A Multicenter, Open-label, Randomized, Phase 3 Trial to Compare the Efficacy and Safety of Lenvatinib in Combination With Pembrolizumab Versus Treatment of Physician's Choice in Participants With Advanced Endometrial Cancer
Phase: PHASE3
Conditions: Endometrial Neoplasms
Sponsor: Eisai Inc.

Official Protocol Title:
NCT number:
Document Date:
A Multicenter, Open label, Randomized, Phase 3 Trial 
to Compare the Efficacy and Safety of Lenvatinib in 
Combination with Pembrolizumab Versus Treatment of 
Physician’s Choice in Participants with Advanced 
Endometrial Cancer
NCT03517449
30-Nov-2022

Product:  MK-3475/E7080 
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30-Nov-2022
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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 Multicenter, Open label, Randomized, Phase 3 Trial to Compare the 
Efficacy and Safety of Lenvatinib in Combination with Pembrolizumab Versus Treatment of 
Physician’s Choice in Participants with Advanced Endometrial Cancer
Protocol Number: 775-09/E7080-G000-309
Compound Number: MK-3475/E7080
Global Sponsor of the Study
Eisai (Referenced herein as Sponsor)
Eisai Inc.
200 Metro Blvd
Nutley, NJ 07110
US
Eisai Ltd. 
European Knowledge Centre
Mosquito Way
Hatfield, Hertfordshire 
AL10 9SN UK
Eisai Co., Ltd. 
4-6-10 Koishikawa
Bunkyo-Ku,
Tokyo 112 8088
JP
Execution of Study: 
Merck Sharp & Dohme LLC
(hereafter called MSD)
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Regulatory Agency Identifying Number(s):
IND NUMBER: 118,808
EudraCT NUMBER: 2017-004387-35
Approval Date:  30 November 2022
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MSD Signatory
Typed Name:
Title:
Date
Protocol-specific MSD contact information can be found in the Investigator Trial 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
Original protocol
13-FEB-2018
Not applicable.
Amendment 01
21-MAR-2018
Germany-specific amendment to address country-specific request for HIV/HBV/HCV 
testing and pregnancy testing at screening.
Amendment 02
06-JUN-2018
United Kingdom-specific amendment to address country-specific requests for 
HIV/HBV/HCV testing at screening and contraception use.
Amendment 03
31-AUG-2018
Global protocol amendment to provide clarity with respect to the number of prior lines of 
treatment in order to be eligible for the study.
Amendment 04
01-OCT-2018
Germany-specific amendment to address country-specific requests for HIV/HBV/HCV 
testing and pregnancy testing and to incorporate changes implemented in Amendment 03 
to provide clarity with respect to the number of prior lines of treatment in order to be 
eligible for the study.
Amendment 05
02-OCT-2018
United Kingdom-specific amendment to address country-specific requests for 
HIV/HBV/HCV testing and to incorporate changes implemented in Amendment 03 to 
provide clarity with respect to the number of prior lines of treatment in order to be eligible 
for the study.
Amendment 06
18-FEB-2020
Revision to the statistical analysis plan to add an interim efficacy analysis to evaluate the 
superiority of PFS and OS.
Amendment 07
12-JUN-2020
Revision to the statistical analysis plan to revise the timing of interim efficacy analysis 
following communications with health authorities.
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Document
Date of Issue
Overall Rationale
Amendment 08
15-JUN-2021
To allow crossover from TPC to the lenvatinib plus pembrolizumab arm at time of 
progression and to remove interim analysis 2 since primary objectives already met,
including the final analysis of PFS.
Amendment 09
30-NOV-2022
To incorporate the option of an extension study; to remove the collection of further PRO 
data, as sufficient data have been collected for analyses.
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment 09
Overall Rationale for the Amendment:
To incorporate the option of an extension study; to remove the collection of further PRO data, as sufficient data have been collected 
for analyses.
Summary of Changes Table:
Section # and Name
Description of Change
Brief Rationale
1.1 Synopsis
6.7 Intervention After the End of 
the Study 
Study extension language incorporated:
Revision to allow eligible participants to 
transition to an extension study.
1.3.1 Schedule of Activities
4.2.2.3 Rationale for Patient
Reported Outcomes
8.2.2 Health-Related Quality of 
Life Assessments
The collection of PRO data will be 
discontinued following implementation of 
Amendment 09.
Sufficient PRO data have been collected for 
analyses based on collection of data for 2 years 
beyond the last participant enrolled, and further 
data collection is not needed.
Title Page
10.1 Regulatory, Ethical and Study 
Oversight Considerations
Throughout
Executor name and address change.
Merck Sharp & Dohme Corp. underwent an 
entity name and address change to Merck Sharp 
& Dohme LLC, Rahway, NJ, USA. This 
conversion resulted only in an entity name 
change and update to the address.
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Section # and Name
Description of Change
Brief Rationale
Title Page
Sponsor address change.
Eisai Inc. underwent an address change to 
Nutley, NJ, USA. This conversion resulted only 
in an update to the address
4.4 Beginning and End of Study 
Definition
Added text about the beginning and end of 
the study in the European Economic Area.
Revision to align with the EU clinical trial 
regulation (CTR) No. 536/2014 of the European 
Parliament and of the Council.
5 Study Population
Added text about the collection and use of 
demographic data.
Removed a note from Table 1 for adequate 
organ function.
6.1 Study Intervention(s) 
Administered
Updated “Use” of pembrolizumab from 
experimental to test product.
8.4 Adverse Events (AEs), Serious 
Adverse Events (SAEs), and Other 
Reportable Safety Events
Added that investigators need to document 
if an SAE was associated with a 
medication error, misuse, or abuse.
8.5 Treatment of Overdose
Added text about participation observation 
for signs of toxicity and the provision of 
appropriate supportive treatment, in the 
event of an overdose.
10.3.1 Definitions of Medication 
Error, Misuse, and Abuse
Added a new section with definitions of 
medication error, misuse, and abuse. 
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Section # and Name
Description of Change
Brief Rationale
6.5 Concomitant Therapy
Removed the exclusion criterion regarding 
prohibited medications or vaccinations, 
and restructured the criteria based on 
concomitant therapy that requires
discontinuation of study intervention 
versus that which would require 
consultation with the sponsor.
Clarify criteria due to investigator questions 
related to exclusion criteria component and 
concomitant therapy.
6.5.2 Prohibited Concomitant 
Medications
Added text to clarify that live vaccines 
must not be administered within 30 days 
prior to the first dose of study intervention, 
while participating in the study, and for 
120 days after the last dose of study 
intervention.
Additionally, the list of specific examples 
of live vaccines was removed.
To clarify live vaccine administration. 
Added asthma as justification for 
glucocorticoid use.
To provide additional clarity.
10.9.2 United Kingdom
Added note about timing for COVID-19 
vaccine administration.
To clarify when COVID-19 vaccines are 
allowed to be administered while on-study and 
to provide guidance on time window of 
administration.
10.9.3 Japan
Added country-specific text clarifying 
post-marketing terminology applicable for 
Japan.
Revision to address a request from the 
Pharmaceuticals and Medical Devices Agency. 
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Section # and Name
Description of Change
Brief Rationale
Throughout
Minor administrative, formatting, 
grammatical, and typographical changes 
were made throughout the protocol 
(including those from Global PCL from 
2021). 
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...............................................5
1
Protocol Summary .....................................................................................................20
1.1
Synopsis....................................................................................................................20
1.2
Schema .....................................................................................................................26
1.3
Schedule of Activities (SoA) ...................................................................................27
1.3.1
Schedule of Activities –Treatment Period ...........................................................27
1.3.2
Schedule of Activities – Second Course Phase (Retreatment) ............................42
1.3.3
Schedule of Activities – Crossover Phase for TPC Arm Only ............................49
2
Introduction................................................................................................................58
2.1
Study Rationale .......................................................................................................58
2.1.1
Background..........................................................................................................58
2.1.2
Pharmaceutical and Therapeutic Background .....................................................58
2.1.2.1
Lenvatinib .....................................................................................................58
2.1.2.2
Pembrolizumab .............................................................................................59
2.1.2.3
Endometrial Cancer: Epidemiology and Current Therapeutic 
Options..........................................................................................................60
2.1.2.4
Scientific Rationale for the Combination of Lenvatinib with 
Pembrolizumab.............................................................................................60
2.1.2.5
Clinical Data on Lenvatinib in Combination with Pembrolizumab 
for Treatment of EC......................................................................................61
2.1.2.6
Clinical Data on Lenvatinib and Pembrolizumab as Single Agents 
for the Treatment of EC................................................................................61
2.1.3
Preclinical and Clinical Studies ...........................................................................63
2.1.4
Ongoing Clinical Studies .....................................................................................63
2.1.5
Information on Other Study-related Therapy ......................................................63
2.2
Benefit/Risk Assessment.........................................................................................63
3
Objectives/Hypotheses and Endpoints.....................................................................64
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4
Study Design...............................................................................................................67
4.1
Overall Design .........................................................................................................67
4.1.1
Screening Period ..................................................................................................68
4.1.2
Treatment Period..................................................................................................69
4.1.3
Crossover for Participants in TPC Arm to Lenvatinib 20 mg QD plus
Pembrolizumab 200 mg Q3W Arm .....................................................................70
4.1.4
Efficacy Follow-up Period...................................................................................70
4.1.5
Data Monitoring Committee................................................................................71
4.1.6
Interim Analyses ..................................................................................................71
4.2
Scientific Rationale for Study Design....................................................................71
4.2.1
Rationale for Patient Population ..........................................................................71
4.2.2
Rationale for Endpoints .......................................................................................72
4.2.2.1
Efficacy Endpoints........................................................................................72
4.2.2.1.1
RECIST 1.1............................................................................................72
4.2.2.1.2
Modified RECIST 1.1 for Immune-based Therapeutics 
(iRECIST)..............................................................................................72
4.2.2.2
Safety Endpoints...........................................................................................73
4.2.2.3
Rationale for Patient Reported Outcomes.....................................................73
4.2.2.3.1
EORTC QLQ-30....................................................................................73
4.2.2.3.2
EORTC QLQ-EN24 ..............................................................................73
4.2.2.3.3
EuroQoL EQ-5D-5L..............................................................................74
4.2.2.4
Pharmacodynamic Endpoints........................................................................74
4.2.2.5
Planned Exploratory Biomarker Research....................................................74
4.2.3
Rationale for the Use of Comparator...................................................................76
4.3
Justification for Dose ..............................................................................................76
4.3.1
Lenvatinib ............................................................................................................76
4.3.2
Pembrolizumab ....................................................................................................76
4.3.3
Chemotherapy......................................................................................................77
4.3.4
Maximum Dose/Exposure for This Study ...........................................................77
4.4
Beginning and End of Study Definition ................................................................77
4.4.1
Clinical Criteria for Early Study Termination .....................................................78
5
Study Population........................................................................................................78
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5.1
Inclusion Criteria....................................................................................................78
5.2
Exclusion Criteria ...................................................................................................80
5.3
Lifestyle Considerations .........................................................................................83
5.3.1
Meals and Dietary Restrictions............................................................................83
5.3.2
Contraception.......................................................................................................83
5.3.3
Pregnancy.............................................................................................................83
5.3.4
Use in Nursing Women........................................................................................84
5.4
Screen Failures ........................................................................................................84
5.5
Participant Replacement Strategy.........................................................................84
6
Treatments..................................................................................................................84
6.1
Treatments Administered.......................................................................................84
6.2
Preparation/Handling/Storage/Accountability ....................................................86
6.2.1
Dose Preparation..................................................................................................86
6.2.2
Handling, Storage and Accountability.................................................................86
6.3
Measures to Minimize Bias: Randomization and Blinding.................................87
6.3.1
Method of Treatment Assignment .......................................................................87
6.3.1.1
Stratification..................................................................................................87
6.3.2
Blinding................................................................................................................87
6.4
Treatment Compliance...........................................................................................87
6.5
Concomitant Therapy.............................................................................................87
6.5.1
Allowed Concomitant Medication.......................................................................88
6.5.2
Prohibited Concomitant Medications...................................................................88
6.5.3
Drug-Drug Interactions........................................................................................89
6.5.4
Rescue Medications and Supportive Care ...........................................................90
6.5.5
Hematopoietic Growth Factors............................................................................90
6.6
Dose Modification (Escalation/Titration/Other)..................................................90
6.6.1
Lenvatinib ............................................................................................................91
6.6.1.1
Management of Hypertension.......................................................................92
6.6.1.2
Management of Proteinuria...........................................................................94
6.6.1.3
Management of Diarrhea ..............................................................................95
6.6.1.4
Management of Hepatotoxicity.....................................................................95
6.6.1.5
Management of Thromboembolic Events.....................................................95
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6.6.1.6
Management of Posterior Reversible Encephalopathy 
Syndrome/Reversible Encephalopathy Syndrome/Reversible 
Posterior Leukoencephalopathy Syndrome ..................................................95
6.6.1.7
Management of Hypocalcemia .....................................................................96
6.6.1.8
Management of Hemorrhage ........................................................................96
6.6.1.9
Management of Gastrointestinal Perforation or Fistula Formation..............96
6.6.2
Pembrolizumab ....................................................................................................96
6.6.2.1
Dose Modification and Toxicity Management for Immune-related 
AEs Associated with Pembrolizumab...........................................................96
6.6.2.2
Dose Modification and Toxicity Management of Infusion-reactions 
Related to Pembrolizumab..........................................................................100
6.6.3
Dose Modifications for Overlapping Toxicities ................................................103
6.6.4
Other Allowed Dose Interruptions for Lenvatinib and Pembrolizumab............104
6.6.5
Second Course Phase (Retreatment Period).......................................................104
6.6.6
Treatment of Physician’s Choice.......................................................................105
6.7
Intervention After the End of the Study.............................................................105
6.8
Clinical Supplies Disclosure.................................................................................105
7
Discontinuation of Study Treatment and Participant Withdrawal ....................105
7.1
Discontinuation of Study Treatment...................................................................105
7.1.1
Discontinuation of Pembrolizumab After Complete Response.........................107
7.1.2
Crossover Phase.................................................................................................107
7.2
Participant Withdrawal From the Study............................................................107
7.3
Lost to Follow-up ..................................................................................................108
8
Study Assessments and Procedures........................................................................108
8.1
Administrative and General Procedures ............................................................109
8.1.1
Informed Consent...............................................................................................109
8.1.1.1
General Informed Consent..........................................................................109
8.1.2
Inclusion/Exclusion Criteria ..............................................................................109
8.1.3
Participant Identification Card...........................................................................109
8.1.4
Medical History .................................................................................................110
8.1.5
Prior and Concomitant Medications Review .....................................................110
8.1.5.1
Prior Medications........................................................................................110
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8.1.5.2
Concomitant Medications...........................................................................110
8.1.6
Assignment of Screening Number.....................................................................110
8.1.7
Assignment of Treatment/Randomization Number...........................................111
8.1.8
Treatment Administration..................................................................................111
8.1.8.1
Timing of Dose Administration..................................................................111
8.1.8.1.1
Lenvatinib............................................................................................111
8.1.8.1.2
Pembrolizumab....................................................................................111
8.1.8.1.3
Treatment of Physician’s Choice.........................................................112
8.1.9
Discontinuation and Withdrawal .......................................................................112
8.1.10 Participant Blinding/Unblinding........................................................................112
8.1.11 Calibration of Equipment...................................................................................112
8.1.12 Demography.......................................................................................................112
8.2
Efficacy/Immunogenicity Assessments ...............................................................112
8.2.1
Tumor Imaging and Assessment of Disease......................................................112
8.2.1.1
Initial Tumor Imaging.................................................................................113
8.2.1.2
Tumor Imaging During the Study...............................................................114
8.2.1.2.1
Bone Imaging During the Study..........................................................114
8.2.1.2.2
Brain Imaging During the Study..........................................................115
8.2.1.3
End of Treatment and Follow-up Tumor Imaging......................................115
8.2.1.4
Second Course (Retreatment) Tumor Imaging...........................................115
8.2.1.4.1
Bone Imaging During Second Course .................................................116
8.2.1.4.2
Brain Imaging During Second Course.................................................116
8.2.1.5
RECIST 1.1 Assessment of Disease...........................................................116
8.2.1.6
iRECIST Assessment of Disease................................................................116
8.2.2
Health-Related Quality of Life Assessments.....................................................119
8.2.3
Crossover Phase Assessments and Procedures..................................................120
8.3
Safety Assessments................................................................................................121
8.3.1
Physical Examinations.......................................................................................121
8.3.2
Vital Signs..........................................................................................................121
8.3.3
Electrocardiograms ............................................................................................122
8.3.4
Echocardiogram or Multiple Gated Acquisition Scan.......................................122
8.3.5
Clinical Safety Laboratory Assessments............................................................122
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8.3.5.1
Hematology and Clinical Chemistry...........................................................123
8.3.5.2
Urine Dipstick.............................................................................................123
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Reportable Safety Events .....................................................................................123
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ................................................................123
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events............126
8.4.3
Follow-up of AE, SAE and Other Reportable Safety Event Information..........126
8.4.4
Regulatory Reporting Requirements for SAE ...................................................126
8.4.5
Disease-related Events and/or Disease-related Outcomes Not 
Qualifying as AEs or SAEs................................................................................126
8.4.6
Pregnancy and Exposure During Breastfeeding ................................................127
8.4.7
Events of Clinical Interest (ECIs)......................................................................127
8.5
Treatment of Overdose.........................................................................................127
8.6
Pharmacokinetics..................................................................................................128
8.7
Pharmacodynamics...............................................................................................128
8.8
Mismatch Repair Status.......................................................................................128
8.9
Biomarkers ............................................................................................................128
8.9.1
Blood and Tissue Biomarker Assessment..........................................................129
8.10
Future Biomedical Research Sample Collection................................................129
8.11
Medical Resource Utilization and Health Economics........................................129
8.12
Visit Requirements................................................................................................129
8.12.1 Screening............................................................................................................129
8.12.2 Treatment Period................................................................................................130
8.12.2.1 Crossover Phase..........................................................................................130
8.12.3 Post-treatment Visit ...........................................................................................131
8.12.3.1 Safety Follow-up.........................................................................................131
8.12.3.2 Efficacy Follow-up Visits...........................................................................131
8.12.3.3 Survival Follow-up Contact........................................................................132
8.12.4 Survival Status ...................................................................................................132
9
Statistical Analysis Plan ..........................................................................................132
9.1
Statistical Analysis Plan Summary......................................................................133
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9.2
Responsibility for Analyses/In-house Blinding...................................................134
9.3
Hypotheses/Estimation .........................................................................................135
9.4
Analysis Endpoints................................................................................................135
9.4.1
Primary Endpoints .............................................................................................135
9.4.2
Secondary Endpoints .........................................................................................135
9.4.3
Exploratory Endpoints .......................................................................................136
9.5
Analysis Populations.............................................................................................136
9.5.1
Efficacy Analysis Population.............................................................................136
9.5.2
Safety Analysis Population................................................................................136
9.5.3
Health-Related Quality of Life Analysis Population.........................................137
9.5.4
Population Pharmacokinetic Analysis Set .........................................................137
9.6
Statistical Methods................................................................................................137
9.6.1
Statistical Methods for Efficacy Analyses.........................................................137
9.6.1.1
Primary Efficacy Analysis..........................................................................137
9.6.1.2
Secondary Efficacy Analysis......................................................................139
9.6.2
Statistical Analysis for Safety Analysis.............................................................139
9.6.3
Statistical Analysis for Health-Related Quality of Life Data ............................141
9.6.4
Summaries of Baseline Characteristics and Demographics...............................141
9.7
Interim Analyses ...................................................................................................141
9.7.1
Safety Interim Analyses.....................................................................................142
9.7.2
Efficacy Interim Analyses..................................................................................142
9.8
Multiplicity ............................................................................................................143
9.9
Sample Size and Power Calculations ..................................................................145
9.10
Subgroup Analyses................................................................................................146
9.11
Compliance (Medication Adherence)..................................................................146
9.12
Extent of Exposure................................................................................................147
10
Supporting Documentation and Operational Considerations.............................148
10.1
Appendix 1:  Regulatory, Ethical and Study Oversight Considerations .........148
Code of Conduct for Clinical Trials...............................................................................148
Financial Disclosure.......................................................................................................150
Data Protection...............................................................................................................150
Confidentiality of Data ..................................................................................................150
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Confidentiality of Participant Records...........................................................................150
Confidentiality of IRB/IEC Information........................................................................151
Committees Structure.....................................................................................................151
Scientific Advisory Committee..................................................................................151
Joint Executive Oversight Committee .......................................................................151
Data Monitoring Committee......................................................................................151
Publication Policy..........................................................................................................151
Compliance with Study Registration and Results Posting Requirements .....................152
Compliance with Law, Audit, and Debarment ..............................................................152
Data Quality Assurance .................................................................................................153
Source Documents .........................................................................................................154
Study and Site Closure...................................................................................................154
10.2
Appendix 2:  Contraceptive Guidance and Pregnancy Testing........................155
Definitions......................................................................................................................155
Contraception Requirements..........................................................................................155
Pregnancy Testing..........................................................................................................157
10.3
Appendix 3: Adverse Events:  Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting............................................158
Definitions of Medication Error, Misuse, and Abuse....................................................158
Definition of AE ............................................................................................................158
Definition of SAE ..........................................................................................................160
Additional Events Reported in the Same Manner as SAE.............................................161
Recording AE and SAE .................................................................................................161
Reporting of AEs, SAEs, and Other Reportable Safety Events to MSD.......................165
10.4
Appendix 4:  Clinical Laboratory Tests..............................................................166
10.5
Appendix 5:  Description of the iRECIST Process for Assessment of 
Disease Progression...............................................................................................168
10.6
Appendix 6:  Abbreviations .................................................................................172
10.7
Appendix 7:  Carcinoma of the Endometrium – FIGO Staging.......................177
10.8
Appendix 8:  New York Heart Association Cardiac Disease 
Classification..........................................................................................................178
10.9
Appendix 9: Country-specific Requirements .....................................................179
10.9.1 Germany.............................................................................................................179
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10.9.2 United Kingdom.................................................................................................179
10.9.3 Japan ..................................................................................................................180
11
References.................................................................................................................181
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LIST OF TABLES
Table 1
Adequate Organ Function Laboratory Values......................................................80
Table 2
Study Treatment(s) ...............................................................................................85
Table 3
Dose Modification Guidelines for Lenvatinib-Related Adverse Events 
(for the Lenvatinib-Pembrolizumab Combination Arm)......................................91
Table 4
Dose Modification and Toxicity Management Guidelines for Immune-
related Adverse Events Associated with Pembrolizumab Monotherapy, 
Coformulations or IO Combinations ....................................................................97
Table 5
Pembrolizumab Infusion Reaction Dose Modification and Treatment 
Guidelines...........................................................................................................101
Table 6
Imaging and Treatment After First Radiologic Evidence of Progressive 
Disease................................................................................................................118
Table 7
Reporting Time Periods and Time Frames for Adverse Events and 
Other Reportable Safety Events..........................................................................125
Table 8
Censoring Rules for Primary Analysis of Progression-Free Survival 
Based on RECIST 1.1.........................................................................................138
Table 9
Analysis Strategy for Safety Parameters ............................................................141
Table 10
Summary of Interim and Final Analysis Strategy for the pMMR 
Participants .........................................................................................................142
Table 11
Boundary Properties for Planned Analyses of OS Based on Potential 
Alpha-Levels to be Used for Testing in the pMMR Participants.......................145
Table 12
Highly Effective Contraception Methods...........................................................156
Table 13
Protocol-required Safety Laboratory Assessments.............................................166
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LIST OF FIGURES
Figure 1
Study Diagram......................................................................................................26
Figure 2
Imaging and Treatment for Clinically Stable Participants Treated with 
Pembrolizumab After First Radiologic Evidence of PD Assessed by the 
Investigator .........................................................................................................119
Figure 3
Multiplicity Graph for Type I Error Control of Study Hypotheses....................143
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title:
A Multicenter, Open label, Randomized, Phase 3 Trial to Compare the Efficacy 
and Safety of Lenvatinib in Combination with Pembrolizumab Versus Treatment 
of Physician’s Choice in Participants with Advanced Endometrial Cancer
Short Title:
Phase 3 study of lenvatinib plus pembrolizumab for advanced endometrial cancer
Objectives/Hypotheses and Endpoints:
In all randomized participants with advanced endometrial cancer:
Objective/Hypothesis
Endpoint
Primary

Objective: To demonstrate that lenvatinib 
in combination with pembrolizumab is 
superior to Treatment of Physician’s 
Choice (TPC) in improving progression-
free survival (PFS).
Hypothesis (H1): The combination of 
lenvatinib and pembrolizumab is superior 
to TPC as assessed by PFS in pMMR 
participants.
Hypothesis (H4): The combination of 
lenvatinib and pembrolizumab is superior 
to TPC as assessed by PFS in all-comer 
participants.

PFS, defined as the time from date of 
randomization to the date of the first 
documentation of disease progression, 
as determined by blinded independent 
central review (BICR) per Response 
Evaluation Criteria in Solid Tumors 
version 1.1 (RECIST 1.1), or death 
from any cause (whichever occurs 
first).

Objective: To demonstrate that lenvatinib 
in combination with pembrolizumab is 
superior to TPC in improving overall 
survival (OS).
Hypothesis (H2): The combination of 
lenvatinib and pembrolizumab is superior 
to TPC as assessed by OS in pMMR 
participants.
Hypothesis (H5): The combination of 
lenvatinib and pembrolizumab is superior 
to TPC as assessed by OS in all-comer 
participants.

OS, defined as the time from date of 
randomization to date of death from
any cause.
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Secondary

Objective: To compare the objective 
response rate (ORR) of participants 
treated with lenvatinib in combination 
with pembrolizumab versus TPC by 
BICR.
Hypothesis (H3): The combination of 
lenvatinib and pembrolizumab is superior 
to TPC as assessed by ORR in pMMR 
participants.
Hypothesis (H6): The combination of 
lenvatinib and pembrolizumab is superior 
to TPC as assessed by ORR in all-comer 
participants.

ORR, defined as the proportion of 
participants who have best overall 
response of either complete response 
(CR) or partial response (PR), as 
determined by BICR per RECIST 1.1.

Objective: To evaluate the impact of 
treatment on Health-Related Quality of 
Life (HRQoL) as assessed by using the 
global score of the European 
Organisation for the Research and 
Treatment of Cancer (EORTC) QLQ-
C30 for participants treated with 
lenvatinib in combination with 
pembrolizumab versus TPC in pMMR 
and in all-comer participants.

HRQoL will be assessed using the 
global score of the EORTC QLQ-C30.

Objective: To assess safety and 
tolerability of treatment with lenvatinib 
in combination with pembrolizumab 
versus TPC in pMMR participants and in 
all-comer participants.

Incidence of treatment-emergent
adverse events (TEAEs), serious AEs
(SAEs), and immune-related AEs.

Proportion of participants 
discontinuing study treatment due to 
TEAEs.

Time to treatment failure due to 
toxicity, defined as the time from the 
date of randomization to the date that a 
participant discontinues study 
treatment due to TEAEs.

Objective: To characterize the population 
pharmacokinetics (PK) of lenvatinib 
when co-administered with 
pembrolizumab in pMMR participants 
and in all-comer participants.

Plasma concentration of lenvatinib 
versus time.
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
Objective: To assess the relationship 
between exposure to lenvatinib and 
safety events related to lenvatinib in 
pMMR participants and in all-comer 
participants.

Clearance and area under the 
concentration-time curve (AUC) for 
lenvatinib.
Overall Design:
Study Phase
Phase 3
Clinical Indication
Treatment of advanced endometrial cancer
Population
Participants with advanced endometrial cancer who have 
been treated with at least one prior platinum-based 
chemotherapy regimen.
Study Type
Interventional
Type of Design
Multicenter, randomized, parallel
Type of Control
Active control without placebo
Study Blinding
Open-label
Estimated Duration 
of Study
The Sponsor estimates that the study will require 
approximately 43 months from the time the first participant 
(or their legally acceptable representative) provides 
documented informed consent until the last participant’s last 
study-related contact. 
Number of Participants:
Approximately 780 participants (660 mismatch repair [MMR] proficient participants 
and up to 120 MMR deficient participants) will be randomized to 1 of 2 treatment arms.
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Treatment Groups and Duration:
Treatment Groups
Arm A: Lenvatinib 20 mg (orally [PO] once daily [QD]) plus 
pembrolizumab 200 mg (intravenously [IV] every 3 
weeks [Q3W]).
Arm B: TPC consisting of either doxorubicin 60 mg/m2 (by 
IV bolus injection, 1-hour infusion, or per 
institutional guidelines) Q3W, or paclitaxel 
80 mg/m2 (by 1-hour IV infusion or per institutional 
guidelines) given weekly, 3 weeks on/1 week off.
Prior to randomization, investigators must select and record 
the TPC option in the event the participant will be assigned to 
that arm. Randomization will follow a predefined 
randomization scheme based on the following stratification 
factors: MMR status (proficient [pMMR] or deficient 
[dMMR]), Eastern Cooperative Oncology Group (ECOG) 
performance status (0 or 1), geographic region (Region 1:
Europe, USA, Canada, Australia, New Zealand, and Israel or 
Region 2: rest of the world), and prior history of pelvic 
radiation (yes or no). First, participants will be stratified 
according to MMR status. Then, only within the pMMR 
stratum, participants will be further stratified according to 
ECOG performance status, geographic region, and prior 
history of pelvic radiation. A total of 9 strata will be utilized 
for the study.
Duration of 
Participation
After a screening phase of 28 days, each eligible participant 
will be assigned to receive study treatment until disease 
progression is radiographically documented and verified by
BICR per RECIST 1.1, and only when clinically appropriate, 
confirmed by the site per modified RECIST 1.1 for immune-
based therapeutics (iRECIST), unacceptable adverse event(s) 
(AEs), withdrawal of consent, intercurrent illness that 
prevents further administration of treatment, investigator’s 
decision to discontinue the participant, noncompliance with 
study treatment or procedure requirements or administrative 
reasons requiring cessation of treatment, until the participant 
has received 35 administrations of pembrolizumab 
(approximately 2 years), or the participant has received a 
lifetime cumulative dose of 500 mg/m² of doxorubicin.
Participants who stop study treatment after receiving 
35 administrations of pembrolizumab for reasons other than 
disease progression or intolerability, or participants who attain 
a complete response (CR) and stop study treatment may be 
eligible for up to 1 year of treatment with pembrolizumab 
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(17 cycles) ± lenvatinib upon experiencing disease 
progression (Second Course Phase; Section 6.6.5).
Participants who complete treatment with pembrolizumab 
after 35 cycles (approximately 2 years) or CR will continue to 
receive lenvatinib alone until disease progression is confirmed 
by BICR, development of unacceptable toxicity, or 
withdrawal of consent.
Participants will be permitted to continue study treatment 
beyond RECIST 1.1-defined disease progression as long as 
the maximum dose of the study drugs have not been reached 
(eg, 35 administrations of pembrolizumab or lifetime 
cumulative dose of 500 mg/m² of doxorubicin), if the treating 
investigator considers that the participant may experience 
clinical benefit with continued treatment, and the participant 
is tolerating study treatment. All decisions to continue 
treatment beyond 2 consecutive scans (at least 4 weeks apart)
showing progression must be discussed with the MSD 
Medical Monitor (Section 8.2.1.6 and Appendix 5).
After the end of treatment, each participant will be followed 
for the occurrence of AEs and spontaneously reported 
pregnancy as described under Section 8.4.
Participants who discontinue for reasons other than 
radiographic disease progression will have post-treatment 
follow-up imaging for disease status until disease progression 
is documented radiographically per RECIST 1.1 and verified 
by BICR, initiating a non-study cancer treatment, 
withdrawing consent, or becoming lost to follow-up. All 
participants will be followed by telephone for overall survival 
until death, withdrawal of consent, or the end of the study.
Following demonstration of a survival benefit in the interim 
analysis, eligible participants who were randomized to Arm B 
(TPC) and experience disease progression may have the 
opportunity to crossover to lenvatinib plus pembrolizumab.
The end of the study will be the date of data cutoff for the 
final analysis or the time of last participant/last treatment, 
whichever occurs later.
Upon study completion, participants are to be discontinued and 
may be enrolled in an extension study using pembrolizumab 
monotherapy, coformulations, or in combination as in the 
parent study, if available.
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Study Governance:
Study Governance 
Committees
Committee
Included in this study?
Steering Committee
No
Executive Oversight 
Committee
Yes
Data Monitoring Committee
Yes
Clinical Adjudication 
Committee
No
Study governance considerations are outlined in Appendix 1.
A list of abbreviations used in this document can be found in Appendix 6.
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1.2
Schema
The study design is depicted in Figure 1.
Abbreviations: ICF = informed consent form; OS = overall survival; PFS2 = progression-free survival on next 
line of therapy; R = randomization; TPC = Treatment of Physician’s Choice.
a.
Lenvatinib 20 mg orally once daily plus pembrolizumab 200 mg intravenously every 3 weeks.
b.
Doxorubicin 60 mg/m2 (by intravenous bolus, 1-hour infusion, or per institutional guidelines) every 
3 weeks or paclitaxel 80 mg/m2 (by 1-hour infusion or per institutional guidelines) given weekly, 3 weeks 
on/1 week off.
c.
Imaging to be performed Q8W from the date of randomization, or sooner if clinically indicated, until 
BICR-confirmation of disease progression per RECIST 1.1.
d.
If End of Treatment visit occurs ≥30 days from last dose of study treatment, a safety follow-up visit is not 
required.
e.
For participants discontinuing for reasons other than BICR-confirmed PD, tumor imaging should be 
performed Q8W from the date of randomization, or more frequently if clinically indicated, until BICR-
confirmed PD during Efficacy Follow-up. Following the primary analysis for the study, follow-up visits 
and tumor assessments should be performed Q12W or more frequently if required by local standard of care.
f. 
Participants who were randomized to Arm B (TPC) and who experience disease progression may have the 
opportunity to crossover to lenvatinib plus pembrolizumab. Participants entering the crossover phase need 
to meet all eligibility criteria with the exception of the following exclusion criteria: #20, #21, #24 and #28.
Figure 1
Study Diagram
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1.3
Schedule of Activities (SoA)
1.3.1
Schedule of Activities –Treatment Period
Study Period
Screeninga
Treatment Period
Arm A: 21-Day Cycles
Arm B: 21-Day or 28-Day Cycles
EOT
Post Treatment Visits
Notes
Treatment Cycle
Cycle 1
Cycle 2
Cycle 3 - last
Cycle Day
1
8
15
1
8
15
1
8
15
Safety 
FUb
Efficacy 
FU Visits
Survival 
FU
Scheduling 
Window (Days):
–28 to –1
±1
±1
±3
±3
±3
±3
±3
±3
At 
DC
30 Days 
After 
Last Dose 
(+ 7 days)
Q8Wc
(± 7 days)
Q12W 
(± 7 days)
Administrative and General Procedures
Informed consent
X
Documented consent can be 
obtained at any time prior to any 
protocol-specific screening 
procedures being performed.
If MMR result is unavailable within 
28 days from when original consent 
was obtained, an extension may be 
granted after consultation with MSD
as long as all other screening 
procedures are performed within the 
protocol-specified timeframe.
If the investigator plans to treat 
beyond disease progression, 
additional consent is required.
Inclusion/ 
exclusion
X
Participant ID 
card
X
Document TPC 
decision 
(doxorubicin or 
paclitaxel)
X
The proposed TPC agent that is to be 
given, if the participant is 
randomized to the TPC arm, must be 
selected and recorded by the 
investigator prior to randomization.
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Study Period
Screeninga
Treatment Period
Arm A: 21-Day Cycles
Arm B: 21-Day or 28-Day Cycles
EOT
Post Treatment Visits
Notes
Treatment Cycle
Cycle 1
Cycle 2
Cycle 3 - last
Cycle Day
1
8
15
1
8
15
1
8
15
Safety 
FUb
Efficacy 
FU Visits
Survival 
FU
Scheduling 
Window (Days):
–28 to –1
±1
±1
±3
±3
±3
±3
±3
±3
At 
DC
30 Days 
After 
Last Dose 
(+ 7 days)
Q8Wc
(± 7 days)
Q12W 
(± 7 days)
Demographics
X
Medical/surgical 
history
X
Significant medical history to be 
captured for last 10 years.
All medical history related to any 
cancer other than EC should be 
collected, regardless of when it 
occurred. 
FIGO staging
X
At initial diagnosis; see protocol 
Appendix 7
Prior/ 
concomitant 
medication 
reviewc
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications will be 
recorded for 30 days after last dose 
(or for up to 120 days after last dose 
for SAEs), including any anticancer
therapies taken for any cancer other 
than EC.
Randomization 
and study 
treatment 
assignment via 
IRT
X
Participants may be randomized up 
to 3 days prior to C1D1. All 
screening procedures, if performed 
on the date of randomization, must 
be performed prior to randomization.
Subsequent anti-
neoplastic 
treatment
X
X
X
All anticancer therapy will be 
recorded until time of death or 
termination of survival follow-up.
If a clinic visit is not feasible, 
follow-up information may be 
obtained via telephone or e-mail.
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Study Period
Screeninga
Treatment Period
Arm A: 21-Day Cycles
Arm B: 21-Day or 28-Day Cycles
EOT
Post Treatment Visits
Notes
Treatment Cycle
Cycle 1
Cycle 2
Cycle 3 - last
Cycle Day
1
8
15
1
8
15
1
8
15
Safety 
FUb
Efficacy 
FU Visits
Survival 
FU
Scheduling 
Window (Days):
–28 to –1
±1
±1
±3
±3
±3
±3
±3
±3
At 
DC
30 Days 
After 
Last Dose 
(+ 7 days)
Q8Wc
(± 7 days)
Q12W 
(± 7 days)
Date of 
progression on 
subsequent 
anti-neoplastic 
treatment
X
X
X
Participants will be followed for 
PFS2 (unless this information is not 
allowed to be provided due to 
confidentiality).
Phone contact 
visit
X
Telephone contact or visit on C1D8 
will assess participants for 
development of early toxicity. An 
unscheduled visit can occur prior to 
C1D15 if deemed necessary by the 
investigator.
Survival status
Participants will be followed for 
survival (unless this information is 
not allowed to be provided due to 
confidentiality).
Administration of Study Treatment
Lenvatinib plus 
pembrolizumab
X
X
X
Lenvatinib 20 mg QD plus 
pembrolizumab 200 mg Q3W; 
21-day cycle.
Doxorubicin
X
X
X
60 mg/m2 Q3W; 21-day cycle.
Paclitaxel
X
X
X
X
X
X
X
X
X
80 mg/m2 QW; 3 weeks on, 1 week 
off of each 28-day cycle.
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Study Period
Screeninga
Treatment Period
Arm A: 21-Day Cycles
Arm B: 21-Day or 28-Day Cycles
EOT
Post Treatment Visits
Notes
Treatment Cycle
Cycle 1
Cycle 2
Cycle 3 - last
Cycle Day
1
8
15
1
8
15
1
8
15
Safety 
FUb
Efficacy 
FU Visits
Survival 
FU
Scheduling 
Window (Days):
–28 to –1
±1
±1
±3
±3
±3
±3
±3
±3
At 
DC
30 Days 
After 
Last Dose 
(+ 7 days)
Q8Wc
(± 7 days)
Q12W 
(± 7 days)
Efficacy Procedures
Tumor 
assessment –
chest, abdomen 
and pelvis 
(CT/MRI)d
X
X
X
Prior scans performed within the 
screening period but before
documented informed consent is 
provided, may be used if consistent 
with protocol requirements per CIV.
All imaging visits have a scheduling 
window of ±7 days.
Imaging to be performed Q8W from 
the date of randomization, or sooner 
if clinically indicated, until BICR 
confirmation of disease progression
per RECIST 1.1. Progression should
be confirmed by BICR prior to 
discontinuing study treatment.
For participants DCing for reasons 
other than BICR-confirmed PD, 
imaging should continue Q8W from 
the date of randomization until 
BICR-confirmed PD during Efficacy 
FU.
Imaging at EOT is not required if the 
previous tumor imaging assessment
was within 4 weeks prior to the EOT 
visit.
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Study Period
Screeninga
Treatment Period
Arm A: 21-Day Cycles
Arm B: 21-Day or 28-Day Cycles
EOT
Post Treatment Visits
Notes
Treatment Cycle
Cycle 1
Cycle 2
Cycle 3 - last
Cycle Day
1
8
15
1
8
15
1
8
15
Safety 
FUb
Efficacy 
FU Visits
Survival 
FU
Scheduling 
Window (Days):
–28 to –1
±1
±1
±3
±3
±3
±3
±3
±3
At 
DC
30 Days 
After 
Last Dose 
(+ 7 days)
Q8Wc
(± 7 days)
Q12W 
(± 7 days)
Bone scand
X
X
All imaging visits have a scheduling 
window of ±7 days.
Only for participants with a history 
of bone metastases or who are 
clinically symptomatic, a bone scan 
will be required at screening (within 
6 weeks of randomization), then 
Q24W, or as clinically indicated, 
and within 1 week, but no more than 
2 weeks, of suspected CR.
Imaging at EOT is not required if the 
previous tumor imaging assessment
was within 4 weeks prior to the EOT 
visit.
Brain scand
X
X
All imaging visits have a scheduling 
window of ±7 days.
Only for participants with a history 
of protocol-eligible treated brain 
metastases or who are clinically 
symptomatic, a brain scan will be 
required at screening, at all tumor 
assessment time points (eg, Q8W or 
as clinically indicated) and within 
1 week, but no more than 2 weeks,
of suspected CR.
Imaging at EOT is not required if the 
previous tumor imaging assessment
was within 4 weeks prior to the EOT 
visit.
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Study Period
Screeninga
Treatment Period
Arm A: 21-Day Cycles
Arm B: 21-Day or 28-Day Cycles
EOT
Post Treatment Visits
Notes
Treatment Cycle
Cycle 1
Cycle 2
Cycle 3 - last
Cycle Day
1
8
15
1
8
15
1
8
15
Safety 
FUb
Efficacy 
FU Visits
Survival 
FU
Scheduling 
Window (Days):
–28 to –1
±1
±1
±3
±3
±3
±3
±3
±3
At 
DC
30 Days 
After 
Last Dose 
(+ 7 days)
Q8Wc
(± 7 days)
Q12W 
(± 7 days)
Safety Procedures
AE monitoringc
X
X
X
X
X
X
X
X
X
X
X
X
X
AEs: monitored up to 30 days after 
last dose.
SAEs and pregnancy: monitored up 
to 120 days after last dose, or 
30 days after last dose if participant 
starts a new anticancer therapy, 
whichever is sooner.
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Study Period
Screeninga
Treatment Period
Arm A: 21-Day Cycles
Arm B: 21-Day or 28-Day Cycles
EOT
Post Treatment Visits
Notes
Treatment Cycle
Cycle 1
Cycle 2
Cycle 3 - last
Cycle Day
1
8
15
1
8
15
1
8
15
Safety 
FUb
Efficacy 
FU Visits
Survival 
FU
Scheduling 
Window (Days):
–28 to –1
±1
±1
±3
±3
±3
±3
±3
±3
At 
DC
30 Days 
After 
Last Dose 
(+ 7 days)
Q8Wc
(± 7 days)
Q12W 
(± 7 days)
Vital signs 
(resting BP, HR, 
RR, and temp) 
and weight
X
X
X
X
X
X
X
X
X
Vital sign measurements captured on 
the day of randomization can be 
used for eligibility requirements if 
they are recorded prior to 
randomization via IRT.
Participants with initial or recurrent 
systolic BP ≥160 mm Hg or diastolic 
BP ≥100 mm Hg must have their BP 
monitored on D15 (or more 
frequently as clinically indicated) 
until systolic BP is ≤150 mm Hg and 
diastolic BP is ≤95 mm Hg for 
2 consecutive treatment cycles. 
D15 visit is mandatory in C1 and C2
for all participants. During C3 and 
subsequent cycles, participants may 
return for the D15 visit if BP 
monitoring is required as specified 
above.
Additional vital signs required per 
standard of care for the TPC arm, 
but not included here, should be 
obtained per local guidance.
Comprehensive 
physical 
examination
X
X
X
X
X
To be performed within 7 days prior 
to start of study treatment.
A symptom-directed PE may be 
performed at any time during the 
study, as clinically indicated.
Height
X
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Product:  MK-3475/E7080 
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Protocol/Amendment No.: 775-09/E7080-G000-309
MK-3475-775-09/E7080-G000-309 Final Protocol
30-Nov-2022
Confidential
Study Period
Screeninga
Treatment Period
Arm A: 21-Day Cycles
Arm B: 21-Day or 28-Day Cycles
EOT
Post Treatment Visits
Notes
Treatment Cycle
Cycle 1
Cycle 2
Cycle 3 - last
Cycle Day
1
8
15
1
8
15
1
8
15
Safety 
FUb
Efficacy 
FU Visits
Survival 
FU
Scheduling 
Window (Days):
–28 to –1
±1
±1
±3
±3
±3
±3
±3
±3
At 
DC
30 Days 
After 
Last Dose 
(+ 7 days)
Q8Wc
(± 7 days)
Q12W 
(± 7 days)
NYHA
X
See Appendix 8.
Only required for participants with 
cardiovascular impairment within 
12 months of the first dose of study 
treatment.
12-lead ECG
X
X
X
X
X
X
Single 12-lead ECG. Participants 
must be in the recumbent position 
for a period of 5 minutes prior to the 
ECG.
ECG at screening, C1D1, C2D1, D1 
of every 4th cycle (12 weeks) 
thereafter (eg, C6, C10, C14, etc.), 
EOT, and safety follow-up. 
ECG at C1D1 and C2D1 should be 
performed approximately 2 hours 
post-lenvatinib dose. For high-risk 
participants (as defined in Sec. 
8.3.3), conduct ECG monitoring 
every cycle. If lenvatinib is 
discontinued, ECGs are only 
required at the EOT and Safety 
Follow-up visits. 
ECGs on C1D1 are required to be on 
the day of dosing for participants on 
both arms of the study.
092KCC

Product:  MK-3475/E7080 
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Protocol/Amendment No.: 775-09/E7080-G000-309
MK-3475-775-09/E7080-G000-309 Final Protocol
30-Nov-2022
Confidential
Study Period
Screeninga
Treatment Period
Arm A: 21-Day Cycles
Arm B: 21-Day or 28-Day Cycles
EOT
Post Treatment Visits
Notes
Treatment Cycle
Cycle 1
Cycle 2
Cycle 3 - last
Cycle Day
1
8
15
1
8
15
1
8
15
Safety 
FUb
Efficacy 
FU Visits
Survival 
FU
Scheduling 
Window (Days):
–28 to –1
±1
±1
±3
±3
±3
±3
±3
±3
At 
DC
30 Days 
After 
Last Dose 
(+ 7 days)
Q8Wc
(± 7 days)
Q12W 
(± 7 days)
MUGA or ECHO 
for LVEF 
assessment
X
X
Additional assessments as clinically 
indicated. Assessments should use 
the same method (MUGA or ECHO)
throughout the study.
MUGA or ECHO captured on the 
day of randomization can be used for 
eligibility requirements if performed
and recorded prior to randomization
via IRT.
Hematology and 
clinical chemistry
laboratory 
assessmentse
X
X
X
X
X
X
X
Performed locally within 7 days 
prior to start of treatment. Every 
effort should be made to collect 
samples at the same time of day.
Hematology and clinical chemistry 
laboratory assessments captured on 
the day of randomization can be 
used for eligibility requirements if 
they are measured and results are 
available prior to randomization via 
IRT.
Additional laboratory assessments 
required per standard of care for the 
TPC arm, but not included here, 
should be obtained per local 
guidance.
After C1, retrospective review of 
lipase results is allowed when the 
results are not available prior to 
dosing.
092KCC

Product:  MK-3475/E7080 
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Protocol/Amendment No.: 775-09/E7080-G000-309
MK-3475-775-09/E7080-G000-309 Final Protocol
30-Nov-2022
Confidential
Study Period
Screeninga
Treatment Period
Arm A: 21-Day Cycles
Arm B: 21-Day or 28-Day Cycles
EOT
Post Treatment Visits
Notes
Treatment Cycle
Cycle 1
Cycle 2
Cycle 3 - last
Cycle Day
1
8
15
1
8
15
1
8
15
Safety 
FUb
Efficacy 
FU Visits
Survival 
FU
Scheduling 
Window (Days):
–28 to –1
±1
±1
±3
±3
±3
±3
±3
±3
At 
DC
30 Days 
After 
Last Dose 
(+ 7 days)
Q8Wc
(± 7 days)
Q12W 
(± 7 days)
Urine dipstick 
testing
X
X
X
X
X
X
X
Performed locally within 7 days 
prior to start of treatment. During 
screening, proteinuria of >1+ 
requires a 24-hour urine collection. 
Participants with urine protein 
≥1 g/24 h will not be eligible.
During treatment period, repeat 
testing for participants with 
proteinuria ≥2+ should be performed 
on D15 (or more frequently as 
clinically indicated) until the results 
have been 1+ or negative for 
2 consecutive treatment cycles. 
D15 visit is mandatory in C1 and 
C2. During C3 and subsequent 
cycles, participants may return for 
the D15 visit if monitoring is 
required as specified above.
PT/INR and 
aPTT/PTT
X
Screening samples collected within 
7 days of treatment initiation.
Additional testing to be conducted as 
clinically indicated for participants 
taking anticoagulant therapy.
PTT is acceptable at sites where 
aPTT is not performed.
092KCC

Product:  MK-3475/E7080 
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Protocol/Amendment No.: 775-09/E7080-G000-309
MK-3475-775-09/E7080-G000-309 Final Protocol
30-Nov-2022
Confidential
Study Period
Screeninga
Treatment Period
Arm A: 21-Day Cycles
Arm B: 21-Day or 28-Day Cycles
EOT
Post Treatment Visits
Notes
Treatment Cycle
Cycle 1
Cycle 2
Cycle 3 - last
Cycle Day
1
8
15
1
8
15
1
8
15
Safety 
FUb
Efficacy 
FU Visits
Survival 
FU
Scheduling 
Window (Days):
–28 to –1
±1
±1
±3
±3
±3
±3
±3
±3
At 
DC
30 Days 
After 
Last Dose 
(+ 7 days)
Q8Wc
(± 7 days)
Q12W 
(± 7 days)
T3, FT4, TSH
X
X
X
X
Screening samples to be collected 
within 7 days of treatment initiation.
Thyroid function tests will be 
performed every other cycle starting 
with Cycle 2 (eg, Cycle 4, 6, 8, etc.).
Free T3 is acceptable where T3 
cannot be determined.
After C1, retrospective review of 
thyroid function testing results is 
allowed when the results are not 
available prior to dosing.
Pregnancy test 
(WOCBP only)
X
X
X
X
X
To be assessed within 3 days of 
treatment initiation. A serum or 
urine pregnancy test will be 
performed as indicated and at least 
every 30 days up to 120 days post 
last dose of study medication or the 
start of a new anticancer therapy, 
whichever comes first.
Postmenopausal women who have 
not had menses for >12 months must 
have 2 FSH tests.
Refer to Appendix 9 for country-
specific requirements.
HIV, HBV, HCV
X
Testing is not required unless 
mandated by local health authority.
Refer to Appendix 9 for country-
specific requirements.
092KCC

Product:  MK-3475/E7080 
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Protocol/Amendment No.: 775-09/E7080-G000-309
MK-3475-775-09/E7080-G000-309 Final Protocol
30-Nov-2022
Confidential
Study Period
Screeninga
Treatment Period
Arm A: 21-Day Cycles
Arm B: 21-Day or 28-Day Cycles
EOT
Post Treatment Visits
Notes
Treatment Cycle
Cycle 1
Cycle 2
Cycle 3 - last
Cycle Day
1
8
15
1
8
15
1
8
15
Safety 
FUb
Efficacy 
FU Visits
Survival 
FU
Scheduling 
Window (Days):
–28 to –1
±1
±1
±3
±3
±3
±3
±3
±3
At 
DC
30 Days 
After 
Last Dose 
(+ 7 days)
Q8Wc
(± 7 days)
Q12W 
(± 7 days)
ECOG 
performance 
status
X
X
X
X
To be assessed within 7 days of
starting study treatment.
ECOG performance status captured
on the day of randomization can be
used for eligibility requirements if
measured and recorded prior to
randomization via IRT.
Should be assessed prior to dosing at
treatment visits.
092KCC

Product:  MK-3475/E7080 
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Protocol/Amendment No.: 775-09/E7080-G000-309
MK-3475-775-09/E7080-G000-309 Final Protocol
30-Nov-2022
Confidential
Study Period
Screeninga
Treatment Period
Arm A: 21-Day Cycles
Arm B: 21-Day or 28-Day Cycles
EOT
Post Treatment Visits
Notes
Treatment Cycle
Cycle 1
Cycle 2
Cycle 3 - last
Cycle Day
1
8
15
1
8
15
1
8
15
Safety 
FUb
Efficacy 
FU Visits
Survival 
FU
Scheduling 
Window (Days):
–28 to –1
±1
±1
±3
±3
±3
±3
±3
±3
At 
DC
30 Days 
After 
Last Dose 
(+ 7 days)
Q8Wc
(± 7 days)
Q12W 
(± 7 days)
Patient Reported Outcomes
HRQoL
X
X
X
X
X
Every effort should be made to 
administer HRQoL surveys prior to 
dosing and before other assessments 
and procedures.
Participants will be asked to 
complete the HRQoL questionnaires 
for the equivalent of 4 cycle lengths 
(ie, either every 21 or 28 days 
depending on assigned treatment) 
following EOT visit. Completion of 
the HRQoL questionnaires following 
the EOT visit is not mandatory; 
however, every effort should be 
made to collect this information.
At the EOT visit, participants should 
be invited to register for the Web 
Diary in order to receive access to 
the HRQoL questionnaires online. 
Questionnaire-completion reminders 
will be sent to those who register. 
The collection of PRO data will be 
discontinued following 
implementation of Amendment 09.
092KCC

Product:  MK-3475/E7080 
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Protocol/Amendment No.: 775-09/E7080-G000-309
MK-3475-775-09/E7080-G000-309 Final Protocol
30-Nov-2022
Confidential
Study Period
Screeninga
Treatment Period
Arm A: 21-Day Cycles
Arm B: 21-Day or 28-Day Cycles
EOT
Post Treatment Visits
Notes
Treatment Cycle
Cycle 1
Cycle 2
Cycle 3 - last
Cycle Day
1
8
15
1
8
15
1
8
15
Safety 
FUb
Efficacy 
FU Visits
Survival 
FU
Scheduling 
Window (Days):
–28 to –1
±1
±1
±3
±3
±3
±3
±3
±3
At 
DC
30 Days 
After 
Last Dose 
(+ 7 days)
Q8Wc
(± 7 days)
Q12W 
(± 7 days)
PK/Pharmacodynamic/Biomarker Assessment
MMR status
X
Archived tumor specimen from most 
recent biopsy or fresh sample 
collected prior to randomization.
Lenvatinib PK 
blood sample 
(Arm A only)
X
X
X
C1D1: 0.5-4 h and 6-10 h postdose.
C1D15: predose and 2-12 h 
postdose.
C2D1: predose, 0.5-4 h, and 6-10 h 
postdose.
Note: all predose samples should be 
collected within 30 minutes of 
lenvatinib dosing.
Note: postdose samples not needed 
if lenvatinib administration is 
skipped.
Blood for serum 
biomarkerf
X
X
X
X
Collect predose at C1D1, C2D1, 
C3D1, and C5D1 .Collect at time of 
DC.
Blood for RNA 
analysisf
X
X
X
X
Plasma for 
ctDNAf
X
X
X
X
Collect predose. Following C3, 
samples to be collected on D1 of 
every other cycle (C5, C7, C9, C11, 
etc.).
Blood for genetic 
analysisf
X
Collect predose.
092KCC

Product:  MK-3475/E7080 
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Protocol/Amendment No.: 775-09/E7080-G000-309
MK-3475-775-09/E7080-G000-309 Final Protocol
30-Nov-2022
Confidential
Study Period
Screeninga
Treatment Period
Arm A: 21-Day Cycles
Arm B: 21-Day or 28-Day Cycles
EOT
Post Treatment Visits
Notes
Treatment Cycle
Cycle 1
Cycle 2
Cycle 3 - last
Cycle Day
1
8
15
1
8
15
1
8
15
Safety 
FUb
Efficacy 
FU Visits
Survival 
FU
Scheduling 
Window (Days):
–28 to –1
±1
±1
±3
±3
±3
±3
±3
±3
At 
DC
30 Days 
After 
Last Dose 
(+ 7 days)
Q8Wc
(± 7 days)
Q12W 
(± 7 days)
Tumor block or 
slides
X
Archived tumor tissue from most 
recent surgery or biopsy (if 
available) will also be collected for 
exploring biomarkers of response.
Abbreviations: AE = adverse event; BICR = blinded independent central review; BP = blood pressure; C1 = Cycle 1; C2 = Cycle 2; CIV = central imaging vendor; CR = complete 
response; CT = computed tomography; D1 = Day 1; D15 = Day 15; D8 = Day 8; DC = discontinuation; ECG = electrocardiogram; ECHO = echocardiogram; 
ECOG = Eastern Cooperative Oncology Group; EOT = end of treatment; FIGO = International Federation of Gynecology and Obstetrics; FT4 = free thyroxine; 
HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = human immunodeficiency virus; HR = heart rate; HRQoL = Health-Related Quality of Life; ID = identification; 
IEC = Independent Ethics Committee; IRB = Independent Review Board; IRT = interactive response technology; LVEF = left ventricular ejection fraction; MMR = mismatch 
repair; MRI = magnetic resonance imaging; MUGA = multigated acquisition; nAb = neutralizing antibodies; NYHA = New York Heart Association; PD = progressive 
disease; PE = physical examination; PFS2 = progression-free survival on next line therapy; PK = pharmacokinetics; Q3W = every 3 weeks; Q8W = every 8 weeks; Q12W = 
every 12 weeks; Q24W = every 24 weeks; QD = once daily; QW = every week; RNAseq = RNA sequencing; RR = respiratory rate; SAE = serious adverse event; T3 = 
triiodothyronine; TPC = treatment of physician’s choice; TSH = thyroid stimulating hormone; WES = whole exome sequencing; WOCBP = women of childbearing potential.
a.
Screening procedures should be performed within 28 days prior to first dose of study treatment unless there is another timeframe specified within the procedure-specific note.
b.
If EOT visit occurs ≥30 days from last dose of study treatment, a safety follow-up visit is not required. In this situation, all procedures required at both the EOT visit and the 
safety follow-up visit should be performed.
c.
For participants receiving either pembrolizumab plus lenvatinib or doxorubicin, a review of concomitant medications and AEs should be performed on Day 8 of Cycle 1; a 
clinic visit is not required and can be performed via a telephone-call. Following Cycle 1, the review of concomitant medications and AEs on Day 8 is not required for 
participants receiving either pembrolizumab plus lenvatinib or doxorubicin. The Day 8 visit is required for participants receiving paclitaxel.
d.
Following the primary analysis for the study: follow-up visits and tumor assessments should be performed Q12W or more frequently if required by local standard of care. 
Bone and brain scans should be performed per local standard of care.
e.
From C2D1 onwards, clinical laboratory assessments may be conducted up to 72 hours prior to the scheduled visit, unless otherwise specified. Procedures/assessments should
be performed prior to administration of study treatment.
f.
If a documented law or regulation prohibits (or local IRB/IEC does not approve) sample collection for these purposes, then such samples should not be collected at the 
corresponding sites.
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Product:  MK-3475/E7080 
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Protocol/Amendment No.: 775-09/E7080-G000-309
MK-3475-775-09/E7080-G000-309 Final Protocol
30-Nov-2022
Confidential
1.3.2
Schedule of Activities – Second Course Phase (Retreatment)
Study Period
Second Course Phase (Retreatment)
21-Day Cycles
EOT
Post Treatment Visits
Notes
Treatment Cycle
1
2
3
4
5
6
7
8-17
Cycle Day
1
1
1
1
1
1
1
1
Safety FU
Efficacy 
FU Visit
Survival 
FU

If EOT visit occurs ≥30 days from 
last dose of study treatment, a 
safety follow-up visit is not 
required. In this situation, all 
procedures required at both the 
EOT visit and the safety follow-up 
visit should be performed
Scheduling 
Window (Days):
±3
±3
±3
±3
±3
±3
±3
At DC
30 Days 
After 
Last Dose 
(+ 7 days)
Q12W 
(±7 days)
Q12W
(± 7 days)
Administrative and General Procedures
Inclusion/exclusion
X
Prior/Concomitant 
medication review
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications will be 
recorded for 30 days after last dose (or 
for up to 120 days after last dose for 
SAEs).
Subsequent anti-
neoplastic 
treatment
X
X
X
All anticancer therapy will be recorded 
until time of death or termination of 
survival follow-up.
If a clinic visit is not feasible, follow-up 
information may be obtained via 
telephone or e-mail.
Date of progression 
on subsequent anti-
neoplastic 
treatment
X
X
X
Participants will be followed for PFS2 
(unless this information is not allowed to 
be provided due to confidentiality).
Survival status
X
Participants will be followed for survival 
(unless this information is not allowed to 
be provided due to confidentiality).
Administration of Study Treatment
Pembrolizumab ±
lenvatinib
X
X
X
X
X
X
X
X
Pembrolizumab 200 mg Q3W ±
lenvatinib 20 mg QD; 21-day cycle.
092KCC

Product:  MK-3475/E7080 
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Protocol/Amendment No.: 775-09/E7080-G000-309
MK-3475-775-09/E7080-G000-309 Final Protocol
30-Nov-2022
Confidential
Study Period
Second Course Phase (Retreatment)
21-Day Cycles
EOT
Post Treatment Visits
Notes
Treatment Cycle
1
2
3
4
5
6
7
8-17
Cycle Day
1
1
1
1
1
1
1
1
Safety FU
Efficacy 
FU Visit
Survival 
FU

If EOT visit occurs ≥30 days from 
last dose of study treatment, a 
safety follow-up visit is not 
required. In this situation, all 
procedures required at both the 
EOT visit and the safety follow-up 
visit should be performed
Scheduling 
Window (Days):
±3
±3
±3
±3
±3
±3
±3
At DC
30 Days 
After 
Last Dose 
(+ 7 days)
Q12W 
(±7 days)
Q12W
(± 7 days)
Efficacy Procedures
Tumor assessment 
(CT/MRI)
X
X
All imaging visits have a scheduling 
window of ±7 days.
Imaging to be performed within 28 days 
prior to restarting treatment in Second 
Course and then Q12W, or sooner if 
clinically indicated.
Imaging at EOT is not required if the 
previous tumor imaging assessment was 
within 4 weeks prior to the EOT visit.
Bone scan
X
Only for participants with a history of 
bone metastases or who are clinically 
symptomatic.
All imaging visits have a scheduling 
window of ±7 days.
A bone scan is required prior to 
restarting treatment in the Second 
Course Phase, only if the previous 
imaging assessment was not performed 
within 6 weeks of restarting treatment, 
and then Q24W, or as clinically 
indicated.
Imaging at EOT is not required if the 
previous tumor imaging assessment was 
within 4 weeks prior to the EOT visit.
092KCC

Product:  MK-3475/E7080 
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Protocol/Amendment No.: 775-09/E7080-G000-309
MK-3475-775-09/E7080-G000-309 Final Protocol
30-Nov-2022
Confidential
Study Period
Second Course Phase (Retreatment)
21-Day Cycles
EOT
Post Treatment Visits
Notes
Treatment Cycle
1
2
3
4
5
6
7
8-17
Cycle Day
1
1
1
1
1
1
1
1
Safety FU
Efficacy 
FU Visit
Survival 
FU

If EOT visit occurs ≥30 days from 
last dose of study treatment, a 
safety follow-up visit is not 
required. In this situation, all 
procedures required at both the 
EOT visit and the safety follow-up 
visit should be performed
Scheduling 
Window (Days):
±3
±3
±3
±3
±3
±3
±3
At DC
30 Days 
After 
Last Dose 
(+ 7 days)
Q12W 
(±7 days)
Q12W
(± 7 days)
Brain scan
X
All imaging visits have a scheduling 
window of ±7 days.
Only for participants with a history of 
protocol-eligible treated brain metastases 
or who are clinically symptomatic, a 
brain scan will be required within 
28 days of restarting treatment in Second 
Course and then at all tumor assessment 
time points (eg, Q8W or as clinically 
indicated).
Imaging at EOT is not required if the 
previous tumor imaging assessment was 
within 4 weeks prior to the EOT visit.
Safety Procedures

Clinical laboratory assessments 
may be conducted anytime within 
72 hours prior to the scheduled 
visit, unless otherwise specified.

Procedures/assessments should be 
performed prior to administration 
of study treatment.
AE monitoring
X
X
X
X
X
X
X
X
X
X
X
AEs: monitored up to 30 days after last 
dose.
SAEs and pregnancy: monitored up to 
120 days after last dose, or 30 days after 
last dose if participant starts a new 
anticancer therapy, whichever is sooner.
Vital signs (resting 
BP, HR, RR, and 
temp) and weight
X
X
X
X
X
X
X
X
X
X
092KCC

Product:  MK-3475/E7080 
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Protocol/Amendment No.: 775-09/E7080-G000-309
MK-3475-775-09/E7080-G000-309 Final Protocol
30-Nov-2022
Confidential
Study Period
Second Course Phase (Retreatment)
21-Day Cycles
EOT
Post Treatment Visits
Notes
Treatment Cycle
1
2
3
4
5
6
7
8-17
Cycle Day
1
1
1
1
1
1
1
1
Safety FU
Efficacy 
FU Visit
Survival 
FU

If EOT visit occurs ≥30 days from 
last dose of study treatment, a 
safety follow-up visit is not 
required. In this situation, all 
procedures required at both the 
EOT visit and the safety follow-up 
visit should be performed
Scheduling 
Window (Days):
±3
±3
±3
±3
±3
±3
±3
At DC
30 Days 
After 
Last Dose 
(+ 7 days)
Q12W 
(±7 days)
Q12W
(± 7 days)
Physical 
examination
X
X
X
A symptom-directed PE as clinically 
indicated.
12-lead ECG
X
X
X
X
X
X
X
X
X
X
An ECG is required prior to restarting 
treatment only if it was not already 
completed within 28 days prior.
An ECG assessment prior to 
administration of study treatment is only 
required for participants who are 
receiving lenvatinib in the Second 
Course Phase.
ECG at screening, C1D1, C2D1, D1 of 
every 4th cycle (12 weeks) thereafter 
(eg, C6, C10, C14, etc.), EOT, and 
safety follow-up. 
ECG at C1D1 and C2D1 should be 
performed approximately 2 hours post-
lenvatinib dose. For high-risk 
participants (as defined in Sec. 8.3.3), 
conduct ECG monitoring every cycle. If 
lenvatinib is discontinued, ECGs are 
only required at the EOT and Safety 
Follow-up visits. 
ECGs on C1D1 are required to be on the 
day of dosing for participants on both 
arms of the study.
092KCC

Product:  MK-3475/E7080 
46
Protocol/Amendment No.: 775-09/E7080-G000-309
MK-3475-775-09/E7080-G000-309 Final Protocol
30-Nov-2022
Confidential
Study Period
Second Course Phase (Retreatment)
21-Day Cycles
EOT
Post Treatment Visits
Notes
Treatment Cycle
1
2
3
4
5
6
7
8-17
Cycle Day
1
1
1
1
1
1
1
1
Safety FU
Efficacy 
FU Visit
Survival 
FU

If EOT visit occurs ≥30 days from 
last dose of study treatment, a 
safety follow-up visit is not 
required. In this situation, all 
procedures required at both the 
EOT visit and the safety follow-up 
visit should be performed
Scheduling 
Window (Days):
±3
±3
±3
±3
±3
±3
±3
At DC
30 Days 
After 
Last Dose 
(+ 7 days)
Q12W 
(±7 days)
Q12W
(± 7 days)
MUGA or ECHO 
for LVEF 
assessment
X
X
Required prior to restarting treatment 
only if it was not already completed 
within 28 days prior.
Only required if lenvatinib is 
administered. Additional assessments as 
clinically indicated. Assessment should 
use the same method (MUGA or ECHO) 
throughout the study.
Hematology and 
clinical chemistry
X
X
X
X
X
X
X
X
X
X
Performed locally within 3 days prior to 
starting second course treatment. After 
second course Cycle 1, may be collected 
up to 72 hours prior to dosing.
Retrospective review of lipase results is 
allowed when the results are not 
available prior to dosing.
Urine dipstick 
testing
X
X
X
X
X
X
X
X
X
X
Performed locally within 3 days prior to 
starting second course treatment. 
For participants only receiving 
pembrolizumab: testing is to be 
performed every other cycle (eg, Cycle 
1, 3, 5, etc.).
For participants receiving 
pembrolizumab and lenvatinib: testing 
is to be performed on Day 1 of every 
cycle. Repeat testing for participants 
with initial or repeat proteinuria ≥2+ 
should be performed on Day 15 (or more 
frequently as clinically indicated) until 
the results have been 1+ or negative for
2 consecutive treatment cycles.
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Study Period
Second Course Phase (Retreatment)
21-Day Cycles
EOT
Post Treatment Visits
Notes
Treatment Cycle
1
2
3
4
5
6
7
8-17
Cycle Day
1
1
1
1
1
1
1
1
Safety FU
Efficacy 
FU Visit
Survival 
FU

If EOT visit occurs ≥30 days from 
last dose of study treatment, a 
safety follow-up visit is not 
required. In this situation, all 
procedures required at both the 
EOT visit and the safety follow-up 
visit should be performed
Scheduling 
Window (Days):
±3
±3
±3
±3
±3
±3
±3
At DC
30 Days 
After 
Last Dose 
(+ 7 days)
Q12W 
(±7 days)
Q12W
(± 7 days)
PT/INR and 
aPTT/PTT
X
Performed locally within 3 days prior to 
starting second course treatment. 
Additional testing to be conducted as 
clinically indicated for participants 
taking anticoagulant therapy.
PTT is acceptable at sites where aPTT is 
not performed.
T3, FT4, TSH
X
X
X
X
X
X
X
Performed locally within 3 days prior to 
starting second course treatment, then on 
Day 1 of every other cycle (Cycles 3, 5, 
7, etc.).
Free T3 is acceptable where T3 cannot 
be determined.
Retrospective review of thyroid function 
testing results is allowed when the 
results are not available prior to dosing.
Pregnancy test
X
X
X
X
X
X
X
X
X
X
X
A serum or urine pregnancy test will be 
performed in women of childbearing 
potential (ie, premenopausal women and 
postmenopausal women who have been 
amenorrheic for less than 12 months) as 
indicated and at least every 30 days up to 
120 days post last dose of study 
medication or the start of a new 
anticancer therapy, whichever comes 
first.
Postmenopausal women who have not 
had menses for >12 months must have 
2 FSH tests.
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Study Period
Second Course Phase (Retreatment)
21-Day Cycles
EOT
Post Treatment Visits
Notes
Treatment Cycle
1
2
3
4
5
6
7
8-17
Cycle Day
1
1
1
1
1
1
1
1
Safety FU
Efficacy 
FU Visit
Survival 
FU

If EOT visit occurs ≥30 days from 
last dose of study treatment, a 
safety follow-up visit is not 
required. In this situation, all 
procedures required at both the 
EOT visit and the safety follow-up 
visit should be performed
Scheduling 
Window (Days):
±3
±3
±3
±3
±3
±3
±3
At DC
30 Days 
After 
Last Dose 
(+ 7 days)
Q12W 
(±7 days)
Q12W
(± 7 days)
ECOG 
performance status
X
X
X
X
X
X
X
X
X
X
X
Performed within 7 days prior to starting 
second course treatment
Abbreviations: AE = adverse event; aPTT = activated partial thromboplastin time; BP = blood pressure; C1 = Cycle 1; C2 = Cycle 2; CT = computed tomography; D1 = Day 1; 
D15 = Day 15; ECG = electrocardiogram; ECHO = echocardiogram; ECOG = Eastern Cooperative Oncology Group; FT4 = free thyroxine; HR = heart rate; INR = 
international normalized ratio; LVEF = left ventricular ejection fraction; MRI = magnetic resonance imaging; MUGA = multigated acquisition; PD = progressive disease; PE 
= physical examination; PFS2 = progression-free survival on next line therapy; PT = prothrombin time; Q3W = every 3 weeks; RR = respiratory rate; T3 = triiodothyronine; 
TSH = thyroid stimulating hormone; SAE = serious adverse event.
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1.3.3
Schedule of Activities – Crossover Phase for TPC Arm Only
Study Period
Eligibilitya
Crossover Phase
(21-Day Cycles)
EOT
Post-Crossover Phase Visits
Notes
Treatment Cycle
Cycle 1
Cycle 2
Cycle 3 – Last
Cycle Day
1
8
15
1
8
15
1
8
15
Safety 
FUb
Efficacy 
FU Visits
Survival 
FU
Scheduling 
Window (Days):
–28 to –1
±1
±1
±3
±3
±3
±3
±3
±3
At 
DC
30 Days 
After 
Last Dose 
(+ 7 days)
Q12Wd
(± 7 days)
Q12W 
(± 7 days)
Administrative and General Procedures
Inclusion/ 
exclusion
X
Concomitant 
medication 
reviewc
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications will be 
recorded for 30 days after last dose 
(or for up to 120 days after last dose 
for SAEs). 
Subsequent anti-
neoplastic 
treatment
X
X
X
All anticancer therapy will be 
recorded until time of death or 
termination of survival follow-up.
If a clinic visit is not feasible, 
follow-up information may be 
obtained via telephone or e-mail.
Date of 
progression on 
subsequent 
anti-neoplastic 
treatment
X
X
X
Participants will be followed for 
PFS2 (unless this information is not 
allowed to be provided due to 
confidentiality).
Phone contact 
visit
X
Telephone contact or visit on C1D8 
will assess participants for 
development of early toxicity. An 
unscheduled visit can occur prior to 
C1D15 if deemed necessary by the 
investigator.
Survival status
Participants will be followed for 
survival (unless this information is 
not allowed to be provided due to 
confidentiality).
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Study Period
Eligibilitya
Crossover Phase
(21-Day Cycles)
EOT
Post-Crossover Phase Visits
Notes
Treatment Cycle
Cycle 1
Cycle 2
Cycle 3 – Last
Cycle Day
1
8
15
1
8
15
1
8
15
Safety 
FUb
Efficacy 
FU Visits
Survival 
FU
Scheduling 
Window (Days):
–28 to –1
±1
±1
±3
±3
±3
±3
±3
±3
At 
DC
30 Days 
After 
Last Dose 
(+ 7 days)
Q12Wd
(± 7 days)
Q12W 
(± 7 days)
Administration of Study Treatment
Lenvatinib plus 
pembrolizumab
X
X
X
Lenvatinib 20 mg QD plus 
pembrolizumab 200 mg Q3W; 
21-day cycle.
Efficacy Procedures
Tumor 
assessment –
chest, abdomen 
and pelvis 
(CT/MRI)d
X
X
X
All imaging visits have a scheduling 
window of ±7 days.
Imaging to be performed Q12W 
from first dose of crossover at C1D1 
or sooner if clinically indicated until 
confirmation of disease progression 
per RECIST 1.1. 
Imaging at EOT is not required if the 
previous tumor imaging assessment 
was within 4 weeks prior to the EOT 
visit.
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Study Period
Eligibilitya
Crossover Phase
(21-Day Cycles)
EOT
Post-Crossover Phase Visits
Notes
Treatment Cycle
Cycle 1
Cycle 2
Cycle 3 – Last
Cycle Day
1
8
15
1
8
15
1
8
15
Safety 
FUb
Efficacy 
FU Visits
Survival 
FU
Scheduling 
Window (Days):
–28 to –1
±1
±1
±3
±3
±3
±3
±3
±3
At 
DC
30 Days 
After 
Last Dose 
(+ 7 days)
Q12Wd
(± 7 days)
Q12W 
(± 7 days)
Bone scand
X
X
X
Only for participants with a history 
of bone metastases or who are 
clinically symptomatic.
All imaging visits have a scheduling 
window of ±7 days.
A bone scan is required prior to 
starting treatment in the Crossover
Phase, only if the previous imaging 
assessment was not performed 
within 6 weeks of initial treatment, 
and then Q24W, or as clinically 
indicated.
Imaging at EOT is not required if the 
previous tumor imaging assessment 
was within 4 weeks prior to the EOT 
visit.
Brain scand
X
X
X
All imaging visits have a scheduling 
window of ±7 days.
Only for participants with a history 
of protocol-eligible treated brain 
metastases or who are clinically 
symptomatic, a brain scan will be 
required within 28 days from 
starting treatment in Crossover 
Phase, and at all tumor assessment 
time points (eg, Q12W or as 
clinically indicated) Imaging at EOT 
is not required if the previous tumor 
imaging assessment was within 4 
weeks prior to the EOT visit.
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Study Period
Eligibilitya
Crossover Phase
(21-Day Cycles)
EOT
Post-Crossover Phase Visits
Notes
Treatment Cycle
Cycle 1
Cycle 2
Cycle 3 – Last
Cycle Day
1
8
15
1
8
15
1
8
15
Safety 
FUb
Efficacy 
FU Visits
Survival 
FU
Scheduling 
Window (Days):
–28 to –1
±1
±1
±3
±3
±3
±3
±3
±3
At 
DC
30 Days 
After 
Last Dose 
(+ 7 days)
Q12Wd
(± 7 days)
Q12W 
(± 7 days)
Safety Procedures
AE monitoringc
X
X
X
X
X
X
X
X
X
X
X
X
X
AEs: monitored up to 30 days after 
last dose.
SAEs and pregnancy: monitored up 
to 120 days after last dose, or 
30 days after last dose if participant 
starts a new anticancer therapy, 
whichever is sooner.
Vital signs 
(resting BP, HR, 
RR, and temp) 
and weight
X
X
X
X
X
X
X
X
X
Participants with initial or recurrent 
systolic BP ≥160 mm Hg or diastolic 
BP ≥100 mm Hg must have their BP 
monitored on D15 (or more 
frequently as clinically indicated) 
until systolic BP is ≤150 mm Hg and 
diastolic BP is ≤95 mm Hg for 
2 consecutive treatment cycles. 
D15 visit is mandatory in C1 and C2 
for all participants. During C3 and 
subsequent cycles, participants may 
return for the D15 visit if BP 
monitoring is required as specified 
above.
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Study Period
Eligibilitya
Crossover Phase
(21-Day Cycles)
EOT
Post-Crossover Phase Visits
Notes
Treatment Cycle
Cycle 1
Cycle 2
Cycle 3 – Last
Cycle Day
1
8
15
1
8
15
1
8
15
Safety 
FUb
Efficacy 
FU Visits
Survival 
FU
Scheduling 
Window (Days):
–28 to –1
±1
±1
±3
±3
±3
±3
±3
±3
At 
DC
30 Days 
After 
Last Dose 
(+ 7 days)
Q12Wd
(± 7 days)
Q12W 
(± 7 days)
12-lead ECG
X
X
X
X
X
X
Single 12-lead ECG. Participants 
must be in the recumbent position 
for a period of 5 minutes prior to the 
ECG.
ECG at screening, C1D1, C2D1, D1 
of every 4th cycle (12 weeks) 
thereafter (eg, C6, C10, C14, etc.), 
EOT, and safety follow-up. 
ECG at C1D1 and C2D1 should be 
performed approximately 2 hours 
post-lenvatinib dose. For high-risk 
participants (as defined in Sec. 
8.3.3), conduct ECG monitoring 
every cycle. If lenvatinib is 
discontinued, ECGs are only 
required at the EOT and Safety 
Follow-up visits. 
ECGs on C1D1 are required to be on 
the day of dosing for participants on 
both arms of the study
MUGA or ECHO 
for LVEF 
assessment
X
X
Required prior to restarting 
crossover phase only if it was not 
already completed within 28 days 
prior.
Additional assessments as clinically 
indicated. Assessments should use 
the same method (MUGA or ECHO) 
throughout the study.
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Study Period
Eligibilitya
Crossover Phase
(21-Day Cycles)
EOT
Post-Crossover Phase Visits
Notes
Treatment Cycle
Cycle 1
Cycle 2
Cycle 3 – Last
Cycle Day
1
8
15
1
8
15
1
8
15
Safety 
FUb
Efficacy 
FU Visits
Survival 
FU
Scheduling 
Window (Days):
–28 to –1
±1
±1
±3
±3
±3
±3
±3
±3
At 
DC
30 Days 
After 
Last Dose 
(+ 7 days)
Q12Wd
(± 7 days)
Q12W 
(± 7 days)
Hematology and 
clinical chemistry 
laboratory 
assessmentse
X
X
X
X
X
X
X
Performed locally within 7 days 
prior to start of crossover phase. 
Every effort should be made to 
collect samples at the same time of 
day.
After C1, retrospective review of 
lipase results is allowed when the 
results are not available prior to 
dosing.
Urine dipstick 
testing
X
X
X
X
X
X
X
Performed locally within 7 days 
prior to start of treatment. 
Participants with urine protein 
≥1 g/24 h will not be eligible.
During crossover phase, repeat 
testing for participants with 
proteinuria ≥2+ should be performed 
on D15 (or more frequently as 
clinically indicated) until the results 
have been 1+ or negative for 
2 consecutive treatment cycles. 
D15 visit is mandatory in C1 and 
C2. During C3 and subsequent 
cycles, participants may return for 
the D15 visit if monitoring is 
required as specified above.
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Study Period
Eligibilitya
Crossover Phase
(21-Day Cycles)
EOT
Post-Crossover Phase Visits
Notes
Treatment Cycle
Cycle 1
Cycle 2
Cycle 3 – Last
Cycle Day
1
8
15
1
8
15
1
8
15
Safety 
FUb
Efficacy 
FU Visits
Survival 
FU
Scheduling 
Window (Days):
–28 to –1
±1
±1
±3
±3
±3
±3
±3
±3
At 
DC
30 Days 
After 
Last Dose 
(+ 7 days)
Q12Wd
(± 7 days)
Q12W 
(± 7 days)
PT/INR and 
aPTT/PTT
X
Eligibility samples collected within 
7 days of crossover phase initiation.
Additional testing to be conducted as 
clinically indicated for participants 
taking anticoagulant therapy.
PTT is acceptable at sites where 
aPTT is not performed.
T3, FT4, TSH
X
X
X
X
Eligibility samples to be collected 
within 7 days of crossover phase
initiation.
Thyroid function tests will be 
performed every other cycle starting 
with Cycle 2 (eg, Cycle 4, 6, 8, etc.).
Free T3 is acceptable where T3 
cannot be determined.
After C1, retrospective review of 
thyroid function testing results is 
allowed when the results are not 
available prior to dosing.
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Study Period
Eligibilitya
Crossover Phase
(21-Day Cycles)
EOT
Post-Crossover Phase Visits
Notes
Treatment Cycle
Cycle 1
Cycle 2
Cycle 3 – Last
Cycle Day
1
8
15
1
8
15
1
8
15
Safety 
FUb
Efficacy 
FU Visits
Survival 
FU
Scheduling 
Window (Days):
–28 to –1
±1
±1
±3
±3
±3
±3
±3
±3
At 
DC
30 Days 
After 
Last Dose 
(+ 7 days)
Q12Wd
(± 7 days)
Q12W 
(± 7 days)
Pregnancy test 
(WOCBP only)
X
X
X
X
X
To be assessed within 3 days of 
crossover phase initiation. A serum 
or urine pregnancy test will be 
performed as indicated and at least 
every 30 days up to 120 days post 
last dose of study medication or the 
start of a new anticancer therapy, 
whichever comes first.
Postmenopausal women who have 
not had menses for >12 months must 
have 2 FSH tests.
Refer to Appendix 9 for country-
specific requirements.
ECOG 
performance 
status
X
X
X
X
To be assessed within 7 days of 
starting crossover phase for 
eligibility requirement. 
Should be assessed prior to dosing at 
treatment visits.
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Study Period
Eligibilitya
Crossover Phase
(21-Day Cycles)
EOT
Post-Crossover Phase Visits
Notes
Treatment Cycle
Cycle 1
Cycle 2
Cycle 3 – Last
Cycle Day
1
8
15
1
8
15
1
8
15
Safety 
FUb
Efficacy 
FU Visits
Survival 
FU
Scheduling 
Window (Days):
–28 to –1
±1
±1
±3
±3
±3
±3
±3
±3
At 
DC
30 Days 
After 
Last Dose 
(+ 7 days)
Q12Wd
(± 7 days)
Q12W 
(± 7 days)
Abbreviations: AE = adverse event; BP = blood pressure; C1 = Cycle 1; C2 = Cycle 2; CR = complete response; CT = computed tomography; D1 = Day 1; D15 = Day 15; D8 = 
Day 8; DC = discontinuation; ECG = electrocardiogram; ECHO = echocardiogram; ECOG = Eastern Cooperative Oncology Group; EOT = end of treatment; FT4 = free 
thyroxine; HR = heart rate; IEC = Independent Ethics Committee; IRB = Independent Review Board; IRT = interactive response technology; LVEF = left ventricular ejection 
fraction; MRI = magnetic resonance imaging; MUGA = multigated acquisition; PD = progressive disease; PE = physical examination; PFS2 = progression-free survival on 
next line therapy;; Q3W = every 3 weeks; Q8W = every 8 weeks; Q12W = every 12 weeks; Q24W = every 24 weeks; QD = once daily; QW = every week; RR = respiratory 
rate; SAE = serious adverse event; T3 = triiodothyronine; TSH = thyroid stimulating hormone; WOCBP = women of childbearing potential.
a.
Eligibility procedures should be performed within 28 days prior to first dose of crossover phase unless there is another timeframe specified within the procedure-specific note.
b.
If EOT visit occurs ≥30 days from last dose of crossover phase, a safety follow-up visit is not required. In this situation, all procedures required at both the EOT visit and the 
safety follow-up visit should be performed.
c.
For participants receiving pembrolizumab plus lenvatinib, a review of concomitant medications and AEs should be performed on Day 8 of Cycle 1; a clinic visit is not 
required and can be performed via a telephone-call. Following Cycle 1, the review of concomitant medications and AEs on Day 8 is not required for participants receiving 
pembrolizumab plus lenvatinib. 
d.
Following the primary analysis for the study: follow-up visits and tumor assessments should be performed Q12W or more frequently if required by local standard of care. 
Bone and brain scans should be performed per local standard of care.
e.
From C2D1 onwards, clinical laboratory assessments may be conducted up to 72 hours prior to the scheduled visit, unless otherwise specified. Procedures/assessments should 
be performed prior to administration of crossover study treatment.
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2
INTRODUCTION
2.1
Study Rationale
2.1.1
Background
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody 
(mAb) with high specificity of binding to the programmed cell death 1 (PD-1) receptor, thus 
inhibiting its interaction with programmed cell death 1 ligand 1 (PD-L1) and programmed 
cell death 1 ligand 2 (PD-L2). Lenvatinib (also known as E7080 or MK-7902) inhibits the 
kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), 
VEGFR2 (KDR), and VEGFR3 (FLT4). Lenvatinib inhibits other kinases that have been 
implicated in pathogenic angiogenesis, tumor growth, and cancer progression in addition to 
their normal cellular functions, including fibroblast growth factor (FGF) receptors FGFR1, 2, 
3, and 4; platelet-derived growth factor receptor alpha (PDGFRα), KIT, and RET. Lenvatinib 
also exhibited antiproliferative activity in cell lines dependent on activated FGFR signaling 
with a concurrent inhibition of FGF-receptor substrate 2α phosphorylation. Pembrolizumab 
combined with once daily (QD) dosing of lenvatinib is currently being developed for the 
treatment of advanced endometrial cancer.
Refer to the respective Investigator’s Brochure (IB) for detailed background information on 
pembrolizumab and lenvatinib.
2.1.2
Pharmaceutical and Therapeutic Background
2.1.2.1
Lenvatinib
Angiogenesis, the formation of new blood vessels from a pre-existing vascular network, is 
essential for tumor growth and metastasis. VEGF and its family of receptors (VEGRs 1-3) 
play a major role in tumor angiogenesis [Ferrara, N., et al 2003] [Ellis, L. M. 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 human umbilical vein endothelial cells 
(HUVEC) with IC50 values of 2.1 and 7.3 nmol/L, respectively. Analysis of the signal 
transduction molecules revealed that lenvatinib inhibited both the mitogen activated protein 
kinase (MAPK) pathway and the mammalian target of rapamycin (mTOR)-S6 kinase (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 
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in vivo model [Yamamoto, Y., et al 2014]. In vivo, lenvatinib exhibited antitumor activity 
against various human tumor xenografts in athymic mice including 5 types of thyroid 
carcinomas (differentiated [papillary and follicular], anaplastic, squamous, and medullary 
thyroid carcinomas), renal cell carcinoma (RCC), hepatocellular carcinoma (HCC), 
melanoma, gastric cancer, non–small cell lung 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.
2.1.2.2
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 cluster of differentiation 8 
positive (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 RCC. Tumor-infiltrating lymphocytes can be expanded ex vivo and 
reinfused, inducing durable objective tumor responses in cancers such as melanoma [Dudley, 
M. E., et al 2005] [Hunder, N. N., et al 2008].
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control. The normal function of PD-1, expressed on the cell surface of activated 
T-cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an Ig 
superfamily member related to CD28 and cytotoxic T-lymphocyte-associated protein 4 
(CTLA-4) that has been shown to negatively regulate antigen receptor signaling upon 
engagement of its ligands (PD L1 and/or PD-L2) [Greenwald, R. J., et al 2005] [Okazaki, T., 
et al 2001]. 
The structure of murine PD-1 has been resolved [Zhang, X., et al 2004]. PD-1 and its family 
members are type I transmembrane glycoproteins containing an Ig-variable–type (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 CD3 zeta (CD3ζ), protein 
kinase C-theta (PKCθ), and zeta-chain-associated protein kinase (ZAP70), which are 
involved in the CD3 T-cell signaling cascade [Okazaki, T., et al 2001] [Chemnitz, J. M., et al 
2004] [Sheppard, K-A, et al 2004] [Riley, J. L. 2009]. The mechanism by which PD-1 down-
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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 endometrial cancer (EC).
2.1.2.3
Endometrial Cancer: Epidemiology and Current Therapeutic Options
Endometrial cancer is the fifth most common cancer in women worldwide, with 
approximately 320,000 new cases diagnosed in 2012 [Ferlay, J., et al 2015]. In the United 
States, the estimated numbers of new cases and deaths occurring in 2017 are 61,380 and 
10,920, respectively. A majority of EC cases are identified at an early stage with a 5-year 
survival rate of 95.3% for localized EC [National Cancer Institute 2017]. However, despite 
early detection, approximately 13% of all endometrial cancers recur [Fung-Kee-Fung, M., et 
al 2006]. In general, for patients with advanced or recurrent EC, median survival is only 
approximately 12 months [Obel, J. C., et al 2006].
For patients presenting with advanced disease, treatment options are limited with no 
consensus on a standard regimen. Chemotherapy has been the standard of care in the 
first-line treatment of EC, with platinum compounds, anthracyclines, and taxanes being the 
most commonly used, alone and in combination [National Comprehensive Cancer Network 
2017] [Colombo, N., et al 2013]. Cytotoxic therapy is also a de facto standard in second-line 
treatment; however, response rates are low, progression-free survival (PFS) and overall 
survival (OS) are short, and no drug has proven to be effective. To date, studies in this setting 
have shown response rates of 15% or lower with median OS and PFS of approximately 12 
months and 4 months, respectively [McMeekin, S., et al 2015]. Given the unmet clinical need 
in this patient population, exploration of novel therapeutic approaches is warranted.
The proposed multicenter, randomized, open-label, Phase 3 study (KEYNOTE-775/E7080-
G000-309, hereafter referred to as “Study 309”) will compare the efficacy and safety of 
lenvatinib in combination with pembrolizumab versus treatment of physician’s choice (TPC)
in participants with advanced EC.
2.1.2.4
Scientific Rationale for the Combination of Lenvatinib with Pembrolizumab
In preclinical models, lenvatinib decreased the tumor associated macrophage (TAM) 
population, which is known as an immune-regulator in the tumor microenvironment. 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/PD-L1 signal inhibitors. The effect of 
combining lenvatinib with an anti-human PD-1 humanized mAb was investigated in 4 
murine tumor isograft models, which showed significant tumor growth inhibition compared 
to control. In the RAG murine tumor isograft tumor model, survival in the group treated with 
the combination was significantly longer than that of the respective monotherapy groups. In 
the CT26 murine tumor isograft model, treatment with the combination significantly 
increased the population of activated cytotoxic T-cells compared to that of the respective 
monotherapy groups [Kato, Y., et al 2019]. All treatments were well tolerated, and severe 
body weight loss was not observed.
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2.1.2.5
Clinical Data on Lenvatinib in Combination with Pembrolizumab for 
Treatment of EC
Promising activity was observed in 53 EC participants analyzed for efficacy and safety 
during an interim analysis of the Phase 2 Study 111/KEYNOTE-146; all participants initiated 
treatment at the 20 mg lenvatinib QD + 200 mg pembrolizumab IV Q3W dosing level 
[Makker, V., et al 2018]. The EC participants were predominantly Caucasian (83%), with a 
median age of 63.7 years, and all had an ECOG performance status score of 0 (38%) or 1 
(62%). All participants had received prior anticancer therapy regimens (1 prior [42%], 2 prior 
[42%], ≥3 prior [17%]). At baseline, 85% of participants had microsatellite stable (MSS) 
tumors, 7.5% had microsatellite instability (MSI)-high (MSI-H) tumors, and 7.5% of 
participants had an unknown MSI status. Thirteen participants (24.5%) were PD-L1 positive, 
11 (20.8%) were PD-L1 negative, and 29 (54.7%) were not tested for PD-L1 status.
The best overall response (BOR) was evaluated per immune-related Response Evaluation 
Criteria for Solid Tumors (irRECIST) by both investigator assessment and independent 
radiology review (IRR). As of the 15-DEC-2017 data cutoff, the BOR by investigator 
assessment included 1 CR (1.9%), 20 PR (37.7%) and 25 SD (47.2%). The BOR as assessed 
by independent radiology review (3 CR [5.7%], 22 PR [41.5%], and 19 SD [35.8%]) was 
comparable to the BOR by investigator assessment.
By investigator assessment, the primary endpoint of objective response rate (ORR) at 
Week 24 (ORRWeek24) was equal to the overall ORR (39.6% [21/53; 95% CI: 26.5–54.0]).
Comparable ORRs were observed in subgroups of participants with MSI-H tumors (2/4 
[50.0%]; 95% CI: 6.8–93.2) versus those with MSS tumors (16/45 [35.6%]; 95% CI: 21.9–
51.2). In participants that responded, 83.0% had a DOR ≥6 months and 64.5% had a DOR 
≥12 months. Secondary analysis of tumor efficacy by IRR showed an ORRWeek24 of 45.3% 
and an overall ORR of 47.2%. Median PFS by investigator assessment per irRECIST was 7.4 
months (95% CI: 5.0-not estimable). 
Treatment with lenvatinib plus pembrolizumab was associated with an acceptable safety 
profile in this patient population. Toxicities were generally manageable with supportive
medications, dose interruptions, and/or lenvatinib dose reductions. The most frequently 
reported treatment-related AEs (any grade) were hypertension (59%), fatigue (55%), diarrhea 
(51%), hypothyroidism (47%), and decreased appetite (40%). Of the 5 deaths that occurred in 
this study, only 1 death (caused by an AE of intracranial hemorrhage) was considered related 
to the study intervention by the investigator.
2.1.2.6
Clinical Data on Lenvatinib and Pembrolizumab as Single Agents for the 
Treatment of EC
Eisai and MSD have conducted studies of lenvatinib and pembrolizumab as single agents, 
respectively, in the treatment of advanced EC. 
Eisai has conducted a Phase 2 open-label, single-arm study of lenvatinib monotherapy in 
advanced EC following first-line platinum-based chemotherapy with 133 treated participants 
(E7080-G000-204). The primary endpoint was ORR, based on RECIST 1.1, as determined 
by independent radiologic review (IRR). Per IRR, 19 (14.3%) participants achieved a best 
overall response of either complete response (CR; 1 participant) or PR (18 participants), and 
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per investigator assessment, 28 (21.1%) participants achieved either CR (2 participants) or 
PR (26 participants). The median PFS was 5.6 months based on IRR assessment and was 
5.4 months based on investigator assessment. For the responders, the median duration of 
response was 7.2 months based on IRR assessment and 8.0 months based on investigator 
assessment. Median OS was 10.6 months with a median duration of follow-up of 
15.2 months (Eisai Data on File).
Most participants experienced at least 1 treatment-emergent AE (TEAE; 126/133 
participants, 94.7%) and at least 1 TEAE reported as treatment-related (116/133 participants, 
87.2%). The most frequently reported TEAEs (>20% of all participants, in descending 
frequency) were hypertension, fatigue, diarrhea, decreased appetite, nausea, abdominal pain, 
headache, asthenia, vomiting, stomatitis, proteinuria, dysphonia and weight decreased. The 
most commonly reported TEAEs reported as treatment-related (>20% of participants, in 
order of descending frequency) were as follows: hypertension, fatigue, decreased appetite, 
diarrhea, headache, nausea, proteinuria, and stomatitis. TEAEs that were Grade 3 or above 
(severe) occurred in 97 (72.9%) participants; this includes 14 participants (10.5%) with 
Grade 5 events. Among the 14 Grade 5 SAEs, 6 of these were also associated with disease 
progression. Observed toxicities were consistent with previously reported events associated 
with lenvatinib and other drugs that target the VEGFR (Eisai Data on File).
MSD has conducted a Phase 1b study evaluating pembrolizumab monotherapy (10 mg/kg 
administered IV every 2 weeks [Q2W]) in 24 participants with PD-L1 positive advanced EC, 
including 22 participants who received 1 or more prior lines of therapy for advanced disease 
(KEYNOTE-028 [KN028], NCT02054806). At the time of the data cutoff (17-FEB-2016),
the ORR, based on RECIST 1.1, was 13% (n=3), and median PFS observed was 1.8 months 
with 6- and 12-month PFS rates of 19.0% and 14.3%, respectively. Median duration of 
response (DOR) was not reached (range: 63.7+ to 64.7+ weeks) at the time of the data cutoff.
The median OS was not reached, and the 6- and 12-month OS rates were 67.0% and 51.0%, 
respectively [Ott, P. A., et al 2017]. 
At the time of the data cutoff, the median follow-up duration was 76.2 weeks (range: 2.6 to 
94.3 weeks). Thirteen participants (54.2%) experienced treatment-related AEs, with fatigue 
(20.8%), pruritus (16.7%), pyrexia (12.5%), and decreased appetite (12.5%) occurring in 
≥10% of participants. Grade 3 treatment-related AEs were reported in 4 participants (16.7%): 
1 participant had asthenia and back pain; 1 participant had anemia, hyperglycemia, and 
hyponatremia; 1 participant had chills and pyrexia; and 1 participant had diarrhea. No 
participant experienced a Grade 4 AE or immune-mediated AE of any grade, no participant
discontinued treatment because of an AE, and no participant experienced treatment-related 
death [Ott, P. A., et al 2017].
MSD is further investigating the clinical benefit of pembrolizumab monotherapy (200 mg 
administered IV Q3W) for in advanced EC, regardless of PD-L1 positivity, in the 
multi-cohort Phase 2 KN158 (NCT02628067) study.
As of 28-APR-2017, 107 EC participants have been treated. A majority of participants 
(62.6%) had not received prior neoadjuvant/adjuvant therapy. Most participants had received 
prior therapy for recurrent/metastatic disease (1 prior [29.0%], 2 prior [27.1%], 3 or more 
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prior [31.8%]), with 10.3% of participants receiving no prior therapy for recurrent/metastatic 
disease (MSD Data on File).
The ORR based on RECIST 1.1 per blinded independent central review (BICR) assessment 
is 11.2% (95% CI: 5.9%, 18.8%), with all 12 participants achieving a best overall response of 
PR. Median PFS observed was 2.1 months. The median DOR was not reached (range: 4.7+ 
to 10.0+ months) at the time of the data cutoff. The median OS was 11.1 months (MSD Data 
on File).
The majority of participants had at least 1 AE (n=103; 96.3%), with 64.5% (n=69) 
considered related to the study drug by the investigator. Grade 3, 4, or 5 events occurred in 
57.9% of participants, with 15.9% considered related to the study drug by the investigator. 
There were 3 participants who died while on study. One death case was due to pulmonary 
sepsis (starting 32 days after start of treatment), 1 death was due to dyspnea (starting 45 days 
after start of treatment), and 1 death was due to general physical deterioration, with cardiac 
arrest (starting 14 days after the start of treatment). These deaths were not attributed to 
clinical or radiological progression. The most common AEs of any grade occurring in ≥25% 
of participants were decreased appetite (26.2%), nausea (29.0%), and fatigue (29.9%; MSD 
Data on File).
The observed toxicities of pembrolizumab monotherapy in advanced EC are consistent with 
previously reported events associated with pembrolizumab. 
The ORR from these studies suggest that the activity observed for the combination of 
lenvatinib with pembrolizumab in Study 111/KEYNOTE-146 is greater than can be 
accounted for by each of these single agents on their own.
2.1.3
Preclinical and Clinical Studies
Refer to the respective IBs for preclinical and clinical study data for pembrolizumab and 
lenvatinib.
2.1.4
Ongoing Clinical Studies
Refer to the respective IBs for ongoing clinical study data for pembrolizumab and lenvatinib.
2.1.5
Information on Other Study-related Therapy
For additional information on doxorubicin and paclitaxel, refer to the respective approved 
product labels.
2.2
Benefit/Risk Assessment
It cannot be guaranteed that participants in clinical studies will directly benefit from 
treatment during participation, as clinical studies are designed to provide information about 
the safety and effectiveness of an investigational medicine.
As discussed in Sections 2.1.2.5 and 2.1.2.6, both lenvatinib and pembrolizumab (alone and 
in combination), have shown promising efficacy in participants with EC. Given the short 
median survival [Obel, J. C., et al 2006] and limited treatment options for patients with 
advanced or recurrent EC, there is an unmet need for clinical need for novel therapies in this 
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setting. The existing data suggest that inhibiting angiogenesis in combination with PD-1 
blockade is a promising therapeutic strategy and the benefit:risk assessment for participants 
included in this study is considered to be favorable.
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.
3
OBJECTIVES/HYPOTHESES AND ENDPOINTS
In all randomized participants with advanced endometrial cancer:
Objective/Hypothesis
Endpoint
Primary

Objective: To demonstrate that lenvatinib 
in combination with pembrolizumab is 
superior to Treatment of Physician’s 
Choice (TPC) in improving progression-
free survival (PFS).
Hypothesis (H1): The combination of 
lenvatinib and pembrolizumab is superior 
to TPC as assessed by PFS in pMMR 
participants.
Hypothesis (H4): The combination of 
lenvatinib and pembrolizumab is superior 
to TPC as assessed by PFS in all-comer 
participants.

PFS, defined as the time from date of 
randomization to the date of the first 
documentation of disease progression, 
as determined by blinded independent 
central review (BICR) per Response 
Evaluation Criteria in Solid Tumors 
version 1.1 (RECIST 1.1), or death
from any cause, whichever occurs first.

Objective: To demonstrate that lenvatinib 
in combination with pembrolizumab is 
superior to TPC in improving overall 
survival (OS).
Hypothesis (H2): The combination of 
lenvatinib and pembrolizumab is superior 
to TPC as assessed by OS in pMMR 
participants.
Hypothesis (H5): The combination of 
lenvatinib and pembrolizumab is superior 
to TPC as assessed by OS in all-comer 
participants.

OS, defined as the time from date of 
randomization to date of death from 
any cause.
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Objective/Hypothesis
Endpoint
Secondary

Objective: To compare the objective 
response rate (ORR) of participants 
treated with lenvatinib in combination 
with pembrolizumab versus TPC by 
BICR
Hypothesis (H3): The combination of 
lenvatinib and pembrolizumab is superior 
to TPC as assessed by ORR in pMMR 
participants.
Hypothesis (H6): The combination of 
lenvatinib and pembrolizumab is superior 
to TPC as assessed by ORR in all-comer
participants.

ORR, defined as the proportion of 
participants who have best overall 
response of either complete response 
(CR) or partial response (PR), as 
determined by BICR per RECIST 1.1.

Objective: To evaluate the impact of 
treatment on Health-Related Quality of 
Life (HRQoL) as assessed by using the 
global score of the European 
Organisation for the Research and 
Treatment of Cancer (EORTC) QLQ-C30 
for participants treated with lenvatinib in
combination with pembrolizumab versus 
TPC in pMMR participants and in all-
comer participants.

HRQoL will be assessed using the
global score of the EORTC QLQ-C30.

Objective: To assess safety and 
tolerability of treatment with lenvatinib in 
combination with pembrolizumab versus 
TPC in pMMR participants and in all-
comer participants.

Incidence of treatment-emergent 
adverse events (TEAEs), serious AEs 
(SAEs), and immune-related AEs.

Proportion of participants discontinuing 
study treatment due to TEAEs.

Time to treatment failure due to 
toxicity, defined as the time from the 
date of randomization to the date that a 
participant discontinues study treatment 
due to TEAEs.

Objective: To characterize the population 
pharmacokinetics (PK) of lenvatinib 
when co-administered with 
pembrolizumab in pMMR participants 
and in all-comer participants.

Plasma concentration of lenvatinib 
versus time.
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Objective/Hypothesis
Endpoint

Objective: To assess the relationship 
between exposure to lenvatinib and safety
events related to lenvatinib in pMMR 
participants and in all-comer participants.

Clearance and area under the 
concentration-time curve (AUC) for 
lenvatinib.
Exploratory

Objective: To compare the ORR of 
participants treated with lenvatinib in 
combination with pembrolizumab versus 
TPC.

ORR, defined as the proportion of 
participants who have best overall 
response of either CR or PR, as 
determined by investigator per RECIST 
1.1.

Objective: To compare the PFS of 
participants treated with lenvatinib in 
combination with pembrolizumab versus 
TPC.

PFS, defined as the time from date of 
randomization to the date of the first 
documentation of disease progression, 
as determined by investigator per 
RECIST 1.1, or death from any cause, 
whichever occurs first.

Objective: To assess duration of response 
(DOR) in both treatment arms in pMMR 
participants and in all-comer participants.

DOR, defined as the time from the date 
a response was first documented until 
the date of the first documentation of 
disease progression, by BICR and 
investigator assessment of objective 
radiographic disease assessment per 
RECIST 1.1, or date of death, 
whichever occurs first.

To assess disease control rate (DCR) and 
clinical benefit rate (CBR) of participants 
treated with lenvatinib in combination 
with pembrolizumab versus TPC in 
pMMR participants and in all-comer 
participants.

DCR, defined as the proportion of 
participants who have best overall 
response of CR, PR, or stable disease 
(SD) by BICR and investigator 
assessment per RECIST 1.1. SD must 
be achieved at ≥7 weeks after 
randomization to be considered best 
overall response.

CBR, defined as the proportion of 
participants who have best overall 
response of CR, PR, or SD by BICR 
and investigator assessment per 
RECIST 1.1 (duration of SD 
≥23 weeks after randomization).
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Objective/Hypothesis
Endpoint

Objective: To assess efficacy outcomes 
using modified RECIST 1.1 for immune-
based therapeutics (iRECIST) in 
participants treated with lenvatinib in 
combination with pembrolizumab versus 
TPC by investigator assessment in 
pMMR participants and in all-comer 
participants.

PFS, ORR, DOR, DCR, and CBR as 
determined by investigator assessment 
using iRECIST. PFS using iRECIST 
will be defined as the time from the 
date of randomization to the date of the 
first documentation of confirmed 
immune-related progressive disease 
(iPD) or death (whichever occurs first).

Objective: To evaluate the impact of 
treatment on HRQoL as assessed by 
using the EORTC QLQ-C30, EORTC 
QLQ-EN24 and European Quality of Life
(EuroQoL) EQ-5D-5L instruments for 
participants treated with lenvatinib in 
combination with pembrolizumab versus 
TPC in pMMR participants and in all-
comer participants.

HRQoL will be assessed using the 
EORTC QLQ-C30 (scores other than 
global score), EORTC QLQ-EN24, and 
EuroQoL EQ-5D-5L.

To assess PFS on next line therapy 
(PFS2) by investigator assessment in 
pMMR participants and in all-comer 
participants.

PFS2, defined as the time from 
randomization to disease progression, 
as determined by investigator 
assessment, on next line of treatment or 
death (whichever occurs first).

To identify molecular (genomic, 
metabolic, and/or proteomic) biomarkers 
that may be indicative of clinical 
response/resistance, safety, 
pharmacodynamic activity, and/or the 
mechanism of action of lenvatinib and 
pembrolizumab in pMMR participants 
and in all-comer participants.

Molecular (genomic, metabolic, and/or 
proteomic) determinants of response or 
resistance to treatments, using blood 
and/or tumor tissue.
4
STUDY DESIGN
4.1
Overall Design
This is a multicenter, randomized, open-label, Phase 3 study to compare the efficacy and 
safety of lenvatinib in combination with pembrolizumab versus TPC in participants with 
advanced EC who have been treated with at least 1 prior platinum-based chemotherapy 
regimen.
Approximately 780 eligible participants (660 mismatch repair proficient [pMMR]
participants and up to 120 MMR deficient [dMMR] participants) will be randomized to 1 of 
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the following 2 treatment arms in a 1:1 ratio, with approximately 390 participants in each 
arm:
•
Arm A: lenvatinib 20 mg (orally, QD) plus pembrolizumab 200 mg (IV Q3W)
•
Arm B: TPC consisting of either doxorubicin 60 mg/m2 (by IV bolus injection, 1-hour 
infusion, or per institutional guidelines) Q3W, or paclitaxel 80 mg/m2 (by 1-hour IV 
infusion or per institutional guidelines) given weekly, 3 weeks on/1 week off
The study will have been considered to have completed enrollment when 660 pMMR 
participants have enrolled. Enrollment of dMMR participants will be capped at 120.
Prior to randomization, investigators must select and record the TPC option in the event the 
participant will be assigned to that arm. Randomization will follow a predefined 
randomization scheme based on the following stratification factors: MMR status (pMMR or 
dMMR), ECOG performance status (0 or 1), geographic region (Region 1: Europe, USA, 
Canada, Australia, New Zealand, and Israel or Region 2: rest of the world), and prior history 
of pelvic radiation (yes or no). First, participants will be stratified according to MMR status. 
Then, only within the pMMR stratum, participants will be further stratified according to 
ECOG performance status, geographic region, and prior history of pelvic radiation. A total of 
9 strata will be utilized for the study.
The end of the study will be the date of data cutoff for the final OS analysis (ie, 526 deaths in 
pMMR participants) or the time of last participant/last treatment, whichever occurs later.
4.1.1
Screening Period
Screening will occur between Day -28 and Day -1. The purpose of the Screening Period is to 
obtain informed consent and to establish protocol eligibility according to the inclusion and 
exclusion criteria listed in Section 5.1 and Section 5.2, respectively.
Informed consent will be obtained after the study has been fully explained to each participant
and before the conduct of any screening procedures or assessments. Procedures to be 
followed when obtaining informed consent are detailed in Section 8.1.1. 
Eligible participants must have measurable disease according to RECIST 1.1 [Eisenhauer, E. 
A., et al 2009] confirmed by BICR prior to randomization. Available historical tumor or 
fresh tumor biopsy specimen must be submitted for all participants prior to randomization for 
determination of MMR status by a designated central laboratory.
Laboratory tests should be performed within 7 days of the first dose of study treatment. A 
pregnancy test (for women of childbearing potential [WOCBP]) should be performed within 
72 hours of the first dose of study treatment. Repeated laboratory evaluation to establish 
eligibility is not allowed unless discussed and agreed upon with MSD.
Participants who complete the Screening Period and meet the criteria for inclusion/exclusion 
(Sections 5.1 and 5.2) will begin the Treatment Period. The appropriate case report form 
(CRF) page must be completed to indicate whether the participant is eligible to participate in 
the study and to provide reasons for screen failure, if applicable. If the MMR result is not 
available within 28 days from when the original consent was obtained, an extension may be 
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granted after consultation with MSD as long as all other screening procedures are performed 
within the correct timeframe.
4.1.2
Treatment Period
The Treatment Period begins at the time of randomization and will end with the completion 
of the EOT visit 
Participants will receive study treatment as continuous 21-day cycles (for participants treated 
with lenvatinib plus pembrolizumab and doxorubicin as the TPC choice), or continuous 
28-day cycles (for participants receiving weekly paclitaxel as the TPC choice). Participants 
will undergo safety and efficacy assessments as defined in the SoA (Section 1.3.1). 
Participants will continue to receive study treatment until disease progression is confirmed by 
BICR, development of unacceptable toxicity, withdrawal of consent, receipt of 
35 administrations of pembrolizumab (approximately 2 years), or a lifetime cumulative dose 
of 500 mg/m² of doxorubicin. Discontinuation of pembrolizumab treatment may be 
considered for participants who have attained a confirmed CR, have been treated for at least 
8 cycles (at least 24 weeks) with pembrolizumab, and had at least 2 treatments with 
pembrolizumab beyond the date when the initial CR was declared. Participants who stop 
study treatment after receiving 35 administrations of pembrolizumab for reasons other than 
disease progression or intolerability, or participants who attain a CR and stop pembrolizumab
may be eligible for up to an additional year of treatment with pembrolizumab (17 cycles) ±
lenvatinib upon experiencing disease progression (Second Course Phase; Section 6.6.5). 
Participants who complete treatment with pembrolizumab after 35 cycles (approximately 2 
years) or CR will continue to receive lenvatinib alone until disease progression is confirmed 
by BICR, development of unacceptable toxicity, or withdrawal of consent.
Participants will be permitted to continue study treatment beyond RECIST 1.1-defined 
disease progression as long as the maximum dose of the study drugs have not been reached 
(e.g. 35 administrations of pembrolizumab or a lifetime cumulative dose of 500 mg/m² of 
doxorubicin), the treating investigator considers that the participant may experience clinical 
benefit with continued treatment, and, the participant is tolerating study treatment (Section 
8.2.1.6 and Appendix 5). All decisions to continue treatment beyond 2 consecutive scans 
showing progression at least 4 weeks apart must be discussed with the MSD Medical 
Monitor. 
Disease progression (per RECIST 1.1) must be confirmed by BICR by the central imaging 
vendor (CIV) prior to the investigator discontinuing study treatment for a participant. In 
situations where the investigator judges that alternative treatments must be instituted 
immediately for a participant’s safety study drug may be discontinued without waiting for 
confirmation of radiographic evidence of disease progression by BICR. In these cases, the 
investigator should consult with MSD before discontinuation of the participant from study 
treatment, if possible.
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4.1.3
Crossover for Participants in TPC Arm to Lenvatinib 20 mg QD plus 
Pembrolizumab 200 mg Q3W Arm
The study’s interim analysis results demonstrated that lenvatinib 20 mg QD plus 
pembrolizumab 200 mg Q3W was associated with superior overall survival (OS) compared 
to the TPC arm (investigator’s choice: doxorubicin or paclitaxel) in the overall study 
population. Based on the positive outcome of the OS analysis, participants in the TPC arm, 
who experience investigator-defined disease progression (per RECIST 1.1), will have the 
opportunity to participate in the Crossover Phase, receiving lenvatinib 20 mg QD plus 
pembrolizumab 200 mg Q3W. Participants who have started a new anticancer therapy since 
last dose of study treatment or have withdrawn consent from study treatment, efficacy 
follow-up or survival follow-up are not eligible for crossover. All eligibility criteria should 
be met, except for exclusion criteria #20, #21, #24 and #28 (Refer to Sections 5.1 and 5.2). 
An overview of the study design is presented in Figure 1.
4.1.4
Efficacy Follow-up Period
The Efficacy Follow-up Period will begin the day after the EOT Visit and will continue as 
long as the participant is alive, until the data cutoff date for the primary OS analysis, or when 
all participants have discontinued study treatment, unless the participant withdraws consent, 
or is lost to follow-up. If a participant discontinues study treatment and withdraws consent to 
continued follow-up, the investigator must not access confidential records that require the 
participant’s consent. However, an investigator may consult public records to establish 
survival status if permitted by local regulations.
If participants in the TPC arm meet the eligibility criteria and enter the Crossover phase, the 
procedures for Crossover phase will be followed (Section 8.2.3).
During the follow-up period, participants will be treated by the investigator according to the 
prevailing local standard of care. Participants will be followed every 8 weeks (±1 week), or 
more frequently as needed, for PFS on next line therapy (PFS2), survival, and all subsequent 
anticancer treatments received. This information will be recorded unless this information is 
not allowed to be provided due to confidentiality. Participants will also be asked to complete 
HRQoL questionnaires as outlined in Section 8.2.2.
If a participant fails to attend a scheduled assessment (eg, visit/phone), the investigator or 
designee will make every attempt to contact the participant to determine his or her status. All 
attempts at contact will be recorded in the participant’s medical notes. Participants will be 
judged as lost to follow-up as outlined in Section 7.3.
All participants who discontinue study drug treatment prior to disease progression will 
continue to undergo tumor assessments every 8 weeks from the date of randomization in the
Efficacy Follow-up Period until disease progression is documented and confirmed by BICR 
or a new anticancer therapy is initiated, unless the participant withdraws consent. Following 
the primary analysis for the study, tumor assessments should be performed every 12 weeks or 
more frequently per local standard of care.
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Specific procedures to be performed during the study, as well as their prescribed times and 
associated visit windows, are outlined in the Schedule of Activities (SoA), Section 1.3. 
Details of each procedure are provided in Section 8.
4.1.5
Data Monitoring Committee
An external data monitoring committee (DMC) will be assembled and will be responsible for 
periodic monitoring of safety and efficacy data as well as the results from the interim 
analysis. The function and membership of the DMC will be described in the DMC charter.
4.1.6
Interim Analyses
Two interim analyses are planned (IA1 and IA2), but IA2 will not be performed. Following 
Amendment 08, the pre-planned IA2 is no longer required because the success criteria for the 
study hypotheses of PFS, OS, and ORR were met at the first interim analysis (IA1). Details 
are described in Section 9.7.
4.2
Scientific Rationale for Study Design
This multicenter, randomized, open-label, Phase 3 study was designed to compare the 
efficacy and safety of lenvatinib in combination with pembrolizumab versus TPC in 
participants with advanced EC who have been treated with at least 1 prior platinum-based 
chemotherapy regimen. Randomization will be used in this study to avoid bias in the 
assignment of participants to treatment, to increase the likelihood that known and unknown 
participant attributes (eg, demographics and baseline characteristics) are balanced across 
treatment arms, and to ensure the validity of statistical comparisons across treatment arms. 
Treatments will be open-labeled, since the dosage and administration is different between 
lenvatinib, pembrolizumab, doxorubicin, and paclitaxel. 
The sample size is estimated based on the primary endpoints of PFS and OS, and the required 
target events to detect the superiority of lenvatinib to TPC in the comparison of PFS and OS.
4.2.1
Rationale for Patient Population
Tumors that have a large number of somatic mutations have been shown to be more 
susceptible to PD-1 inhibition. One mechanism that generates increased numbers of somatic 
mutations is through defects in MMR. MMR corrects errors that spontaneously occur during 
DNA replication, such as single-base mismatches, short insertions, and deletions. Tumors 
with defects in MMR are known to harbor hundreds to thousands of somatic mutations. 
Regions of repetitive DNA, known as microsatellites, are known to be particularly 
susceptible to these deficiencies. Although the length of these microsatellite regions is highly 
variable from person to person, each individual has microsatellite regions of a set length. 
MMR deficiency leads to the accumulation of mutations in these regions, termed 
microsatellite instability (MSI).
Patients with MSI-H/dMMR-mutant EC appear to have more favorable response rates to 
pembrolizumab alone, which was recently granted accelerated approval by the FDA for the 
treatment of patients with unresectable or metastatic MSI-H or dMRR tumors, including EC.
In order to account for the improved efficacy of pembrolizumab in the MSI-H/dMRR EC 
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population, the sample size will be powered for the pMMR population. Thus, the study will 
enroll all EC participants (both pMMR and dMMR) and the sample size would increase to 
account for the additional dMMR patients (an estimated 10-15% increase in sample size). 
The study will stop recruitment once fully enrolled for pMMR participants (n=660) and the 
number of participants with dMMR will be capped (n=120). The primary statistical analysis 
will be completed for pMMR participants first, then the entire study population (all-comers).
4.2.2
Rationale for Endpoints
4.2.2.1
Efficacy Endpoints
This study will use PFS based on RECIST 1.1 criteria as assessed by BICR and OS as the 
primary endpoints. Progression-free survival is an acceptable measure of clinical benefit for a 
late stage study that demonstrates superiority of a new antineoplastic therapy, especially if 
the magnitude of the effect is large and the therapy has an acceptable risk/benefit profile. The 
use of BICR and RECIST 1.1 to assess PFS is typically considered acceptable by regulatory 
authorities. Images will be read by a CIV blinded to treatment assignment to minimize bias in 
the response assessments. In addition, the final determination of radiologic progression will 
be based on the central assessment of progression, rather than a local site 
investigator/radiology assessment. Real time determination of radiologic progression as 
determined by central review will be communicated to the site.
Overall survival has been recognized as the gold standard for the demonstration of 
superiority of a new antineoplastic therapy in randomized clinical studies.
4.2.2.1.1
RECIST 1.1
RECIST 1.1 will be used by the BICR when assessing images for efficacy measures and by 
the local site when determining eligibility (Section 8.2.1.5). Although traditional RECIST 1.1 
references a maximum of 5 target lesions in total and 2 per organ, this protocol has 
implemented a modification to RECIST 1.1 to allow a maximum of 10 target lesions in total 
and 5 per organ.
4.2.2.1.2
Modified RECIST 1.1 for Immune-based Therapeutics (iRECIST)
RECIST 1.1 will be adapted to account for the unique tumor response characteristics seen 
following treatment with pembrolizumab (Section 8.2.1.6). Immunotherapeutic agents such 
as pembrolizumab may produce antitumor effects by potentiating endogenous cancer-specific 
immune responses. The response patterns seen with such an approach may extend beyond the 
typical time course of responses seen with cytotoxic agents, and patients treated with 
pembrolizumab may manifest a clinical response after an initial increase in tumor burden or 
even the appearance of new lesions. Thus, standard RECIST 1.1 may not fully capture the 
treatment benefits from immunotherapeutic agents such as pembrolizumab. Based on an 
analysis of participants with melanoma enrolled in KEYNOTE-001 (KN001), 7% of 
evaluable participants experienced delayed or early tumor pseudo-progression. Of note, 
participants who had PD by RECIST 1.1 but not by the immune-related response criteria 
[Wolchok, J. D., et al 2009] had longer OS than participants with PD by both criteria [Hodi, 
F. S., et al 2014]. Additionally, the data suggest that RECIST 1.1 may underestimate the 
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benefit of pembrolizumab in approximately 15% of participants. These findings support the 
need to apply a modification to RECIST 1.1 that takes into account the unique patterns of 
atypical responses in immunotherapy and enables treatment beyond initial radiographic 
progression, if the participant is clinically stable. 
iRECIST assessment has been developed and published by the RECIST Working Group, 
with input from leading experts from industry and academia, along with participation from 
the US Food and Drug Administration and the European Medicines Agency [Seymour, L., et 
al 2017]. The unidimensional measurement of target lesions, qualitative assessment of non-
target lesions, and response categories are identical to RECIST 1.1, until progression is seen 
by RECIST 1.1. However, if a participant is clinically stable, additional imaging may be 
performed to confirm radiographic progression. iRECIST will be used by investigators to 
assess tumor response and progression and make treatment decisions as well as for 
exploratory efficacy analyses where specified.
4.2.2.2
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/serious AEs (SAEs), and changes in vital signs and laboratory
values. Adverse events will be assessed as defined by the National Cancer Institute (NCI)
Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03.
4.2.2.3
Rationale for Patient Reported Outcomes
Symptomatic improvement is considered a clinical benefit and accepted by health authorities. 
As part of the analyses for this study, participants will provide information regarding their 
health-related QoL (HRQoL) via the following assessment tools: European Organisation for 
the Research and Treatment of Cancer (EORTC) QLQ-C30, EORTC QLQ-EN24, and the 
EQ-5D-5L questionnaires. These measures are not pure efficacy or safety endpoints because 
they are affected by both disease progression and treatment tolerability.
The collection of PRO data will be discontinued following implementation of 
Amendment 09.
4.2.2.3.1
EORTC QLQ-30
The EORTC QLQ-C30 is the most widely used cancer-specific health-related quality of life 
(QoL) instrument, which contains 30 items and measures 5 functional dimensions (physical, 
role, emotional, cognitive, and social), 3 symptom items (fatigue, nausea/vomiting, and pain), 
6 single items (dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, and financial 
impact), and a global health and QoL scale [Aaronson, N. K., et al 1993]. The EORTC QLQ-
C30 is a psychometrically and clinically validated instrument appropriate for assessing QoL 
in oncology studies [Aaronson, N. K., et al 1993].
4.2.2.3.2
EORTC QLQ-EN24
The EORTC QLQ-EN24 is a standardized questionnaire which permits evaluation of QoL in 
participants with all stages of EC managed with a specific treatment. The module consists of 
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24 items including 10 symptom scales (Lymphoedema, Urological and Gastrointestinal 
symptoms, Poor body image, Sexual/vaginal problems, Pain in back and pelvis, 
Tingling/numbness, Muscular pain, Hair loss and Taste change) and 3 functional scales 
(Sexual interest, Sexual activity, Sexual enjoyment).
4.2.2.3.3
EuroQoL EQ-5D-5L
The EuroQoL-5D (EQ-5D) is a standardized instrument for use as a measure of health 
outcome and will provide data to develop health utilities for use in health economic analyses 
[Rabin, R. and de Charro, F. 2001]. The 5 health state dimensions in the EQ-5D include the 
following: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each 
dimension is rated on a 5-point scale from 1 (no problem) to 5 (unable to/extreme problems). 
The EQ-5D also includes a graded (0 to 100) vertical visual analog scale on which the 
participant rates his or her general state of health at the time of the assessment. This 
instrument has been used extensively in cancer studies and published results from these 
studies support its validity and reliability [Pickard, A. S., et al 2007].
4.2.2.4
Pharmacodynamic Endpoints
No pharmacodynamic endpoints are planned for this study.
4.2.2.5
Planned Exploratory Biomarker Research
Cancer immunotherapies represent an important and novel class of antitumor agents. 
However, the mechanism of action of these exciting new therapies, including novel 
combination with antiangiogenesis therapy, is not completely understood and much remains 
to be learned regarding how best to leverage these new drugs in treating patients. Thus, to aid 
future patients, it is important to investigate the determinants of response or resistance to 
cancer immunotherapy and other treatments administered, as well as determinants of AEs in 
the course of our clinical studies. These efforts may identify novel predictive/PD biomarkers 
and generate information that may better guide single-agent and combination therapy with 
immuno-oncology drugs. To identify novel biomarkers, biospecimens (ie, blood components, 
tumor material) will be collected to support analyses of cellular components (eg, protein, 
DNA, RNA, metabolites) and other circulating molecules. Investigations may include but are 
not limited to:
Germline (blood) genetic analyses (eg, SNP analyses, whole exome sequencing, whole 
genome sequencing)
This research may evaluate whether genetic variation within a clinical study population 
correlates with response to the treatment(s) under evaluation. If genetic variation is found to 
predict efficacy or AEs, the data might inform optimal use of therapies in the patient 
population. Furthermore, it is important to evaluate germline DNA variation across the 
genome in order to interpret tumor-specific DNA mutations.
Genetic (DNA) analyses from tumor
The application of new technologies, such as next generation sequencing, has provided 
scientists the opportunity to identify tumor-specific DNA changes (ie, mutations, methylation 
status, microsatellite instability) contributing towards the development/progression of cancer 
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and/or driving response to therapy. Key molecular changes of interest to immuno-oncology 
drug development include the mutational burden of tumors and the clonality of T-cells in the 
tumor microenvironment. Increased mutational burden (sometimes referred to as a ‘hyper-
mutated’ state) may generate neo-antigen presentation in the tumor microenvironment. To 
conduct this type of research, it is important to identify tumor-specific mutations that occur 
across all genes in the tumor genome. Evaluation of molecular targets and signaling 
pathways including angiogenesis and/or growth factor related signaling pathways related to 
pembrolizumab and lenvatinib may also be explored. Thus, genome-wide approaches may be 
used for this effort. Note that in order to understand tumor-specific mutations, it is necessary 
to compare the tumor genome with the germline genome. Circulating tumor DNA and/or 
RNA may also be evaluated from blood samples.
Tumor and blood RNA analyses
Both genome-wide and targeted messenger RNA (mRNA) expression profiling and 
sequencing in tumor tissue and in blood may be performed to define gene signatures that 
correlate to clinical response to treatment with pembrolizumab or other immunotherapies. 
Pembrolizumab induces a response in tumors that likely reflects an inflamed/immune 
phenotype. Specific immune-related gene sets (ie, those capturing interferon-gamma 
transcriptional pathways) may be evaluated and new signatures may be identified. Individual 
genes related to the immune system and growth factor signaling pathways (eg, VEGF and 
FGF) may also be evaluated. MicroRNA profiling may also be pursued as well as exosomal 
profiling.
Proteomics and immunohistochemistry (IHC) using blood or tumor
Tumor and blood samples from this study may undergo proteomic analyses (eg, PD-L1 IHC). 
PD-L1 protein level in tumor sections, assessed by IHC, has been shown to correlate with 
response to pembrolizumab in patients with NSCLC, and an in vitro diagnostic (IVD) device 
has been developed for use with pembrolizumab in NSCLC. Preliminary data indicates that 
this association may also be true in additional cancer types (ie, triple negative breast cancer, 
head and neck, and gastric). Additional tumor or blood-derived proteins may also correlate 
with response to pembrolizumab and lenvatinib combination therapy. Therefore, tumor tissue 
may be subjected to proteomic analyses using a variety of platforms that could include but 
are not limited to immunoassays and liquid chromatography/mass spectrometry. This 
approach could identify novel protein biomarkers that could aid in patient selection for 
pembrolizumab (MK-3475) and lenvatinib combination therapy.
Other blood-derived biomarkers
In addition to expression on the tumor tissue, PD-L1, circulating cytokines and angiogenic 
factors, and other tumor derived proteins can be shed from tumor and released into the blood. 
Assays such as enzyme-linked immunosorbent assay (ELISA) measure such proteins in 
serum. Correlation of expression with response to pembrolizumab and lenvatinib 
combination therapy may identify new approaches for predictive biomarkers in blood, 
representing a major advance from today’s reliance on assessing tumor biomarkers. This 
research would serve to develop such assays for future clinical use.
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Other molecular changes of interest include the subtype of T-cells in the tumor 
microenvironment. The T-cell repertoire from tumor tissue and blood components may be 
evaluated.
4.2.3
Rationale for the Use of Comparator
The TPC options of doxorubicin or paclitaxel will be used as a comparator to reflect standard 
clinical practice.
4.3
Justification for Dose
4.3.1
Lenvatinib
The dosing regimen of lenvatinib for Arm A was selected based on the results of the 
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 EC, and 1 had melanoma.
There were 2 dose-limiting toxicities (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 plus 
pembrolizumab 200 mg Q3W dose.
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], three Phase 3 studies have been initiated for both of these tumor 
types, Study E7080-G000-309/KEYNOTE-775, Study E7080-G000-307/KEYNOTE-581, 
and LEAP-001.
4.3.2
Pembrolizumab
The planned dose of pembrolizumab for this study is 200 mg Q3W. Based on the totality of 
data generated in the Keytruda development program, 200 mg Q3W is the appropriate dose 
of pembrolizumab for adults across all indications and regardless of tumor type. As outlined 
below, this dose is justified by:
•
Clinical data from 8 randomized studies demonstrating flat dose- and exposure-
efficacy relationships from 2 mg/kg Q3W to 10 mg/kg Q2W, 
•
Clinical data showing meaningful improvement in benefit-risk including overall 
survival at 200 mg Q3W across multiple indications, and
•
Pharmacology data showing full target saturation in both systemic circulation 
(inferred from pharmacokinetic [PK] data) and tumor (inferred from 
physiologically based PK [PBPK] analysis) at 200 mg Q3W
Among the 8 randomized dose-comparison studies, a total of 2262 participants were enrolled 
with melanoma and NSCLC, covering different disease settings (treatment naïve, previously 
treated, PD-L1 enriched, and all-comers) and different treatment settings (monotherapy and 
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in combination with chemotherapy). Five studies compared 2 mg/kg Q3W versus 10 mg/kg 
Q3W (KN001 Cohort B2, KN001 Cohort D, KN002, KN010, and KN021), and 3 studies 
compared 10 mg/kg Q3W versus 10 mg/kg Q2W (KN001 Cohort B3, KN001 Cohort F2 and 
KN006). All of these studies demonstrated flat dose- and exposure-response relationships 
across the doses studied representing an approximate 5- to 7.5-fold difference in exposure. 
The 2 mg/kg (or 200 mg fixed-dose) Q3W provided similar responses to the highest doses 
studied. Subsequently, flat dose-exposure-response relationships were also observed in other 
tumor types including head and neck cancer, bladder cancer, gastric cancer and classical 
Hodgkin Lymphoma, confirming 200 mg Q3W as the appropriate dose independent of the 
tumor type. These findings are consistent with the mechanism of action of pembrolizumab, 
which acts by interaction with immune cells, and not via direct binding to cancer cells.
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W. First, PK 
data in KN001 evaluating target-mediated drug disposition (TMDD) conclusively 
demonstrated saturation of PD-1 in systemic circulation at doses much lower than 200 mg 
Q3W. Second, a PBPK analysis was conducted to predict tumor PD-1 saturation over a wide 
range of tumor penetration and PD-1 expression. This evaluation concluded that 
pembrolizumab at 200 mg Q3W achieves full PD-1 saturation in both blood and tumor.
Finally, population PK analysis of pembrolizumab, which characterized the influence of 
body weight and other participant covariates on exposure, has shown that the fixed-dosing 
provides similar control of PK variability as weight-based dosing, with considerable overlap 
in the distribution of exposures from the 200 mg Q3W fixed-dose and 2 mg/kg Q3W dose. 
Supported by these PK characteristics and given that fixed-dose has advantages of reduced 
dosing complexity and reduced potential of dosing errors, the 200 mg Q3W fixed-dose was 
selected for evaluation across all pembrolizumab protocols.
4.3.3
Chemotherapy
Doses and regimens for TPC (Arm B; doxorubicin 60 mg/m2 Q3W or paclitaxel 80 mg/m2
3 weeks on/1 week off) were selected based on standard clinical practice.
4.3.4
Maximum Dose/Exposure for This Study
The maximum dose/exposure of pembrolizumab allowed in this study is 200 mg Q3W up to 
2 years; however, participants may be eligible for an additional 17 administrations (1 year; 
Section 6.6.5). The lifetime maximum cumulative dose of doxorubicin allowed is 500 mg/m2.
There is no maximum dose/exposure for lenvatinib or paclitaxel. The maximum dose for 
paclitaxel is determined by site’s standard of care.
4.4
Beginning and End of Study Definition
The overall study begins when the first participant (or their legally acceptable representative) 
provides documented informed consent. The overall study ends when the last participant 
completes the last study-related contact, withdraws consent, or is lost to follow-up (ie, the 
participant is unable to be contacted by the investigator).
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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 FSR in any Member State.      
4.4.1
Clinical Criteria for Early Study Termination
The clinical study may be terminated early if the extent (incidence and/or severity) of 
emerging effects/clinical endpoints is such that the risk/benefit ratio to the study population 
as a whole is unacceptable. In addition, further recruitment in the study or at (a) particular 
study site(s) may be stopped due to insufficient compliance with the protocol, Good Clinical 
Practice (GCP) and/or other applicable regulatory requirements, procedure-related problems 
or the number of discontinuations for administrative reasons is too high.
5
STUDY POPULATION
As stated in the Code of Conduct for Clinical Trials (Appendix 10.1.1) this study includes 
participants of varying age, race, and ethnicity. The collection and use of these demographic 
data will follow all local laws and participant confidentiality guidelines while supporting the 
study of the disease, its related factors, and the IMP under investigation. 
Female participants at least 18 years of age with advanced EC will be enrolled in this study.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Type of Participant and Disease Characteristics

Histologically confirmed diagnosis of endometrial carcinoma.

Documented evidence of advanced, recurrent or metastatic EC.

Radiographic evidence of disease progression after 1 prior systemic, platinum-based 
chemotherapy regimen for EC. Participants may have received up to 1 additional line 
of platinum-based chemotherapy if given in the neoadjuvant or adjuvant treatment 
setting.
Note: There is no restriction regarding prior hormonal therapy.

Available historical or fresh tumor biopsy specimen for determination of MMR 
status.

At least 1 measurable target lesion according to RECIST 1.1 and confirmed by BICR, 
including the following criteria:
-
Non-nodal lesion that measures ≥1.0 cm in the longest diameter
-
Lymph node (LN) lesion that measures as ≥1.5 cm in the short axis
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-
The lesion is suitable for repeat measurement using computed 
tomography/magnetic resonance imaging (CT/MRI). Lesions that have had 
external beam radiotherapy (EBRT) or locoregional therapy must show 
radiographic evidence of subsequent growth.
Demographics

ECOG performance status of 0 or 1 within 7 days of starting study treatment.

Female participants age ≥18 years and considered an adult per local regulations at the 
time of informed consent.
Female participants:

A female participant is eligible to participate if she is not pregnant (see Appendix 2), 
not breastfeeding, and at least one of the following conditions applies: 
a.) Not a WOCBP as defined in Appendix 2 
OR 
b.) A WOCBP who agrees to follow the contraceptive guidance in Appendix 2 during 
the treatment period and for at least 120 days (for participants treated with lenvatinib 
plus pembrolizumab) or at least 180 days (for participants treated with TPC) after the 
last dose of study treatment.
Informed Consent

The participant provides documented informed consent for the study.
Additional Criteria

Adequately controlled blood pressure (BP) with or without antihypertensive 
medications, defined as BP ≤150/90 mm Hg at Screening and no change in 
antihypertensive medications within 1 week before C1D1.

Have adequate organ function as defined in Table 1. Specimens must be collected 
within 7 days prior to the start of study treatment.
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Table 1
Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
≥1500/µL
Platelets
≥100 000/µL
Hemoglobin
≥9.0 g/dL or ≥5.6 mmol/L1
Renal
Creatinine OR
Measured or calculated2 creatinine clearance
(GFR can also be used in place of creatinine or CrCl)
≤1.5 × ULN OR
≥30 mL/min for participant with creatinine levels 
>1.5 × institutional ULN
Hepatic
Total bilirubin
≤1.5 ×ULN OR direct bilirubin ≤ULN for 
participants with total bilirubin levels >1.5 × ULN
except for unconjugated hyperbilirubinemia of 
Gilbert’s syndrome.
AST (SGOT), ALT (SGPT), and ALP
≤3 × ULN (≤5 × ULN for participants with liver 
metastases)3
Coagulation
International normalized ratio (INR) OR 
prothrombin time (PT)
Activated partial thromboplastin time (aPTT) or 
partial thromboplastin time (PTT)4
≤1.5 × ULN unless participant is receiving 
anticoagulant therapy as long as PT or aPTT is 
within therapeutic range of intended use of 
anticoagulants
Abbreviations: ALP = alkaline phosphatase; 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.
1. Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) 
transfusion within 2 weeks of randomization.
2. Creatinine clearance (CrCl) should be calculated per institutional standard.
3. Participants with ALP values >3 times the ULN and known to have bone metastases can be included.
4.
PTT may be performed if local lab is unable to perform aPTT.
5.2
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. Carcinosarcoma (malignant mixed Műllerian tumor), endometrial leiomyosarcoma 
and endometrial stromal sarcomas.
2. Participants with CNS metastases are not eligible, unless they have completed local 
therapy (eg, whole brain radiation therapy [WBRT], surgery or radiosurgery) and 
have discontinued the use of corticosteroids for this indication for at least 4 weeks 
before starting treatment in this study. Any signs (eg, radiologic) or symptoms of 
CNS metastases must be stable for at least 4 weeks before starting study treatment.
3. Active malignancy (except for endometrial cancer, definitively treated in-situ 
carcinomas [e.g. breast, cervix, bladder], or basal or squamous cell carcinoma of the 
skin) within the past 24 months.
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4. Gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition 
that might affect the absorption of lenvatinib.
5. Has a pre-existing Grade ≥3 gastrointestinal or non-gastrointestinal fistula.
6. Radiographic evidence of major blood vessel invasion/infiltration. The degree of 
tumor invasion/infiltration of major blood vessels should be considered because of 
the potential risk of severe hemorrhage associated with tumor shrinkage/necrosis 
following lenvatinib therapy.
7. Clinically significant hemoptysis or tumor bleeding within 2 weeks prior to the first 
dose of study drug.
8. Significant cardiovascular impairment within 12 months of the first dose of study 
drug: such as history of congestive heart failure greater than New York Heart 
Association (NYHA) Class II, unstable angina, myocardial infarction or 
cerebrovascular accident (CVA) stroke, or cardiac arrhythmia associated with 
hemodynamic instability.
9. Active infection (any infection requiring systemic treatment).
10. Participants who have not recovered adequately from any toxicity and/or 
complications from major surgery prior to starting therapy.
11. Participants known to be positive for Human Immunodeficiency Virus (HIV). No 
HIV testing is required unless mandated by local health authority. Refer to 
Appendix 9 for country-specific requirements.
12. Known active Hepatitis B (eg, HBsAg reactive) or Hepatitis C (eg, HCV RNA 
[qualitative] is detected). No testing for hepatitis B or C is required unless mandated 
by local health authority. Refer to Appendix 9 for country-specific requirements.
13. Has a history of (noninfectious) pneumonitis that required treatment with steroids, or 
has current pneumonitis.
14. 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.
15. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the study.
16. 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 to the first dose of study drug.
17. Active autoimmune disease (with the exception of psoriasis) that has required 
systemic treatment in the 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.
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18. Has had an allogenic tissue/solid organ transplant.
19. Females who are breastfeeding or pregnant at Screening or Baseline (as documented 
by a positive beta-human chorionic gonadotropin [β-hCG] (or hCG) test with a 
minimum sensitivity of 25 IU/L or equivalent units of β-hCG [or hCG]). A separate 
baseline assessment is required if a negative screening pregnancy test was obtained 
more than 72 hours before the first dose of study drug.
Prior/Concomitant Therapy
20. Greater than 1 prior systemic chemotherapy regimen (other than adjuvant or 
neoadjuvant) for EC. Participants may receive up to 2 regimens of platinum-based 
chemotherapy in total, as long as one is given in the neoadjuvant or adjuvant 
treatment setting.
21. Prior anticancer treatment within 28 days (or 5 times the half-life time, whichever is 
shorter). All acute toxicities related to prior treatments must be resolved to Grade ≤1, 
except for alopecia and Grade ≤2 peripheral neuropathy.
22. Prior treatment with any treatment targeting VEGF-directed angiogenesis, any 
anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
23. Participants who received prior treatment with an agent directed to a stimulatory or 
co-inhibitory T-cell receptor (eg, CTLA-4, OX 40, CD137) other than an anti-PD-1, 
anti-PD-L1, or anti-PD-L2 agent, and who discontinued from that treatment due to a 
Grade 3 or higher immune-related adverse event (irAE).
24. Prior radiation therapy within 21 days prior to start of study treatment with the 
exception of palliative radiotherapy to bone lesions, which is allowed if completed 
2 weeks prior to study treatment start. Participants must have recovered from all 
radiation-related toxicities and/or complications prior to randomization.
25. Received a live vaccine within 30 days of planned start of study treatment (C1D1).
Examples of live vaccines include, but are not limited to, the following: measles, 
mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus 
Calmette–Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for 
injection are generally killed virus vaccines and are allowed; however, intranasal 
influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed.
26. Known intolerance to study treatment (or any of the excipients).
Prior/Concurrent Clinical Study Experience
27. Prior enrollment on a clinical study evaluating pembrolizumab and lenvatinib for 
endometrial carcinoma, regardless of treatment received.
28. 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 
treatment.
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.
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Diagnostic Assessments
29. Participants with proteinuria >1+ on urine dipstick testing will undergo 24-h urine 
collection for quantitative assessment of proteinuria. Participants with urine protein 
≥1 g/24 h will be ineligible.
30. Prolongation of QTc interval to >480 ms.
31. Left ventricular ejection fraction (LVEF) below the institutional (or local laboratory) 
normal range as determined by multigated acquisition scan (MUGA) or 
echocardiogram (ECHO).
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 2 for approved methods of contraception. Refer to the respective IB for detailed 
information on pembrolizumab and lenvatinib.
Participants should be informed that taking the study medication may involve unknown risks 
to the fetus (unborn baby) if pregnancy were to occur during the study. In order to participate 
in the study, participants of childbearing potential must adhere to the contraception 
requirement (Appendix 2) from the day of study medication initiation (or 14 days prior to the 
initiation of study medication for oral contraception) throughout the study period up to 120 
days (for participants treated with lenvatinib plus pembrolizumab) or up to 180 days (for 
participants treated with TPC) after the last dose of study medication. If there is any question 
that a participant of childbearing potential will not reliably comply with the requirements for 
contraception, that participant should not be entered into the study. 
5.3.3
Pregnancy
If a participant inadvertently becomes pregnant while on study treatment, the participant will 
be immediately discontinued from study treatment. The site will contact the participant at 
least monthly and document the participant’s status until the pregnancy has been completed 
or terminated. The outcome of the pregnancy will be reported to MSD without delay and 
within 24 hours if the outcome is a serious adverse experience (eg, death, abortion, 
congenital anomaly, or other disabling or life-threatening complication to the mother or 
newborn). The study Investigator will make every effort to obtain permission to follow the 
outcome of the pregnancy and report the condition of the fetus or newborn to MSD as 
described in Section 8.4.1.
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5.3.4
Use in Nursing Women
It is unknown whether the study treatments are excreted in human milk. Since many drugs 
are excreted in human milk, and because of the potential for serious adverse reactions in the 
nursing infant, participants who are breastfeeding are not eligible for enrollment.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomized. A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure participants to meet the Consolidated Standards 
of Reporting Trials (CONSORT) publishing requirements and to respond to queries from 
regulatory authorities. Minimal information includes demography, screen failure details, 
eligibility criteria, and any adverse events (AEs) or serious adverse events (SAEs) meeting 
reporting requirements as outlined in the data entry guidelines.
5.5
Participant Replacement Strategy
A participant who is discontinued from study treatment will not be replaced.
6
TREATMENTS
Study treatment is defined as any investigational treatment(s), marketed product(s), placebo, 
or medical device(s) intended to be administered to a study participant according to the study 
protocol.
6.1
Treatments Administered
The study treatments to be used in this study are outlined below in Table 2 Study 
Treatment(s).
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Table 2
Study Treatment(s)
Study 
Treatment 
Name
Dose Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Use
Sourcing
Lenvatinib
Capsule
10 mg, 4 mg
20 mg
Orally QD
Test Product
Central
Pembrolizumab
Solution for infusion
25 mg/mL
200 mg Q3W
IV 
Test Product
Central
Doxorubicin
Solution for infusion
Variable
60 mg/m2 Q3W
IV
Comparator
Local or Central
Paclitaxel
Solution for infusion
Variable
80 mg/m2 QW
IV
Comparator
Local or Central
Abbreviations: IV = intravenous; Q3W = every 3 weeks; QD = once daily; QW = every week.
Note: 4 mg capsules provided for successive dose reduction of lenvatinib, if needed, as described in Section 6.6.1.
Note: Doxorubicin and paclitaxel provided centrally by the Sponsor except in specific countries where commercial product may be sourced 
locally.
Note: Paclitaxel is administered as a 28-day cycle with weekly administration; 3 weeks on and 1 week off.
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All supplies indicated in Table 2 will be provided per the ‘Sourcing’ row depending upon 
local country operational requirements. Every attempt should be made to source these 
supplies from a single lot/batch number where possible (eg, not applicable in the case where 
multiple lots or batches may be required due to the length of the study etc.).
Refer to Section 8.1.8 for details regarding administration of the study treatment.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
Details on preparation and administration of pembrolizumab are provided in the Pharmacy 
manual. Doxorubicin and paclitaxel should be prepared as outlined in the respective 
approved labeling or Institutional guidelines. Lenvatinib is a capsule for oral administration 
and does not require preparation.
6.2.2
Handling, Storage and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are reported 
and resolved before use of the study treatment.
Only participants enrolled in the study may receive study treatment and only authorized site 
staff may supply or administer study treatment. All study treatments 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 treatment accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study sites, the local country MSD personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by MSD.
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 
treatments in accordance with the protocol and any applicable laws and regulations.
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6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Method of Treatment Assignment 
Treatment allocation/randomization will occur centrally using an interactive response 
technology (IRT) system. There are 2 study treatment arms. Participants will be assigned 
randomly in a 1:1 ratio to either Arm A (lenvatinib + pembrolizumab) or Arm B (TPC), 
respectively.
6.3.1.1
Stratification
Treatment allocation/randomization will be stratified according to the following factors:
1. MMR status (pMMR or dMMR)
2. ECOG performance status (0 or 1)
3. Geographic region (Region 1 [Europe, USA, Canada, Australia, New Zealand, and Israel]
or Region 2 [rest of the world])
4. Prior history of pelvic radiation (yes or no)
First, participants will be stratified according to MMR status. Then, only within the pMMR 
stratum, participants will be further stratified according to ECOG performance status, 
geographic region, and prior history of pelvic radiation. A total of 9 strata will be utilized for 
the study. 
6.3.2
Blinding
This study is an open-label study; therefore, the Sponsor, MSD, investigator and participant 
will know the treatment administered.
6.4
Treatment Compliance
Interruptions from the protocol specified treatment plan for >28 days (lenvatinib and TPC) or
for >6 weeks (pembrolizumab) require consultation between the investigator and MSD and 
written documentation of the collaborative decision on participant management.
6.5
Concomitant Therapy
If there is a clinical indication for any medication or vaccination prohibited, investigator must
discuss any questions regarding this with the MSD 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 treatment 
requires the mutual agreement of the investigator, MSD, and the Sponsor.
Any medication (including over-the-counter medications) or therapy administered to the 
participant during the study (starting at the date of informed consent) will be recorded on the 
appropriate CRF. The investigator will record the AE for which the concomitant 
medication/therapy was administered on the appropriate CRF. If the concomitant 
medication/therapy is being administered for a medical condition present at the time of entry 
into the study, the investigator will record the medical condition on the appropriate CRF.
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All prior medications (including over-the-counter medications) administered 30 days before 
the first dose of study drug and any concomitant therapy administered to the participant
during the course of the study (starting at the date of informed consent) until 30 days after the 
final dose of study drug will be recorded. Additionally, all diagnostic, therapeutic, or surgical 
procedures relating to malignancy should be recorded. Any medication that is considered 
necessary for the participant’s health and that is not expected to interfere with the evaluation 
of or interact with the study medication may be continued during the study.
6.5.1
Allowed Concomitant Medication
Treatment of complications or AEs, or therapy to ameliorate symptoms (including blood 
products, blood transfusions, fluid transfusions, antibiotics, and anti-diarrheal drugs), may be 
given at the discretion of the investigator, unless it is expected to interfere with the evaluation 
of (or to interact with) the study medication. Anti-emetic or any other prophylaxis should be 
considered in accordance with institutional guidelines.
The following concomitant medications are also allowed:
•
Hormone replacement therapy 
•
Thyroid hormone suppressive therapy
•
Adjuvant hormonal therapy for history of definitely treated breast cancer
•
Anticoagulants including low molecular weight heparin (LMWH), warfarin, anti-Xa 
agents
•
Anti-inflammatory agents
•
Bisphosphonates or denosumab
•
Antihypertensive therapy (including additional antihypertensive treatment as 
appropriate if BP increases once the participant is enrolled)
•
Palliative radiotherapy to non-target bone metastases or brain lesions may be 
permitted after consultation with MSD
Any additional procedural or participant-specific particularities should be discussed with the 
investigator and MSD.
6.5.2
Prohibited Concomitant Medications
Participants are prohibited from receiving the following therapies during the Screening and 
Treatment Phase of this study:
•
Concurrent anticancer therapies such as chemotherapy, targeted therapies (e.g. 
tyrosine kinase inhibitors), hormonal therapy directed at EC, radiotherapy (with the 
exception of palliative radiotherapy as specified in Section 6.5.1), antitumor
interventions (surgical resection, surgical debulking of tumor, etc.), or cancer 
immunotherapy
•
Other concurrent investigational drugs
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•
Live vaccines must not be administered within 30 days prior to the first dose of study 
intervention, while participating in the study, and for 120 days after the last dose of 
study intervention.

Note: Any licensed COVID-19 vaccines (including for Emergency Use) in a 
particular country are allowed in the study as long as they are mRNA vaccines, 
replication-incompetent 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.
For participants in the lenvatinib plus pembrolizumab arm, systemic glucocorticoids are
permitted only for the following purposes:
•
To modulate symptoms of an AE that is suspected to have an immunologic etiology
•
As needed for the prevention of emesis
•
Premedication for IV contrast allergies
•
Short-term oral or IV use in doses >10mg/day prednisone equivalent to treat asthma
or COPD exacerbations
•
For chronic systemic replacement not to exceed 10 mg/day prednisone equivalent
In addition, the following glucocorticoid use is allowed:
•
For topical use or ocular use
•
Intraarticular joint use
•
For inhalation in the management of asthma or chronic obstructive pulmonary disease
For participants who, in an assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management, continuation of the study medication 
and further participation in the study must be discussed and agreed upon with MSD.
If participants receive additional anticancer therapies, this will be judged to represent 
evidence of disease progression, and study medication will be discontinued. These 
participants should complete all end of treatment assessments and continue to be followed for 
survival in the Follow-Up Period.
For further information on the prohibited concomitant therapies for doxorubicin or paclitaxel, 
please refer to their respective Prescribing Information.
6.5.3
Drug-Drug Interactions
There are no drug-drug interaction (DDI)-related concomitant medication prohibitions or 
restrictions. 
Lenvatinib is not expected to clinically meaningfully alter exposure to CYP3A4/
P-glycoprotein (P-gp) substrates based on results from a lenvatinib DDI study with 
midazolam (a sensitive CYP3A and P-gp substrate). 
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Clinical studies also showed that co-administration of lenvatinib with either inducers or 
inhibitors of CYP3A4/P-gp 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).
6.5.4
Rescue Medications and Supportive Care
Participants should receive appropriate supportive care measures as deemed necessary by the 
treating investigator. Suggested supportive care measures for the management of AEs with 
potential immunologic etiology are outlined along with the dose modification guidelines in 
Table 4. 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 and/or lenvatinib. 
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 4 in 
Section 6.6.2.1 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.
6.5.5
Hematopoietic Growth Factors
Primary prophylactic use of granulocyte colony stimulating factors (G-CSF) may be used per
the discretion of the treating physician and in line with local guidelines. 
6.6
Dose Modification (Escalation/Titration/Other)
Adverse events will be graded using NCI CTCAE Version 4.03. 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 
lenvatinib plus pembrolizumab combination.
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6.6.1
Lenvatinib
Lenvatinib dose reduction and interruption for participants who experience lenvatinib-
pembrolizumab combination therapy-related toxicity will be in accordance with the dose 
modification guidelines described in Table 3. An interruption of study treatment for more 
than 28 days will require MSD approval before treatment can be resumed.
The starting dose of lenvatinib is 20 mg/day for participants enrolled in Arm A. Dose 
reductions of lenvatinib occur in succession based on the previous dose level (14, 10, and 
8 mg/day). Any dose reduction below 8 mg/day must be discussed with MSD. Once the 
lenvatinib dose has been reduced, it may not be increased at a later date, unless the dose has 
been mistakenly decreased; in this situation, MSD’s approval is required to increase the dose.
Refer to the subsections below for management of hypertension (Section 6.6.1.1), proteinuria 
(Section 6.6.1.2), diarrhea (Section 6.6.1.3), hepatotoxicity (Section 6.6.1.4), 
thromboembolic events (Section 6.6.1.5), posterior reversible encephalopathy syndrome/
reversible posterior leukoencephalopathy syndrome (PRES/RPLS; Section 6.6.1.6), 
hypocalcemia (Section 6.6.1.7), and hemorrhage (Section 6.6.1.8), and gastrointestinal 
perforation or fistula formation (Section 6.6.1.9), as appropriate, before consulting the dose 
modification table (Table 3). For overlapping toxicities of pembrolizumab and lenvatinib, 
please refer to Section 6.6.3.
Table 3
Dose Modification Guidelines for Lenvatinib-Related Adverse Events (for the 
Lenvatinib-Pembrolizumab Combination Arm)
Treatment-Related 
Toxicitya,b
Management
Dose Adjustment
Grade 1 or Tolerable Grade 2
Continue treatment
No change
Intolerable Grade 2c, d or Grade 3e
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 MSD
Grade 4f: Discontinue Study Treatment
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Treatment-Related 
Toxicitya,b
Management
Dose Adjustment
Abbreviations: AE = adverse event; BMI = body mass index; CTCAE = Common Terminology Criteria for 
Adverse Events.
Note: For grading see CTCAE version 4.03. Collect all AE grades (ie, decreasing and increasing CTCAE 
grade). 
a. An interruption of study treatment for more than 28 days will require MSD’s approval before treatment 
can be resumed.
b. Initiate optimal medical management for nausea, vomiting, hypertension, hypothyroidism and/or diarrhea 
prior to any lenvatinib interruption or dose reduction. 
c. Applicable only to Grade 2 toxicities judged by the participant and/or physician to be intolerable.
d. Obese participants (BMI ≥30) with weight loss do not need to return to the baseline weight or 10% of 
baseline weight (ie, Grade 1weight loss). These participants may restart the study drug(s) 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 without dose modification 
should be discussed with MSD.
f.
Excluding laboratory abnormalities judged to be non-life-threatening, in which case manage as Grade 3.
6.6.1.1
Management of Hypertension
Hypertension is a recognized side effect of treatment with drugs inhibiting VEGF signaling. 
Investigators should therefore ensure that participants enrolled to receive treatment with 
lenvatinib have BP of ≤150/90 mm Hg at the time of study entry and, if known to be 
hypertensive, have been on a stable dose of antihypertensive therapy for at least 1 week 
before 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 1.3.2). 
Hypertension will be graded using NCI CTCAE v4.03, 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 
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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 with significant risk factors 
for severe complications (eg, BP ≥160/100 mm Hg, significant risk factors for cardiac 
disease, intracerebral hemorrhage, or other significant co-morbidities). Once the participant
has been on the same antihypertensive medications for at least 48 hours and the BP is 
controlled, lenvatinib should be resumed as described below.
Participants who have had systolic BP ≥160 mm Hg or diastolic BP ≥100 mm Hg must have 
their BP monitored on Day 15 (or more frequently as clinically indicated) until systolic BP
has been ≤150 mm Hg and diastolic BP has been ≤95 mm Hg for 2 consecutive treatment 
cycles. If a repeat event of systolic BP ≥160 mm Hg or diastolic BP ≥100 mm Hg occurs, the 
participant must resume the Day 15 evaluation until systolic BP has been ≤150 mm Hg and 
diastolic BP has been ≤95 mm Hg for 2 consecutive treatment cycles. A diary will be 
provided to the participant to capture the blood pressure evaluations between study visits.
The following guidelines should be followed for the management of systolic BP 
≥160 mm Hg or diastolic BP ≥100 mm Hg confirmed on 2 BP assessments at least 
30 minutes apart:
1. Continue study drug and institute antihypertensive therapy for participants not already 
receiving this.
2. For those participants already on antihypertensive medication, the dose of the current 
agent may be increased, if appropriate, or 1 or more agents of a different class of 
antihypertensive should be added. Study 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 
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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 MSD.
The following guidelines should be followed for the management of Grade 4 hypertension 
(life-threatening consequences):
1. Institute appropriate medical management
2. Discontinue study drug
6.6.1.2
Management of Proteinuria
Regular assessment of proteinuria should be conducted as detailed in the SoA (Section 1.3).
Guidelines for assessment and management of proteinuria are as follows:
Detection and Confirmation
1. Perform urine dipstick testing per the SoA (Section 1.3.1)
2. A 24-hour urine collection initiated as soon as possible and at least within 72 hours 
(or an immediate spot urine protein-to-creatinine ratio [UPCR] test) is required in the 
following situations:
-
The first (initial) occurrence of ≥2+ proteinuria on urine dipstick while the 
participant is receiving lenvatinib
-
A subsequent increase in severity of urine dipstick proteinuria occurring on the 
same lenvatinib dose level
-
When there has been a lenvatinib dose reduction and at the new dose level the 
urine protein dipstick result is ≥2+.
3. A 24-hour urine collection (initiated as soon as possible and at least within 72 hours) 
to verify the grade of proteinuria is required when UPCR is ≥2.4.
Grading of Proteinuria
-
Grading according to NCI CTCAE v4.03 will be based on the 24-hour urinary protein 
result if one has been obtained. 
Management of Proteinuria

Management of lenvatinib administration will be based on the grade of proteinuria 
according to Table 3.

In the event of nephrotic syndrome, lenvatinib must be discontinued.
Monitoring

Urine dipstick testing for participants with proteinuria ≥2+ should be performed on 
Day 15 (or more frequently as clinically indicated) until the results have been 1+ or 
negative for 2 consecutive treatment cycles. 

Proteinuria monitoring can be performed at the local laboratory or investigator site, but 
must be managed by the site physician.
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6.6.1.3
Management of Diarrhea
An anti-diarrheal agent should be recommended to the participant at the start of study 
treatment and participants should be instructed and educated to initiate anti-diarrheal 
treatment at the first onset of soft bowel movements. The choice of anti-diarrheal agent 
should be individualized to the participant’s clinical circumstances and follow standard 
medical practice. If signs/symptoms of diarrhea persist despite optimal medical management, 
instructions contained in Table 3 should be followed.
6.6.1.4
Management of Hepatotoxicity
Liver function tests (alanine transaminase [ALT], aspartate transaminase [AST], bilirubin 
levels) should be conducted as detailed in the SoA (Section 1.3.1 and Section 1.3.2) and as 
clinically indicated. If signs/symptoms indicating liver injury occur, instructions contained in 
Table 3 should be followed. Appropriate supportive care should be provided together with 
close monitoring. If hepatic failure occurs the study drug must be discontinued.
6.6.1.5
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 3 should be 
followed. Appropriate supportive care should be provided together with close monitoring. If 
a participant experiences life-threatening (Grade 4) thromboembolic reactions, including 
pulmonary embolism, lenvatinib must be discontinued.
Arterial thromboembolic events (eg, new onset, worsening, or unstable angina, myocardial 
infarction, transient ischemic attack, and cerebrovascular accident) of any grade require study 
treatment discontinuation.
6.6.1.6
Management of Posterior Reversible Encephalopathy Syndrome/Reversible 
Encephalopathy Syndrome/Reversible Posterior Leukoencephalopathy 
Syndrome
Posterior Reversible Encephalopathy Syndrome/Reversible Encephalopathy Syndrome/ 
Reversible Posterior Leukoencephalopathy Syndrome (PRES/RPLS) is a neurological 
disorder that can present with headache, seizure, lethargy, confusion, altered mental function, 
blindness, and other visual or neurological disturbances. Mild to severe hypertension may be 
present. MRI is necessary to confirm the diagnosis of PRES/RPLS. Appropriate measures 
should be taken to control BP. In participants with signs or symptoms of PRES/RPLS, 
instructions in Table 3 should be followed. 
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6.6.1.7
Management of Hypocalcemia
Serum calcium should be monitored per the SoA (Section 1.3.1 and Section 1.3.2). Corrected 
serum calcium should be used to assess the grade of hypocalcemia per CTCAE v4.03, using 
the following formula: 
Corrected calcium = ([4 – serum albumin in g/dL] × 0.8 + serum calcium)
The formula is not applicable when serum albumin concentration is normal (˃4 g/dL); in 
such situations, the total (uncorrected) serum calcium should be used instead. 
Hypocalcemia should be treated per institutional guidelines (eg, using appropriate calcium, 
magnesium, and vitamin D supplementation) until resolution.
6.6.1.8
Management of Hemorrhage
Instructions in Table 3 should be followed for the management of hemorrhage. Either resume 
at a reduced dose or discontinue lenvatinib depending on the severity and persistence of 
hemorrhage.
6.6.1.9
Management of Gastrointestinal Perforation or Fistula Formation
Lenvatinib should be discontinued in any participants who develop gastrointestinal 
perforation of any grade or any Grade 4 gastrointestinal or non-gastrointestinal fistula.
6.6.2
Pembrolizumab
6.6.2.1
Dose Modification and Toxicity Management for Immune-related AEs 
Associated with Pembrolizumab
AEs associated with pembrolizumab exposure may represent an immune-related response. 
These irAEs may occur shortly after the first dose or several months after the last dose of 
pembrolizumab treatment and may affect more than one body system simultaneously. 
Therefore, early recognition and initiation of treatment is critical to reduce complications. 
Based on existing clinical study data, most irAEs were reversible and could be managed with 
interruptions of pembrolizumab, administration of corticosteroids and/or other supportive 
care. For suspected irAEs, ensure adequate evaluation to confirm etiology or exclude other 
causes. Additional procedures or tests such as bronchoscopy, endoscopy, skin biopsy may be 
included as part of the evaluation. Based on the severity of irAEs, withhold or permanently 
discontinue pembrolizumab and administer corticosteroids.
Dose Modification and Toxicity Management Guidelines for irAEs associated with 
pembrolizumab monotherapy, coformulations, or IO combinations are provided in Table 4.
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Table 4
Dose Modification and Toxicity Management Guidelines for Immune-related Adverse Events Associated with 
Pembrolizumab Monotherapy, Coformulations or IO Combinations
General instructions:
1.
Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive treatment should 
begin if the irAEs are not controlled by corticosteroids.
2.
Pembrolizumab monotherapy, coformulations or IO combinations must be permanently discontinued if the irAE does not resolve or the corticosteroid 
dose is not ≤10 mg/day within 12 weeks of the last treatment. 
3.
The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks.
4.
If pembrolizumab monotherapy, coformulations or IO combinations have been withheld, treatment may resume after the irAE decreased to ≤Grade 1 
after corticosteroid taper.
irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Pneumonitis 
Grade 2
Withhold 
Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper
Monitor participants for signs and symptoms of 
pneumonitis
Evaluate participants with suspected pneumonitis 
with radiographic imaging and initiate corticosteroid 
treatment
Add prophylactic antibiotics for opportunistic 
infections
Recurrent Grade 2 
or Grade 3 or 4 
Permanently 
discontinue
Diarrhea / Colitis 
Grade 2 or 3
Withhold
Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper
Monitor participants for signs and symptoms of 
enterocolitis (ie, diarrhea, abdominal pain, blood or 
mucus in stool with or without fever) and of bowel 
perforation (ie, peritoneal signs and ileus)
Participants with ≥Grade 2 diarrhea suspecting colitis 
should consider GI consultation and performing 
endoscopy to rule out colitis
Participants with diarrhea/colitis should be advised to 
drink liberal quantities of clear fluids. If sufficient 
oral fluid intake is not feasible, fluid and electrolytes 
should be substituted via IV infusion.
Recurrent Grade 3 
or Grade 4
Permanently 
discontinue
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irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
AST / ALT 
Elevation or 
Increased 
Bilirubin
Grade 2
Withhold
Administer corticosteroids 
(initial dose of 0.5-1 mg/kg 
prednisone or equivalent) 
followed by taper
Monitor with liver function tests (consider weekly or 
more frequently until liver enzyme value returned to 
baseline or is stable)
Grade 3 or 4 
Permanently 
discontinue
Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper
T1DM or 
Hyperglycemia
New onset T1DM 
or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of β-cell 
failure
Withhold a
Initiate insulin replacement 
therapy for participants with 
T1DM
Administer anti-
hyperglycemic in 
participants with 
hyperglycemia
Monitor participants for hyperglycemia or other signs 
and symptoms of diabetes
Hypophysitis
Grade 2
Withhold
Administer corticosteroids 
and initiate hormonal 
replacements as clinically 
indicated
Monitor for signs and symptoms of hypophysitis 
(including hypopituitarism and adrenal insufficiency)
Grade 3 or 4
Withhold or 
permanently 
discontinue a
Hyperthyroidism 
Grade 2
Continue
Treat with non-selective 
beta-blockers (eg, 
propranolol) or thionamides 
as appropriate
Monitor for signs and symptoms of thyroid disorders
Grade 3 or 4
Withhold or 
Permanently 
discontinue a
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irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Hypothyroidism
Grade 2-4
Continue
Initiate thyroid replacement 
hormones (eg, 
levothyroxine or 
liothyronine) per standard 
of care
Monitor for signs and symptoms of thyroid disorders
Nephritis and 
renal dysfunction
Grade 2
Withhold
Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by 
taper
Monitor changes of renal function
Grade 3 or 4
Permanently 
discontinue
Myocarditis
Grade 1 
Withhold
Based on severity of AE 
administer corticosteroids
Ensure adequate evaluation to confirm etiology 
and/or exclude other causes
Grade 2, 3 or 4
Permanently 
discontinue
All Other irAEs
Persistent Grade 2
Withhold
Based on severity of AE 
administer corticosteroids
Ensure adequate evaluation to confirm etiology or 
exclude other causes
Grade 3
Withhold or 
discontinue b
Recurrent Grade 3 
or Grade 4 
Permanently 
discontinue
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for Adverse Events; DRESS=Drug Rash 
with Eosinophilia and Systemic Symptom; GI=gastrointestinal; IO=immuno-oncology; ir=immune related; IV=intravenous; SJS=Stevens-Johnson Syndrome; T1DM=type 
1 diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal.
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations.
a
The decision to withhold or permanently discontinue pembrolizumab monotherapy, coformulations or IO combinations is at the discretion of the investigator or treating 
physician. If control achieved or ≤ Grade 2, pembrolizumab monotherapy, coformulations or IO combinations may be resumed.
b
Events that require discontinuation include, but are not limited to: Guillain-Barre Syndrome, encephalitis, myelitis, DRESS, SJS, TEN and other clinically important irAEs 
(eg, vasculitis and sclerosing cholangitis).
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6.6.2.2
Dose Modification and Toxicity Management of Infusion-reactions Related 
to Pembrolizumab
Pembrolizumab may cause severe or life-threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion. 
Dose modification and toxicity management guidelines on pembrolizumab associated 
infusion reaction are provided in Table 5.
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Table 5
Pembrolizumab Infusion Reaction Dose Modification and Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at Subsequent Dosing
Grade 1
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated
Increase monitoring of vital signs as medically indicated until the participant 
is deemed medically stable in the opinion of the investigator.
None
Grade 2
Requires therapy or infusion 
interruption but responds 
promptly to symptomatic 
treatment (eg, antihistamines, 
NSAIDs, narcotics, IV fluids); 
prophylactic medications 
indicated for ≤24 hrs
Stop Infusion.
Additional appropriate medical therapy may include but is not limited to:
-
IV fluids
-
Antihistamines
-
NSAIDs
-
Acetaminophen
-
Narcotics
Increase monitoring of vital signs as medically indicated until the participant 
is deemed medically stable in the opinion of the investigator.
If symptoms resolve within 1 hour of stopping drug infusion, the infusion 
may be restarted at 50% of the original infusion rate (eg, from 100 mL/hr to 
50 mL/hr). Otherwise dosing will be held until symptoms resolve and the 
participant should be premedicated for the next scheduled dose.
Participants who develop Grade 2 toxicity despite adequate 
premedication should be permanently discontinued from further study 
drug treatment
Participant may be premedicated 1.5 h 
(± 30 minutes) prior to infusion of 
pembrolizumab with:

Diphenhydramine 50 mg PO (or 
equivalent dose of antihistamine).

Acetaminophen 500-1000 mg PO (or 
equivalent dose of analgesic).
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NCI CTCAE Grade
Treatment
Premedication at Subsequent Dosing
Grades 3 or 4
Grade 3:
Prolonged (ie, not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial improvement; 
hospitalization indicated for 
other clinical sequelae (eg, renal 
impairment, pulmonary 
infiltrates)
Grade 4:
Life-threatening; pressor or 
ventilatory support indicated
Stop Infusion.
Additional appropriate medical therapy may include but is not limited to:

Epinephrine**

IV fluids

Antihistamines

NSAIDs

Acetaminophen

Narcotics

Oxygen

Pressors

Corticosteroids
Increase monitoring of vital signs as medically indicated until the participant 
is deemed medically stable in the opinion of the investigator.
Hospitalization may be indicated.
**In cases of anaphylaxis, epinephrine should be used immediately.
Participant is permanently discontinued from further study drug 
treatment.
No subsequent dosing
Abbreviations: CTCAE = Common Terminology Criteria for Adverse Events; IV = intravenous; NCI = National Cancer Institute; NSAIDs = nonsteroidal anti-inflammatory 
drugs; PO = by mouth.
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of drug administration.
For further information, please refer to the CTCAE v4.03 at http://ctep.cancer.gov
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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 Q3W due to a long half-life, lenvatinib can be 
interrupted to assess whether an AE improves/resolves with dechallenge (ie, 
interruption of treatment) based on the following 2 scenarios:
o
If an AE is identified during a treatment cycle (ie, between 2 pembrolizumab 
doses), only lenvatinib dose interruption is needed. 
o
If an AE is identified at the beginning of a treatment cycle, lenvatinib can be 
interrupted and dosing of pembrolizumab should be held.
If the participant recovers from an AE in response to lenvatinib interruption (ie, 
positive dechallenge), the event is more likely to be related to lenvatinib. Otherwise, 
after excluding other alternative explanations, an immune-related AE should be 
considered. 
2. Severity of AE
If an AE is suspected to be treatment-related and is severe/life-threatening at the time of 
onset or is rapidly worsened, action including interrupting both drugs and initiating 
treatment with a corticosteroid (with exception of hypothyroidism, TIDM) and other 
supportive care should be taken promptly.
3. Participants receiving the combination therapy (pembrolizumab plus lenvatinib) must 
discontinue study intervention if any of the following occur: 
1) ALT or AST >5 × ULN for more than 2 weeks.
Pembrolizumab will have already been permanently discontinued per Table 4, but 
lenvatinib may be administered at a reduced dose by the time this criterion is met 
and must be permanently discontinued immediately.
2) ALT or AST >3 × ULN and (TBL >2 × ULN or INR >1.5).
Although Table 4 advises pembrolizumab to be withheld (interrupted), and Table 3
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 for Lenvatinib and Pembrolizumab 
If the participant is receiving treatment with lenvatinib and requires surgery during the study, 
the stop time and restart time of lenvatinib should be as follows:
•
For minor procedures: stop lenvatinib at least 2 days before the procedure and restart 
it at least 2 days after, once there is evidence of adequate healing and no risk of 
bleeding.
•
For major procedures: stop lenvatinib at least 1 week (5 half-lives) prior to surgery 
and then restart it at least 1 week after, once there is evidence of adequate healing and 
no risk of bleeding.
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as 
medical/surgical events or logistical reasons not related to study therapy. Participants should 
be placed back on study therapy within 3 weeks of the scheduled interruption, unless 
otherwise discussed with MSD. The reason for interruption should be documented in the 
participant's study record.
6.6.5
Second Course Phase (Retreatment Period)
All participants who stop treatment with lenvatinib plus pembrolizumab with SD or better 
may be eligible for up to an additional year of treatment with pembrolizumab (17 cycles) ±
lenvatinib if they progress after stopping study treatment from the initial treatment period. If 
lenvatinib is stopped due to toxicity during the initial treatment period, only pembrolizumab 
will be administered during second course, otherwise lenvatinib may be administered with 
pembrolizumab during second course. This retreatment is termed the Second Course Phase of 
this study and is only available if the study remains open and the participant meets the 
following conditions:
Either 
•
Stopped initial treatment with pembrolizumab +/- stopping lenvatinib after attaining 
an investigator-determined confirmed CR according to RECIST 1.1
-
Was treated for at least 8 cycles with l pembrolizumab +/- lenvatinib before 
discontinuing therapy
-
Received at least 2 treatment cycles of pembrolizumab +/- lenvatinib beyond the 
date when the initial CR was declared
OR
•
Had SD, PR or CR and stopped pembrolizumab +/- stopping lenvatinib treatment 
after completion of 35 administrations (approximately 2 years) of study treatment for 
reasons other than disease progression or intolerability
AND
•
Experienced an investigator-determined radiographic disease progression by 
RECIST 1.1 after stopping initial treatment with pembrolizumab, and
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•
No new anticancer treatment was administered after the last dose of study treatment, 
and
•
The participant meets all of the safety parameters listed in the inclusion criteria and 
none of the safety parameters listed in the exclusion criteria, and
•
The study is ongoing
An objective response or disease progression that occurs during the Second Course Phase for 
a participant will not be counted as an event for the primary analysis of either endpoint in this 
study.
Note: Participants in the crossover phase are not eligible for the Second Course Phase.
Visit requirements for the Second Course Phase are outlined in Section 1.3.2.
6.6.6
Treatment of Physician’s Choice
Management for participants who experience doxorubicin-related or paclitaxel-related 
toxicity will be in accordance with the respective doxorubicin or paclitaxel prescribing 
information in each country/region or local institutional guidelines.
6.7
Intervention After the End of the Study
Upon study completion, participants are to be discontinued and may be enrolled in an 
extension study in which they are administered pembrolizumab monotherapy, 
coformulations, or in combination as in the parent study, if available.
6.8
Clinical Supplies Disclosure
This study is open-label; therefore, the participant, the study site personnel, the Sponsor, 
MSD and/or designee are not blinded. Study treatment (name, strength or potency) is 
included in the label text; random code/disclosure envelopes or lists are not provided.
7
DISCONTINUATION OF STUDY TREATMENT AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Treatment
Discontinuation of study treatment does not represent withdrawal from the study.
As certain data on clinical events beyond study treatment 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 treatment. Therefore, all participants who 
discontinue study treatment prior to completion of the protocol-specified treatment period
will still continue to participate in the study as specified in Section 1.3 and Section 8.12.3.
Participants may discontinue study treatment at any time for any reason or be discontinued 
from the study treatment at the discretion of the investigator should any untoward effect 
occur. In addition, a participant may be discontinued from study treatment by the investigator 
or MSD if study treatment is inappropriate, the study plan is violated, or for administrative 
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and/or other safety reasons. Specific details regarding procedures to be performed at study 
treatment discontinuation are provided in Section 8.1.9.
A participant must be discontinued from study treatment 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 treatment.
o
Radiographic disease progression documented per RECIST 1.1 by BICR, and when 
clinically appropriate, confirmed by the site per iRECIST (Section 8.2.1.6).
Note: An exception to continue study treatment beyond confirmed PD per iRECIST
(iCPD) may be considered following consultation with MSD (Section 8.2.1.6).
o
Any progression or recurrence of any malignancy, or any occurrence of another 
malignancy that requires active treatment
o
Noncompliance with study treatment or procedure requirements
o
Any study treatment-related toxicity specified as a reason for permanent discontinuation 
as defined in the guidelines for dose modification due to AEs in Section 6.6
o
Unacceptable adverse event(s)
o
Completion of 35 treatments (approximately 2 years) with pembrolizumab or a lifetime 
cumulative dose of 500 mg/m2 of doxorubicin. 
Note: Participants in Arm A will continue on lenvatinib alone until disease progression is 
confirmed by BICR, development of unacceptable toxicity, or withdrawal of consent (see 
Section 4.1.2).
Note: The number of treatments is calculated starting with the first dose of 
pembrolizumab.
o
The participant has a confirmed positive serum/urine pregnancy test.
o
ALT or AST elevation meeting the following criteria:

ALT or AST >5 × ULN for more than 2 weeks
Pembrolizumab will have already been permanently discontinued per Table 4, but 
lenvatinib may be administered at a reduced dose by the time this criterion is met and 
must be permanently discontinued immediately. 

ALT or AST >3 × ULN and (TBL >2 × ULN or INR > 1.5)
Although Table 4 advises pembrolizumab to be withheld (interrupted), and Table 3
advises lenvatinib to have no dose modification or a reduction, if this criterion is met, 
both drugs must be permanently discontinued immediately.

If a participant with liver metastasis has Grade 2 AST or ALT at the start of study 
treatment, and the AST or ALT value increases by ≥50% relative to baseline and lasts 
for ≥1 week, then the participant should permanently discontinue study intervention.
For participants who are discontinued from study treatment but continue to be monitored in 
the study, all visits and procedures, as outlined in the SoA, should be completed.
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7.1.1
Discontinuation of Pembrolizumab After Complete Response
Discontinuation of pembrolizumab may be considered for participants who have attained a 
confirmed CR that have been treated for at least 8 cycles (at least 24 weeks) with lenvatinib 
plus pembrolizumab and had at least 2 treatments with lenvatinib plus pembrolizumab 
beyond the date when the initial CR was declared. Participants who then experience 
radiographic disease progression may be eligible for up to 1 year of additional treatment with 
lenvatinib plus pembrolizumab at the discretion of the investigator as detailed in 
Section 6.6.5.
Participants will resume therapy at the same dose and schedule at the time of initial 
discontinuation. Additional details are provided in Section 6.6.5. Response or progression in 
this Second Course Phase will not count towards the ORR and PFS of the primary endpoint 
in this study.
7.1.2
Crossover Phase
Participants who were randomized to Arm B (TPC) and experience investigator-defined
disease progression per RECIST 1.1, while in the study treatment phase or after stopping 
treatment on study but remaining in Efficacy Follow-up or Survival Follow-up, and have not 
yet started subsequent anticancer therapy, or withdrawn consent (from either study treatment 
or follow-up phases), may be eligible for the Crossover Phase. Prior to entering the 
Crossover Phase, provided the study is still ongoing, participants should meet all eligibility
criteria, with the exception of exclusion criteria #20, #21, #24 and #28 (refer to Sections 5.1 
and 5.2). 
Participants may be eligible for up to two years (35 cycles) of treatment with lenvatinib plus 
pembrolizumab. A Second Course Phase will not be made available for participants in the 
Crossover Phase. Participants who complete the Crossover phase will enter the Post-
Crossover Phase. Additional details are provided in Section 1.3.3. Response or progression in 
the Crossover Phase will not count towards the ORR and PFS of the primary endpoint in this 
study.
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study treatment or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study are outlined in Section 8.1.9. The procedures to be performed should a participant 
repeatedly fail to return for scheduled visits and/or if the study site is unable to contact the 
participant are outlined in Section 7.3.
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7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
●
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
●
The investigator or designee must make every effort to regain contact with the 
participant at each missed visit (eg, telephone calls and/or a certified letter to the 
participant’s last known mailing address or locally equivalent methods). These 
contact attempts should be documented in the participant’s medical record.
●
Note:  A participant is not considered lost to follow-up until the last scheduled visit 
for the individual participant. The missing data for the participant will be managed 
via the prespecified statistical data handling and analysis guidelines.
8
STUDY ASSESSMENTS AND PROCEDURES
●
Study procedures and their timing are summarized in the SoA. 
●
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
●
The investigator is responsible for assuring that procedures are conducted by 
appropriately qualified or trained staff. Delegation of study site personnel 
responsibilities will be documented in the Investigator Trial File Binder (or 
equivalent).
●
All 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 
MSD for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, Hepatitis C, etc.), and thus local 
regulations may require that additional informed consent be obtained from the 
participant. In these cases, such evaluations/testing will be performed in accordance 
with those regulations.
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8.1
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented informed consent from each potential participant (or their legally 
acceptable representative) prior to participating in this clinical study. If there are changes to 
the participant’s status during the study (eg, health or age of majority requirements), the 
investigator or medically qualified designee must ensure the appropriate documented 
informed consent is in place.
8.1.1.1
General Informed Consent
Informed consent given by the participant or their legally acceptable representative must be 
documented on a consent form. The form must include the study protocol number, study 
protocol title, dated signature, and agreement of the participant (or their 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 their 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.
Specifics about a study and the study population will be added to the consent form template 
at the protocol level. 
The informed consent will adhere to IRB/IEC requirements, applicable laws and regulations 
and MSD requirements.
If the investigator recommends continuation of study intervention beyond disease 
progression, the participant or her legally acceptable representative will be asked to provide 
documented informed consent.
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the participant qualifies for the study and Crossover Phase, if applicable.
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 utilized in the event of an emergency. The 
investigator or qualified designee will provide the participant with a participant identification 
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card immediately after the participant provides documented informed consent. At the time of 
treatment allocation/randomization, 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 health care provider can obtain information about study 
treatment in emergency situations where the investigator is not available.
8.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee. The medical 
history will collect all active conditions and any condition diagnosed within the prior 
10 years that the investigator considers to be clinically significant. All medical history related 
to any cancer other than EC should be collected, regardless of when it occurred.
Comprehensive details regarding the participant’s EC history will be recorded separately and 
not listed as medical history. These details include but are not limited to FIGO stage at initial
diagnosis, histopathology, location(s) of tumor burden, and all prior treatment (including 
prior radiation, prior chemotherapy, and prior surgery).
Participants must have measurable disease according to RECIST 1.1 as defined in Eligibility 
Criteria. Participants must also fulfill the medical and physical characteristics identified in 
the inclusion criteria and not otherwise meet any of the exclusion criteria.
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant 
within 30 days before the first dose of study medication.
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study.
8.1.6
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur prior to randomization. Each participant 
will be assigned only one 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 visit requirements (screening/re-screening) are provided in 
Section 8.12.1. 
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8.1.7
Assignment of Treatment/Randomization Number
All eligible participants will be randomly allocated and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment allocation/randomization. Once a 
treatment/randomization number is assigned to a participant, it can never be re-assigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
8.1.8
Treatment Administration
Study treatments will be administered by the investigator and/or study staff according to the 
specifications within the pharmacy manual. Lenvatinib may be administered at home except 
on Day 1 of Cycle 1 and Cycle 2. Please refer to Section 8.1.8.1.1 for further detail.
Lenvatinib may be also be administered at home during the Crossover Treatment Phase 
except on Day 1 of Cycle 1 and Cycle 2.
Lenvatinib compliance will be calculated by the Sponsor based on the drug accountability 
documented by the site staff and monitored by the Sponsor/designee. The objective is 100% 
compliance and investigators and their staff should evaluate compliance at each visit and take 
appropriate steps to optimize compliance.
Study Treatment should begin within 3 days of randomization.
8.1.8.1
Timing of Dose Administration
8.1.8.1.1
Lenvatinib
Lenvatinib 20 mg (two 10-mg capsules) once daily will be taken orally with water (with or 
without food) at approximately the same time each day in each 21-day cycle. However, on 
Day 1 of Cycles 1 and 2, lenvatinib will be administered 0 to 4 hours after completion of 
pembrolizumab administration.
If a lenvatinib dose is missed and cannot be taken within 12 hours then that dose should be 
skipped, and the next dose should be taken at the usual time of administration.
8.1.8.1.2
Pembrolizumab
Pembrolizumab will be administered as a 30-minute IV infusion on Day 1 of each 21-day 
cycle. Sites should make every effort to target infusion timing to be as close to 30 minutes as 
possible. However, given the variability of infusion pumps from site to site, a window of –5
minutes and +10 minutes is permitted (ie, infusion time is 30 minutes: –5 min/+10 min).
After Cycle 1 Day 1, pembrolizumab may be administered up to 3 days before or after the 
scheduled Day 1 of each subsequent cycle due to administrative reasons.
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8.1.8.1.3
Treatment of Physician’s Choice
TPC consists of either doxorubicin hydrochloride or paclitaxel. Doxorubicin hydrochloride 
will be administered by IV bolus or 1-hour infusion (or per institutional guidelines) at a dose 
of 60 mg/m2 on Day 1 of each 21-day cycle.
Paclitaxel will be administered IV at a dose of 80 mg/m2 administered as a 1-hour IV 
infusion (or per institutional guidelines on Days 1, 8, and 15 of each 28-day cycle; i.e. 
3 weeks on, 1 week off). The administration procedure should follow the approved 
prescribing information for doxorubicin or paclitaxel in each country/region or institutional 
guidelines.
8.1.9
Discontinuation and Withdrawal
Participants who discontinue study treatment prior to completion of the treatment period
should be encouraged to continue to be followed for all remaining study visits.
When a participant withdraws from participation in the study, all applicable activities 
scheduled for the discontinuation visit (End of Treatment visit) should be performed (at the 
time of withdrawal). Any AEs which are present at the time of withdrawal should be 
followed in accordance with the safety requirements outlined in Section 8.4 .
If discontinuation occurs ≥30 days after the last dose of study treatment, a Safety Follow-up 
Visit (Section 8.12.3.1) is not required. In this situation, all procedures required at both the 
EOT visit and the safety follow-up visit should be performed.
8.1.10
Participant Blinding/Unblinding
This is an open label study; there is no blinding for this study.
8.1.11
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained is reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
8.1.12
Demography
Participant demography information will be collected at the Screening Visit. Demography 
information includes date of birth (or age), sex, race/ethnicity.
8.2
Efficacy/Immunogenicity Assessments
8.2.1
Tumor Imaging and Assessment of Disease
The process for image collection and transmission to the CIV can be found in the Site 
Imaging Manual (SIM). Tumor imaging of the chest is to be acquired by computed 
tomography (CT). For the abdomen and pelvis, contrast-enhanced magnetic resonance 
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imaging (MRI) is the preferred modality; however, CT with iodinated contrast may be used 
when contrast-enhanced MRI is contraindicated, or when mandated by local practice. MRI is 
the strongly preferred modality for imaging the brain. The same imaging technique regarding 
modality, ideally the same scanner, and the use of contrast should be used in a participant 
throughout the study to optimize the reproducibility of the assessment of existing and new 
tumor burden and improve the accuracy of the assessment of response or progression based 
on imaging. Note: for the purposes of assessing tumor imaging, the term “Investigator” refers 
to the local investigator at the site and/or the radiological reviewer located at the site or at an 
offsite facility.
Participant eligibility will be determined using prospective BICR assessment based on 
RECIST 1.1. All scheduled images for all study participants from the sites will be submitted 
to the CIV. In addition, images (including via other modalities) that are obtained at an 
unscheduled time point to determine disease progression, as well as imaging obtained for 
other reasons, but which demonstrate radiologic progression, should also be submitted to the 
CIV.
When the Investigator identifies radiographic progression per RECIST 1.1, the CIV will 
perform expedited verification of radiologic PD and communicate the results to the study site
and MSD (See Section 8.2.1.5 and Figure 2). Treatment should continue until PD has been 
verified. All decisions to continue treatment beyond 2 consecutive scans showing progression 
at least 4 weeks apart must be discussed with the MSD Medical Monitor (Section 8.2.1.6 and 
Appendix 5). If iRECIST is implemented, the Investigator will assess for confirmation of 
progression by iRECIST at subsequent time points. Images should continue to be submitted 
to the CIV.
8.2.1.1
Initial Tumor Imaging
Initial tumor imaging at Screening must be performed within 28 days prior to the date of 
randomization. The site study team must submit screening images to the CIV to confirm the 
participant has measurable disease per RECIST 1.1.
Tumor imaging performed as part of routine clinical management is acceptable for use as 
screening tumor imaging if it is of diagnostic quality and performed within 28 days prior to 
the date of randomization and can be assessed by the CIV.
If brain imaging is performed to document the stability of existing metastases, MRI should 
be used if possible. If MRI is medically contraindicated, CT with contrast is an acceptable 
alternative.
Tumor imaging at baseline includes the following:
CT or MRI (preferred) of the abdomen and pelvis
CT of the chest
Bone scan for participants with a history of bone metastases or who are clinically 
symptomatic
Brain scan for participants with a history of protocol-eligible treated brain metastases or 
who are clinically symptomatic
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8.2.1.2
Tumor Imaging During the Study
The first on study imaging assessment should be performed at 8 weeks (56 days ±7 days) 
from the date of randomization. Subsequent tumor imaging should be performed every 
8 weeks (56 days ±7 days) or more frequently if clinically indicated. Following the primary 
analysis for the study, tumor imaging should be performed Q12W (84 days ±7 days) or more 
frequently if required by local standard of care and bone and brain scans should be performed 
per local standard of care. Imaging timing should follow calendar days from randomization 
and should not be adjusted for delays in cycle starts. Imaging should continue to be 
performed until disease progression is identified by the Investigator and verified by the CIV
(and when clinically appropriate confirmed by the site per iRECIST), the start of new 
anticancer treatment, withdrawal of consent, or death, whichever occurs first. All 
supplemental imaging must be submitted to the CIV.
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 CIV.
Per iRECIST (Section 8.2.1.6), disease progression should be confirmed by the site 4 to 
8 weeks after central verification of site-assessed first radiologic evidence of PD in clinically 
stable participants. Participants who have unconfirmed disease progression may continue on 
treatment at the discretion of the Investigator until progression is confirmed by the site, 
provided they have met the conditions detailed in Section 8.2.1.6. Participants who receive 
confirmatory imaging do not need to undergo the next scheduled tumor imaging if it is less 
than 4 weeks later; tumor imaging may resume at the subsequent scheduled imaging time 
point, if clinically stable. Participants who have confirmed disease progression by iRECIST, 
as assessed by the site, will discontinue study treatment. Exceptions are detailed in 
Section 8.2.1.6.
For participants in the Crossover Phase, on study imaging will be performed every 12 weeks 
(84 ±7 days) from first dose of Crossover study treatment or more frequently, if clinically 
indicated. Local reading of imaging (investigator assessment with site radiology reading) will 
be used for participant management. Imaging timing should follow calendar days and should 
not be adjusted for delays in cycle starts. The same imaging technique should be used in a 
participant throughout the trial. Local reading (investigator assessment with site radiology 
reading) will be used to determine eligibility and for participant management. Bone and/or
brain imaging should be performed per the SoA in Section 1.3.3, as appropriate. During the 
Crossover Phase, imaging scans do not need to be sent to the CIV.
8.2.1.2.1
Bone Imaging During the Study
A bone scan (99m-technetium-based scintigraphy, whole body bone MRI, or 18F-sodium 
fluoride positron emission tomography [NaF PET]) at screening will only be performed in 
participants who have a history of bone metastases or are clinically symptomatic. The 
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screening bone scan should be performed within 6 weeks prior to randomization (historical is 
acceptable). Subsequent bone scans in these participants will be performed every 24 weeks
(±7 days) after randomization, or as clinically indicated, and within a target of 1 week but no 
more than 2 weeks following a CR as assessed by the investigator.
8.2.1.2.2
Brain Imaging During the Study
A brain scan (CT of the brain with contrast or MRI of the brain pre- and post-gadolinium) at 
screening will only be performed in participants who have a history of protocol-eligible brain 
metastases or are clinically symptomatic. Subsequent brain scans in these participants will be 
performed every 8 weeks (±7 days) after randomization, or as clinically indicated thereafter, 
and within a target of 1 week but no more than 2 weeks following achievement of a CR as 
assessed by the investigator.
8.2.1.3
End of Treatment and Follow-up Tumor Imaging
For participants who discontinue study treatment, 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 treatment due to documented 
disease progression, this is the final required tumor imaging if the Investigator elects not to 
implement iRECIST.
For participants who discontinue study treatment 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 (Q8W) 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 ± lenvatinib. Local reading (Investigator assessment with site radiology 
reading) will be used to determine eligibility. All second course imaging should be submitted 
to the CIV 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.
Per iRECIST (Section 8.2.1.6), if tumor imaging shows initial PD, tumor assessment should 
be repeated 4 to 8 weeks later in order to confirm PD with the option of continuing treatment 
while awaiting radiologic confirmation of progression. Participants who obtain confirmatory 
imaging do not need to undergo scheduled tumor imaging if it is less than 4 weeks later and 
may wait until the next scheduled imaging time point, if clinically stable.
Imaging should continue to be performed until disease progression, the start of a new 
anticancer treatment, withdrawal of consent, death, or notification by MSD, whichever 
occurs first. In clinically stable participants, disease progression may be confirmed by the 
investigator using iRECIST 4 to 8 weeks after the first tumor imaging indicating PD.
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For participants who discontinue Second Course study treatment, 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 treatment due to 
documented disease progression, this is the final required tumor imaging.
For participants who discontinue Second Course study treatment 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) or as clinically indicated thereafter
until either the start of a new anticancer treatment, disease progression, death, withdrawal of 
consent, or the end of the study, whichever occurs first.
8.2.1.4.1
Bone Imaging During Second Course
A bone scan (99m-technetium-based scintigraphy, whole body bone MRI, or NaF PET) prior 
to restarting pembrolizumab ± lenvatinib will only be performed in participants who have a 
history of bone metastases or are clinically symptomatic. The bone scan prior to restarting 
treatment is only required if the previous scan was not performed within the prior 6 weeks. 
Subsequent bone scans in these participants will be performed every 24 weeks (±7 days) after 
restarting pembrolizumab ± lenvatinib, or as clinically indicated.
8.2.1.4.2
Brain Imaging During Second Course
A brain scan (CT of the brain with contrast or MRI of the brain pre- and post-gadolinium) 
within 28 days of restarting pembrolizumab ± lenvatinib will only be performed in 
participants who have a history of protocol-eligible brain metastases or are clinically 
symptomatic. Subsequent brain scans in these participants will be performed every 8 weeks 
(±7 days) after restarting pembrolizumab ± lenvatinib.
8.2.1.5
RECIST 1.1 Assessment of Disease
RECIST 1.1 will be used by BICR as the primary measure for assessment of tumor response, 
date of disease progression, and as a basis for all protocol guidelines related to disease status 
(eg, discontinuation of study treatment). Although RECIST 1.1 references a maximum of 
5 target lesions in total and 2 per organ, this protocol allows a maximum of 10 target lesions 
in total and 5 per organ, if clinically relevant to enable a broader sampling of tumor burden.
Initial tumor imaging showing site-assessed PD should be submitted immediately for BICR 
verification of PD. The site will be notified if the BICR verifies PD using RECIST 1.1.
Figure 2 illustrates the imaging flow involving verification of PD for clinically stable 
participants.
8.2.1.6
iRECIST Assessment of Disease
iRECIST is based on RECIST 1.1, but adapted to account for the unique tumor response seen 
with immunotherapeutic drugs. iRECIST will be used by the Investigator to assess tumor 
response and progression, and make treatment decisions. When clinically stable, participants 
should not be discontinued until progression is confirmed by the Investigator, working with 
local radiology, according to the rules outlined in Appendix 5. This allowance to continue 
treatment despite initial radiologic PD takes into account the observation that some 
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participants can have a transient tumor flare in the first few months after the start of 
immunotherapy, and then experience subsequent disease response. This data will be captured 
in the clinical database.
Clinical stability is defined as the following: 
•
Absence of symptoms and signs indicating clinically significant progression of 
disease
•
No decline in ECOG performance status 
•
No requirements for intensified management, including increased analgesia, 
radiation, or other palliative care
Any participant deemed clinically unstable should be discontinued from study treatment at 
site-assessed first radiologic evidence of PD, and is not required to have repeat tumor 
imaging for confirmation of PD by iRECIST.
If the Investigator decides to continue treatment, the participant may continue to receive 
study treatment and the tumor assessment should be repeated 4 to 8 weeks later to confirm 
PD by iRECIST, per Investigator assessment. Images should continue to be sent in to the 
CIV for potential retrospective BICR. 
If repeat imaging does not confirm PD per iRECIST, as assessed by the Investigator, and the 
participant continues to be clinically stable, study treatment may continue and follow the 
regular imaging schedule. If PD is confirmed, participants will be discontinued from study 
treatment.
If a participant has confirmed radiographic progression (iCPD) as defined in Appendix 5, 
study treatment should be discontinued; however, if the participant is achieving a clinically 
meaningful benefit, an exception to continue study treatment may be considered following 
consultation with MSD. In this case, if study treatment is continued, tumor imaging should 
continue to be performed following the intervals as outlined in Section 1.3 and submitted to 
the CIV.
A description of the adaptations and iRECIST process is provided in Appendix 5, with 
additional details in the iRECIST publication [Seymour, L., et al 2017]. A summary of 
imaging and treatment requirements after first radiologic evidence of progression is provided 
in Table 6 and illustrated as a flowchart in Figure 2.
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Table 6
Imaging and Treatment After First Radiologic Evidence of Progressive Disease
Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
First radiologic 
evidence of PD by 
RECIST 1.1 per 
investigator 
assessment
Repeat imaging 
at 4 to 8 weeks to 
confirm PD per 
iRECIST.
May continue study 
treatment at the 
discretion of the 
investigator after 
obtaining the 
participant’s consent.
No additional 
imaging required.
Discontinue 
treatment
Repeat tumor 
imaging confirms 
PD (iCPD) by 
iRECIST per 
Investigator 
assessment
No additional 
imaging required.
Discontinue 
treatment (exception 
is possible upon 
consultation with 
MSD).
No additional 
imaging required.
Not applicable
Repeat tumor 
imaging shows 
iUPD by iRECIST 
per Investigator 
assessment
Repeat imaging 
at 4 to 8 weeks to 
confirm PD.
Continue study 
treatment at the 
Investigator’s 
discretion.
No additional 
imaging required.
Discontinue 
treatment
Repeat tumor 
imaging shows 
iSD, iPR, or iCR 
by iRECIST per 
Investigator 
assessment.
Continue 
regularly 
scheduled 
imaging 
assessments.
Continue study 
treatment at the 
Investigator’s 
discretion.
No additional 
imaging required.
Discontinue 
treatment
Abbreviations:  BICR = blinded independent central review; iCPD = iRECIST confirmed progressive disease; 
iCR = iRECIST complete response; iRECIST = modified Response Evaluation Criteria in Solid Tumors 1.1 for 
immune-based therapeutics; iSD = iRECIST stable disease; iUPD = iRECIST unconfirmed progressive disease; 
PD = progressive disease; RECIST 1.1 = Response Evaluation Criteria in Solid Tumors 1.1; VOP = verification of 
progression
Note: If progression has been centrally verified, further management is by the site, based on iRECIST. Any further 
imaging should still be submitted to the central imaging vendor, but no rapid review will occur. If RECIST 1.1 disease 
progression has not been centrally verified, ideally the site should continue treatment. Whether or not treatment 
continues, imaging should be collected and submitted to the central imaging vendor with VOP request until RECIST 1.1 
progression is verified by BICR.
Note: After treatment is held because of clinical instability, the investigator may restart study intervention if the condition 
has improved and the participant is clinically stable per investigator’s discretion. Next tumor imaging should occur 
according to the regular imaging schedule
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Figure 2
Imaging and Treatment for Clinically Stable Participants Treated with 
Pembrolizumab After First Radiologic Evidence of PD Assessed by the Investigator
Abbreviations: CIV = central imaging vendor; iRECIST = modified Response Evaluation Criteria in Solid 
Tumors 1.1 for immune-based therapeutics; PD = progressive disease; RECIST = Response Evaluation 
Criteria in Solid Tumors.
8.2.2
Health-Related Quality of Life Assessments
HRQoL will be assessed at Cycle 1 Day 1 (prior to first dose of study drug), on Day 1 of 
each subsequent cycle, and at time of discontinuation (End of Treatment visit). Participants 
will be asked to complete the HRQoL questionnaires for the equivalent of 4 cycle lengths (ie, 
either every 21 or 28 days depending on assigned treatment) following the End of Treatment 
visit. Completion of the HRQoL questionnaires following the End of Treatment visit is not 
mandatory; however, every effort should be made to collect this information. Following the 
End of Treatment visit, the HRQoL questionnaires will be completed via the Web Diary from 
the participants’ personal electronic device. At the time of the End of Treatment visit, 
participants should be invited to register for the Web Diary to ensure they receive reminders 
when the questionnaires are due for completion. Detailed instructions can be found in the 
CRF Health Site Manual.
Every effort should be made to administer HRQoL surveys prior to study drug administration 
and before other assessments and procedures. Participants will complete the questionnaires in 
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the following order: 1) EuroQol EQ-5D-5L, 2) EORTC QLQ-C30, then 3) EORTC QLQ-
EN24.
NOTE: If at the time of enrollment of a participant, the translated version of the EORTC 
QLQ-EN24 is not available for that language/country, and therefore cannot be completed by 
the participant at Cycle 1 Day 1, then the EORTC QLQ-EN24 will not be required for this 
participant at any point during the study. The other study PRO measures must be completed 
as scheduled. NOTE: For some sites, the translated EORTC QLQ-EN24 might become 
available after study startup and should be administered to participants at their time of 
enrollment; for some sites, the EORTC QLQ-EN24 translation might not be available for the 
entire duration of the study.
NOTE: The collection of PRO data will be discontinued following implementation of 
Amendment 09.
8.2.3
Crossover Phase Assessments and Procedures
Crossover participants can initiate treatment with lenvatinib 20 mg QD plus pembrolizumab 
200 mg Q3W once investigators confirm that participant meets the required eligibility 
criteria. All inclusion/exclusion criteria should be met to participate in the crossover phase, 
except for exclusions #20, #21, #24 and #28 (Sections 5.1 and 5.2). The participant will then 
start the Crossover Phase as outlined in the Crossover SoA in Section 1.3.3. Participants must 
have baseline imaging scans performed within 30 days prior to the first dose of lenvatinib 
plus pembrolizumab in the Crossover Phase. 
On study imaging will be performed every 12 weeks (84 ±7 days) from the first dose of 
Crossover study treatment or more frequently, if clinically indicated. Local reading of 
imaging (investigator assessment with site radiology reading) will be used for participant 
management. During Crossover Phase, imaging scans no longer need to be sent to the CIV.
Participants may continue on lenvatinib plus pembrolizumab until investigator-assessed
progressive disease as assessed by RECIST 1.1 (as described in Section 8.2.1 and Table 6) 
and only when clinically appropriate, confirmed by the site per modified RECIST 1.1 for 
immune-based therapeutics (iRECIST), or up to two years (35 cycles) from starting 
crossover treatment on C1D1 with lenvatinib 20 mg plus pembrolizumab 200 mg Q3W, 
whichever comes first. In participants who discontinue treatment in the Crossover Phase 
without documented disease progression, every effort should be made to continue monitoring 
their disease status by radiologic imaging every 12 weeks (±7 days) until (1) the start of post-
crossover new anticancer treatment, (2) disease progression, (3) death, or (4) the end of the 
study, whichever occurs first.
Participants who discontinue study treatment in the Crossover Phase will follow the post-
crossover phase procedures as outlined in Sections 1.3.3 and 8.12.3.
As described in Section 7.1.1, participants who attain a confirmed CR per RECIST 1.1 will 
have the option to hold lenvatinib plus pembrolizumab while continuing in the study. Please 
note the following exception: crossover participants will not be eligible for Second Course 
Phase as outlined in Section 6.6.5.
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8.3
Safety Assessments
Safety assessments will consist of monitoring and recording all AEs, including all NCI 
CTCAE v4.03 grades (for both increasing and decreasing severity), and SAEs; regular 
laboratory evaluation for hematology, blood chemistry, and urine values; periodic 
measurement of vital signs, ECGs and MUGA or echocardiogram; and the performance of 
physical examinations as detailed in Section 1.3.
Progression of EC and signs and symptoms clearly related to the progression of EC should 
not be captured as an AE. Disease progression is a study endpoint and should be captured in 
the CRF as per the guidelines for reporting disease progression.
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
Physical examinations (comprehensive or symptom-directed) will be performed as specified 
in the SoA (Section 1.3.1, Section 1.3.2, and Section 1.3.3). A comprehensive physical 
examination will include evaluations of the head, eyes, ears, nose, throat, neck, chest 
(including heart and lungs), abdomen, limbs, skin, and a complete neurological examination.
Documentation of the physical examination will be included in the source documentation at 
the investigational site. Significant findings prior to participant informed consent will be 
recorded on the appropriate CRF. Changes from screening physical examination findings that 
meet the definition of an AE will be recorded on the appropriate CRF.
8.3.2
Vital Signs
Vital sign measurements (ie, systolic and diastolic BP [mm Hg], pulse [beats per minute], 
respiratory rate [per minute], body temperature [in centigrade]), and weight (kg) will be 
obtained at the visits designated in the SoA (Section 1.3.1 and Section 1.3.2) by a validated 
method.
-
Blood pressure and heart rate will be measured after the participant has been resting for 
5 minutes. All BP measurements should be performed on the same arm, preferably by the 
same person.
-
Only 1 BP measurement is needed for participants with systolic BP <140 mm Hg and 
diastolic BR <90 mm Hg. If the participant’s first BP measurement of the current 
assessment is elevated (ie, systolic BP ≥140 mm Hg or diastolic BP ≥90 mm Hg), the BP 
measurement should be repeated at least 5 minutes later. One BP assessment is defined as 
the mean value of 2 measurements at least 5 minutes apart. If the BP assessment (ie, the 
mean of the 2 BP measurements obtained at least 5 minutes apart) is elevated (systolic 
BP ≥140 mm Hg or diastolic BP ≥90 mm Hg), a confirmatory assessment should be 
obtained at least 30 minutes later by performing 2 measurements (at least 5 minutes 
apart) to yield a mean value.
-
Under exceptional circumstances, participants will have the option of having BP 
measured between visits obtained locally by a health care professional. A diary will be 
provided as a tool to aid the participant in collecting BP evaluations between study visits.
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8.3.3
Electrocardiograms
Electrocardiograms will be obtained as designated in the SoA (Section 1.3.1, Section 1.3.2, 
and Section 1.3.3). Complete, standardized, 12-lead ECG recordings that permit all 12 leads 
to be displayed on a single page with an accompanying lead II rhythm strip below the 
customary 3 × 4 lead format are to be used. In addition to a rhythm strip, a minimum of 3 full 
complexes should be recorded from each lead simultaneously. Participants must be in the 
recumbent position for a period of 5 minutes prior to the ECG. The Fridericia correction 
method for calculating QTc will be used.
An ECG abnormality may meet the criteria of an AE as described in this protocol (see 
Appendix 3) and the CRF Completion Guidelines. In these instances, the AE corresponding 
to the ECG abnormality will be recorded on the appropriate CRF.
QTc prolongation has been seen in some lenvatinib studies. Monitor electrocardiograms 
every cycle (as specified in the SoA) 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. Refer to the lenvatinib IB.
8.3.4
Echocardiogram or Multiple Gated Acquisition Scan
A MUGA scan (using technetium-based tracer) or an echocardiogram will be performed to 
assess left ventricular ejection fraction (LVEF) as designated in the SoA (Section 1.3.1, 
Section 1.3.2, and Section 1.3.3). 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 4 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency. 
●
The investigator must review the laboratory report, document this review, and record 
any clinically relevant changes occurring during the study in the AE section of the 
case report form (CRF). The laboratory reports must be filed with the source 
documents. Clinically significant abnormal laboratory findings are those which are 
not associated with the underlying disease, unless judged by the investigator to be 
more severe than expected for the participant's condition.
●
All protocol-required laboratory assessments, as defined in Appendix 4, 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).
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●
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 
treatment, every attempt should be made to perform repeat assessments until the 
values return to normal or baseline or if a new baseline is established as determined 
by the investigator. 
8.3.5.1
Hematology and Clinical Chemistry
Hematology and clinical chemistry results must be reviewed prior to administration of study 
therapy. Electrolytes such as potassium, calcium, and magnesium should be monitored and 
abnormalities, when considered clinically significant, should be corrected in all participants 
before starting treatment.
8.3.5.2
Urine Dipstick
Urine dipstick testing is required at the time points specified in the SoA. Additionally, urine 
dipstick testing is required on Day 15 of Cycles 1 and 2.
Urine dipstick testing for participants with proteinuria ≥2+ should be performed on Day 15 
(or more frequently as clinically indicated) until the results have been 1+ or negative for 
2 consecutive treatment cycles. Urine dipstick testing should be performed preferably at the 
investigational site (but may be performed locally by the primary care physician or a local 
laboratory if the participant does not have to come for a visit to the site). If a new event of 
proteinuria ≥2+ occurs, the participant must resume the Day 15 urine dipstick testing for 
evaluation of proteinuria until results are 1+ or negative for 2 consecutive treatment cycles.
For participants with proteinuria ≥2+, see subsection for management of proteinuria section.
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Reportable 
Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3.
Progression of the cancer under study is not considered an AE as described in Section 8.4.5 
and Appendix 3.
AE, SAEs, and other reportable safety events will be reported by the participant (or, when 
appropriate, by a caregiver, surrogate, or the participant's legally authorized representative). 
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events.
Investigators need to document if an SAE was associated with a medication error, misuse, or 
abuse. Investigators remain responsible for following up AEs, SAEs, and other reportable 
safety events for outcome according to Section 8.4.3.
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
All AEs, SAEs, and other reportable safety events that occur after the consent form is signed 
but before treatment allocation/randomization must be reported by the investigator if the 
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participant is receiving placebo run-in or other run-in treatment, if the event causes the 
participant to be excluded from the study, or is the result of a protocol-specified intervention, 
including but not limited to washout or discontinuation of usual therapy, diet, or a procedure. 
●
All AEs from the time of treatment allocation/randomization through 30 days following 
cessation of study treatment must be reported by the investigator. 
●
All AEs meeting serious criteria, from the time of treatment allocation/randomization 
through 120 days following cessation of study treatment, or 30 days following cessation of 
study treatment if the participant initiates new anticancer therapy, whichever is earlier must 
be reported by the investigator. 
●
All pregnancies and exposure during breastfeeding, from the time of treatment 
allocation/randomization through 120 days following cessation of study treatment, or 30 days 
following cessation of study treatment 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 MSD if the event is 
considered to be drug-related.
Investigators are not obligated to actively seek AE or SAE or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study treatment or study participation, the 
investigator must promptly notify MSD.
All initial and follow-up AEs, SAEs and other reportable safety events will be recorded and 
reported to MSD or designee within the time frames as indicated in Table 7.
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Table 7
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of Event
Time Period
Time Frame 
to Report 
Event and 
Follow-up 
Information 
to MSD:
Consent to 
Randomization/ 
Allocation
Randomization/ 
Allocation 
through 
Protocol-
Specified 
Follow-up 
Period
After the Protocol 
Specified Follow-up 
Period
Non-Serious 
Adverse Event 
(NSAE) 
Report if:
- due to protocol-
specified 
intervention
- causes 
exclusion
- participant is 
receiving 
placebo run-in or 
other run-in 
treatment
Report all
Not required
Per data 
entry 
guidelines
Serious Adverse 
Event (SAE) 
including Cancer 
and Overdose
Report if:
- due to protocol-
specified 
intervention
- causes 
exclusion
- participant is 
receiving 
placebo run-in or 
other run-in 
treatment
Report all
Report if:
- drug/vaccine 
related.
(Follow ongoing to 
outcome)
Within 24 
hours of 
learning of 
event
Pregnancy/
Lactation Exposure
Report if:
- due to 
intervention
- causes 
exclusion
Report all
Previously reported –
Follow to 
completion/
termination; report 
outcome
Within 24 
hours of 
learning of 
event
Event of Clinical 
Interest (require 
regulatory 
reporting)
Report if:
- due to 
intervention
- causes 
exclusion
Report
- Potential drug-
induced liver 
injury (DILI)
- Require 
regulatory 
reporting
Not required
Within 24 
hours of 
learning of 
event
Event of Clinical 
Interest (Do not 
require regulatory 
reporting)
Report if:
- due to 
intervention
- causes 
exclusion
Report
- non-DILI ECIs 
and those not 
requiring 
regulatory 
reporting
Not required
Within 5 
calendar 
days of 
learning of 
event
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8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AE and/or SAE and other reportable 
safety events. Open-ended and nonleading verbal questioning of the participant is the 
preferred method to inquire about AE occurrence.
8.4.3
Follow-up of AE, SAE and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AE, SAE, and other reportable safety events 
including pregnancy and exposure during breastfeeding, events of clinical interest (ECIs), 
Cancer and Overdose will be followed until resolution, stabilization, until the event is 
otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). In 
addition, the investigator will make every attempt to follow all nonserious AEs that occur in 
randomized participants for outcome. Further information on follow-up procedures is given 
in Appendix 3.
8.4.4
Regulatory Reporting Requirements for SAE
●
Prompt notification (within 24 hours) by the investigator to MSD of SAE is essential 
so that legal obligations and ethical responsibilities towards the safety of participants 
and the safety of a study treatment under clinical investigation are met. 
●
The Sponsor and MSD have a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about the safety of a study treatment under 
clinical investigation. All AEs will be reported to regulatory authorities, IRB/IECs 
and investigators in accordance with all applicable global laws and regulations, ie, per 
ICH Topic E6 (R2) Guidelines for GCP.
●
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and MSD 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 MSD will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local 
requirements.
8.4.5
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 sponsor/designee as 
described in Section 8.4.1. 
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study.
The sponsor/designee will monitor unblinded aggregated efficacy endpoint events and safety 
data to ensure the safety of the participants in the study.
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8.4.6
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 MSD.
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.
8.4.7
Events of Clinical Interest (ECIs)
Selected nonserious and serious adverse events are also known as ECIs and must be reported 
to the Sponsor.
Events of clinical interest for this study include: 
1. an overdose of study treatment, as defined in Section 8.5, that is not associated with 
clinical symptoms or abnormal laboratory results.
2. an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit 
of normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less 
than 2X the upper limit of normal, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.*
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that 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 Trial File 
Binder (or equivalent).
8.5
Treatment of Overdose
For the purposes of this study, an overdose will be defined as any dose exceeding the 
prescribed dose for:
-
Pembrolizumab: ≥5 times the prescribed dose specified in the protocol. 
-
Lenvatinib: any dose above the prescribed dose specified in the protocol if associated 
with an AE.
-
Chemotherapy: any dose ≥20% over the prescribed dose specified in the protocol.
No specific information is available on the treatment of overdose of pembrolizumab or 
lenvatinib. In the event of overdose, the participant should be observed closely for signs of 
toxicity. Appropriate supportive treatment should be provided if clinically indicated. 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 
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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 as specified in Table 7.
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”. The investigator should consult with the Medical Monitor 
prior to resuming treatment.
8.6
Pharmacokinetics
Blood samples will be collected as specified in the SoA (Section 1.3.1 and Section 1.3.2).
Study sites must have appropriately trained staff and adequate equipment for procuring and 
processing specimens. Instructions for the collection, handling, and shipping procedures of 
PK samples will be provided in the laboratory manual. 
Blood samples will be collected from all participants in Arm A. Plasma concentrations of 
lenvatinib will be measured. Lenvatinib will be analyzed using a population PK approach.
Lenvatinib will be quantified by use of validated High Performance Liquid Chromatography-
tandem mass spectroscopy method.
8.7
Pharmacodynamics
Data from Arm A of the study will be used to explore the relationship between exposure to 
lenvatinib and safety events related to lenvatinib.
8.8
Mismatch Repair Status
Archived tumor tissue from the most recent surgery/biopsy or from a fresh biopsy (if there is 
no archival tumor tissue available), will be collected from all enrolled participants for 
determination of MMR status by central assessment prior to randomization. When available, 
a tissue sample collected after the latest systemic treatment is preferred.
8.9
Biomarkers
To identify novel biomarkers, the following biospecimens to support exploratory analyses of 
cellular components (eg, protein, RNA, DNA, metabolites) and other circulating molecules 
will be collected from all participants in this study as specified in the SoA:

Blood for serum biomarkers

Blood for ctDNA

Blood for genetic analysis

Blood for RNA analysis

Tumor blocks or slides
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8.9.1
Blood and Tissue Biomarker Assessment
Blood samples for exploration of biomarkers will be collected as specified in the SoA
(Section 1.3.1 and Section 1.3.2).
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.
If providing slides, it is requested that the remainder of the tissue block be maintained at the 
site until the end of the study in the event that a bridging study is required for development of 
the MMR assay.
Sample collection, storage and shipment instructions for the exploratory biomarker 
specimens will be provided in the laboratory manual.
8.10
Future Biomedical Research Sample Collection
Future biomedical research samples will not be collected in this study.
8.11
Medical Resource Utilization and Health Economics
Medical resource utilization and health economics data, associated with medical encounters, 
will be collected in the CRF by the investigator and study site personnel for all participants 
throughout the study. Protocol-mandated procedures, tests, and encounters are excluded. 
The data collected may be used to conduct exploratory economic analyses and will include:
All-cause hospitalizations and emergency room visits, from the time of treatment 
allocation/randomization through 90 days following cessation of study treatment, or 30 days 
following cessation of study treatment, if the participant initiates new anticancer therapy, 
whichever is earlier.
8.12
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
above in Section 8.
8.12.1
Screening
Approximately 28 days prior to treatment randomization, potential participants will be 
evaluated to determine that they fulfill the entry requirements as set forth in Section 5.
Documented informed consent must be obtained prior to performing any protocol-specific 
procedure. Results of a test performed prior to the participant providing documented 
informed consent as part of routine clinical management are acceptable in lieu of a screening 
test if performed within the specified time frame. Screening procedures are to be completed 
within 28 days prior to the first dose of study treatment except for the following:
a.
Laboratory tests are to be performed within 7 days prior to the first dose of study 
treatment. An exception is hepatitis and HIV testing which may be done up to 28 days 
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prior to the first dose of study treatment if required by the local health authority.
Repeated laboratory evaluation to establish eligibility is not allowed unless discussed 
and agreed upon with MSD. Refer to Appendix 9 for country-specific requirements.
b. Evaluation of ECOG is to be performed within 7 days prior to the date of first dose of 
study treatment.
c.
For women of reproductive potential, a urine or serum pregnancy test will be performed 
within 72 hours prior to the first dose of study treatment. If urine pregnancy results 
cannot be confirmed as negative, a serum pregnancy test will be required (performed by 
the local study site laboratory).
d. Centrally assessed MMR status must be available prior to randomization. If MMR 
result is unavailable within 28 days from when original consent was obtained, an 
exception may be granted after consultation with MSD.
Upon consultation with the MSD Medical Monitor, 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.
8.12.2
Treatment Period
Visit requirements are outlined in the SoA (Section 1.3.1, Section 1.3.2, and Section 1.3.3).
Assessments/procedures are to be performed prior to the administration of study treatment.
8.12.2.1
Crossover Phase 
Participants on the TPC arm (as initial treatment) who develop investigator-assessed disease 
progression per RECIST 1.1 and stop receiving the investigator’s treatment of choice, 
doxorubicin or paclitaxel, may enter the Crossover Phase to receive lenvatinib plus 
pembrolizumab, if all eligibility criteria are met. These participants were initially randomized 
to the TPC arm, taken at least one dose and subsequently discontinued treatment with 
doxorubicin or paclitaxel.
Participants who initiate a new anticancer therapy or withdraw consent (from either study 
treatment, Efficacy Follow-up, or Survival Follow-up) are not eligible for crossover.
Participants will have laboratory assessments while receiving study treatment as outlined in 
the Crossover Schedule of Activities in Section 1.3.3.
The Crossover Phase of the study is only available if the study remains open and the 
participant meets all the required eligibility criteria, except exclusions #20, #21, #24 and #28.
Inclusion and exclusion criteria are defined in Sections 5.1 and 5.2. 
Visit requirements are outlined in Section 1.3.3 – SoA.
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8.12.3
Post-treatment Visit
8.12.3.1
Safety Follow-up
The mandatory safety follow-up visit should be conducted approximately 30 days after the 
last dose of study treatment or before the initiation of a new anticancer treatment, whichever 
comes first. 
All AEs that occur prior to the Safety Follow-Up Visit should be recorded. Participants with 
an AE of Grade >1 will be followed until the resolution of the AE to Grade 0-1 or until the 
beginning of a new anticancer therapy, whichever occurs first. Serious AEs that occur within 
120 days of the end of treatment or before initiation of a new anticancer treatment should 
also be followed and recorded. 
Participants who are eligible for retreatment with pembrolizumab may have up to 2 safety 
follow-up visits, 1 after the Initial Treatment Period and 1 after the Second Course 
Treatment.
Participants in the TPC arm who are eligible for treatment with lenvatinib plus 
pembrolizumab in the Crossover Phase (as described in Section 8.12.2.1) may have up to two 
safety follow-up visits, one after the initial Treatment Period and one after the Crossover 
Phase.
8.12.3.2
Efficacy Follow-up Visits
Participants who complete the protocol-required cycles of study treatment or who 
discontinue study treatment for a reason other than disease progression will move into the 
Efficacy Follow-Up Phase and should be assessed approximately every 8 weeks (or more 
frequently as needed) by clinic visit to monitor disease status; if a clinic visit is not feasible, 
the participant may be contacted by telephone or e-mail. The Sponsor may request survival 
status to be assessed at additional time points during the course of the study (not to exceed 
approximately 12 weeks). 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 post-study anticancer treatment will be collected if new 
treatment is initiated. Participants will also be asked to complete HRQoL questionnaires as 
outlined in Section 8.2.2. Participants who completed all efficacy assessments and/or will not 
have further efficacy assessments must enter the Survival Follow-up Phase.
All participants who discontinue study drug treatment prior to disease progression will 
continue to undergo tumor assessments every 8 weeks in the Follow-up Period until disease 
progression is documented and confirmed by BICR or a new anticancer therapy is initiated, 
unless the participant withdraws consent. Following the primary analysis for the study, tumor 
assessments should be performed every 12 weeks or more frequently per local standard of 
care.
Participants who are eligible for retreatment with pembrolizumab according to the criteria in 
Section 6.6.5 will move from the Efficacy Follow-Up Phase to the Second Course Phase 
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when they experience disease progression. Details are provided in the SoA (Section 1.3.2) for 
retreatment with pembrolizumab.
Participants in the TPC arm who have discontinued study treatment and opt to receive 
treatment with lenvatinib plus pembrolizumab in the Crossover Phase (according to the 
criteria in Section 8.12.2.1) may move from the Efficacy Follow-up Phase to the Crossover 
Phase, if they experience investigator-defined disease progression by RECIST 1.1. Details 
are provided in Section 1.3.3 – Crossover Phase for TPC Arm Only.
8.12.3.3
Survival Follow-up Contact
Participant survival follow-up status will be assessed approximately every 12 weeks 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 treatment 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 efficacy assessment 
follow-up visit has been performed.

For participants who are in the Crossover phase, the first survival follow-up contact will 
be scheduled 12 weeks after the investigator-assessed disease progression by RECIST 
1.1.

Participants who are in Survival Follow-up may be eligible for the Crossover Phase if 
they have an investigator-determined PD (by RECIST 1.1) and meet all eligibility 
criteria, except exclusions #20, #21, #24 and #28 (Section 8.12.2.1), but have not 
withdrawn consent (from either study treatment or Efficacy Follow-up), or started a new 
anticancer therapy.
8.12.4
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 external 
DMC review, interim and/or final analysis. Upon Sponsor notification, all participants who 
do not/will not have a scheduled study visit or study contact during the Sponsor-defined time 
period will be contacted for their survival status. 
9
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study. If, after the 
study has begun, changes are made to primary and/or key secondary hypotheses, or the 
statistical methods related to those hypotheses, then the protocol will be amended (consistent 
with ICH Guideline E-9). Changes to exploratory or other non-confirmatory analyses made 
after the protocol has been finalized, but prior to the conduct of any analysis, will be 
documented in a supplemental statistical analysis plan (sSAP) and referenced in the Clinical 
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Study Report (CSR) for the study. Separate analysis plans will be provided for PK, 
biomarker, and PRO analyses. Post hoc exploratory analyses will be clearly identified in the 
CSR. 
9.1
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan (SAP) are summarized here. The comprehensive 
plan is provided in Sections 9.2 through 9.12.
Study Design
Overview
A Multicenter, Open label, Randomized, Phase 3 Trial to Compare the Efficacy and 
Safety of Lenvatinib in Combination with Pembrolizumab Versus Treatment of 
Physician’s Choice in Participants with Advanced Endometrial Cancer
Treatment
Assignment
Approximately 780 eligible participants (660 mismatch repair proficient [pMMR]
participants and 120 MMR deficient [dMMR] participants) will be randomized to one 
of the following 2 treatment arms in a 1:1 ratio:
•
Arm A: lenvatinib 20 mg (orally, QD) plus pembrolizumab 200 mg (IV Q3W)
•
Arm B: TPC consisting of either doxorubicin 60 mg/m2 Q3W, or paclitaxel 
80 mg/m2 given weekly, 3 weeks on/1 week off
Randomization will follow a predefined randomization scheme based on the following 
stratification factors: MMR status (pMMR or dMMR), ECOG performance status (0 
or 1), geographic region (Region 1: Europe, USA, Canada, Australia, New Zealand, 
and Israel or Region 2: rest of the world), and prior history of pelvic radiation (yes or 
no). First, participants will be stratified according to MMR status. Then, only within 
the pMMR stratum, participants will be further stratified according to ECOG 
performance status, geographic region, and prior history of pelvic radiation. A total of 
9 strata will be utilized for the study.
Analysis
Populations
Efficacy: Intention to Treat (ITT)
Safety: All Participants as Treated (APaT)
Primary
Endpoints

Progression-free survival (PFS) based on RECIST 1.1 as assessed by BICR.

Overall survival (OS).
Secondary 
Endpoints

Objective response rate (ORR) by BICR using RECIST 1.1.

Health-Related Quality of Life using the EORTC QLQ-C30.

Safety and tolerability of the two treatment groups.

Plasma concentration of lenvatinib versus time.

Model-predicted clearance and AUC for lenvatinib.
Statistical
Methods for Key 
Efficacy Analyses
The primary hypotheses will be evaluated by comparing in PFS and OS using a 
stratified Log-rank test. The hazard ratio (HR) will be estimated using a stratified Cox 
regression model. Event rates over time will be estimated within each treatment group 
using the Kaplan-Meier method. 
Statistical
Methods for Key
Safety Analyses
The analysis of safety results will follow a tiered approach. The tiers differ with 
respect to the analyses that will be performed. There are no events of interest that 
warrant elevation to Tier 1 events in this study. Tier 2 parameters will be assessed via 
point estimates with 95% confidence intervals (CIs) provided for between-group 
comparisons; only point estimates by treatment group are provided for Tier 3 safety 
parameters. The 95% CIs for the between-treatment differences in percentages will be 
provided using the Miettinen and Nurminen method.
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Interim Analyses
Two interim analyses are planned in this study and will be performed by an 
independent unblinded statistician and programmer. Results of these analyses will be 
reviewed by the DMC. Details are provided in Section 9.7. 

Interim Analysis 1 (IA1)
o
Timing: to be performed after both ~368 OS events have been observed in the 
pMMR participants and at least 6 months after last participant randomized
o
Primary purpose: final efficacy analysis for PFS and interim efficacy analysis 
for OS

Interim Analysis 2 (IA2)
o
Timing: to be performed after both ~463 OS events have been observed in the 
pMMR participants and at least 12 months after last participant randomized
o
Primary purpose: interim efficacy analysis for OS

Final Analysis (FA)
o
Timing: to be performed after both ~526 OS events have been observed in the 
pMMR participants and at least 18 months after last participant randomized
o
Primary purpose: final efficacy analysis for OS
Multiplicity
The total family-wise error rate (Type I error) among the 2 primary PFS and OS 
analyses, ORR analysis, and for pMMR and all-comer participants is strongly 
controlled at one-sided 0.025 level. 
A 0.0005 Type I error rate is initially allocated to test PFS and 0.0245 Type I error rate 
is initially allocated to test OS between two treatment arms in pMMR participants. 
Details of alpha allocation strategy among hypotheses of PFS, OS, and ORR are 
provided in Section 9.8 Multiplicity. The study will be considered positive if either 
testing of PFS or testing of OS is significant in pMMR participants.
Sample Size and
Power
The planned sample size is approximately 780 participants (660 pMMR participants 
and 120 dMMR participants) with 330 pMMR participants and 60 dMMR participants 
in each arm. For the pMMR participants: With approximately 564 PFS events at the 
planned PFS analysis, the study will have at least 99% of power to detect a hazard 
ratio of 0.55 at the one-sided 0.0005 significance level. With approximately 368, 463, 
and 526 OS events in the pMMR participants at the planned IA1, IA2, and final OS 
analysis (FA), respectively, the study will have 90% power to detect a hazard ratio of 
0.75 at the one-sided 0.0245 significance level.
Following Amendment 08, the pre-planned second interim analysis (IA2) is no longer 
required and will not be performed. This is because the success criteria for the study 
hypotheses of PFS, OS, and ORR were met at the first interim analysis (IA1).The 
prespecified final analysis will be performed without multiplicity adjustment after 
approximately 526 OS events have been observed in the pMMR participants and at least 
18 months after the last participant was randomized. Updated analyses may be performed 
during the trial at any time point to provide additional estimates with longer follow-up.
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 MSD. 
MSD will generate the randomized allocation schedule(s) for study treatment assignment for 
this protocol, and the randomization will be implemented in IRT. 
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Although the study is open label, analyses or summaries generated by randomized treatment 
assignment, and actual treatment received status will be limited and documented.
The external DMC will serve as the primary reviewer of the unblinded results of the interim 
analyses and will make recommendations for discontinuation of the study or modification to 
a Joint Executive Oversight Committee (EOC). Depending on the recommendation of the 
external DMC, the Sponsor or MSD may prepare a regulatory submission. If the external 
DMC recommends modifications to the design of the protocol or discontinuation of the 
study, this EOC and limited additional Sponsor/MSD personnel may be unblinded to results 
at the treatment level in order to act on these recommendations. Additional logistical details, 
revisions to the above plan and data monitoring guidance will be provided in the DMC 
charter.
9.3
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3 – Objectives/Hypotheses and 
Endpoints. 
9.4
Analysis Endpoints
9.4.1
Primary Endpoints
•
PFS by BICR - defined as the time from the date of randomization to the date of the 
first documentation of disease progression, as determined by blinded BICR of 
objective radiographic disease progression per RECIST 1.1 or death due to any cause
(whichever occurs first). See Section 9.6.1 – Statistical Methods for Efficacy 
Analyses for definition of censoring.
•
OS - defined as the time from the date of randomization to the date of death due to
any cause. Participants who are lost to follow-up and those who are alive at the date 
of data cutoff will be censored at the date the participant was last known alive, or date 
of data cutoff, whichever occurs first.
9.4.2
Secondary Endpoints
•
ORR - defined as the proportion of participants who have best overall response of 
either CR or PR as determined by BICR per RECIST 1.1.
•
HRQoL will be assessed using the global score of the EORTC QLQ-C30.
•
Safety will be assessed summarizing the incidence of TEAEs, SAEs, and irAEs; 
proportion of participants who discontinued treatment due to TEAEs; and time to 
treatment failure due to toxicity (defined as the time from the date of randomization 
to the date that a participant discontinues study treatment due to TEAEs). 
•
Plasma concentration of lenvatinib versus time.
•
Model-predicted clearance and AUC for lenvatinib.
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9.4.3
Exploratory Endpoints
•
DOR is defined as the time from the date a response was first documented until the 
date of the first documentation of disease progression, by BICR and investigator 
assessment of objective radiographic disease assessment per RECIST 1.1, or date of 
death (whichever occurs first).
•
PFS and ORR as determined by investigator review of radiographic disease 
assessment per RECIST 1.1.
•
DCR is the proportion of participants who have best overall response of CR or PR or 
SD by BICR and investigator assessment per RECIST 1.1. Stable disease must be 
achieved at ≥7 weeks after randomization to be considered best overall response.
•
CBR is the proportion of participants who have best overall response of CR, PR, or 
durable SD (duration of SD ≥23 weeks after randomization) by BICR and 
investigator assessment per RECIST 1.1.
•
PFS, ORR, DOR, DCR, and CBR as determined by investigator assessment using 
iRECIST. PFS using iRECIST will be defined as the time from the date of 
randomization to the date of the first documentation of confirmed immune-related 
progressive disease (iPD) or death (whichever occurs first). 
•
HRQoL will be assessed using the EORTC QLQ-C30 (scores other than global 
score), EORTC QLQ EN24, and the EuroQoL EQ-5D-5L instrument.
•
PFS2 is defined as the time from randomization to disease progression by investigator 
assessment on next line of treatment, or death (whichever occurs first).
•
Blood and tumor biomarkers will be assessed for exploring potential correlation with 
clinical outcomes-related endpoints.
9.5
Analysis Populations
9.5.1
Efficacy Analysis Population
The Intention to Treat (ITT) population will serve as the population for the primary efficacy 
analyses. All randomized participants will be included in this population. Participants will be 
analyzed in the treatment group to which they are randomized. 
9.5.2
Safety Analysis Population
The All Participants as Treated (APaT) population will be used for the analysis of safety data 
in this study. The APaT population consists of all randomized participants who received at 
least 1 dose of study treatment. Participants will be included in the treatment group 
corresponding to the study treatment they actually received. For most participants, this will 
be the treatment group to which they are randomized. Participants who take incorrect study 
treatment for the entire treatment period will be included in the treatment group 
corresponding to the study treatment actually received. Any participant who receives the 
incorrect study treatment for 1 cycle, but receives the correct treatment for all other cycles, 
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will be analyzed according to the correct treatment group and a narrative will be provided for 
any events that occur during the cycle for which the participant is incorrectly dosed.
At least 1 laboratory or vital sign measurement obtained subsequent to at least 1 dose of 
study treatment is required for inclusion in the analysis of each specific parameter. To assess 
change from baseline, a baseline measurement is also required.
9.5.3
Health-Related Quality of Life Analysis Population
The HRQoL analyses are based on the HRQoL full analysis set (FAS) population, defined as 
participants who have received treatment and have at least one HRQoL assessment available.
9.5.4
Population Pharmacokinetic Analysis Set
The Population Pharmacokinetic Analysis Set includes all the participants who have received 
at least 1 dose of study treatment with documented dosing history in the lenvatinib plus 
pembrolizumab arm (Arm A), and have measurable plasma levels of lenvatinib.
9.6
Statistical Methods
9.6.1
Statistical Methods for Efficacy Analyses
This section describes the statistical methods that address the primary and secondary 
objectives. Methods related to exploratory objectives will be described in the sSAP.
Efficacy results for pMMR participants and all-comer participants that will be deemed to be 
statistically significant after consideration of the Type I error control strategy are described in 
Section 9.8 – Multiplicity. Nominal p-values will be computed for other efficacy analyses,
but should be interpreted with caution due to potential issues of multiplicity.
9.6.1.1
Primary Efficacy Analysis
Progression-free Survival
The non-parametric Kaplan-Meier method will be used to estimate the PFS curve in each 
treatment group. The treatment difference in PFS will be assessed by the stratified log-rank 
test (based on the stratification factors defined in Section 6.3.1.1). A stratified Cox 
proportional hazard model with Efron's method of tie handling will be used to assess the 
magnitude of the treatment difference (ie, the HR) between the treatment arms. The HR and 
its 95% CI from the stratified Cox model with Efron's method of tie handling and with a 
single treatment covariate will be reported. The stratification factors used for randomization 
(Section 6.3.1.1) will be applied to both the stratified log-rank test and the stratified Cox 
model.
Since disease progression is assessed periodically, PD can occur any time in the time interval 
between the last assessment where PD was not documented and the assessment when PD is 
documented. For the primary analysis, for the participants who have PD, the true date of 
disease progression will be approximated by the date of the first assessment at which PD is 
objectively documented per RECIST 1.1 (based on BICR), regardless of discontinuation of 
study drug. Death is always considered as a confirmed PD event.
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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.
In order to evaluate the robustness of the PFS endpoint per RECIST 1.1 based on BICR, 
2 sensitivity analyses with a different set of censoring rules will be performed. The first 
sensitivity analysis handles participants who miss more than 1 disease assessment (with or 
without a subsequent death or progression) differently from the primary analysis. The second 
sensitivity analysis handles participants who discontinue treatment or initiate an anticancer 
treatment subsequent to discontinuation of study-specified treatments differently from the 
primary analysis. The censoring rules for primary and sensitivity analyses are summarized in 
Table 8. 
If a participant meets multiple criteria for censoring, the censoring criterion that occurs 
earliest will be applied.
Table 8
Censoring Rules for Primary Analysis of Progression-Free Survival Based on 
RECIST 1.1
Situation
Primary Analysis
Sensitivity
Analysis 1
Sensitivity
Analysis 2
PD or death 
documented after 
≤1 missed disease 
assessment, and before 
new anticancer therapy, 
if any
Progressed at date of 
documented PD or 
death
Progressed at date of 
documented PD or death
Progressed at date of 
documented PD or death
PD or death 
documented 
immediately after 
≥2 consecutive missed 
disease assessments or 
after new anticancer
therapy, if any
Censored at last 
disease assessment 
prior to the earlier 
date of 
≥2 consecutive 
missed disease 
assessment and new 
anticancer therapy, if 
any
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 or completed 
study treatment.
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Situation
Primary Analysis
Sensitivity
Analysis 1
Sensitivity
Analysis 2
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 if new 
anticancer treatment is 
initiated; otherwise 
progressed at treatment 
discontinuation if treatment 
is discontinued due to 
reasons other than complete 
response; otherwise censored 
at last disease assessment if 
still on study therapy or 
completed the study therapy
Abbreviations: PD = progressive disease; RECIST = Response Evaluation Criteria in Solid Tumors.
Overall Survival
The non-parametric Kaplan-Meier method will be used to estimate the survival curves. The 
treatment difference in survival will be assessed by the stratified log-rank test (based on the 
stratification factors defined in Section 6.3.1.1). A stratified Cox proportional hazard model 
with Efron's method of tie handling will be used to assess the magnitude of the treatment 
difference (ie, the HR). The HR and its 95% CI from the stratified Cox model with a single 
treatment covariate will be reported. The stratification factors used for randomization 
(Section 6.3.1.1) will be applied to both the stratified log-rank test and the stratified Cox 
model. Participants without documented death at the time of analysis will be censored at the 
date of last known contact. Restricted Mean Survival Time (RMST) method may be 
conducted for OS to account for the possible non-proportional hazards effect.
9.6.1.2
Secondary Efficacy Analysis
Objective Response Rate (ORR)
Stratified Miettinen and Nurminen’s method will be used for comparison of the ORR 
between two treatment groups. The difference in ORR and its 95% confidence interval from 
the stratified Miettinen and Nurminen’s method with strata weighting by sample size will be 
reported. The stratification factors used for randomization (See Section 6.3.1.1) will be 
applied to the analysis. 
9.6.2
Statistical Analysis for Safety Analysis
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, laboratory tests, vital signs, and ECG measurements.
The analysis of safety results will follow a tiered approach (Table 9). The tiers differ with 
respect to the analyses that will be performed. AEs (specific terms as well as system organ 
class terms) and events that meet predefined limits of change (PDLCs) in laboratory values, 
vital signs and ECG parameters are either prespecified as “Tier 1” endpoints or will be 
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classified as belonging to “Tier 2” or “Tier 3” based on the observed proportions of 
participants with an event.
Tier 1 Events
Safety parameters that are identified a priori constitute “Tier 1” safety endpoints that will be 
subject to inferential testing for statistical significance with p-values and 95% confidence 
intervals provided for between-group comparisons. AEs of special interest (AEOSIs) that are 
immune-mediated or potentially immune-mediated are well documented and will be 
evaluated separately; however, these events have been characterized consistently throughout 
the pembrolizumab clinical development program and determination of statistical 
significance is not expected to add value to the safety evaluation. Further, the combination of 
pembrolizumab and lenvatinib has not been associated with any new safety signals.
Additionally, there are no known AEs associated with participants for which determination 
of a p-value is expected to impact the safety assessment. Therefore, there are no Tier 1 events 
in this study.
Tier 2 Events
Tier 2 parameters will be assessed via point estimates with 95% CIs provided for differences 
in the proportion of participants with events using the Miettinen and Nurminen method, an 
unconditional, asymptotic method [Miettinen, O. and Nurminen, M. 1985].
Membership in Tier 2 requires that at least 10% of participants in any treatment group exhibit 
the event; all other AEs and predefined limits of change will belong to Tier 3. The threshold 
of at least 10% of participants was chosen for Tier 2 events because the population enrolled 
in this study is in critical condition and usually experiences various AEs of similar types 
regardless of treatment; events reported less frequently than 10% of participants would
obscure the assessment of the overall safety profile and add little to the interpretation of 
potentially meaningful treatment differences. In addition, Grade 3 to 5 AEs (≥5% of 
participants in 1 of the treatment groups) and SAEs (≥1% of participants in 1 of the treatment 
groups) will be considered Tier 2 endpoints. Because many 95% CIs may be provided 
without adjustment for multiplicity, the CIs should be regarded as a helpful descriptive 
measure to be used in safety review, not as a formal method for assessing the statistical 
significance of the between-group differences.
Tier 3 Events
Safety endpoints that are not Tier 1 or 2 events are considered Tier 3 events. The broad AE 
categories consisting of the proportion of participants with any AE, a drug-related AE, a 
serious AE, an AE which is both drug-related and serious, a Grade 3-5 AE, a drug-related 
Grade 3-5 AE, and discontinuation due to an AE will be considered Tier 3 endpoints. Only 
point estimates by treatment group are provided for Tier 3 safety parameters.
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Table 9
Analysis Strategy for Safety Parameters
Safety 
Tier
Safety Endpoint
p-Value
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 2
Grade 3-5 AE (incidence ≥5% of participants in one of 
the treatment groups)
X
X
Serious AE (incidence ≥1% of participants in one of 
the treatment groups)
X
X
AEs (incidence ≥10% of participants in one of the 
treatment groups)
X
X
Tier 3
Any AE
X
Any Grade 3-5 AE
X
Any Serious AE 
X
Any Drug-Related AE
X
Any Serious and Drug-Related AE
X
Any Grade 3-5 and Drug-Related AE
X
Discontinuation due to AE
X
Death
X
Specific AEs, SOCs (incidence >0% of participants 
in all of the treatment groups)
X
Change from Baseline Results (lab toxicity shift,
vital signs)
X
Abbreviations: AE = adverse event; CI = confidence interval; SOC = system organ class.
9.6.3
Statistical Analysis for Health-Related Quality of Life Data
For HRQoL analyses, summary statistics of the scores for the derived functional/symptom 
scales according to the scoring manual and global health status scores will be summarized by 
treatment arm at each time point. A detailed prespecified HRQoL analysis plan following 
FDA and EMA PRO Guidelines will be described in a separate SAP. 
9.6.4
Summaries of Baseline Characteristics and Demographics
The comparability of the treatment groups for each relevant characteristic will be assessed by 
the use of tables and/or graphs. No statistical hypothesis tests will be performed on these 
characteristics. The number and percentage of participants screened, randomized, and the 
primary reason for screening failure, and the primary reason for discontinuation will be 
displayed. Demographic variables (eg, age, race, etc.) and baseline characteristics will be 
summarized by treatment either by descriptive statistics or categorical tables.
9.7
Interim Analyses
The safety monitoring and efficacy interim analyses will be conducted by the external DMC.
Minutes from the open meetings of the DMC will be provided if requested by regulatory 
agencies. The recommendation whether to stop the study will be reached by the DMC based 
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on their review of data with treatment information. The function and membership of the 
DMC will be described in the DMC charter.
9.7.1
Safety Interim Analyses
The external DMC will conduct regular safety monitoring. The timing of the safety 
monitoring will be specified in the DMC charter. 
9.7.2
Efficacy Interim Analyses
Two interim analyses are planned in addition to the final analysis for this study. The interim 
analyses will be performed by an independent unblinded statistician and programmer. Results 
of these analyses will be reviewed by the external DMC.
The PFS analysis will be performed only at the time of the first interim analysis of the study 
and this will be the final PFS analysis. OS analyses will be performed at the first interim, 
second interim, and final analysis. The Lan-DeMets spending function with O’Brien-Fleming 
boundary will be used for alpha allocation among the interim and final analyses of OS. 
Details of the boundaries for establishing statistical significance with regard to efficacy are 
discussed in Section 9.8. The analyses planned, endpoints evaluated, and drivers of timing 
are summarized in Table 10. 
Table 10
Summary of Interim and Final Analysis Strategy for the pMMR Participants
Analyses 
Key 
Endpoints 
Timing
Estimated Time 
after First 
Participant 
Randomized 
Primary Purpose of Analysis
IA1
PFS
OS
Both ~368 OS events 
and at least 6 months 
after last participant 
randomized
~27 months

Final PFS analysis

Interim OS analysis
IA2
OS
Both ~463 OS events 
and at least 12 months 
after last participant 
randomized
~35 months

Interim OS analysis
FA
OS
Both ~526 OS events 
and at least 18 months 
after last participant 
randomized †
~43 months †

Final OS analysis
Abbreviations: FA = final analysis; IA1 = interim analysis 1; IA2 = interim analysis 2; OS = overall survival; 
PFS = progression-free survival; pMMR = mismatch repair proficient.
†
Note that if events accrue slower than expected for the FA, the Sponsor may conduct the analysis up to 
3 months after the estimated timing of the FA (ie., ~46 months after first participant randomized).   
As described in Section 9.8, the PFS and OS analyses for the all-comer participants will be 
performed as listed in Table 10 if the respective analyses are successful in the pMMR 
participants.
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Following Amendment 08, the pre-planned IA2 is no longer required and will not be 
performed; further details are described in Section 9.1. 
9.8
Multiplicity
The total family-wise error rate (Type I error) among the 2 primary PFS and OS analyses, 
ORR analysis, and for pMMR and all-comer participants is strongly controlled at one-sided 
0.025 level. The multiplicity strategy will follow the graphical approach of Maurer and Bretz 
[Maurer, W. and Bretz, F. 2013]. Figure 3 shows the initial one-sided α-allocation for each 
hypothesis in the ellipse representing the hypothesis. The initial weights for reallocation from 
each hypothesis to the others are represented in the boxes on the lines connecting hypotheses. 
Figure 3
Multiplicity Graph for Type I Error Control of Study Hypotheses
Abbreviations: ORR = objective response rate; OS = overall survival; PFS = progression-free survival; 
pMMR = mismatch repair proficient.
The study initially allocates α = 0.0005, one-sided, to test PFS for pMMR participants and 
initially allocates α =0.0245, one-sided to test OS for pMMR participants between the two 
treatment arms. As shown in Figure 3, if the null hypothesis for PFS for pMMR is rejected, 
α = 0.0005 will be passed to the test for PFS for all-comer participants. And if the null 
hypothesis for PFS for all-comer participants is rejected, α = 0.0005 will be passed to the test 
for OS for pMMR, therefore OS for pMMR will be tested at α =0.025. The study will be 
considered positive if either testing of PFS or testing of OS is significant in pMMR 
participants.
Table 11 shows the bounds and boundary properties for OS hypothesis testing derived using 
a Lan-DeMets spending function approximating O’Brien-Fleming bounds. The bounds 
provided in the table assume that the expected number of OS events at IA1, IA2, and FA are 
368, 463, and 526, respectively. At the time of an analysis, the observed number of events 
may differ from the expected. To avoid overspending at an interim analysis and leave 
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reasonable alpha for the final analysis, the minimum alpha spending strategy will be adopted. 
At an IA, the information fraction used in Lan-DeMets spending function to determine the 
alpha spending at the IA will be based on the minimum of the expected information fraction 
and the actual information fraction at each analysis. Specifically:

In the scenario that the events accrue slower than expected and the observed number of 
events is less than the expected number of events at a given analysis, the information 
fraction will be calculated as the observed number of events at the interim analysis over 
the target number of events at FA.

In the scenario that the events accrue faster than expected and the observed number of 
events exceeds the expected number of events at a given analysis, the information 
fraction will be calculated as the expected number of events at the interim analysis over 
the target number of events at FA.
The final analysis will use the remaining Type I error that has not been spent at the earlier 
analyses. The observed event counts for all analyses will be used to compute correlations.
Of note, while the information fraction used for the alpha spending calculation will be the 
minimum of the actual information fraction and the expected information fraction, the 
correlations required for deriving the bounds will still be computed using the actual 
information fraction based on the observed number of events at each analysis over the target 
number of events at FA.
The minimum spending approach assumes timing is not based on any observed Z-value and 
thus the Z test statistics used for testing conditioned on timing are multivariate normal. Given 
the probabilities derived with the proposed spending method, the correlations based on actual 
event counts are used to compute bounds that control the Type I error at the specified alpha 
level for a given hypothesis conditioned on the interim analysis timing. Since this is true 
regardless of what is conditioned on, the overall Type I error for a given hypothesis 
unconditionally is controlled at the specified level. By using more conservative spending 
early in the study, power can be retained to detect situations where the treatment effect may 
be delayed.
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Table 11
Boundary Properties for Planned Analyses of OS Based on Potential Alpha-
Levels to be Used for Testing in the pMMR Participants
Analysis
Value
α =0.0245
α =0.025
IA1
N: 660
OS events: 368 (70%*)
Month: 27
Z
2.448
2.440
p (1-sided) †
0.0072
0.0073
HR at bound ‡
0.7747
0.7753
P(Cross) if HR=1 §
0.0072
0.0073
P(Cross) if HR=0.75 ǁ
0.6234
0.6259
IA2
N: 660
OS Events: 463 (88%*)
Month: 35
Z
2.187
2.178
p (1-sided) †
0.0144
0.0147
HR at bound ‡
0.8160
0.8167
P(Cross) if HR=1 §
0.0165
0.0169
P(Cross) if HR=0.75 ǁ
0.8260
0.8285
FA
N: 660
OS Events: 526
Month: 43
Z
2.069
2.061
p (1-sided) †
0.0193
0.0196
HR at bound ‡
0.8348
0.8355
P(Cross) if HR=1 §
0.0245
0.0250
P(Cross) if HR=0.75 ǁ
0.9009
0.9025
Abbreviation: HR = hazard ratio; IA= interim analysis; FA= final analysis.
The number of events and timings are estimated.
*
Percentage of total planned events at the interim analysis.
†
p (1-sided) is the nominal α for group sequential testing.
‡
HR at bound is the approximate observed HR required to reach an efficacy bound. 
§
P(Cross) if HR=1 is the probability of crossing a bound under the null hypothesis.
ǁ
P(Cross) if HR=0.75 is the probability of crossing a bound under the alternative hypothesis.
The study will continue if the interim OS analyses are not statistically significant. If the IA2 
or final OS analysis is statistically significant, ORR will be tested at the time of IA2 or final 
OS analysis using interim data (at IA1) to protect family-wise type I error rate.
Following Amendment 08, the pre-planned IA2 is no longer required and will not be 
performed; further details are described in Section 9.1. 
9.9
Sample Size and Power Calculations
The sample size is estimated based on the primary endpoints PFS and OS. A total of 
approximately 780 participants (including 660 participants from pMMR and 120 participants 
from dMMR participants) will be randomized in a 1:1 ratio (approximately 330 participants
from pMMR and 60 participants from dMMR participants in each treatment arm). 
The study will have been considered to have completed enrollment when 660 pMMR 
participants have enrolled. Enrollment of dMMR participants will be capped at 120.
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Sample size and power calculations are based on pMMR participants: 
The study is designed to have 90% power to detect a statistically significant difference in OS
at one-sided α=0.0245 and as a result, the study will also have at least 99% power to detect a 
statistical significant difference in PFS at one-sided α=0.0005.
Assuming an accrual period of 19 months and a follow-up period of 24 months, a total of 
660 participants are required to observe 526 death events by the time of 43 months after the 
first participant is randomized (19 months enrollment plus 24 months follow-up period).
For OS, a total of 526 OS events are required to detect a statistically significant difference at 
0.0245 level with 90% power, under the following assumptions that: 1) the hazard ratio is 
0.75 (median OS is 16.4 months in Arm A and 12.3 months in Arm B), 2) the first interim 
analysis is performed when approximately 368 OS events are observed (i.e. 70% of the total 
target death events), 3) the second interim analysis is performed when approximately 463 OS 
events are observed (i.e. 88% of the total target death events), and 4) Lan-DeMets spending 
function with O’Brien-Fleming boundary is used.
The final PFS analysis is planned to be performed at the time of the first OS interim analysis
(IA1) at 27 months after the first participant is randomized. A total of 564 PFS events are 
estimated to be observed to detect a statistically significant difference at 0.0005 level with 
>99% power under the assumption that the hazard ratio is 0.55 (median PFS is 7.3 months in 
Arm A and 4 months in Arm B).
Following Amendment 08, the pre-planned IA2 is no longer required and will not be 
performed; further details are described in Section 9.1. 
9.10
Subgroup Analyses
Both efficacy and safety may be analyzed for the following subgroups as appropriate. For 
efficacy endpoints, the hazard ratio and two-sided 95% confidence interval (CI) for 
comparing PFS as assessed by BICR and OS of Arm A vs. Arm B will be presented in forest 
plots for the subgroups. Median PFS and 95% CIs will be presented for all subgroups.
Similar plots will be provided for OS. For safety endpoints, all TEAEs, TEAEs of CTCAE 
Grades 3 and 4, and treatment-emergent SAEs will be summarized by the subgroups. 

Age group (<65 years vs. ≥65 years) 

Race (White, Asian, Other)

Geographic region (Region 1: Europe, USA, Canada, Australia, New Zealand, and 
Israel or Region 2: rest of the world)

MMR Status (pMMR, dMMR)
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.
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9.12
Extent of Exposure
The extent of exposure for lenvatinib will be summarized as duration of treatment in days. 
The extent of exposure for pembrolizumab will be summarized as duration of treatment in 
cycles. Dose interruption for each drug, dose reduction for lenvatinib will be summarized.
Summary statistics will be provided on Extent of Exposure for the APaT population.
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical and Study Oversight Considerations
Code of Conduct for Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
I.
Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing, and reporting these trials in 
compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design of clinical trials. In all cases, MSD clinical trials will be conducted in compliance 
with local and/or national regulations (e.g., International Council for Harmonisation Good Clinical Practice [ICH-
GCP]) and in accordance with the ethical principles that have their origin in the Declaration of Helsinki. 
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD irrespective of the party (parties) employed for their execution (e.g., contract research organizations, 
collaborative research efforts). This Code is not intended to apply to trials which 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. Participants must meet protocol entry criteria to be enrolled in the trial.
2. Site Selection
MSD selects investigative sites based on medical expertise, access to appropriate participants, adequacy of 
facilities and staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial
initiation, sites are evaluated by MSD personnel to assess the ability to successfully conduct the trial. 
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and general principles of Good 
Clinical Practice (GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data are verified 
versus source documentation according to standard operating procedures. Per MSD policies and procedures, if 
fraud, scientific/research misconduct or serious GCP-non-compliance is suspected, the issues are investigated. 
When necessary, the clinical site will be closed, the responsible regulatory authorities and ethics review 
committees notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the pre-specified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important to 
patients, physicians, and payers. Some early phase or pilot trials are intended to be hypothesis-generating rather than 
hypothesis testing; in such cases, publication of results may not be appropriate since the trial may be underpowered 
and the analyses complicated by statistical issues such as multiplicity.
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MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). In summary, authorship should reflect significant contribution to the design and 
conduct of the trial, performance or interpretation of the analysis, and/or writing of the manuscript. All named 
authors must be able to defend the trial results and conclusions. MSD funding of a trial will be acknowledged in 
publications.
III. Participant Protection
A. Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics Committee [IEC])
All clinical trials will be reviewed and approved by an IRB/IEC before being initiated at each site. Significant 
changes or revisions to the protocol will be approved by the ethics committee prior to implementation, except 
changes required urgently to protect participant safety that may be enacted in anticipation of ethics committee 
approval. For each site, the ethics committee and MSD will approve the participant informed consent form. 
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance. 
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At a 
minimum, trial designs will take into account the local standard of care. 
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Participants may withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible. Unless required by law, 
only the investigator, Sponsor (or representative), ethics committee, and/or regulatory authorities will have access to 
confidential medical records that might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD does not pay incentives to enroll 
participants in its trials. However, when enrollment is particularly challenging, additional payments may be made to 
compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent on 
chart review to identify potentially eligible participants.
B. Clinical Research Funding 
Informed consent forms will disclose that the trial is sponsored by MSD, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may wish 
to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As noted 
above, all publications resulting from MSD trials will indicate MSD as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices. 
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
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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 MSD'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 MSD in accordance with 21 CFR 
Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor or 
MSD 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 
MSD. The investigator/subinvestigator(s) also consent to the transmission of this information 
to the Sponsor or MSD in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
Data Protection
Participants will be assigned a unique identifier by MSD. Any participant records or datasets 
that are transferred to MSD will contain the identifier only; participant names or any 
information which 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 and MSD 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 MSD, by appropriate 
IRB/IEC members, and by inspectors from regulatory authorities.
Confidentiality of Data
By signing this protocol, the investigator affirms to MSD that information furnished to the 
investigator by MSD 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.
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor, MSD (or Sponsor or MSD 
representative), IRB/IEC, or regulatory authority representatives may consult and/or copy 
study documents in order 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 MSD.
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By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules 
and regulations.
Confidentiality of IRB/IEC Information
MSD is required to record the name and address of each IRB/IEC that reviews and approves 
this study. MSD is also required to document that each IRB/IEC meets regulatory and ICH 
GCP requirements by requesting and maintaining records of the names and qualifications of 
the IRB/IEC members and to make these records available for regulatory agency review 
upon request by those agencies.
Committees Structure
Scientific Advisory Committee
The Scientific Advisory Committee (SAC) is comprised of both Sponsor and non-Sponsor 
scientific experts who provide input with respect to study design, interpretation of study 
results and subsequent peer-reviewed scientific publications.
Joint Executive Oversight Committee
The Joint Executive Oversight Committee (EOC) is comprised of members of Sponsor and 
MSD Senior Management. The EOC will receive and decide upon any recommendations 
made by the DMC regarding the study.
Data Monitoring Committee
To supplement the routine study monitoring outlined in this protocol, an external DMC will 
monitor the interim data from this study. The voting members of the committee are external 
to the Sponsor and MSD. The members of the DMC must not be involved with the study in 
any other way (eg, they cannot be study investigators) and must have no competing interests 
that could affect their roles with respect to the study. 
The DMC will make recommendations to the EOC regarding steps to ensure both participant 
safety and the continued ethical integrity of the study. Also, the DMC will review interim 
study results, consider the overall risk and benefit to study participants (see Section 9.7) and 
recommend to the EOC whether the study should continue in accordance with the protocol.
Specific details regarding composition, responsibilities, and governance, including the roles 
and responsibilities of the various members and the Sponsor and MSD protocol team; 
meeting facilitation; the study governance structure; and requirements for and proper 
documentation of DMC reports, minutes, and recommendations will be described in the 
DMC charter that is reviewed and approved by all the DMC members.
Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
and MSD will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the Sponsor and MSD will generally support 
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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 and MSD, the investigator agrees to 
submit all manuscripts or abstracts to the Sponsor and MSD before submission. This allows 
the Sponsor and MSD 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.
Compliance with Study Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Amendments Act (FDAAA) of 2007 
and the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, the Sponsor 
of the study is solely responsible for determining whether the study and its results are subject 
to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries. MSD will review this protocol and 
submit the information necessary to fulfill these requirements. 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 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.
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of GCP
(eg, International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals for Human Use Good Clinical Practice: Consolidated Guideline and other 
generally accepted standards of GCP); and all applicable federal, state and local laws, rules 
and regulations relating to the conduct of the clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored or executed 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 MSD.
The investigator will promptly inform MSD of any regulatory authority inspection conducted 
for this study.
The investigator agrees to provide MSD with relevant information from inspection 
observations/findings to allow MSD to assist in responding to any citations resulting from 
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regulatory authority inspection, and will provide MSD 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 study. The investigator will 
immediately disclose in writing to MSD 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.
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to MSD or designee electronically (eg, laboratory data). The investigator or 
qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF. 
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
Study documentation will be promptly and fully disclosed to MSD 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 MSD or any regulatory 
authorities. The investigator agrees to promptly take any reasonable steps that are requested 
by MSD or any regulatory authorities as a result of an audit or inspection to cure deficiencies 
in the study documentation and worksheets/CRFs.
MSD or designee is responsible for the data management of this study including quality 
checking of the data. 
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements. 
Records and documents, including participants’ documented informed consent , pertaining to 
the conduct of this study must be retained by the investigator for 15 years after study 
completion unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written approval of 
MSD. No records may be transferred to another location or party without written notification 
to MSD. 
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Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on
the study. Also, current medical records must be available.
Study and Site Closure
MSD, in collaboration with 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 MSD prematurely terminates a particular study site, MSD will promptly notify 
that study site’s IRB/IEC.
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10.2
Appendix 2:  Contraceptive Guidance and Pregnancy Testing
Definitions 
Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below) 
Women in the following categories are not considered WOCBP:
●
Premenarchal
●
Premenopausal female with 1 of the following:
○
Documented hysterectomy
○
Documented bilateral salpingectomy
○
Documented bilateral oophorectomy
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
●
Postmenopausal female
○
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
▪
A high follicle stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormone replacement therapy (HRT). However, in the absence 
of menses for ≥12 months, 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.
Contraception Requirements
Female Participants
Female participants of childbearing potential are eligible to participate if they agree to use a 
highly effective method of contraception consistently and correctly as described in Table 12
during the protocol-defined time frame in Section 5.1. 
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Table 12
Highly Effective Contraception Methods
Highly Effective Contraceptive Methods That Are User Dependent a
Failure rate of <1% per year when used consistently and correctly.
●
Combined (estrogen- and progestogen-containing) hormonal contraception b, c
○
Oral 
○
Intravaginal 
○
Transdermal 
○
Injectable
●
Progestogen-only hormonal contraception b, c
○
Oral 
○
Injectable 
Highly Effective Methods That Have Low User Dependency 
Failure rate of <1% per year when used consistently and correctly.
●
Progestogen-only contraceptive implant b, c 
●
Intrauterine hormone-releasing system (IUS) b
●
Intrauterine device (IUD)
●
Bilateral tubal occlusion
●
Vasectomized partner 
A vasectomized partner 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. 
●
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 treatment. 
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.
Abbreviation: WOCBP = women of childbearing potential.
Notes: 
Use should be consistent with local regulations regarding the use of contraceptive methods for 
participants of clinical studies. 
a) Typical use failure rates are higher than perfect-use failure rates (ie, when used consistently and 
correctly). 
b) If hormonal contraception efficacy is potentially decreased due to interaction with study 
treatment, condoms must be used in addition to the hormonal contraception during the treatment 
period and for at least 120 days (for participants treated with lenvatinib plus pembrolizumab) or for 
at least 180 days (for participants treated with TPC)  after the last dose of study treatment.
c) If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, 
acceptable hormonal contraceptives are limited to those which inhibit ovulation. 
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Pregnancy Testing
WOCBP should only be included after a negative highly sensitive urine or serum pregnancy 
test. 
Following initiation of treatment additional pregnancy testing will be performed as indicated 
in Section 1.3 during the treatment period and at least every 30 days up to 120 days after the 
last dose of study treatment and as required locally. Refer to Appendix 9 for country-specific 
requirements.
Pregnancy testing will be performed whenever an expected menstrual cycle is missed or 
when pregnancy is otherwise suspected.
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
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 non-therapeutic 
effect.
Definition of AE
AE definition
●
An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study treatment, whether or not considered 
related to the study treatment.
●
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 treatment.
●
NOTE: for purposes of AE definition, study treatment includes any pharmaceutical 
product, biological product, vaccine, device, diagnostic agent or protocol specified 
procedure whether investigational (including placebo or active comparator product) or 
marketed, manufactured by, licensed by, provided by or distributed by the Sponsor or 
MSD for human use in this study.
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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, or are considered clinically significant in 
the medical and scientific judgment of the investigator.
●
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.
●
New conditions detected or diagnosed after study treatment 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 
treatment 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 
of study treatment without any associated clinical symptoms or abnormal laboratory 
results is reported using the terminology “accidental or intentional overdose without 
adverse effect.”
●
Any new cancer (that is not a condition of the study). 
Note: Progression of the cancer under study is not a reportable event. Refer to 
Section 8.4.5 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 8.4.5 for protocol specific exceptions
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Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met 
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b. Is life-threatening
●
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
●
Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not an SAE. A pre-existing condition is a clinical condition that is diagnosed 
prior to the use of study treatment and is documented in the patient’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) which 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 one 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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Additional Events Reported in the Same Manner as SAE
Additional events which 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 MSD in the same time frame as SAEs to meet 
certain local requirements. Therefore, these events are considered serious by MSD for 
collection purposes.
●
Is a new cancer (that is not a condition of the study);
●
Is associated with an overdose.
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 MSD in lieu of completion of the AE CRF page.
●
There may be instances when copies of medical records for certain cases are requested 
by MSD. 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 
MSD.
●
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.
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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 Common Terminology Criteria for 
Adverse Events (CTCAE), version 4.03. Any AE which changes CTCAE grade over 
the course of a given episode will have each change of grade recorded on the AE
CRFs/worksheets.
●
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated.
●
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (ADL).
●
Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care ADL.
●
Grade 4: Life threatening consequences; urgent intervention indicated.
●
Grade 5: Death related to AE.
Assessment of causality
●
Did the study treatment cause the AE?
●
The determination of the likelihood that study treatment 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 
study treatment 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 study 
treatment 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 study treatment? Is the time of onset of the AE compatible 
with a drug-induced effect (applies to studies with investigational medicinal 
product)?
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●
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
●
Dechallenge: Was study treatment 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 
study treatment; (3) the study is a single-dose drug study; or (4) study 
treatment(s) is/are only used one time.)
●
Rechallenge:  Was the participant re-exposed to study treatment 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) study 
treatment(s) is/are used only one time.)
NOTE:  IF A RECHALLENGE IS PLANNED FOR AN AE WHICH WAS SERIOUS 
AND WHICH MAY HAVE BEEN CAUSED BY STUDY TREATMENT, OR IF RE-
EXPOSURE TO STUDY TREATMENT POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE 
APPROVED IN ADVANCE BY THE MSD CLINICAL DIRECTOR AS PER DOSE 
MODIFICATION GUIDELINES IN THE PROTOCOL, AND IF REQUIRED, THE 
INIRB/IEC.
●
Consistency with Study treatment Profile:Is the clinical/pathological 
presentation of the AE consistent with previous knowledge regarding the study 
treatment or drug class pharmacology or toxicology?
●
The assessment of relationship will be reported on the CRFs/worksheets by an 
investigator who is a qualified physician according to his/her best clinical judgment, 
including consideration of the above elements.
●
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a study treatment relationship).
●
Yes, there is a reasonable possibility of study treatment relationship:
There is evidence of exposure to study treatment product. The temporal sequence 
of the AE onset relative to the administration of study treatment is reasonable. The 
AE is more likely explained by study treatment than by another cause. 
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●
No, there is not a reasonable possibility of study treatment relationship:
Participant did not receive study treatment OR temporal sequence of the AE onset 
relative to administration of study treatment is not reasonable OR the AE is more 
likely explained by another cause than study treatment. (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 MSD. 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 MSD.
●
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 one of the criteria used when determining regulatory 
reporting requirements
●
For studies in which multiple agents are administered as part of a combination 
regimen, the investigator may attribute each AE causality to the combination regimen 
or to a single agent of the combination. In general, causality attribution should be 
assigned to the combination regimen (ie, to all agents in the regimen). However, 
causality attribution may be assigned to a single agent if in the investigator’s opinion, 
there is sufficient data to support full attribution of the AE to the single agent.
Follow-up of AE and SAE
●
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested MSD 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 MSD within 24 hours of receipt 
of the information.
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Reporting of AEs, SAEs, and Other Reportable Safety Events to MSD
AE, SAE, and other reportable safety event reporting to MSD via electronic data 
collection tool
●
The primary mechanism for reporting to MSD will be the electronic data collection 
(EDC) tool. 
●
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
●
If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper AE Reporting form. 
●
Reference Section 8.4.1 for reporting time requirements 
●
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
●
After the study is completed at a given site, the EDC tool will be taken off-line to 
prevent the entry of new data or changes to existing data.
●
If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the EDC tool has been taken off-line, then the 
site can report this information on a paper SAE form or by telephone (see next section).
●
Contacts for SAE reporting can be found in the Investigator Trial File Binder (or 
equivalent).
SAE reporting to MSD 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 MSD.
●
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
●
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
●
Contacts and instructions for SAE reporting and paper reporting procedures can be 
found in the Investigator Trial File Binder (or equivalent).
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10.4
Appendix 4: Clinical Laboratory Tests

The tests detailed in Table 13 will be performed by the local laboratory. 

Protocol-specific requirements for inclusion or exclusion of participants are detailed 
in Section 5.1 and Section 5.2 of the protocol.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.
Table 13
Protocol-required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count 
WBC count with Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Chemistry
Carbon dioxide (CO2
or bicarbonate)a
Calcium
Chloride
Magnesium
Phosphorus
Potassium
Sodium
Alanine 
aminotransferase 
(ALT) / Serum 
Glutamic Pyruvic 
Transaminase (SGPT)
Aspartate 
aminotransferase 
(AST) / Serum 
Glutamic Oxaloacetic 
Transaminase (SGOT)
Alkaline phosphatase
Total bilirubin (and 
direct bilirubin if 
total bilirubin is 
elevated above the 
upper limit of 
normal)
Blood urea nitrogen or 
ureab
Creatinine
Thyroid stimulating 
hormonec
Free thyroxine 
(FT4)c
Albumin
Cholesterol
Glucose 
Lactate 
dehydrogenase
Total protein
Triglycerides
Amylase
Lipased
CPKe
Pregnancy test
Triiodothyronine (T3)c
Urinalysis/Urine 
dipstick testingf

Specific gravity

Glucose, hemoglobin or blood, ketones, pH, proteing, by dipstick
Other Tests

PT/INR and aPTT/PTTh

Serology (HIV antibody, hepatitis B surface antigen [HBsAg], and hepatitis C virus antibody)] 
if required by local health authority. Refer to Appendix 9 for country-specific requirements.
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Laboratory 
Assessments
Parameters
Abbreviations: aPTT = activated partial thromboplastin time; CPK = creatine phosphokinase; HIV = human 
immunodeficiency virus; INR = international normalized ratio; PT = Prothrombin Time; RBC = red blood cell; 
TSH = thyroid-stimulating hormone; WBC = white blood cell.
NOTES:
a.
Performed only if considered local standard of care.
b.
Blood urea nitrogen is preferred; if not available, urea may be tested.
c.
Free T4, T3, and TSH levels will be performed during screening and then repeated on Day 1 of every other cycle 
(starting with Cycle 2), at the time of discontinuation (End of Treatment), and at the Safety-Follow-up visit. Free T3 
is acceptable where T3 cannot be determined. There may be instances when sites are unable to obtain the thyroid 
function testing results prior to scheduled dosing. After Cycle 1, review of thyroid function test results after dosing 
is acceptable.
d.
After Cycle 1, retrospective review of lipase results is allowed when the results are not available prior to dosing.
e.
CPK isoenzymes (CK-MM and CK-MB) should be evaluated if CPK is greater than 3 × ULN.
f.
If urine dipstick testing suggests a urinary tract infection, or if clinically indicated, a urine microscopy, culture, and 
sensitivity should be performed at the institution’s laboratory.
g.
If urine protein is ≥2+ (first occurrence or a subsequent increase in severity of urine dipstick proteinuria occurring 
on the same lenvatinib dose level), then a 24-hour urine collection should be done to quantify the 24-hour urine 
protein excretion.
h.
Performed as part of the screening assessment and as clinically indicated for participants taking anticoagulation 
therapy.
Investigators must document their review of each laboratory safety report.
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10.5
Appendix 5:  Description of the iRECIST Process for Assessment of Disease 
Progression
Assessment at Screening and Prior to RECIST 1.1 Progression
Until radiographic disease progression based on RECIST 1.1, there is no distinct iRECIST 
assessment.
Assessment and Decision at RECIST 1.1 Progression
For participants who show evidence of radiological PD by RECIST 1.1 as determined by the 
Investigator, the Investigator will decide whether to continue a participant on study treatment 
until repeat imaging is obtained (using iRECIST for participant management) (see Table 6
and Figure 2). This decision by the Investigator should be based on the participant’s overall 
clinical condition.
Clinical stability is defined as the following: 

Absence of symptoms and signs indicating clinically significant progression of
disease

No decline in ECOG performance status 

No requirements for intensified management, including increased analgesia, 
radiation, or other palliative care
Any participant deemed clinically unstable should be discontinued from study treatment at 
site-assessed first radiologic evidence of PD, and is not required to have repeat tumor 
imaging for confirmation of PD by iRECIST.
If the Investigator decides to continue treatment, the participant may continue to receive 
study treatment and the tumor assessment should be repeated 4 to 8 weeks later to confirm 
PD by iRECIST, per Investigator assessment. Images should continue to be sent into the 
central imaging vendor for potential retrospective BICR.
Tumor flare may manifest as any factor causing radiographic progression per RECIST 1.1, 
including:

Increase in the sum of diameters of target lesion(s) identified at baseline to ≥20% and 
≥5 mm from nadir
o
Note: the iRECIST publication uses the terminology “sum of measurements”, but 
“sum of diameters” will be used in this protocol, consistent with the original 
RECIST 1.1 terminology.

Unequivocal progression of non-target lesion(s) identified at baseline

Development of new lesion(s)
iRECIST defines new response categories, including iUPD (unconfirmed progressive 
disease) and iCPD (confirmed progressive disease). For purposes of iRECIST assessment, 
the first visit showing progression according to RECIST 1.1 will be assigned a visit (overall) 
response of iUPD, regardless of which factors caused the progression.
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At this visit, target and non-target lesions identified at baseline by RECIST 1.1 will be 
assessed as usual.
New lesions will be classified as measurable or non-measurable, using the same size 
thresholds and rules as for baseline lesion assessment in RECIST 1.1. From measurable new 
lesions, up to 5 lesions total (up to 2 per organ), may be selected as New Lesions – Target.
The sum of diameters of these lesions will be calculated, and kept distinct from the sum of 
diameters for target lesions at baseline. All other new lesions will be followed qualitatively 
as New Lesions – Non-target.
Assessment at the Confirmatory Imaging
On the confirmatory imaging, the participant will be classified as progression confirmed 
(with an overall response of iCPD), or as showing persistent unconfirmed progression (with 
an overall response of iUPD), or as showing disease stability or response (iSD/iPR/iCR).
Confirmation of Progression
Progression is considered confirmed, and the overall response will be iCPD, if ANY of the 
following occurs:

Any of the factors that were the basis for the iUPD at the previous visit show 
worsening
o
For target lesions, worsening is a further increase in the sum of diameters of 
≥5 mm, compared to any prior iUPD time point
o
For non-target lesions, worsening is any significant growth in lesions overall, 
compared to a prior iUPD time point; this does not have to meet the 
“unequivocal” standard of RECIST 1.1
o
For new lesions, worsening is any of these:

An increase in the new lesion sum of diameters by ≥5 mm from a prior iUPD 
time point 

Visible growth of new non-target lesions 

The appearance of additional new lesions

Any new factor appears that would have triggered PD by RECIST 1.1
Persistent iUPD
Progression is considered not confirmed, and the overall response remains iUPD, if:

None of the progression-confirming factors identified above occurs AND

The target lesion sum of diameters (initial target lesions) remains above the initial PD 
threshold (by RECIST 1.1)
Additional imaging for confirmation should be scheduled 4 to 8 weeks from the imaging on 
which iUPD is seen. This may correspond to the next visit in the original visit schedule. The 
assessment of the subsequent confirmation imaging proceeds in an identical manner, with 
possible outcomes of iCPD, iUPD, and iSD/iPR/iCR.
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Resolution of iUPD
Progression is considered not confirmed, and the overall response becomes iSD/iPR/iCR, if:

None of the progression-confirming factors identified above occurs, AND

The target lesion sum of diameters (initial target lesions) is not above the PD 
threshold. 
The response is classified as iSD or iPR (depending on the sum of diameters of the target 
lesions), or iCR if all lesions resolve.
In this case, the initial iUPD is considered to be pseudo-progression, and the level of 
suspicion for progression is “reset”. This means that the next visit that shows radiographic 
progression, whenever it occurs, is again classified as iUPD by iRECIST, and the 
confirmation process is repeated before a response of iCPD can be assigned.
Management Following the Confirmatory Imaging
If repeat imaging does not confirm PD per iRECIST, as assessed by the Investigator, and the 
participant continues to be clinically stable, study treatment may continue and follow the 
regular imaging schedule. If PD is confirmed, participants will be discontinued from study 
treatment.
NOTE: If a participant has confirmed radiographic progression (iCPD) as defined above, but 
the participant is achieving a clinically meaningful benefit or if RECIST 1.1 PD has not been 
verified centrally, an exception to continue study treatment may be considered following 
consultation with MSD. In this case, if study treatment is continued, tumor imaging should 
continue to be performed following the intervals as outlined in Section 1.3 and submitted to 
the central imaging vendor.
Detection of Progression at Visits After Pseudo-progression Resolves
After resolution of pseudo-progression (ie, achievement of iSD/iPR/iCR), iUPD is indicated
by any of the following events:

Target lesions
o
Sum of diameters reaches the PD threshold (≥20% and ≥5 mm increase from 
nadir) either for the first time, or after resolution of previous pseudo-progression. 
The nadir is always the smallest sum of diameters seen during the entire study, 
either before or after an instance of pseudo-progression.

Non-target lesions
o
If non-target lesions have never shown unequivocal progression, their doing so for 
the first time results in iUPD.
o
If non-target lesions have shown previous unequivocal progression, and this 
progression has not resolved, iUPD results from any significant further growth of 
non-target lesions, taken as a whole.
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
New lesions
o
New lesions appear for the first time
o
Additional new lesions appear
o
Previously identified new target lesions show an increase of ≥5 mm in the new 
lesion sum of diameters, from the nadir value of that sum
o
Previously identified non-target lesions show any significant growth
If any of the events above occur, the overall response for that visit is iUPD, and the iUPD 
evaluation process (see Assessment at the Confirmatory Imaging above) is repeated. 
Progression must be confirmed before iCPD can occur.
The decision process is identical to the iUPD confirmation process for the initial PD, with 
one exception: if new lesions occurred at a prior instance of iUPD, and at the confirmatory 
imaging the burden of new lesions has increased from its smallest value (for new target 
lesions, the sum of diameters is ≥5 mm increased from its nadir), then iUPD cannot resolve 
to iSD or iPR. It will remain iUPD until either a decrease in the new lesion burden allows 
resolution to iSD or iPR, or until a confirmatory factor causes iCPD.
Additional details about iRECIST are provided in the iRECIST publication [Seymour, L., et 
al 2017].
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10.6
Appendix 6:  Abbreviations
Abbreviation
Term
AE
Adverse event
AEOSI
Adverse event of special interest
ALT
Alanine aminotransferase
APaT
All Participants as Treated
AST
Aspartate aminotransferase
AUC
Area under the concentration-time curve
BCG
Bacillus Calmette–Guérin
β-hCG
beta-human chorionic gonadotropin
BICR
Blinded independent central review
BP
Blood pressure
C1D1
Cycle 1 Day 1
CBR
Clinical benefit rate (CR + PR + durable SD ≥23 weeks)
CD
Cluster of differentiation
CI
Confidence interval
CIV
Central Imaging Vendor
CNS
Central nervous system
CR
Complete response
CRF
Case report form
CRO
Contract research organization
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTLA4
Cytotoxic T-lymphocyte-associated protein 4
CYP
Cytochrome P450
DCR
Disease control rate
DLT
Dose-limiting toxicity
DMC
Data monitoring committee
dMMR
Mismatch repair deficient
DOR
Duration of response
EC
Endometrial cancer
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Abbreviation
Term
ECG
Electrocardiogram
ECHO
Echocardiogram
ECOG
Eastern Cooperative Oncology Group
EEA
European Economic Area
ELISA
Enzyme-linked immunosorbent assay
EOC
Executive Oversight Committee
EORTC
European Organisation for the Research and Treatment of 
Cancer
EuroQoL
European Quality of Life
FAS
FDA
Full Analysis Set
Food and Drug Administration
FGF
Fibroblast growth factor
FGFR
Fibroblast growth factor receptor
FIGO
International Federation of Gynecology and Obstetrics
FSR
First Site Ready
GCP
Good Clinical Practice
HCC
Hepatocellular carcinoma
HIV
Human immunodeficiency virus
HRQoL
Health-Related Quality of Life
HUVEC
Human umbilical vein endothelial cell
IB
Investigator’s Brochure
ICF
Informed consent form
ICH
International Council for Harmonization 
iCPD
iRECIST confirmed progressive disease
IEC
Independent Ethics Committee
Ig
Immunoglobulin
IHC
Immunohistochemistry
INR
International normalized ratio 
iPD
Immune-related progressive disease
IRB
Institutional Review Board
iRECIST
Modified Response Evaluation Criteria in Solid Tumors 1.1 for 
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Abbreviation
Term
immune-based therapeutics
IRR
Independent radiologic review
irRECIST
Immune-related Response Evaluation Criteria in Solid Tumors
IRT
Interactive response technology
ITT
Intention-to-treat 
IV
Intravenous(ly)
Ki
Inhibitory constant
LMWH
Low molecular weight heparin
LN
Lymph node
LVEF
Left ventricular ejection fraction
mAb
Monoclonal antibody
MAPK
Mitogen activated protein kinase
mm Hg
Millimeters of mercury
MMR
Mismatch repair
mRECIST
Modified Response Evaluation Criteria in Solid Tumors
MRI
Magnetic Resonance Imaging
MSI-H
Microsatellite instability-high
MTD
Maximum tolerated dose
mTOR
Mammalian target of rapamycin
MUGA
Multigated acquisition scan
NCI
National Cancer Institute
NSAID
Nonsteroidal anti-inflammatory drug
NSCLC
Non–small cell lung cancer
NYHA
New York Heart Association
ORR
Objective response rate
OS
Overall survival
PBPK
Physiologically-based pharmacokinetic
PCL
Protocol Clarification Letter
PD
Progressive disease
PD-1
Programmed cell death 1
PD-L1
Programmed cell death ligand 1
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Abbreviation
Term
PD-L2
Programmed cell death ligand 2
PDGF
Platelet-derived growth factor
PFS
Progression-free survival
PFS2
PFS on next line therapy
PK
Pharmacokinetic
pMMR
Mismatch repair proficient
PO
Orally
PR
Partial response
PRES/RPLS
Posterior reversible encephalopathy syndrome/reversible 
posterior leukoencephalopathy syndrome
Q2W
Every 2 weeks
Q3W
Every 3 weeks
QD
Once daily
QLQ-C30
Quality of life Questionnaire C30
QoL
Quality of life
RAG
Recombination activation gene
RBC
Red blood cell
RCC
Renal cell carcinoma
RECIST
Response Evaluation Criteria In Solid Tumors
RMST
Restricted Mean Survival Time
RP2D
Recommended Phase 2 dose
RTK
Receptor tyrosine kinase
S6K
S6 kinase
SAE
Serious adverse event
SAP
Statistical analysis plan
SD
Stable disease
SoA
Schedule of Activities
SOC
System Organ Class
SUSAR
Suspected unexpected serious adverse reactions
TAM
Tumor associated macrophage
TEAE
Treatment-emergent adverse event
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Abbreviation
Term
TPC
Treatment of physician’s choice
ULN
Upper limit of normal
UPCR
Urine protein-to-creatinine ratio
VEGF
Vascular endothelial growth factor
VEGFR
Vascular endothelial growth factor receptor
WBRT
whole brain radiation therapy
WOCBP
Woman of childbearing potential
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10.7
Appendix 7:  Carcinoma of the Endometrium – FIGO Staging
Stage I*
Tumor confined to the corpus uteri
IA*
No or less than half myometrial invasion
IB*
Invasion equal to or more than half of the myometrium
Stage II*
Tumor invades cervical stroma but does not extend beyond the 
uterus**
Stage III*
Local and/or regional spread of the tumor
IIIA*
Tumor invades the serosa of the corpus uteri and/or adnexa†
IIIB*
Vaginal and/or parametrial involvement†
IIIC*
Metastases to the pelvic and/or para-aortic lymph nodes†
IIIC1*
Positive pelvic nodes
IIIC2*
Positive para-aortic lymph nodes with or without positive pelvic 
lymph nodes
Stage IV*
Tumor invades bladder and/or bowel mucosa and/or distant 
metastases
IVA*
Tumor invades the bladder and/or bowel mucosa
IVB*
Distant metastases, including intra-abdominal metastases and/or 
inguinal lymph nodes
*
Either Grade 1, Grade 2, or Grade 3.
**
Endocervical glandular involvement only should be considered as Stage I and no longer as Stage II.
†
Positive cytology has to be reported separately without changing the stage.
Adapted from Pecorelli S; for the FIGO Committee on Gynecologic Oncology. Int J Gynaecol Obstet. 2009;105(2):103-4
[Pecorelli, S. 2009].
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10.8
Appendix 8:  New York Heart Association Cardiac Disease Classification
The New York Heart Association (NYHA) Cardiac Disease Classification provides a 
functional and therapeutic classification for the prescription of physical activity for cardiac 
participants. On the basis of NYHA definitions, participants are to be classified as follows:
Class
Definition
Class I
Participants with no limitation of activities; they suffer no symptoms from 
ordinary activities.
Class II
Participants with slight, mild limitation of activity; they are comfortable 
with rest or with mild exertion.
Class III
Participants with marked limitation of activity; they are comfortable only at 
rest.
Class IV
Participants who should be at complete rest, confined to bed or chair; any 
physical activity brings on discomfort and symptoms occur at rest.
Adapted from The Criteria Committee of the New York Heart Association, 1994 [Dolgin, M., et al 1994] 
[Dolgin, M., et al 1994].
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10.9
Appendix 9: Country-specific Requirements
Pregnancy Testing
While the protocol allows for more frequent pregnancy testing per the discretion of the 
investigator, sites should also check with their local health authority to inquire if country-
specific guidance regarding the frequency of pregnancy testing is required.
HIV Status
While the protocol does not require specific testing for HIV at Screening, it does require 
testing if required by the local health authority. Sites should check with their local health 
authority to inquire if country-specific guidance regarding mandatory HIV testing at 
Screening is required. This can also be performed per the discretion of the investigator, if 
desired.
Hepatitis B/C Status
While the protocol does not require specific testing for hepatitis B/C at Screening, it does 
require testing if required by the local health authority. Sites should check with their local 
health authority to inquire if country-specific guidance regarding mandatory hepatitis B/C 
testing at Screening is required. This can also be performed per the discretion of the 
investigator, if desired.
10.9.1
Germany
HIV testing and hepatitis B/C screening are required evaluations for study entry and need to 
be performed in order to evaluate eligibility. This testing can be performed at any time during 
the Screening period.
A pregnancy test will be performed as indicated in the SoA and at least every 30 days up to 
120 days post last dose of study medication or the start of a new anticancer therapy, 
whichever comes first. A pregnancy test is also required at the time of discontinuation (End 
of Treatment visit).
10.9.2
United Kingdom
HIV testing and hepatitis B/C screening are required evaluations for study entry and need to 
be performed in order to evaluate eligibility. This testing can be performed at any time during 
the Screening period.
Live vaccines must not be administered for 90 days after the last dose of study intervention. 
Refer to Section 6.5 for information on COVID-19 vaccines.
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10.9.3
Japan
Per Protocol Clarification Letter dated 15-SEP-2021, due to requirement of Japanese 
regulations, changes were made after marketing approval of pembrolizumab and lenvatinib. 
The terms, “post- marketing clinical trial,” as well as “post-marketing clinical trial drug” will 
be used as the study continues. All applicable laws, rules, and regulations include 
Japan-specific local regulation, Good Post-Marketing Study Practice in Japan.
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11
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