
All concomitant medications received within 28 days prior to the first dose of study 
intervention and up to 30 days after the last dose of study intervention should be recorded. 
Concomitant medications administered >30 days after the last dose of study intervention 
should be recorded for SAEs and ECIs as defined in Section 8.4.7.
6.5.1
Rescue Medications and Supportive Care
Participants should receive appropriate supportive care measures as deemed necessary by the 
treating investigator. Suggested supportive care measures for the management of AEs with 
potential immunologic etiology are outlined along with the dose modification guidelines in
Section 6.6. Where appropriate, these guidelines include the use of oral or IV treatment with 
corticosteroids, as well as additional anti-inflammatory agents if symptoms do not improve 
with administration of corticosteroids. Note that several courses of steroid tapering may be 
necessary as symptoms may worsen when the steroid dose is decreased. For each disorder, 
attempts should be made to rule out other causes such as metastatic disease or bacterial or 
viral infection, which might require additional supportive care. The treatment guidelines are 
intended to be applied when the investigator determines the events to be related to 
pembrolizumab.
Note: If after the evaluation of the event, it is determined not to be related to pembrolizumab, 
the investigator does not need to follow the treatment guidance. Refer to Table 6 in 
Section 6.6.1 for guidelines regarding dose modification and supportive care.
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event.
6.5.2
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 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 their 
divergent metabolic pathways. Pembrolizumab is a monoclonal antibody and is primarily 
catabolized like other proteins, while lenvatinib is metabolized by enzymatic (CYP3A and 
aldehyde oxidase) and non-enzymatic processes (lenvatinib IB).
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6.6
Dose Modification (Escalation/Titration/Other)
Adverse events will be graded using NCI CTCAE Version v5.0. 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 or discontinue one drug in the pembrolizumab + lenvatinib
combination due to toxicity can continue with the other drug in the combination until criteria 
for treatment discontinuation are met (eg, unacceptable toxicity, disease progression).
Refer to Section 6.6.3 for dose modification guidance for overlapping toxicity for the 
pembrolizumab + lenvatinib combination.
6.6.1
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. Dose Modification and Toxicity Management Guidelines 
for irAEs associated with pembrolizumab monotherapy, coformulations, or IO combinations 
are provided in Table 6.
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Table 6
Dose Modification and Toxicity Management Guidelines for Immune-related Adverse Events Associated with 
Pembrolizumab Monotherapy, Coformulations or IO Combinations
General instructions:

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.

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. 

The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks.

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 v5.0)
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, 
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 clear 
fluids. If sufficient oral fluid intake is not 
feasible, fluid and electrolytes should be 
substituted via IV infusion
Recurrent Grade 3 
or Grade 4
Permanently 
discontinue
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irAEs
Toxicity Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
AST or ALT 
Elevation or 
Increased 
Bilirubin
Grade 2 a
Withhold

Administer corticosteroids 
(initial dose of 0.5 to 
1 mg/kg prednisone or 
equivalent) followed by 
taper

Monitor with liver function tests (consider 
weekly or more frequently until liver enzyme 
value returned to baseline or is stable)
Grade 3 b or 4 c
Permanently 
discontinue

Administer corticosteroids 
(initial dose of 1 to 2 mg/kg 
prednisone or equivalent) 
followed by taper
T1DM or 
Hyperglycemia
New onset T1DM 
or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -cell 
failure
Withhold d

Initiate insulin replacement 
therapy for participants with 
T1DM

Administer 
antihyperglycemic in 
participants with 
hyperglycemia

Monitor participants for hyperglycemia or 
other signs and symptoms of diabetes
Hypophysitis
Grade 2
Withhold

Administer corticosteroids 
and initiate hormonal 
replacements as clinically 
indicated

Monitor for signs and symptoms of 
hypophysitis (including hypopituitarism and 
adrenal insufficiency)
Grade 3 or 4
Withhold or 
permanently 
discontinue d
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 
discontinue d
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irAEs
Toxicity Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Hypothyroidism
Grade 2, 3 or 4
Continue

Initiate thyroid replacement 
hormones (eg, 
levothyroxine or 
liothyronine) per standard of 
care

Monitor for signs and symptoms of thyroid 
disorders
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
Myocarditis
Grade 1
Withhold

Based on severity of AE 
administer corticosteroids

Ensure adequate evaluation to confirm 
etiology and/or exclude other causes
Grade 2, 3 or 4
Permanently 
discontinue
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
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irAEs
Toxicity Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
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 event e
Recurrent Grade 3 
or Grade 4 
Permanently 
discontinue
AE(s)=adverse event(s); ALT=alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for Adverse Events; DRESS=Drug Rash 
with Eosinophilia and Systemic Symptom; GI=gastrointestinal; IO=immuno-oncology; ir=immune-related; IV=intravenous; SJS=Stevens-Johnson Syndrome; T1DM=type 1 
diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal.
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations.
a
AST/ALT: >3.0 to5.0 × ULN if baseline normal; >3.0 to 5.0 × baseline, if baseline abnormal; 
bilirubin:>1.5 to 3.0 × ULN if baseline normal; >1.5 to 3.0 × baseline if baseline abnormal
b
AST/ALT: >5.0 to 20.0 × ULN, if baseline normal; >5.0 to 20.0 × baseline, if baseline abnormal; bilirubin:>3.0 to 10.0 × ULN if baseline normal; >3.0 to 10.0 × baseline 
if baseline abnormal
c
AST/ALT: >20.0 × ULN, if baseline normal; >20.0 × baseline, if baseline abnormal; 
bilirubin: >10.0 × ULN if baseline normal; >10.0 × baseline if baseline abnormal
d
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.
e
Events that require discontinuation include, but are not limited to: encephalitis and other clinically important irAEs (eg, vasculitis and sclerosing cholangitis).
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Dose Modification and Toxicity Management of Infusion Reactions Related to 
Pembrolizumab
Pembrolizumab may cause severe or life-threatening infusion reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion. 
Dose modification and toxicity management guidelines on pembrolizumab associated 
infusion reaction are provided in Table 7.
Table 7
Pembrolizumab Infusion Reaction Dose Modification and Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at Subsequent Dosing
Grade 1
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated
Increase monitoring of vital signs 
as medically indicated until the 
participant is deemed medically 
stable in the opinion of the 
investigator
None
Grade 2
Requires therapy or infusion 
interruption but responds 
promptly to symptomatic 
treatment (eg, 
antihistamines, NSAIDs, 
narcotics, IV fluids); 
prophylactic medications 
indicated for ≤24 hrs
Stop Infusion
Additional appropriate medical 
therapy may include but is not 
limited to:
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Increase monitoring of vital signs 
as medically indicated until the 
participant is deemed medically 
stable in the opinion of the 
investigator.
If symptoms resolve within 1 hour 
of stopping drug infusion, the 
infusion may be restarted at 50% of 
the original infusion rate (eg, from 
100 mL/hr to 50 mL/hr). Otherwise 
dosing will be held until symptoms 
resolve and the participant should 
be premedicated for the next 
scheduled dose.
Participants who develop Grade 2 
toxicity despite adequate 
premedication should be 
permanently discontinued from 
further study drug intervention.
Participant may be premedicated 1.5 h 
(±30 minutes) prior to infusion of
study intervention with:
Diphenhydramine 50 mg PO (or 
equivalent dose of antihistamine).
Acetaminophen 500-1000 mg PO (or 
equivalent dose of analgesic).
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NCI CTCAE Grade
Treatment
Premedication at Subsequent Dosing
Grades 3 or 4
Grade 3:
Prolonged (ie, not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial 
improvement; 
hospitalization indicated for 
other clinical sequelae (eg, 
renal impairment, 
pulmonary infiltrates)
Grade 4:
Life-threatening; pressor or 
ventilatory support indicated
Stop Infusion.
Additional appropriate medical 
therapy may include but is not 
limited to:
Epinephrine**
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Increase monitoring of vital signs 
as medically indicated until the 
participant is deemed medically 
stable in the opinion of the 
investigator.
Hospitalization may be indicated.
**In cases of anaphylaxis, 
epinephrine should be used 
immediately.
Participant is permanently 
discontinued from further study 
drug intervention.
No subsequent dosing
IV=intravenous; NCI CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events; 
NSAID=nonsteroidal anti-inflammatory drug; PO=orally.
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 NCI CTCAE version 5.0 at http://ctep.cancer.gov.
Other Allowed Dose Interruption for Pembrolizumab
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as 
medical or surgical events and/or unforeseen circumstances not related to study intervention. 
However, study intervention is to be restarted therapy within 6 weeks (42 days) of the 
originally scheduled dose interruption and within 12 weeks (84 days) of the previously 
administered dose, unless otherwise discussed with the Sponsor. The reason for study 
intervention interruption is to be documented in the participant's study record.
6.6.2
Dose Modification With Lenvatinib
Lenvatinib dose reduction and interruption for participants who experience pembrolizumab +
lenvatinib combination therapy-related toxicity will be in accordance with the dose 
modification guidelines described in Table 8. An interruption of lenvatinib for more than 
28 days will require Sponsor approval before treatment can be resumed.
The starting dose of lenvatinib is 20 mg/day. Dose reductions of lenvatinib occur in 
succession based on the previous dose level (14, 10, 8 mg/day). Any dose reduction below 
8 mg/day must be discussed with the Sponsor. Once the lenvatinib dose has been reduced, it 
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may not be increased at a later date, unless the dose has been mistakenly decreased; in this 
situation, the Sponsor’s approval is required to increase the dose.
Refer to the subsections below for management of hypertension (Section 6.6.2.1), proteinuria 
(Section 6.6.2.2), diarrhea (Section 6.6.2.3), hepatotoxicity (Section 6.6.2.4), 
thromboembolic events (Section 6.6.2.5), posterior reversible encephalopathy syndrome/ 
reversible posterior leukoencephalopathy syndrome (PRES/RPLS; Section 6.6.2.6), 
hypocalcemia (Section 6.6.2.7), hemorrhage (Section 6.6.2.8), gastrointestinal perforation or 
fistula formation (Section 6.6.2.9), QT prolongation (Section 6.6.2.10), and ONJ (Section 
6.6.2.11) as appropriate, before consulting the dose modification table (Table 8). For 
overlapping toxicities of pembrolizumab and lenvatinib, please refer to Section 6.6.3.
Table 8
Dose Modification Guidelines for Lenvatinib-Related Adverse Events 
Treatment-Related 
Toxicitya,b
Management
Dose Adjustment
Grade 1 or Tolerable Grade 2
Continue treatment
No change
Intolerable Grade 2c, d or Grade 3e, f
First occurrence
Interrupt lenvatinib until 
resolved to Grade 0-1, or 
tolerable Grade 2
Reduce lenvatinib dose to 
14 mg once a day (1-level 
reduction) 
Second occurrence (same 
toxicity or new toxicity)
Interrupt lenvatinib until 
resolved to Grade 0-1, or 
tolerable Grade 2
Reduce lenvatinib dose to 
10 mg once a day (1-level 
reduction)
Third occurrence (same 
toxicity or new toxicity)
Interrupt lenvatinib until 
resolved to Grade 0-1, or 
tolerable Grade 2
Reduce lenvatinib dose to 8 mg 
orally once a day (1-level 
reduction)
Fourth occurrence (same 
toxicity or new toxicity)
Interrupt lenvatinib 
Discuss with Sponsor
Grade 4g: Discontinue Study Treatment
AE=adverse event; BMI=body mass index; CTCAE=Common Terminology Criteria for Adverse Events.
Note: For grading see CTCAE version 5.0. Collect all AE grades (ie, decreasing and increasing CTCAE grade). 
a.
An interruption of study treatment for more than 28 days will require Sponsor approval before treatment can be 
resumed.
b.
Initiate optimal medical management for nausea, vomiting, hypertension, hypothyroidism and/or diarrhea prior to 
any lenvatinib interruption or dose reduction. 
c.
Applicable only to Grade 2 toxicities judged by the participant and/or physician to be intolerable.
d.
Obese participants (BMI ≥30) with weight loss do not need to return to their baseline weight or within 10% of their 
baseline weight (ie, Grade 1 weight loss). These participants may restart study intervention at a lower dose once their 
weight remains stable for at least 1 week and they have a minimum BMI of 25. The new stable weight should be 
used as the new baseline for further dose reductions.
e.
For asymptomatic laboratory abnormalities, such as Grade ≥3 elevations of amylase and lipase that are not 
considered clinically relevant by the investigator, continuation of treatment should be discussed with Sponsor.
f.
For Grade 3 thromboembolic event, permanently discontinue lenvatinib/matching placebo. See Section 6.6.2.5.
g.
Excluding laboratory abnormalities judged to be non-life-threatening, in which case manage as Grade 3.
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6.6.2.1
Management of Hypertension
Hypertension is a recognized side effect of treatment with drugs inhibiting VEGF signaling. 
Investigators should therefore ensure that participants enrolled to receive treatment with 
lenvatinib have BP of ≤150/90 mm Hg at the time of study entry and, if known to be 
hypertensive, have been on a stable dose of antihypertensive therapy for at least 1 week 
before C1D1. Early detection and effective management of hypertension are important to 
minimize the need for lenvatinib dose interruptions and reductions.
Regular assessment of BP should be as detailed in the SoA (Section 1.3.1 and Section 1.3.3). 
Hypertension will be graded using NCI CTCAE v5.0, 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 should be withheld in any instance where a participant is at imminent risk to 
develop a hypertensive crisis or has uncontrolled hypertension (eg, BP ≥160/100 mm Hg) 
with significant risk factors for severe complications, significant risk factors for cardiac 
disease, intracerebral hemorrhage, or other significant co-morbidities. Once the participant 
has been on the same antihypertensive medications for at least 48 hours and the BP is 
controlled, lenvatinib should be resumed as described below.
Participants who have had systolic BP ≥160 mm Hg or diastolic BP ≥100 mm Hg must have 
their BP monitored every 2 weeks (or more frequently as clinically indicated) until systolic 
BP has been ≤150 mm Hg and diastolic BP has been ≤95 mm Hg for 6 weeks. If a repeat 
event of systolic BP ≥160 mm Hg or diastolic BP ≥100 mm Hg occurs, the participant must 
resume every 2 week evaluation until systolic BP has been ≤150 mm Hg and diastolic BP has 
been ≤95 mm Hg for 6 weeks.
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The following guidelines should be followed for the management of systolic BP 
≥160 mm Hg or diastolic BP ≥100 mm Hg confirmed on 2 BP assessments at least 
30 minutes apart:
1. Continue study drug and institute antihypertensive therapy for participants not already 
receiving this.
2. For those participants already on antihypertensive medication, the dose of the current 
agent may be increased, if appropriate, or 1 or more agents of a different class of 
antihypertensive should be added. Study treatment can be continued without dose 
modification.
3. If systolic BP ≥160 mm Hg or diastolic BP ≥100 mm Hg persists despite maximal 
antihypertensive therapy, then lenvatinib administration should be interrupted and 
restarted at 1 dose level reduction only when systolic BP ≤150 mm Hg and diastolic BP 
≤95 mm Hg and the participant has been on a stable dose of antihypertensive medication 
for at least 48 hours. 
•
If systolic BP ≥160 mm Hg or diastolic BP ≥100 mm Hg recurs on the first dose 
reduction despite optimal management of hypertension with antihypertensive 
medications (either by dose increase or the addition of a different class of 
antihypertensive), then lenvatinib administration should be interrupted and restarted 
at an additional dose reduction only when systolic BP ≤150 mm Hg and diastolic BP 
≤95 mm Hg and the participant has been on a stable dose of antihypertensive 
medication for at least 48 hours. 
•
If systolic BP ≥160 mm Hg or diastolic BP ≥100 mm Hg recurs on the second dose 
reduction despite optimal management of hypertension with antihypertensive 
medications (either by dose increase or the addition of a different class of 
antihypertensive), then lenvatinib administration should be interrupted and restarted 
at a third dose reduction only when systolic BP ≤150 mm Hg and diastolic BP ≤95 
mm Hg and the participant has been on a stable dose of antihypertensive medication 
for at least 48 hours.
•
Additional dose reduction should be discussed with the Sponsor.
The following guidelines should be followed for the management of Grade 4 hypertension 
(life-threatening consequences):
1. Institute appropriate medical management
2. Discontinue study drug
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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
1. Perform urine dipstick testing or urinalysis per the SoA (Section 1.3.1 and Section 1.3.3). 
Urine dipstick testing is the preferred method for testing for urinary protein, however, 
urinalysis may be used if the use of urine dipsticks is not feasible.
2. A 24-hour urine collection initiated as soon as possible and at least within 72 hours (or an 
immediate spot urine protein-to-creatinine ratio [UPCR] test) is required in the following 
situations:
•
The first (initial) occurrence of ≥2+ (≥100 mg/dL) proteinuria on urine dipstick (or 
urinalysis) while the participant is receiving lenvatinib
•
A subsequent increase in severity of urine dipstick or urinalysis proteinuria occurring 
on the same lenvatinib dose level
•
When there has been a lenvatinib dose reduction and at the new dose level the urine 
protein dipstick result is ≥2+ (≥100 mg/dL)
3. A 24-hour urine collection (initiated as soon as possible and at least within 72 hours) to 
verify the grade of proteinuria is required when UPCR is ≥2.4.
Grading of Proteinuria
•
Grading according to NCI CTCAE v5.0 will be based on the 24-hour urinary protein 
result if one has been obtained. If the participant has 4+ proteinuria by dipstick
(≥1000 mg/dL by urinalysis), a 24-hour urinary protein result is required to confirm 
Grade 3 proteinuria. Management of lenvatinib administration will be based on the 
grade of proteinuria according to Table 8.
Monitoring
•
Urine dipstick or urinalysis testing for participants with proteinuria ≥2+ 
(≥100 mg/dL) should be performed every 2 weeks (or more frequently as clinically 
indicated) until the results have been 1+ (30 mg/dL) or negative for 6 weeks.
•
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 must be discontinued.
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6.6.2.3
Management of Diarrhea
An antidiarrheal agent should be recommended to the participant at the start of study 
treatment, and participants should be instructed and educated to initiate antidiarrheal 
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 
medical practice. If signs/symptoms of diarrhea persist despite optimal medical management, 
instructions contained in Table 8 should be followed.
Diarrhea is a known overlapping toxicity between pembrolizumab and lenvatinib 
(Section 6.6.3). If the causative agent is unknown, investigators should refer to both Table 7
and Table 8 for possible supportive care guidelines to follow.
6.6.2.4
Management of Hepatotoxicity
Liver function tests (ALT, AST, bilirubin levels) should be conducted as detailed in the SoA 
(Section 1.3.1 and Section 1.3.3) and as clinically indicated. If signs/symptoms indicating 
liver injury occur, instructions contained in Table 8 should be followed. Appropriate 
supportive care should be provided together with close monitoring. If hepatic failure occurs,
the study drug must be discontinued. If hepatic failure (any grade per CTCAE v5) occurs, 
lenvatinib 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, 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 8 should be 
followed. Appropriate supportive care should be provided together with close monitoring. If 
a participant experiences a Grade 3 or a life-threatening (Grade 4) thromboembolic reaction, 
including pulmonary embolism, lenvatinib must be discontinued.
Arterial thromboembolic events (eg, new onset, worsening, or unstable angina, myocardial 
infarction, transient ischemic attack, and cerebrovascular accident) of any grade require study 
treatment 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 
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should be taken to control BP. In participants with signs or symptoms of PRES/RPLS, 
instructions in Table 8 should be followed. 
6.6.2.7
Management of Hypocalcemia
Serum calcium should be monitored per the SoA (Section 1.3.1 and Section 1.3.3). Corrected 
serum calcium should be used to assess the grade of hypocalcemia per CTCAE v5.0, using 
the following formula: 
Corrected calcium = ([4 – serum albumin in g/dL] × 0.8 + serum calcium)
The formula is not applicable when serum albumin concentration is normal (˃4 g/dL); in 
such situations, the total (uncorrected) serum calcium should be used instead. 
Hypocalcemia should be treated per institutional guidelines (eg, using appropriate calcium, 
magnesium, and Vitamin D supplementation) until resolution.
6.6.2.8
Management of Hemorrhage
Instructions in Table 8 should be followed for the management of hemorrhage. Either resume 
at a reduced dose or discontinue lenvatinib depending on the severity and persistence of 
hemorrhage.
6.6.2.9
Management of Gastrointestinal Perforation or Fistula Formation
Lenvatinib should be discontinued in any participants who develop gastrointestinal 
perforation of any grade or Grade 4 fistula. Refer to Appendix 7 for country-specific 
requirements.
6.6.2.10
Management of QT Prolongation
Lenvatinib should be withheld in the event of development of QT interval prolongation 
greater than 500 msec. Lenvatinib 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 and periodically during 
lenvatinib treatment. Advise participants regarding good oral hygiene practices. Avoid 
invasive dental procedures, if possible, while on lenvatinib treatment, particularly in 
participants at higher risk. For participants requiring invasive dental procedures, 
discontinuation of bisphosphonate treatment may reduce the risk of ONJ. Withhold 
lenvatinib if ONJ develops and restart based on clinical judgement of adequate resolution
(see Section 6.6.4).
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6.6.3
Dose Modifications for Overlapping Toxicities
Based on the known toxicity profiles of pembrolizumab and lenvatinib, certain treatment-
related AEs are uniquely associated with one drug versus the other. For example, 
hypertension, arterial thrombotic events, proteinuria, and hemorrhagic events are known risks 
for lenvatinib treatment, while immune-related AEs are risks for pembrolizumab treatment. 
However, certain AEs, such as such as diarrhea, hypothyroidism, and liver enzyme elevation, 
may be initially considered attributable to either study drug. Therefore, evaluation of 
attribution is important for determining the study drug most likely related to the AE, or an 
alternative etiology, and subsequently proper clinical management. The following aspects 
should be considered: 
1. Timing of AE onset 
Since lenvatinib is dosed daily and continuously due to a relatively short half-life 
(28 hours), and pembrolizumab is dosed Q6W due to a long half-life, lenvatinib can be 
interrupted to assess whether an AE improves/resolves with dechallenge (ie, interruption 
of treatment) based on the following 2 scenarios:
•
If an AE is identified during a treatment cycle (ie, between 2 pembrolizumab doses), 
only lenvatinib dose interruption is needed. 
•
If an AE is identified at the beginning of a treatment cycle, lenvatinib can be 
interrupted and dosing of pembrolizumab should be held.
If the participant recovers from an AE in response to lenvatinib interruption (ie, 
positive dechallenge), the event is more likely to be related to lenvatinib. Otherwise, 
after excluding other alternative explanations, an irAE 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) 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 6 but 
lenvatinib 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 6 advises pembrolizumab to be withheld (interrupted), and Table 8
advises lenvatinib 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
If the participant is receiving treatment with lenvatinib and requires surgery during the study, 
the stop time and restart time of lenvatinib should be as follows:

For minor procedures: stop lenvatinib at least 2 days before the procedure and restart it at 
least 2 days after, once there is evidence of adequate healing and no risk of bleeding.

For major procedures: stop lenvatinib at least 1 week (5 half-lives) prior to surgery and 
then restart it at least 2 weeks after, once there is evidence of adequate healing and no 
risk of bleeding.
6.6.5
Second Course Treatment Phase
All participants who have completed the first course may be eligible for up to an additional
9 cycles of pembrolizumab if there is investigator-determined progressive disease by 
RECIST 1.1 after initial treatment or first course has been completed or stopped for 
confirmed CR.
Participants may enter the Second Course if all of the following criteria are met:
•
The participant received pembrolizumab, determined on unblinding if applicable
•
No new anticancer treatment was administered after the last dose of study intervention
•
The participant meets all of the inclusion criteria and none of the exclusion criteria
•
The study is ongoing
An objective response or disease progression that occurs during the Second Course will not 
be counted as an event for the primary analysis of either endpoint in this study.
Participants in the Second Course Treatment Phase who continue receiving lenvatinib will be 
treated at the same dose and frequency of lenvatinib that they were receiving when PD 
occurred.
6.7
Intervention After the End of the Study
The study is complete upon consent of the last active treatment participant for an extension 
study using pembrolizumab monotherapy, coformulations, or in combination with a
compound (eg, lenvatinib or lenvatinib alone), if available.
All study-related procedures and data collection as defined per protocol will be terminated at
study completion. In addition, survival follow-up will be stopped upon study completion as
defined in Section 4.4.
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6.8
Clinical Supplies Disclosure
This study is open label; therefore, the participant, the study site personnel, the Sponsor, 
and/or designee are not blinded. Study intervention (name, strength, or potency) is included 
in the label text; random code/disclosure envelopes or lists are not provided.
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7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
Discontinuation of study intervention does not represent withdrawal from the study.
As certain data on clinical events beyond study intervention discontinuation may be 
important to the study, they must be collected through the participant’s last scheduled follow-
up, even if the participant has discontinued study intervention. Therefore, all participants 
who discontinue study intervention prior to completion of the protocol-specified treatment 
period will still continue to be monitored in this study and participate in the study visits and 
procedures as specified in Section 1.3 and Section 8.10.3 unless the participant has 
withdrawn from the study (Section 7.2).
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.
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 interrupts pembrolizumab for more than 12 consecutive weeks or 
lenvatinib for more than 28 consecutive days without prior agreement from the Sponsor.
•
The participant has a medical condition or personal circumstance which, in the opinion of 
the investigator and/or Sponsor, placed the participant at unnecessary risk from continued 
administration of study intervention.
•
The participant has a confirmed positive serum pregnancy test.
•
Radiographic disease progression outlined in Section 8.2.1 (exception if the Sponsor 
approves treatment continuation following confirmed disease progression).
•
Any progression or recurrence of any malignancy, or any occurrence of another 
malignancy that requires active treatment.
•
Any study intervention-related toxicity specified as a reason for permanent 
discontinuation as defined in the guidelines for dose modification due to AEs in 
Section 6.6.
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Completion of pembrolizumab Q6W monotherapy consists of 18 treatments (approximately 
2 years). Discontinuation of treatment may be considered for participants who have attained a 
confirmed CR and have been treated for at least 4 cycles (at least 24 weeks), receiving at 
least 1 dose of pembrolizumab beyond the date when the initial CR was declared. These 
participants may be eligible for second course treatment described in Section 6.6.5.
Note: The number of treatments is calculated starting with the first dose. Participants who 
stop the combination or pembrolizumab after receiving 18 doses may be eligible for 
retreatment if they progress after stopping study intervention provided they meet the 
requirements detailed in Section 8.10.3. Participants may be retreated in the Second Course 
Phase (Retreatment) for up to an additional 9 cycles (approximately 1 year).
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study 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.
•
Note: A participant is not considered lost to follow-up until the last scheduled visit for the 
individual participant. The missing data for the participant will be managed via the 
prespecified statistical data handling and analysis guidelines.
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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 utilized for screening or baseline 
purposes provided the procedure met the protocol-specified criteria and were performed 
within the time frame defined in the SoA.
•
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, Hepatitis C), and thus local regulations 
may require that additional informed consent be obtained from the participant. In these 
cases, such evaluations/testing will be performed in accordance with those regulations.
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.
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8.1.1.1
General Informed Consent
Informed consent given by the participant or their legally acceptable representative must be 
documented on a consent form. The form must include the trial protocol number, trial 
protocol title, dated signature, and agreement of the participant (or his/her legally acceptable 
representative) and of the person conducting the consent discussion.
A copy of the signed and dated informed consent form should be given to the participant (or 
their legally acceptable representative) before participation in the study.
The initial ICF, any subsequent revised ICF, and any written information provided to the 
participant must receive the IRB/IEC’s approval/favorable opinion in advance of use. The 
participant or his/her legally acceptable representative should be informed in a timely manner 
if new information becomes available that may be relevant to the participant’s willingness to
continue participation in the study. The communication of this information will be provided 
and documented via a revised consent form or addendum to the original consent form that 
captures the participant’s or the participant’s legally acceptable representative’s dated 
signature.
If the investigator recommends continuation of study intervention beyond disease 
progression, the participant or their legally acceptable representative will be asked to provide 
documented informed consent.
Specifics about the study and the study population are to be included in the study informed 
consent form.
Informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, and 
Sponsor requirements.
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator, who is a qualified 
physician, to ensure that the participant qualifies for the study.
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,
site personnel will add the treatment/randomization number to the participant identification 
card.
The participant identification card also contains contact information for the emergency 
unblinding call center so that a healthcare provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
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8.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee. The medical 
history will collect all active conditions and any condition diagnosed within the prior 10 
years that the investigator considers to be clinically significant. Details regarding the disease 
for which the participant has enrolled in this study will be recorded separately and not listed 
as medical history.
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant 
within 28 days before the first dose of study intervention.
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. In addition, new medications started 
during the Second Course Treatment Phase through the Second Course Safety Follow-up 
visit should be recorded. Concomitant medications administered >30 days after the last dose 
of study intervention will be recorded for SAEs and ECIs as defined in Section 8.4.1. In the 
posttreatment follow-up period, information about new anticancer therapies will be collected.
8.1.6
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur prior to intervention allocation. Each 
participant will be assigned only 1 screening number. Screening numbers must not be re-used 
for different participants.
Any participant who is screened multiple times will retain the original screening number 
assigned at the initial screening visit. Specific details on the screening/rescreening visit are 
provided in Section 8.10.1.
8.1.7
Assignment of Treatment/Randomization Number
All eligible participants will be allocated, by nonrandom assignment, and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment allocation. Once a 
treatment/randomization number is assigned to a participant, it can never be reassigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
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8.1.8
Study Intervention Administration
The first dose of study intervention should begin as close as possible to the date of allocation 
but can occur up to 3 days following allocation. Every effort should be made to ensure the 
participants receive the first dose of study intervention on the date of allocation. Study 
interventions will be administered by the investigator and/or qualified study staff according 
to the specifications in the Pharmacy Manual.
8.1.8.1
Timing of Dose Administration
8.1.8.1.1
Lenvatinib
Participants should be given clear instructions on how and when to take their study 
intervention. Lenvatinib will be taken orally QD, with doses taken at approximately the same 
time of day. Lenvatinib may be administered at home except on days when clinic visits are 
scheduled to occur. Study intervention on these days will occur in the clinic after completion 
of all other assessments.
If a dose is missed and cannot be taken within 12 hours, study participants should skip that 
dose and take the next dose at the usual time of administration. Participants who vomit after 
study drug administration should not retake that study drug dose but should resume taking 
study drug with the next scheduled dose. Lenvatinib can be taken without regard to food.
8.1.8.1.2
Pembrolizumab
Study treatment with pembrolizumab should be administered on Day 1 of each cycle after all 
procedures/assessments have been completed as detailed in the SoA (Section 1.3). All study 
treatments will be administered on an outpatient basis. Pembrolizumab may be administered 
up to 3 days before or after the scheduled Day 1 of each cycle due to administrative reasons 
except for C1D1, where the window is +3 days from allocation.
Pembrolizumab will be administered using a 30-minute IV infusion. Sites should make every 
effort to target infusion timing to be as close to 30 minutes as possible. However, given the 
variability of infusion pumps from site to site, a window of -5 minutes and +10 minutes is 
permitted (ie, infusion time is 30 minutes -5 min/+10 min).
The Pharmacy Manual contains specific instructions for preparation of the infusion fluid and 
administration.
8.1.9
Discontinuation and Withdrawal
Participants who discontinue study intervention prior to completion of the treatment period
should be encouraged to continue to be followed for all remaining study visits as outlined in 
the SoA and Section 8.10.3.
Participants who withdraw from the study should be encouraged to complete all applicable 
activities scheduled for the final study visit at the time of withdrawal. Any AEs that are 
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present at the time of withdrawal should be followed in accordance with the safety 
requirements outlined in Section 8.4.
8.1.10
Participant Blinding/Unblinding
This is an open-label study; there is no blinding for this study.
8.1.11
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained are reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
8.1.12
Tumor Tissue Collection
During the screening period, a tissue sample is required for each participant consisting of:
•
A newly obtained core or incisional biopsy of a tumor lesion, which was not previously 
irradiated
OR

An archival tumor tissue sample if a new biopsy is unavailable.
FFPE tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived 
tissue.
Newly cut unstained slides must be submitted to the central laboratory within 14 days of cut 
date (details pertaining to tumor tissue submission can be found in the Procedures Manual).
The central laboratory will provide consultative review to confirm nccRCC histology without 
any admixed clear cell component. 
8.2
Efficacy Assessments
8.2.1
Tumor Imaging and Assessment of Disease
In addition to survival, efficacy will be assessed based on imaging evaluation of changes in 
tumor burden over time, until the participant is discontinued from the study or goes into 
survival follow-up. The process for image collection and transmission to the iCRO can be 
found in the SIM. Tumor imaging is strongly preferred to be acquired by CT. For the 
abdomen and pelvis, contrast-enhanced MRI may be used when CT with iodinated contrast is 
contraindicated, or when mandated by local practice. The same imaging technique should be 
used in a participant throughout the study to optimize the reproducibility of the assessment of 
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existing and new tumor burden and improve the accuracy of the response assessment based 
on imaging. Note: for the purposes of assessing tumor imaging, the term “investigator” refers 
to the local investigator at the site and/or the radiological reviewer at the site or at an offsite 
facility.
If brain imaging is performed, MRI is preferred; however, CT imaging will be acceptable, if 
MRI is medically contraindicated.
Bone scans may be performed to evaluate bone metastases. Any supplemental imaging done 
to support a positive or negative bone scan, such as plain X-rays acquired for correlation, 
should be submitted to the iCRO.
Other types of medical imaging (such as ultrasound) should not be submitted to the iCRO,
and will not be included in response assessment.
Expedited confirmation of measurable disease based on RECIST 1.1 by BICR at screening 
will be used to determine participant eligibility. Confirmation by BICR that the participant’s 
imaging shows at least 1 lesion that is appropriate for selection as a target lesion per RECIST 
1.1 is required before participant allocation.
All scheduled imaging for all study participants will be submitted to the iCRO. In addition, 
imaging that is obtained at an unscheduled time point, for any reason (including suspicion of 
progression or other clinical reason), should also be submitted to the iCRO if it shows 
progression, or if it is used to support a response assessment. All imaging acquired within the 
protocol-specified window of time around a scheduled imaging visit can be classified as 
pertaining to that visit.
8.2.1.1
Initial Tumor Imaging
Initial tumor imaging (chest, abdomen, and pelvis) at Screening must be performed within 28 
days prior to the date of allocation. The screening images must be submitted to the iCRO for 
verification of measurable disease per RECIST 1.1 for eligibility before allocation. Tumor 
imaging performed as part of routine clinical management is acceptable for use as the 
Screening tumor imaging if it is of diagnostic quality, performed within 28 days prior to the 
date of allocation, and can be assessed by the iCRO.
Bone imaging will be required for all participants at Screening. Bone imaging are not 
required to be repeated at Screening if they were performed for standard of care within 42 
days prior to allocation and meet protocol requirements.
If brain imaging is required to document the stability of existing metastases, the brain MRI 
should be acquired during the Screening period.
8.2.1.2
Tumor Imaging During the Study
The first on-study imaging assessment should be performed at 12 weeks ([84 days ±7 days]) 
from the date of allocation. Subsequent tumor imaging should be performed every 6 weeks 
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(42 days ±7 days) or more frequently if clinically indicated. After 54 weeks (378 days ±7 
days]), participants who remain on treatment will have imaging performed every 12 weeks 
(84 days ±7 days). Imaging timing should follow calendar days and should not be adjusted 
for delays in cycle starts. Imaging should continue to be performed until disease progression
is identified by the investigator, the start of new anticancer treatment, withdrawal of consent, 
or death, or notification by the Sponsor, whichever occurs first. All supplemental imaging 
must be submitted to the iCRO.
Objective response should be confirmed by a repeat imaging assessment. Tumor imaging to 
confirm PR or CR should be performed at least 4 weeks after the first indication of a 
response is observed. Participants will then return to regular scheduled imaging, starting with 
the next scheduled imaging time point. Participants who receive additional imaging for 
confirmation do not need to undergo the next scheduled tumor imaging if it is less than 
4 weeks later; tumor imaging may resume at the subsequent scheduled imaging time point. 
Note: Response does not typically need to be verified in real time by the BICR.
On-study brain or bone imaging should be performed if clinically indicated or to confirm CR 
(if other lesions indicate CR and brain or bone lesions existed at baseline).
8.2.1.3
End-of-Treatment and Follow-up Tumor Imaging
For participants who discontinue study intervention, tumor imaging should be performed at 
the time of treatment discontinuation (±4 week window). If previous imaging was obtained 
within 4 weeks prior to the date of discontinuation, then imaging at treatment discontinuation 
is not mandatory. For participants who discontinue study intervention due to documented 
disease progression, this is the final required tumor imaging.
For participants who discontinue study intervention without documented disease progression, 
every effort should be made to continue monitoring disease status by tumor imaging using 
the same imaging schedule used while on treatment calculated from the date of allocation 
(see Section 8.2.1.2) until the start of a new anticancer treatment, disease progression,
pregnancy, death, withdrawal of consent, or the end of the study, whichever occurs first.
8.2.1.4
Second Course (Retreatment) Tumor Imaging
Tumor imaging must be performed within 28 days prior to restarting treatment with 
pembrolizumab. Local reading (investigator assessment with site radiology reading) will be 
used to determine eligibility. All Second Course imaging should be submitted to the iCRO 
for quality control, storage, and possible retrospective review.
The first on-study imaging assessment should be performed at 12 weeks (84 days ±7 days) 
after the restart of treatment. Subsequent tumor imaging should be performed every 12 weeks 
(84 days ±7 days) or more frequently, if clinically indicated.
Imaging should continue to be performed until disease progression, the start of a new 
anticancer treatment, withdrawal of consent, death, completion of Second Course treatment 
(9 cycles), or notification by the Sponsor, whichever occurs first.
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For participants who discontinue Second Course study intervention, tumor imaging should be 
performed at the time of intervention discontinuation (±4 week window). If previous imaging 
was obtained within 4 weeks prior to the date of discontinuation, then imaging at intervention
discontinuation is not mandatory. For participants who discontinue study intervention due to 
documented disease progression, this is the final required tumor imaging.
For participants who discontinue Second Course study intervention without documented 
disease progression, every effort should be made to continue monitoring their disease status 
by radiologic imaging every 12 weeks (84 days ±7 days) until either the start of a new 
anticancer treatment, disease progression, death, or the end of the study, whichever occurs 
first.
8.2.1.5
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.
If disease progression is established by the investigator, the process continues as follows:
•
investigator judgement 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 per original protocol schedule
•
send scans to iCRO
For the purpose of this decision process, lack of clinical stability is defined as:
•
unacceptable toxicity
•
clinical signs or symptoms indicating clinically significant disease progression
•
decline in performance status
•
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
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8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided. The total amount of blood/tissue to be drawn/collected over the course of the study 
(from prestudy to poststudy visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per participant, can be found in the Procedures 
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) as per 
institutional standard. Height and weight will also be measured and recorded.
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.
8.3.1.1
Full Physical Examination
The investigator or qualified designee will perform a complete physical examination, 
including oral examination, during the Screening period. Clinically significant abnormal 
findings should be recorded as medical history. The time points for full physical exams are 
described in Section 1.3. After the first dose of study intervention, new clinically significant 
abnormal findings should be recorded as AEs.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.3.1.2
Directed Physical Examination
For cycles that do not require a full physical examination as defined in Section 1.3, the 
investigator or qualified designee will perform a directed physical examination as clinically
indicated prior to study intervention administration. New clinically significant abnormal 
findings should be recorded as AEs.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
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8.3.2
Vital Signs
•
Vital sign measurements (ie, systolic and diastolic BP [mm Hg], heart rate [beats per 
minute], respiratory rate [per minute], and body temperature) will be assessed/ obtained 
at the visits designated in the SoA (Section 1.3) by a validated method.
•
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 BP <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.
•
Under exceptional circumstances, participants taking lenvatinib may have the option of 
having BP measured between visits obtained locally by a health care professional.
8.3.3
Electrocardiograms
ECGs will be obtained as designated in the SoA (Section 1.3). Complete, standardized, 12-
lead ECG recordings that permit all 12 leads to be displayed on a single page with an 
accompanying lead II rhythm strip below the customary 3 × 4 lead format are to be used. In 
addition to a rhythm strip, a minimum of 3 full complexes should be recorded from each lead 
simultaneously. Participants must be in the recumbent position for a period of 5 minutes prior 
to the ECG. The QTcF 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. For participants receiving 
lenvatinib, ECGs will be monitored at every cycle (as specified in the SoA in Section 1.3) in 
participants with congenital long QT syndrome, congestive heart failure, bradyarrhythmias, 
or those who are taking drugs known to prolong the QT interval, including Class Ia and III 
antiarrhythmics. Medicinal products with a known potential to prolong the QT/QTc interval 
must be used cautiously. Please refer to the lenvatinib prescribing information for further 
details.
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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 30 days after the last dose of study intervention, every 
attempt should be made to perform repeat assessments until the values return to normal or 
baseline or if a new baseline is established as determined by the investigator.
Details regarding specific laboratory procedures/assessments to be performed in this study 
are provided below. The total amount of blood/tissue to be drawn/collected over the course 
of the study (from prestudy to poststudy visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per participant can be found in the Study 
Procedures Manual. Refer to the Study Flow Chart (Section 1.3) for the timing of laboratory 
assessments.
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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.
Laboratory tests for hematology, chemistry, and urinalysis are specified in Appendix 2.
8.3.5.2
Pregnancy Test
All women who are being considered for participation in the study, and who are not 
surgically sterilized or postmenopausal, must be tested for pregnancy within 24 hours of the 
first dose of study intervention. If a urine test is positive or not evaluable, a serum test will be 
required. Participants must be excluded/discontinued from the study in the event of a positive 
test result. Repeated pregnancy test (such as monthly testing) may be conducted if required 
by local regulation.
8.3.6
Performance Assessments
8.3.6.1
Eastern Cooperative Oncology Group Performance Scale
The investigator or qualified designee will assess ECOG status as specified in the SoA 
(Section 1.3) [Oken, M.M., et al 1982].
8.3.6.2
Karnofsky Performance Status
The KPS is a standard way of measuring the ability of cancer patients to perform ordinary 
tasks, with scores ranging from 0 to 100% [Karnofsky, D. A., et al 1948]. A higher score 
means the patient is better able to carry out daily activities. The KPS will be assessed as 
specified in the SoA (Section 1.3). A KPS ≥70% is required for study eligibility.
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. 
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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 allocation, must be reported by the 
investigator if the participant is receiving placebo run-in or other run-in treatment, if the 
event cause the participant to be excluded from the study, or is the result of a protocol-
specified intervention, including, but not limited to washout or discontinuation of usual 
therapy, diet, or a procedure.
•
All AEs from the time of intervention allocation through 30 days following cessation of 
study intervention must be reported by the investigator.
•
All AEs meeting serious criteria, from the time of intervention allocation 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 pregnancies and exposure during breastfeeding, from the time of intervention
allocation through 120 days following cessation of study intervention, or 30 days 
following cessation of study intervention if the participant initiates new anticancer 
therapy must be reported by the investigator.
•
Additionally, any SAE brought to the attention of an investigator at any time outside of 
the time period 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 he/she 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 9.
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Table 9
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation 
through 
Protocol-
specified Follow-
up Period
Reporting Time Period:
After the Protocol-
specified Follow-up 
Period
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 including 
Cancer and Overdose
Report if:
- due to protocol-
specified 
intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other 
run-in treatment
Report all
Report if:
- drug/vaccine related.
(Follow ongoing to 
outcome)
Within 24 hours 
of learning of 
event
Pregnancy/
Lactation Exposure
Report if:-
participant has 
been exposed to 
any protocol-
specified 
intervention (eg, 
procedure, 
washout or run-in 
treatment 
including placebo 
run-in)
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
DILI=drug-induced liver injury; ECI=event of clinical interest; NSAE=nonserious adverse event; SAE=serious adverse 
event. 
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8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs 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 allocated participants for 
outcome. Further information on follow-up procedures is given in Appendix 3.
8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. 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.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
Note: To meet EU CTR requirements, the Sponsor will report SUSARs to the Eudravigilance 
database via E2B(R3) electronic ICSR form in compliance with CTR 536/2014.
8.4.5
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to 
the investigator or their designee) that occurs during the study are reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy. 
Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, 
blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth must be reported as 
serious events (Important Medical Events). If the pregnancy continues to term, the outcome 
(health of infant) must also be reported.
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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 monitor unblinded aggregated efficacy endpoint events and safety data to 
ensure the safety of the participants in the study. Any suspected endpoint that on 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. 
Events of clinical interest for this study include: 
a.
An overdose of Sponsor's product, as defined in Section 8.5.
b. 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 may require 
an additional evaluation for an underlying etiology. The study site guidance for 
assessment and follow up of these criteria can be found in the Investigator Study File 
Binder (or equivalent).
8.5
Treatment of Overdose
For this study, an overdose of pembrolizumab will be defined as any dose of 1000 mg or 
greater. For this study, an overdose of lenvatinib will be defined as any dose above the 
protocol-prescribed dose if associated with an adverse event.
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.
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There is no specific antidote for an overdose of lenvatinib. Due to its high degree of plasma 
protein binding, lenvatinib is not expected to be dialyzable. Adverse reactions in patients 
receiving single doses of lenvatinib as high as 40 mg were similar to those in clinical studies 
at the recommended dose for differentiated thyroid cancer, RCC, and HCC.
All reports of pembrolizumab overdose with and without an AE and all reports of lenvatinib 
overdose with an AE must be reported by the investigator within 24 hours to the Sponsor 
either by electronic media or paper.
Reports of pembrolizumab overdose without any associated clinical symptoms or abnormal 
laboratory results, should be reported using the terminology “accidental or intentional 
overdose without adverse effect.”
8.6
Pharmacokinetics
Not applicable.
8.7
Pharmacodynamics
Not applicable
8.8
Biomarkers

Blood for Genetic Analysis

Blood for Serum Biomarkers

Blood for ctDNA Analysis

Archival or Newly Obtained Tumor Tissue Sample Collection

Blood for RNA Analysis

Blood for PBMC
8.8.1
Planned Genetic Analysis Sample Collection
Samples should be collected for planned analysis of associations between genetic variants in 
germline/tumor DNA and drug response. If a documented law or regulation prohibits (or 
local IRB/Independent Ethics Committee [IEC] does not approve) sample collection for these 
purposes, then such samples should not be collected at the corresponding sites. 
8.9
Future Biomedical Research Sample Collection
Not applicable.
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8.10
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.10.1
Screening
Written consent must be obtained prior to performing any protocol-specific procedure. 
Results of a test performed prior to the participant signing consent as part of routine clinical 
management are acceptable in lieu of a screening test if performed within the specified time 
frame. Screening procedures are to be completed within 28 days prior to the date of 
allocation except for the following:
•
Laboratory tests are to be performed within 10 days prior to the first dose of study 
intervention. An exception is hepatitis testing which may be done up to 28 days prior to 
the first dose of study intervention.
•
Evaluation of KPS is to be performed within 10 days prior to the first dose of study 
intervention.
•
Evaluation of ECOG is to be performed within 10 days prior to the first dose of study 
intervention.
•
For women of reproductive potential, a urine or serum pregnancy test will be performed 
within 24 hours prior to the first dose of study intervention. If urine pregnancy results 
cannot be confirmed as negative, a serum pregnancy test will be required (performed by 
the local study site laboratory).
Participants may be rescreened after initially failing to meet the inclusion/exclusion criteria. 
Results from assessments during the initial screening period are acceptable in lieu of a repeat 
screening test if performed within the specified time frame and the corresponding 
inclusion/exclusion criteria is met. Participants who are rescreened will retain their original 
screening number.
8.10.2
Treatment Period Visits
Visit requirements are outlined in the SoA (Section 1.3). Specific procedure-related details 
are provided in Section 8.1. Assessments/procedures will be performed, prior to the 
administration of study intervention.
8.10.3
Discontinued Participants Continuing to be Monitored in the Study
The investigator or qualified designee should clarify what a participant is withdrawing from, 
ie, treatment, follow-up visits, and/or contact. Given the importance of collecting extended 
follow-up data for PFS and OS in this study, efforts should be made to clarify if participants 
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are willing to be followed for a PFS event and/or survival and/or whether review of public 
records is acceptable.
8.10.4
Posttreatment Visits
8.10.4.1
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 the initiation of a new anticancer treatment, 
whichever comes first.
Participants who are eligible for retreatment/crossover with pembrolizumab may have up to 2 
safety follow-up visits, 1 after the Initial Treatment Phase and 1 after the Second Course 
Treatment Phase.
8.10.4.2
Efficacy Follow-up Visits
Participants who complete the protocol-required cycles of study intervention or who 
discontinue study intervention for a reason other than disease progression will begin the 
Efficacy Follow-up Phase and should be assessed according to the SoA (Section 1.3) 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, or if 
the participant begins retreatment with pembrolizumab as detailed in Section 6.6.5. 
Information regarding poststudy anticancer treatment will be collected if new treatment is 
initiated. Participants who completed all efficacy assessments and/or who will not have 
further efficacy assessments must enter the Survival Follow-up Phase.
Participants who are eligible to receive retreatment with pembrolizumab according to the 
criteria in Section 6.6.5 will move from the Efficacy Follow-up Phase to the Second Course 
Treatment Phase when they experience disease progression. Details are provided in the SoA 
(Section 1.3.3) for retreatment with pembrolizumab.
8.10.4.3
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 study intervention and who will not enter the Efficacy 
Follow-up Phase, the first survival follow-up contact will be scheduled 12 weeks after the 
discontinuation visit and/or Safety Follow-up visit (whichever is last).
•
For participants who completed assessments in the Efficacy Follow-up Phase, the first 
survival follow-up contact will be scheduled 12 weeks after the last assessment at the 
Efficacy Follow-up Visit has been performed.
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8.10.5
Survival Status
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 eDMC 
review, interim and/or final analysis. Upon Sponsor notification, all participants who do 
not/will not have a scheduled study visit or study contact during the Sponsor defined time 
period will be contacted for their survival status (excluding participants that have a 
previously recorded death event in the collection tool).
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9
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study. Changes to 
analyses made after the protocol has been finalized, but prior to the final database lock, will 
be documented in a sSAP and referenced in the CSR for the study. Post hoc exploratory 
analyses will be clearly identified in the CSR.  
9.1
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Sections 9.2 through 9.12.  
Study Design Overview
This is a single-arm, open-label, Phase 2 clinical trial to evaluate the 
efficacy and safety of pembrolizumab plus lenvatinib as first-line
treatment for participants with advanced/metastatic nccRCC.
Treatment Assignment
Approximately 152 participants will be allocated to receive treatment 
with pembrolizumab 400 mg Q6W and lenvatinib 20 mg QD.
Analysis Populations
Efficacy: APaT
Safety: APaT
Primary Endpoint
Objective Response per RECIST 1.1 as assessed by BICR
Secondary Endpoints

DOR per RECIST 1.1 as assessed by BICR

PFS per RECIST 1.1 as assessed by BICR

OS

Clinical Benefit per RECIST 1.1 as assessed by BICR

Disease Control per RECIST 1.1 as assessed by BICR

AEs and study intervention discontinuations due to AEs.
Statistical Methods for Key 
Efficacy Analyses
The point estimate of ORR will be provided, together with 95% CI using 
exact binomial method proposed by Clopper and Pearson (1934) [Clopper, 
C. J. and Pearson, E. S. 1934].
Statistical Methods for Key 
Safety Analyses
Counts and percentages of participants with AEs will be provided.
Interim Analyses
No formal interim analysis is planned in this study. 
Multiplicity
No multiplicity adjustment is planned as there is no formal hypothesis 
testing.
Sample Size and Power 
The planned sample size is approximately 152 participants. Section 9.9 
provides the precision of the ORR estimates.
9.2
Responsibility for Analyses/In-house Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
This trial is being conducted as an open-label study, i.e., participants, investigators, and 
Sponsor personnel will be aware of participant treatment assignments after each participant is 
enrolled and treatment is assigned.
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The Sponsor will generate the allocation schedule for study treatment assignment. The 
allocation will be implemented in IVRS.
9.3
Hypotheses/Estimation
Objectives of the study are stated in Section 3. There is no formal hypothesis testing in this 
estimation study. 
9.4
Analysis Endpoints
9.4.1
Efficacy Endpoints
Primary
•
Objective Response Rate 
The ORR is defined as the percentage of participants who achieve a confirmed CR or PR 
per RECIST 1.1 as assessed by BICR.
Secondary
•
Duration of Response 
For participants who demonstrate confirmed CR or PR, DOR is defined as the time from 
the first documented evidence of CR or PR until disease progression or death due to any 
cause, whichever occurs first.
•
Progression-free survival 
PFS is defined as the time from the date of first dose to the first documented disease 
progression per RECIST 1.1 by BICR or death due to any cause, whichever occurs first.
•
Overall Survival 
OS is defined as the time from date of first dose to death due to any cause.
•
Clinical Benefit Rate 
CBR is defined as the percentage of participants who have achieved SD of ≥6 months or 
CR or PR per RECIST 1.1 by BICR.
•
Disease Control Rate 
DCR is defined as the percentage of participants who have achieved SD, CR, or PR per 
RECIST 1.1 by BICR.
9.4.2
Safety Endpoint
The safety endpoints include AEs, SAEs, and study treatment discontinuation due to AEs. In 
addition, safety and tolerability will be assessed by clinical review of all relevant parameters 
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including AEs, laboratory tests, vital signs, and ECGs. A description of safety measures is 
provided in Sections 8.3 and 8.4.
9.5
Analysis Populations
9.5.1
Efficacy Analysis Populations
The APaT population will be used for the primary analysis of efficacy data in this study. The 
APaT population consists of all allocated participants who received at least 1 dose of study
treatment. 
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 allocated participants who received at least one dose of study 
treatment.  
At least one laboratory, vital sign, or ECG measurement obtained subsequent to at least one 
dose of study treatment is required for inclusion in the analysis of each specific parameter. 
To assess change from baseline, a baseline measurement is also required.
9.6
Statistical Methods
This section describes the statistical methods that address the primary and secondary 
objectives. Methods related to the tertiary/exploratory endpoints will be described in the 
sSAP. This is an estimation study. No formal hypothesis tests will be conducted.
9.6.1
Statistical Methods for Efficacy Analysis
The efficacy analyses for ORR, DOR, PFS, CBR, and DCR will include responses and 
documented progression events that occur before Second Course treatment.
9.6.1.1
Objective Response Rate, Clinical Benefit Rate, and Disease Control Rate
The point estimate of ORR, CBR, and DCR will be provided along with the 95% CIs using 
the exact binomial method proposed by Clopper and Pearson (1934) [Clopper, C. J. and 
Pearson, E. S. 1934].
9.6.1.2
Duration of Response
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. Censoring rules for DOR are summarized in Table 10.
For each DOR analysis, a corresponding summary of the reasons responding participants are 
censored will also be provided. Responding participants who are alive, have not progressed, 
have not initiated new anticancer treatment, have not been determined to be lost to follow-up, 
and have had a disease assessment within ~5 months of the data cutoff date are considered 
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ongoing responders at the time of analysis. If a participant meets multiple criteria for 
censoring, the censoring criterion that occurs earliest will be applied.
Table 10
Censoring Rules for Duration of Response
Situation
Date of Progression or Censoring
Outcome
No progression nor death, no new 
anticancer therapy initiated
Last adequate disease assessment
Censor
(non-event)
No progression nor death, new 
anticancer therapy initiated
Last adequate disease assessment before 
new anticancer therapy initiated
Censor
(non-event)
Death or progression immediately 
after ≥ 2 consecutive missed disease 
assessments or after new anticancer 
therapy, if any
Earlier date of last adequate disease 
assessment prior to ≥ 2 missed adequate 
disease assessments and new anticancer 
therapy, if any
Censor
(non-event)
Death or progression after ≤ 1 
missed disease assessments and 
before new anticancer therapy, if any
PD or death
End of response
(Event)
PD=progressive disease.
A missed disease assessment includes any assessment that is not obtained or is considered inadequate for evaluation of 
response.
9.6.1.3
Progression-free Survival
The nonparametric Kaplan-Meier method will be used to estimate the PFS curve.
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 earlier of the 
date of the first assessment at which PD is objectively documented per RECIST 1.1 by BICR 
and the date of death. Death is always considered a PD event.
For the primary analysis, any participant who experiences an event (PD or death) 
immediately after 2 or more missed disease assessments will be censored at the last disease 
assessment prior to the missed visits. In addition, any participant who initiates new 
anticancer therapy prior to documented progression will be censored at the last disease 
assessment prior to the initiation of new anticancer therapy. Participants who do not start new 
anticancer therapy and who do not experience an event will be censored at the last disease 
assessment. If a participant meets multiple criteria for censoring, the censoring criterion that 
occurs earliest will be applied. Sensitivity analyses will be performed for PFS based on 
investigator's assessment.
In order to evaluate the robustness of the PFS endpoint per RECIST 1.1 by BICR, 
2 sensitivity analyses with different sets of censoring rules will be performed. The first 
sensitivity analysis follows the intention-to-treat principle. That is, PDs/deaths are counted as 
events regardless of missed study visits or initiation of new anticancer therapy. The second 
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sensitivity analysis considers initiation of new anticancer treatment or discontinuation of 
treatment due to reasons other than CR, whichever occurs later, to be a PD event for 
participants without documented PD or death. If a participant meets multiple criteria for 
censoring, the censoring criterion that occurs earliest will be applied. The censoring rules for 
the primary and sensitivity analyses are summarized in Table 11.
Table 11
Censoring Rules for Primary and Sensitivity Analysis of PFS
Situation
Primary Analysis
Sensitivity Analysis 1
Sensitivity Analysis 2
PD or death 
documented after ≤ 1 
missed disease 
assessment, and before 
new anticancer 
therapy, if any
Progressed at date of 
documented PD or 
death 
Progressed at date of 
documented PD or 
death
Progressed at date of 
documented PD or 
death
Death or progression 
immediately after ≥2 
consecutive missed 
disease assessments, 
or after new anticancer 
therapy
Censored at last 
disease assessment 
prior to the earlier 
date of ≥ 2 
consecutive missed 
disease assessment 
and new anticancer 
therapy, if any
Progressed at date of 
documented PD or 
death
Progressed at date of 
documented PD or 
death
No PD and no death; 
and new anticancer 
treatment is not 
initiated
Censored at last 
disease assessment 
Censored at last disease 
assessment 
Progressed at 
treatment 
discontinuation due to 
reasons other than 
complete response; 
otherwise censored at 
last disease assessment 
if still on study 
treatment or completed 
study treatment
No PD and no death; 
new anticancer 
treatment is initiated
Censored at last 
disease assessment 
before new anticancer 
treatment 
Censored at last disease 
assessment
Progressed at date of 
new anticancer 
treatment
PD=progressive disease; PFS=progression-free survival.
9.6.1.4
Overall Survival
The nonparametric Kaplan-Meier method will be used to estimate the survival curve.
Participants without documented death at the time of analysis will be censored at the date of 
the last known alive date.
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9.6.1.5
Analysis Strategy for Key Efficacy Variables
A summary of the primary analysis strategy for the key efficacy variables is provided in 
Table 12.
Table 12
Analysis Strategy for Key Efficacy Variables
Endpoint/Variable
Statistical Method
Analysis 
Population
Missing Data Approach
Primary Analyses
ORR per RECIST 
1.1 by BICR
Summary statistics with 
95% CI using Exact 
method based on 
binomial distribution
APaT
Participants with missing 
data are considered 
nonresponders
Secondary Analyses
DOR per RECIST 
1.1 by BICR
Summary statistics using 
Kaplan-Meier method
Responders in 
APaT population
Censored according to 
rules in Table 10
PFS per RECIST 
1.1 by BICR
Summary statistics using 
Kaplan-Meier method
APaT 
Censored according to 
rules in Table 11
OS
Summary statistics using 
Kaplan-Meier method
APaT 
Censored at the date 
participant last known to 
be alive
APaT=all participants as treated; BICR=blinded independent central review; DOR=duration of response; ORR=objective 
response rate; OS=overall survival; PFS=progression-free survival; RECIST 1.1=Response Evaluation Criteria in Solid 
Tumors.
9.6.2
Statistical Methods for Safety Analysis
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, laboratory parameters, vital signs and ECG measurements. The broad AE categories 
consisting of the percentage of participants with any AE, a drug-related AE, a serious AE, an 
AE which is both drug-related and serious, a Grade 3 to 5 AE, a drug-related Grade 3 to 5 
AE, and who discontinued due to an AE will be summarized. The number and percentage of 
participants with increased laboratory toxicity grade shift from baseline will also be 
provided.
The primary safety analyses will include only events that occur before Second Course 
treatment.
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9.6.3
Demographic and Baseline Characteristics
The number and percentage of participants screened and allocated and the primary reasons 
for screening failure and discontinuation will be displayed. Demographic variables, baseline 
characteristics, primary and secondary diagnoses, and prior and concomitant therapies will be 
summarized by descriptive statistics or categorical tables.
9.7
Interim Analyses
No formal interim analyses are planned for this study.
9.7.1
Efficacy Interim Analysis
No formal interim analysis for efficacy is planned for this study. The final analysis is to be 
performed approximately 36 months after the last participant is enrolled. Participants will 
continue to be followed after the final analysis until the overall study ends.
9.7.2
Safety Interim Analysis
The study team will be responsible for periodic safety monitoring and reviews. No formal
interim safety analysis will be performed for this study.
9.8
Multiplicity
Since there is no formal hypothesis testing for this estimation study, no multiplicity 
adjustment is planned.
9.9
Sample Size and Power Calculations
In this study, approximately 152 participants with nccRCC will be enrolled.
Table 13 shows the two-sided 95% confidence intervals for ORR with 152 participants for 
different observed response rates based on the method of Clopper and Pearson (1934) 
[Clopper, C. J. and Pearson, E. S. 1934].
Table 13
Two-sided 95% Confidence Intervals for ORR with 152 Participants
Number of Observed Responders
ORR Estimates
95% CI of ORR (%)
53
34.9%
(27.3, 43.0)
61
40.1%
(32.3, 48.4)
64
42.1%
(34.2, 50.4)
68
44.7%
(36.7, 53.0)
CI=confidence interval; ORR=objective response rate.
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9.10
Subgroup Analyses
To determine whether the treatment effect is consistent across various subgroups, the 
estimate of ORR (with nominal 95% CIs) will be estimated and plotted within each category 
of the following subgroup variables:

Geographic region (US, EU, ROW)

IMDC risk factor (favorable, intermediate, or poor) 

PD-L1 CPS (<1, ≥1)

Age category (<65 years, ≥65 years)

Sex (female, male)

Race (white, all others)

Histologic subtype (papillary, chromophobe, translocation, unclassified)

Sarcomatoid Feature (with, without)
The consistency of the treatment effect will be assessed using descriptive statistics for each 
category of the subgroup variables listed above. If the number of participants in a category of 
a subgroup variable is less than 10% of the APaT population, the subgroup analysis will not 
be performed for this category of the subgroup variable, and this subgroup variable will not 
be displayed in the forest plot.
9.11
Compliance (Medication Adherence)
Drug accountability data for study treatment will be collected during the study. Any 
deviation from protocol-directed administration will be reported.
9.12
Extent of Exposure
Extent of Exposure for a participant is defined as the number of cycles and number of days 
for which the participant receives the study treatment. Summary statistics will be provided on 
the extent of exposure for the overall study treatment, and for pembrolizumab and lenvatinib 
separately, for the APaT population. 
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Code of Conduct for Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing, and reporting these trials 
in compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design and conduct of clinical trials. In all cases, MSD clinical trials will be conducted 
in compliance with local and/or national regulations (including all applicable data protection laws and
regulations), and International Council for Harmonisation Good Clinical Practice (ICH-GCP), and also in 
accordance with the ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD irrespective of the party (parties) employed for their execution (e.g., contract research organizations, 
collaborative research efforts). This Code is not intended to apply to trials that are observational in nature, or 
which are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the 
full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of MSD or comparator products. Alternatively, MSD 
may conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to 
determine patient preferences, etc.
The design (i.e., participant population, duration, statistical power) must be adequate to address the specific 
purpose of the trial and shall respect the data protection rights of all participants, trial site staff and, where 
applicable, third parties. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
MSD selects investigative sites based on medical expertise, access to appropriate participants, adequacy of 
facilities and staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial 
initiation, sites are evaluated by MSD personnel (or individuals acting on behalf of MSD) to assess the ability 
to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and 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 
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Significant Quality Issues are reported, such matters are investigated. When necessary, appropriate corrective 
and/or preventative actions are defined and regulatory authorities and/or ethics review committees are 
notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the pre-specified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important 
to patients, physicians, and payers. Some early phase or pilot trials are intended to be hypothesis-generating rather 
than hypothesis testing; in such cases, publication of results may not be appropriate since the trial may be 
underpowered and the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). In summary, authorship should reflect significant contribution to the design and 
conduct of the trial, performance or interpretation of the analysis, and/or writing of the manuscript. All named 
authors must be able to defend the trial results and conclusions. MSD funding of a trial will be acknowledged in 
publications.
III. Participant Protection
A. Regulatory Authority and Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics 
Committee [IEC])
All protocols and protocol amendments will be submitted by MSD for regulatory authority 
acceptance/authorization prior to implementation of the trial or amendment, in compliance with local and/or 
national regulations.
The protocol, protocol amendment(s), informed consent form, investigator’s brochure, and other relevant trial 
documents must be reviewed and approved by an IRB/IEC before being implemented at each site, in compliance 
with local and/or national regulations. Changes to the protocol that are required urgently to eliminate an 
immediate hazard and to protect participant safety may be enacted in anticipation of ethics committee approval. 
MSD will inform regulatory authorities of such new measures to protect participant safety, in compliance with 
local and/or national regulations.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance. 
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At 
a minimum, trial designs will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Participants may withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible, as well as all 
applicable data protection rights. Unless required by law, only the investigator, Sponsor (or individuals acting on 
behalf of MSD), ethics committee, and/or regulatory authorities will have access to confidential medical records 
that might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
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IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD does not pay incentives to 
enroll participants in its trials. However, when enrollment is particularly challenging, additional payments may be 
made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent 
on chart review and medical evaluation to identify potentially eligible participants.
B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may 
wish to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
10.1.2
Financial Disclosure
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required. It is the investigator's/subinvestigator's 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
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.
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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.
The Sponsor has EU-approved Binding Corporate Rules since 2017, covering all aspects of 
its Global Privacy Program (Corporate Policy 20), and is self-certified pursuant to the EU-US 
Data Privacy Framework.
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 prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules 
and regulations.
10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
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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
Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments.
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
10.1.5
Compliance with Study Registration and Results Posting Requirements
Under the terms of the FDAAA of 2007 and the EMA clinical trials Regulation 536/2014, 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, https://euclinicaltrials.eu, or other local registries. MSD, as 
Sponsor of this study, will review this protocol and submit the information necessary to 
fulfill these requirements. MSD entries are not limited to FDAAA or the EMA clinical trial 
directive mandated trials. Information posted will allow participants to identify potentially 
appropriate studies for their disease conditions and pursue participation by calling a central 
contact number for further information on appropriate study locations and study site contact 
information.
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive, or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this study or its results to those 
registries.
10.1.6
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of GCP
(eg, International Council on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use 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.
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The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in 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.
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, the 
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 that 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.
10.1.7
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.
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Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including participants’ documented informed consent, pertaining to 
the conduct of this study must be retained by the investigator for 15 years after study 
completion unless local regulations or institutional policies require a longer retention period
(eg, EU CTR: 25 years after the end of the study). 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.
10.1.8
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
of the site’s participants. Source documents and data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained if necessary (eg, via 
an audit trail). 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.
10.1.9
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 14 will be performed by the local laboratory.
•
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5.
•
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations.
•
Pregnancy testing:
-
Pregnancy testing requirements for study inclusion are described in Section 5.1.
-
Pregnancy testing (urine and/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 individual’s participation in the study.
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Table 14
Protocol-required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count 
RBC Indices:
MCV
MCH
Reticulocytesa
WBC count with Differentiala:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Chemistry
BUN or ureab
Potassium
AST/SGOT
Total bilirubin (and 
direct bilirubin, if 
total bilirubin is 
elevated above the 
ULN)
Albumin
Bicarbonate or CO2 c
Chloride
Phosphorous
Creatinine
Sodium
ALT/SGPT
Total Protein
Glucose (fasting, or 
nonfasting)
Calcium
Alkaline 
phosphatase
Magnesium
Amylase
Lipase
Routine 
Urinalysis as 
Clinically 
Indicated
•
Specific gravity
•
pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte 
esterase by dipstick/urinalysis
•
Microscopic examination (if blood or protein is abnormal)
Other Screening 
Tests
•
FSH (as needed in WONCBP only)
•
Highly sensitive serum or urine hCG pregnancy test (as needed for WOCBP)
•
Serology (HIV antibody, HBsAg, and/or Hepatitis C virus antibody) as required by 
local health authority
•
T3 (or FT3 if T3 is unavailable), FT4 and TSH
•
PT/INR and aPTT (PTT may be performed if lab cannot perform aPTT)
ALT=alanine aminotransferase; aPTT=activated partial thromboplastin time; AST=aspartate aminotransferase; 
BUN=blood urea nitrogen; FSH=follicle-stimulating hormone; FT3=free triiodothyronine; FT4=free thyroxine; 
HBsAG=hepatitis B surface antigen; hCG=human chorionic gonadotropin; INR=international normalized ratio; 
MCH=mean corpuscular hemoglobin; MCV=mean corpuscular volume; PT=prothrombin time; PTT= partial 
thromboplastin time; RBC=red blood cell; SGOT=serum glutamic-oxaloacetic transaminase; SGPT=serum glutamic-
pyruvic transaminase; T3=triiodothyronine; TSH=thyroid-stimulating hormone; ULN=upper limit of normal; 
WBC=white blood cell; WOCBP=women of childbearing potential; WONCBP=women of nonchildbearing potential.
NOTES:
a.
Report % or absolute results per standard practice. Report the results in the same manner throughout the study.
b.
BUN is preferred; if not available, urea may be tested.
c.
If these tests are not performed as part of standard of care in a particular country, then they do not need to be 
performed for sites in that country.
The investigator (or medically qualified designee) must document their review of each 
laboratory safety report.
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definitions of Medication Error, Misuse, and Abuse
Medication error
This is an unintended failure in the drug treatment process that leads to or has the potential to 
lead to harm to the patient.
Misuse
This refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the terms of the product information.
Abuse
This corresponds to the persistent or sporadic intentional, excessive use of a medicinal 
product for a perceived psychological or physiological reward or desired nontherapeutic 
effect.
10.3.2
Definition of AE
AE definition
•
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.
•
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.
•
NOTE: For purposes of AE definition, study intervention (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, 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.
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•
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.
•
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.
•
For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”
•
Any new cancer (that is not a condition of the study). Progression of the cancer under 
study is not a reportable event. Refer to Section 8.4.6 for additional details.
Events NOT meeting the AE definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
•
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
•
Surgery planned prior to informed consent to treat a pre-existing condition that has not 
worsened.
•
Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.3
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b. Is life-threatening
•
The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
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c.
Requires inpatient hospitalization or prolongation of existing hospitalization
•
Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not an SAE.) A pre-existing condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
d. Results in persistent or significant disability/incapacity
•
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
•
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
•
In offspring of participant taking the product regardless of time to diagnosis.
f.
Other important medical events
•
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
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10.3.4
Additional Events Reported in the Same Manner as SAE
Additional events that require reporting in the same manner as SAE
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor in the same time frame as SAEs to 
meet certain local requirements. Therefore, these events are considered serious by the 
Sponsor for collection purposes.
•
Is a new cancer (that is not a condition of the study)
•
Is associated with an overdose
10.3.5
Recording AE and SAE
AE and SAE recording
•
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.
•
The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.
•
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
•
There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.
•
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity
•
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
•
The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) according to the NCI CTCAE, version 5.0. Any AE that changes 
CTCAE grade over the course of a given episode will have each change of grade 
recorded on the AE CRFs/worksheets.
-
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated.
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-
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental ADL.
-
Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care ADL.
-
Grade 4: Life threatening consequences; urgent intervention indicated.
-
Grade 5: Death related to AE.
Assessment of causality
•
Did the Sponsor’s product cause the AE?
•
The determination of the likelihood that the Sponsor’s product caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed 
document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test product and the AE based upon the available information.
•
The following components are to be used to assess the relationship between the 
Sponsor’s product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Sponsor’s 
product caused the AE:
-
Exposure: Is there evidence that the participant was actually exposed to the 
Sponsor’s product such as: reliable history, acceptable compliance assessment (pill 
count, diary, etc), expected pharmacologic effect, or measurement of 
drug/metabolite in bodily specimen?
-
Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the Sponsor’s product? Is the time of onset of the AE compatible 
with a drug-induced effect (applies to studies with investigational medicinal 
product)?
-
Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors.
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-
Dechallenge: Was the Sponsor’s product discontinued or dose/exposure/frequency 
reduced?
◦
If yes, did the AE resolve or improve?
◦
If yes, this is a positive dechallenge.
◦
If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent 
disability; (2) the AE resolved/improved despite continuation of the Sponsor’s 
product; (3) the study is a single-dose drug study; or (4) Sponsor’s product(s) is/are 
only used 1 time.)
-
Rechallenge: Was the participant re-exposed to the Sponsor’s product in this 
study?
◦
If yes, did the AE recur or worsen?
◦
If yes, this is a positive rechallenge.
◦
If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or 
permanent disability, or (2) the study is a single-dose drug study; or (3) Sponsor’s 
product(s) is/are used only 1 time.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE SPONSOR’S PRODUCT, OR IF RE-EXPOSURE 
TO THE SPONSOR’S PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR AS PER DOSE 
MODIFICATION GUIDELINES IN THE PROTOCOL, AND IF REQUIRED, THE 
INIRB/IEC.
•
Consistency with study intervention profile: Is the clinical/pathological presentation of 
the AE consistent with previous knowledge regarding the Sponsor’s product or drug class 
pharmacology or toxicology?
•
The assessment of relationship will be reported on the case report forms/worksheets by 
an investigator who is a qualified physician according to his/her best clinical judgment, 
including consideration of the above elements.
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•
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Sponsor’s product relationship).
-
Yes, there is a reasonable possibility of Sponsor’s product relationship:
◦
There is evidence of exposure to the Sponsor’s product. The temporal sequence 
of the AE onset relative to the administration of the Sponsor’s product is 
reasonable. The AE is more likely explained by the Sponsor’s product than by 
another cause.
-
No, there is not a reasonable possibility of Sponsor’s product relationship:
◦
Participant did not receive the Sponsor’s product OR temporal sequence of the 
AE onset relative to administration of the Sponsor’s product is not reasonable 
OR the AE is more likely explained by another cause than the Sponsor’s 
product. (Also entered for a participant with overdose without an associated 
AE.)
•
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.
•
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.
•
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.
•
For studies in which multiple agents are administered as part of a combination regimen, 
the investigator may attribute each AE causality to the combination regimen or to a single 
agent of the combination. In general, causality attribution should be assigned to the 
combination regimen (ie, to all agents in the regimen). However, causality attribution 
may be assigned to a single agent if in the investigator’s opinion, there is sufficient data 
to support full attribution of the AE to the single agent.
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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.
-
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
-
If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper AE Reporting form.
◦
Reference Section 8.4.1 for reporting time requirements.
•
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
•
After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.
•
If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).
•
Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF
•
If the EDC tool is not operational, facsimile transmission or secure e-mail of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.
•
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
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•
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
Not applicable.
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10.5
Appendix 5: Contraceptive Guidance
10.5.1
Definitions
Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below):
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
•
Premenarchal
•
Premenopausal female with 1 of the following:
-
Documented hysterectomy
-
Documented bilateral salpingectomy
-
Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
•
Postmenopausal female
-
A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause.
◦
A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. 
However, in the absence of 12 months of amenorrhea, confirmation with two 
FSH measurements in the postmenopausal range is required.
-
Females 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
Contraception Requirements
Contraceptives allowed during the study includea:
Highly Effective Contraceptive Methods That Have Low User Dependency
Failure rate of <1% per year when used consistently and correctly.
•
Progestogen-only subdermal contraceptive implantb
•
IUSc
•
Non-hormonal IUD
•
Bilateral tubal occlusion
•
Azoospermic partner (vasectomized or secondary to medical cause)
This is a highly effective contraception method provided that the partner is the sole male sexual partner of 
the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used. A spermatogenesis cycle is approximately 90 days.
Note: Documentation of azoospermia for a male participant can come from the site personnel’s review of 
the participant’s medical records, medical examination, or medical history interview.
Sexual Abstinence
•
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle 
of the participant.
a    Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for participants of clinical studies.
b    If locally required, in accordance with CTFG guidelines, acceptable contraceptive implants are limited to 
those which inhibit ovulation.
c    IUS is a progestin releasing IUD.
Note: The following are not acceptable methods of contraception:
-  Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and LAM.
-  Male condom with cap, diaphragm, or sponge with spermicide.
-  Male and female condom should not be used together (due to risk of failure with friction).
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
Not applicable.
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10.7
Appendix 7: Country-specific Requirements
10.7.1
UK-specific Requirements
The UK has country-specific requirements for the protocol, which are summarized below.
Section 1.3 – Schedule of Activities
In addition to the assessments and procedures indicated in Section 1.3 – Schedule of 
Activities, participants in the UK should have the following procedures/assessments 
performed:
Study Period:
Screening Phase
Notes
Cycle Number/ Visit Title
Screening Visit
Cycle Day
Safety Procedures
HIV, Hepatitis B, Hepatitis C
X
Required
Section 5.2 – Exclusion Criteria
For Exclusion Criteria No. 24 (HIV infection) and No. 25 (Hepatitis B and Hepatitis C 
infection), testing for HIV, Hepatitis B, and Hepatitis C must be performed in the UK during 
screening in order to determine a participant’s eligibility for the study.
Section 6.5 – Concomitant Therapy
In addition to all restrictions or concomitant medications listed in Section 6.5 – Concomitant 
Therapy, the following restriction applies to participants in the UK:
•
Live vaccines within 30 days prior to the first dose of study intervention, while 
participating in the study, and for 90 days after the last dose of study treatment, are 
prohibited.
10.7.2
Canada-specific Requirements
Please refer to the current lenvatinib product monograph for management of AEs associated 
with lenvatinib administration.
Section 6.6.2.9 – Management of Gastrointestinal Perforation or Fistula Formation
Lenvatinib should be discontinued in any participant who develops gastrointestinal 
perforation of any grade or ≥ Grade 3 fistula.
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10.8
Appendix 8: Description of the iRECIST Process for Assessment of Disease 
Progression
Not applicable.
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10.9
Appendix 9: Abbreviations
Abbreviation
Expanded Term
ADL
activities of daily living  
AE
adverse event 
ALT
alanine aminotransferase
APaT
All Participants as Treated
AST
aspartate transaminase
AUC
area under the curve
BCG
Bacillus Calmette–Guérin
BICR
blinded independent central review
BMI
body mass index
BP
blood pressure
CBR
clinical benefit ratio
CD28
cluster of differentiation 28
CD3ζ
CD3 zeta
Cmax
maximum concentration
Cmin
minimum concentration
CNS
central nervous system 
CONSORT
Consolidated Standards of Reporting Trials
CPS
combined positive score
CR
complete response
CRF
Case Report Form 
CSR
Clinical Study Report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTCAE 5.0
Common Terminology Criteria for Adverse Events, Version 5.0
ctDNA
circulating tumor DNA
CTFG
Clinical Trial Facilitation Group 
CTLA-4
cytotoxic T-lymphocyte-associated protein 4
CTR
Clinical Trial Regulation
DAIDS
Division of AIDS
DCR
disease control rate
DDI
Drug-drug interaction
DILI
drug-induced liver injury
DLT
dose limiting toxicity
DMC
Data Monitoring Committee 
DNA
deoxyribonucleic acid 
DOR
duration of response
DVT
deep vein thrombosis
EAU
European Association of Urology
ECG
electrocardiogram 
ECI
event of clinical interest
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
EDC
electronic data collection 
EEA
European Economic Area
eGFR
estimated glomerular filtration rate
ELISA
enzyme-linked immunosorbent assay
EMA
European Medicines Agency
EU
European Union
FDAAA
Food and Drug Administration Amendments Act
FFPE
formalin-fixed, paraffin embedded
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Abbreviation
Expanded Term
FGF
fibroblast growth factor
FGFR
fibroblast growth factor receptor
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice 
GI
gastrointestinal
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCC
hepatocellular carcinoma
hCG
human chorionic gonadotropin
HCV
Hepatitis C virus
HIV
human immunodeficiency virus
HR
heart rate
HRT
hormone replacement therapy
HUVEC
human umbilical vein endothelial cell
IB
Investigator’s Brochure 
ICF
Informed Consent Form
ICH
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use
iCRO
imaging CRO
ICSR
individual case safety report
IEC
Independent Ethics Committee
Ig
immunoglobulin
IgG4
immunoglobulin G4
IgV
immunoglobulin-variable
IHC
immunohistochemistry
IMDC
International Metastatic RCC Database Consortium
IND
Investigational New Drug 
INR
international normalized ratio
IO
immuno-oncology
irAEs
immune-related AEs
IRB
Institutional Review Board
IRT
interactive response technology
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IV
intravenous
IVD
in vitro diagnostic
IVRS
interactive voice response system
KIT
mast/stem cell growth factor receptor Kit
KPS
Karnofsky performance status
LAM
lactational amenorrhoea method
LVEF
left ventricular ejection fraction
mAb
monoclonal antibody
MAPK
mitogen-activated protein kinase
MRI
magnetic resonance imaging
mRNA
messenger RNA
MSI
microsatellite instability
MTD
maximum tolerated dose 
MUGA
multiple gated acquisition scan
NCCN
National Comprehensive Cancer Network
nccRCC
non-clear cell renal cell carcinoma
NCI
National Cancer Institute
NDA
New Drug Application 
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Abbreviation
Expanded Term
NSCLC
non-small cell lung cancer
ONJ
osteonecrosis of the jaw
OR
objective response
ORR
objective response rate
OS
overall survival
OTC
over-the-counter
PBMC
peripheral blood mononuclear cells
PD
progressive disease
PD-1
programmed cell-death 1
PD-L1
programmed cell-death ligand 1
PD-L2
programmed cell-death ligand 2
PFS
progression-free survival
PGIC
Patient Global Impression Change
PK
pharmacokinetic
PKCθ
protein kinase C-theta
PO
orally
PR
partial response
Q2W
every 2 weeks
Q3W
every 3 weeks
Q6W
every 6 weeks
QD
every day
QOL
quality of life
RCC
renal cell carcinoma
RECIST
response evaluation criteria in solid tumors
RET
proto-oncogene tyrosine-protein kinase receptor Ret
RNA
ribonucleic acid
ROW
rest of world
RP2D
recommended Phase 2 dose
RTK
receptor tyrosine kinase
SAC
Scientific Advisory Committee
SAE
serious adverse event 
SAP
Statistical Analysis Plan
SD
stable disease
SEER
Surveillance, Epidemiology, and End Results Program
SIM
Site Imaging Manual
SITC
Society for Immunotherapy of Cancer
SoA
schedule of activities
sSAP
supplemental Statistical Analysis Plan
SUSAR
suspected unexpected serious adverse reaction
TBL
total bilirubin
TRAE
treatment-related adverse event
ULN
upper limit of normal
US
United States
VEGF
vascular endothelial growth factor
VEGFR
vascular endothelial growth factor receptor
VS
vital sign
WBC
white blood cell
WOCBP
woman/women of childbearing potential 
ZAP70
zeta-chain-associated protein kinase
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11
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