Conditions: Endometrial Neoplasms
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 130
Healthy volunteers: no

Brief summary:
The purpose of this study is to compare the efficacy of pembrolizumab + lenvatinib to chemotherapy in female participants with Stage III, IV, or recurrent endometrial carcinoma. It is hypothesized that the combination of pembrolizumab + lenvatinib will be superior to chemotherapy for progression-free survival (PFS) per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST 1.1) by blinded independent central review (BICR). It is also hypothesized that the combination of pembrolizumab + lenvatinib will be superior to chemotherapy for overall survival (OS).

As of Amendment 7 eligible participants on study completion will be able to transition to an extension study, if available, in which they can continue to receive pembrolizumab monotherapy, lenvatinib monotherapy, or a combination of both pembrolizumab and lenvatinib as received in the parent study.

Detailed description:
This China extension study will include participants previously enrolled in China in the global study for MK-7902-001 (NCT03884101) plus those enrolled during the China extension enrollment period.

Arms:
arm 1: Participants receive lenvatinib daily and pembrolizumab once at the start of each 3-week treatment cycle. arm 2: Participants receive paclitaxel and carboplatin once at the start of each 3-week treatment cycle.

Interventions: intervention 1: Lenvatinib intervention 2: Pembrolizumab intervention 3: Paclitaxel intervention 4: Carboplatin
Intervention descriptions: intervention 1: Lenvatinib 4 mg or 10 mg capsules at a total daily dose of 20 mg taken by mouth once per day. intervention 2: Pembrolizumab 200 mg IV infusion given on Day 1 of each cycle. intervention 3: Paclitaxel 175 mg/m\^2 IV infusion given on Day 1 of each cycle. intervention 4: Carboplatin 10 mg/mL IV infusion at a total dose of are-under-the-curve (AUC) 6 (per Calvert's formula) given on Day 1 of each cycle.

Protocol document:
Prot_SAP_000.pdf: 
Official Protocol Title:
NCT number:
Document Date:
A Phase 3 Randomized, Open-Label, Study of 
Pembrolizumab (MK-3475) Plus Lenvatinib (E7080/MK-7902) 
Versus Chemotherapy for First-line Treatment of Advanced 
or Recurrent Endometrial Carcinoma (LEAP-001)
NCT04865289
13-FEBRUARY-2024


PRODUCT: MK-7902
1
PROTOCOL/AMENDMENT NO.: MK-7902-001-07 (E7080-G000-313; ENGOT-EN9)
MK-7902-001-07 FINAL PROTOCOL
13-FEB-2024
Title Page
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME LLC, RAHWAY, NJ, USA (MSD).
Protocol Title: A Phase 3 Randomized, Open-Label, Study of Pembrolizumab (MK-3475) 
Plus Lenvatinib (E7080/MK-7902) Versus Chemotherapy for First-line Treatment of 
Advanced or Recurrent Endometrial Carcinoma (LEAP-001)
Protocol Number: 001-07 (E7080-G000-313; ENGOT-EN9)
Compound Number: MK-7902 (E7080/lenvatinib) and MK-3475 (pembrolizumab)
Sponsor Name:
Merck Sharp & Dohme LLC
(hereafter referred to as the Sponsor or MSD)
The study is co-funded by MSD and Eisai.
Legal Registered Address:
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Regulatory Agency Identifying Number(s):
IND
EU CT
EudraCT
139875
2023-505614-17
2018-003009-24
Approval Date: 13 February 2024
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PROTOCOL/AMENDMENT NO.: MK-7902-001-07 (E7080-G000-313; ENGOT-EN9)
MK-7902-001-07 FINAL PROTOCOL
13-FEB-2024
Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study 
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date:
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PRODUCT: MK-7902
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PROTOCOL/AMENDMENT NO.:  MK-7902-001-07 (E7080-G000-313; ENGOT-EN9)
MK-7902-001-07 FINAL PROTOCOL
13-FEB-2024
DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 7
13-FEB-2024
To allow eligible participants on study completion to transition to an extension study in 
which they can continue to receive pembrolizumab monotherapy, lenvatinib 
monotherapy, or a combination of both pembrolizumab and lenvatinib as received in the 
parent study. 
Amendment 6
08-JUL-2022
Merck Sharp & Dohme Corp. underwent an entity name and address change to Merck 
Sharp & Dohme LLC, Rahway, NJ, USA. This conversion resulted only in an entity 
name change and update to the address.
Amendment 5
17-MAR-2021
To increase the number of participants in the study from approximately 720 to 
approximately 875.
Amendment 4
15-APR-2020
To expand the participant population to include participants who have received adjuvant 
or neoadjuvant chemotherapy.
Amendment 3
09-DEC-2019
To include protocol eligibility assessment requirements specific to Germany.
Amendment 2
31-MAY-2019
To include justification for overall survival (OS) non-inferiority margin in response to a 
request from the European Medicines Agency’s Committee for Medicinal Products for 
Human Use and to provide clarification and program alignment.
Amendment 1
30-JAN-2019
The FDA requested discontinuation from study intervention of participants meeting 
criteria for elevated liver enzymes.
Original Protocol 
19-NOV-2018
Not applicable.
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 07
Overall Rationale for the Amendment:
To allow eligible participants on study completion to transition to an extension study in 
which they can continue to receive pembrolizumab monotherapy, lenvatinib monotherapy, or 
a combination of both pembrolizumab and lenvatinib as received in the parent study. 
Summary of Changes Table
Section Number 
and Name
Description of Change
Brief Rationale
Primary Reason for Amendment
4.4 Beginning and 
End of Study 
Definition
Added text to indicate that upon study 
completion, eligible participants may be enrolled 
in an extension study in which they are 
administered pembrolizumab monotherapy, 
lenvatinib monotherapy, or a combination of both 
pembrolizumab and lenvatinib as received in the 
parent study.
This change was made to address a study 
extension. On study completion, it enables
eligible participants to transition to an 
extension study in which they can continue 
to receive pembrolizumab monotherapy, 
lenvatinib monotherapy, or a combination 
of both pembrolizumab and lenvatinib as 
received in the parent study. 
Additional Changes
1.3.1 Schedule of 
Activities – Initial 
Treatment Phase
Moved chemistry, hematology, and urinalysis 
panel assessments from Cycle 2 Day 8 to Cycle 2 
Day 15.
To remove a typographical error indicating 
chemistry, hematology, and urinalysis 
panels should be performed on Cycle 2 Day 
8 (which is a telephone contact) instead of 
Cycle 2 Day 15.
Added a note to indicate that the collection of 
Blood for Plasma Biomarker Samples will be 
discontinued following the implementation of 
Amendment 07.
Sufficient PRO, plasma biomarker, and 
circulating tumor nucleic acid data have 
been collected for analysis for >2 years 
beyond the last participant enrolled, and 
further data is not needed.
Added a note to indicate that the collection of 
Blood for circulating tumor nucleic acids will be 
discontinued following the implementation of 
Amendment 07.
Refer to Section 1.3.1 rationale (removal of 
biomarker samples).
Added a note to indicate that the collection of 
PRO data will be discontinued following the 
implementation of Amendment 07.
Refer to Section 1.3.1 rationale (removal of 
biomarker samples).
4.4 Beginning and 
End of Study 
Definition
Added text to define the local start of study in 
EEA.
Revision to align with the EU Clinical Trial 
Regulation No. 536/2014 of the European 
Parliament and of the Council.
5 Study Population
Added text to indicate that the collection and use 
of demographic data will adhere to local laws 
and participant confidentiality guidelines, while 
supporting the study of the disease, its associated 
factors, and the investigated IMP.
Refer to Section 4.4 rationale (EU CTR).
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Section Number 
and Name
Description of Change
Brief Rationale
5.1 Inclusion Criteria
Removed a note from Table 3 indicating that 
laboratory value requirements for treatment 
eligibility should be adjusted based on local 
regulations and guidelines for administering 
specific chemotherapies.
Refer to Section 4.4 rationale (EU CTR).
6.5.2 Prohibited 
Concomitant 
Medications
Added text to indicate that systemic 
glucocorticoids restrictions apply to participants 
in the lenvatinib plus pembrolizumab arm.
Removed the restriction on systemic 
glucocorticoids for any purpose other than 
symptom modulation in suspected immunologic 
etiology AE.
The description prohibiting systemic 
glucocorticoids is listed twice consecutively 
without specifying its application to 
participants in the lenvatinib plus 
pembrolizumab arm.
This allows to clarify that the prohibition of 
systemic glucocorticoids applies only to the 
pembrolizumab plus lenvatinib arm and to 
remove redundant language referring to 
allowable systemic glucocorticoid use.
6.6.5 Second Course 
Phase (Retreatment 
Period)
Modified the eligibility for the second course 
phase from BICR-determined to investigator-
determined radiographic disease progress.
Sufficient centrally confirmed radiographic 
progression data has been collected for 
analysis for >2 years beyond the last 
participant enrolled and further BICR data 
is not needed for participants to be eligible 
for second course.
6.7 Intervention 
After the End of the 
Study
Modified text to indicate that upon study 
completion, participants may be enrolled in an 
extension study in which they are administered 
pembrolizumab, lenvatinib, or both lenvatinib 
and pembrolizumab.
Refer to rationale for primary reason for 
amendment.
8.2.1.5 RECIST 1.1 
Assessment of 
Disease
Added text to indicate that if disease progression 
is not verified and the participant is clinically 
stable, then the study intervention can be 
continued per protocol at investigator discretion.
Removed text indicating that communication 
with the Sponsor is required before stopping 
study intervention or imaging or starting a new 
anticancer therapy in a participant who is 
clinically stable.
Sufficient centrally confirmed radiographic 
progression data has been collected for 
analysis for >2 years beyond the last 
participant enrolled, and Sponsor 
consultation is no longer needed before 
participants discontinue.
8.4 Adverse Events
(AEs), Serious 
Adverse Events
(SAEs), and Other 
Reportable Safety 
Events
Added text that investigators need to document if 
an SAE was associated with a medication error, 
misuse, or abuse.
Refer to Section 4.4 rationale (EU CTR).
8.4.1 Time Period 
and Frequency for 
Collecting AE, SAE, 
and Other Reportable 
Safety Event 
Information
Added text to clarify that from parent study 
randomization to extension study informed 
consent signing, reportable safety events and 
laboratory values must be reported by the 
investigator per parent study protocol. After 
extension study, informed consent signing, 
reportable safety events and laboratory values 
will be reported by the investigator per extension 
study protocol.
Refer to rationale for primary reason for 
amendment.
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PRODUCT: MK-7902
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PROTOCOL/AMENDMENT NO.: MK-7902-001-07 (E7080-G000-313; ENGOT-EN9)
MK-7902-001-07 FINAL PROTOCOL
13-FEB-2024
Section Number 
and Name
Description of Change
Brief Rationale
8.5 Treatment of 
Overdose
Added text to indicate that participant should be 
observed closely for signs of toxicity in the event 
of an overdose and that appropriate supportive 
treatment should be provided if clinically 
indicated.
Refer to Section 4.4 rationale (EU CTR).
8.9 Biomarkers
Added text to indicate that the collection of blood 
for plasma biomarker samples and blood for 
circulating tumor nucleic acids will be 
discontinued following the implementation of 
Amendment 07.
Refer to Section 1.3.1 rationale (removal of 
biomarker samples).
9.5 Analysis 
Population
Modify text to indicate that the China Cohort 
may also be analyzed separately per local 
regulatory requirement.
Clarify to align with contents in other 
sections. 
9.7.2 Efficacy 
Interim Analyses
Added text to indicate that the final analysis for 
participants enrolled in China may occur at the 
same time as the final analysis for the global 
study.
To allow the Final Analysis for participants 
enrolled in China to occur at the same time 
as the Global Study Final Analysis.
10.3.1 Definitions of 
Medication Error, 
Misuse, and Abuse
Added a new section with definitions of 
medication error, misuse, and abuse. 
Refer to Section 4.4 rationale (EU CTR).
Throughout 
document
Minor administrative, formatting, grammatical, 
and/or typographical changes were made 
throughout the document.
To ensure clarity and accurate interpretation 
of the intent of the protocol.
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PROTOCOL/AMENDMENT NO.: MK-7902-001-07 (E7080-G000-313; ENGOT-EN9)
MK-7902-001-07 FINAL PROTOCOL
13-FEB-2024
Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................16
1.1
Synopsis.................................................................................................................16
1.2
Schema ..................................................................................................................20
1.3
Schedule of Activities (SoA)................................................................................22
1.3.1
Schedule of Activities – Initial Treatment Phase.........................................22
1.3.2
Schedule of Activities – Second Course Treatment Phase..........................37
2
INTRODUCTION..........................................................................................................44
2.1
Study Rationale....................................................................................................44
2.2
Background ..........................................................................................................44
2.2.1
Pharmaceutical and Therapeutic Background .............................................45
2.2.1.1
Pembrolizumab ..................................................................................45
2.2.1.2
Lenvatinib ..........................................................................................45
2.2.1.3
Endometrial Carcinoma: Epidemiology and Current Therapeutic 
Options...............................................................................................46
2.2.1.4
Scientific Rationale for the Combination of Lenvatinib with 
Pembrolizumab ..................................................................................47
2.2.1.5
Rationale for Inclusion of Participants Who Have Received Prior 
Adjuvant and/or Neoadjuvant Chemotherapy ...................................48
2.2.1.6
Clinical Data on Lenvatinib in Combination with Pembrolizumab 
for Treatment of Endometrial Carcinoma..........................................48
2.2.1.7
Clinical Data on Lenvatinib and Pembrolizumab as Single Agents 
for the Treatment of Endometrial Carcinoma....................................49
2.2.2
Preclinical and Clinical Studies ...................................................................51
2.2.3
Ongoing Clinical Studies.............................................................................51
2.2.4
Information on Other Study-related Therapy ..............................................51
2.3
Benefit/Risk Assessment......................................................................................51
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................52
4
STUDY DESIGN............................................................................................................54
4.1
Overall Design......................................................................................................54
4.2
Scientific Rationale for Study Design.................................................................56
4.2.1
Rationale for Patient Population..................................................................56
4.2.2
Rationale for Antidrug Antibody (ADA) Assessment.................................57
4.2.3
Rationale for Endpoints ...............................................................................57
4.2.3.1
Efficacy Endpoints.............................................................................57
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4.2.3.1.1
RECIST 1.1..............................................................................58
4.2.3.1.2
Modified RECIST 1.1 for Immune-based Therapeutics 
(iRECIST)................................................................................58
4.2.3.2
Safety Endpoints................................................................................59
4.2.3.3
Patient-reported Outcomes.................................................................59
4.2.3.3.1
EORTC QLQ-C30 ...................................................................59
4.2.3.3.2
EORTC QLQ-EN24.................................................................59
4.2.3.3.3
EuroQoL EQ-5D-5L ................................................................60
4.2.3.4
Pharmacokinetic Endpoints ...............................................................60
4.2.3.5
Pharmacodynamic Endpoints.............................................................60
4.2.3.6
.........................................60
4.2.4
Rationale for the Use of Comparator...........................................................62
4.3
Justification for Dose...........................................................................................62
4.3.1
Lenvatinib ....................................................................................................62
4.3.2
Pembrolizumab ............................................................................................62
4.3.3
Chemotherapy..............................................................................................63
4.3.3.1
Paclitaxel............................................................................................64
4.3.3.2
Carboplatin.........................................................................................64
4.3.4
Maximum Dose/Exposure for This Study ...................................................64
4.4
Beginning and End of Study Definition .............................................................64
4.4.1
Clinical Criteria for Early Study Termination .............................................65
5
STUDY POPULATION ................................................................................................65
5.1
Inclusion Criteria.................................................................................................65
5.2
Exclusion Criteria................................................................................................68
5.3
Lifestyle Considerations......................................................................................70
5.3.1
Meals and Dietary Restrictions....................................................................70
5.3.2
Contraception...............................................................................................70
5.3.3
Pregnancy.....................................................................................................71
5.3.4
Use in Nursing Women................................................................................71
5.4
Screen Failures.....................................................................................................71
5.5
Participant Replacement Strategy......................................................................71
6
STUDY INTERVENTION............................................................................................72
6.1
Study Intervention(s) Administered...................................................................72
6.2
Preparation/Handling/Storage/Accountability .................................................74
6.2.1
Dose Preparation..........................................................................................74
6.2.2
Handling, Storage, and Accountability........................................................74
6.3
Measures to Minimize Bias: Randomization and Blinding..............................75
6.3.1
Intervention Assignment..............................................................................75
CCI
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6.3.2
Stratification.................................................................................................75
6.3.3
Blinding........................................................................................................75
6.4
Study Intervention Compliance..........................................................................75
6.5
Concomitant Therapy..........................................................................................75
6.5.1
Allowed Concomitant Medication...............................................................76
6.5.2
Prohibited Concomitant Medications ..........................................................77
6.5.3
Drug-Drug Interactions................................................................................78
6.5.4
Rescue Medications and Supportive Care ...................................................78
6.5.5
Hematopoietic Growth Factors....................................................................79
6.6
Dose Modification (Escalation/Titration/Other)...............................................79
6.6.1
Lenvatinib Dose Modification.....................................................................79
6.6.1.1
Management of Hypertension............................................................80
6.6.1.2
Management of Proteinuria................................................................82
6.6.1.3
Management of Diarrhea ...................................................................83
6.6.1.4
Management of Hepatotoxicity..........................................................83
6.6.1.5
Management of Thromboembolic Events..........................................83
6.6.1.6
Management of Posterior Reversible Encephalopathy 
Syndrome/Reversible Encephalopathy Syndrome/Reversible 
Posterior Leukoencephalopathy Syndrome .......................................84
6.6.1.7
Management of Hypocalcemia ..........................................................84
6.6.1.8
Management of Hemorrhage .............................................................84
6.6.1.9
Management of Gastrointestinal Perforation or Fistula Formation ...84
6.6.1.10
Management of QT Prolongation ......................................................84
6.6.1.11
Management of Osteonecrosis of the Jaw .........................................85
6.6.2
Pembrolizumab Dose Modification.............................................................85
6.6.2.1
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue).......................................................................................85
6.6.2.2
Dose Modification and Toxicity Management of Infusion 
Reactions Related to Pembrolizumab................................................89
6.6.3
Dose Modifications for Overlapping Toxicities ..........................................92
6.6.4
Other Allowed Dose Interruptions...............................................................93
6.6.5
Second Course Phase (Retreatment Period) ................................................93
6.6.6
Paclitaxel and Carboplatin Chemotherapy...................................................94
6.7
Intervention After the End of the Study............................................................95
6.8
Clinical Supplies Disclosure................................................................................95
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................95
7.1
Discontinuation of Study Intervention...............................................................95
7.2
Participant Withdrawal From the Study...........................................................97
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7.3
Lost to Follow-up .................................................................................................97
8
STUDY ASSESSMENTS AND PROCEDURES........................................................97
8.1
Administrative and General Procedures ...........................................................98
8.1.1
Informed Consent.........................................................................................98
8.1.1.1
General Informed Consent.................................................................98
8.1.2
Inclusion/Exclusion Criteria ........................................................................99
8.1.3
Participant Identification Card.....................................................................99
8.1.4
Medical History ...........................................................................................99
8.1.5
Prior and Concomitant Medications Review.............................................100
8.1.5.1
Prior Medications.............................................................................100
8.1.5.2
Concomitant Medications................................................................100
8.1.6
Assignment of Screening Number.............................................................100
8.1.7
Assignment of Treatment/Randomization Number...................................100
8.1.8
Study Intervention Administration ............................................................100
8.1.8.1
Timing of Dose Administration.......................................................101
8.1.8.1.1
Lenvatinib ..............................................................................101
8.1.8.1.2
Pembrolizumab ......................................................................101
8.1.8.1.3
Chemotherapy........................................................................101
8.1.9
Discontinuation and Withdrawal ...............................................................102
8.1.10
Participant Blinding/Unblinding................................................................102
8.1.11
Calibration of Equipment...........................................................................102
8.2
Efficacy/Immunogenicity Assessments ............................................................102
8.2.1
Tumor Imaging and Assessment of Disease..............................................102
8.2.1.1
Initial Tumor Imaging......................................................................103
8.2.1.2
Tumor Imaging During the Study....................................................103
8.2.1.2.1
Bone Imaging During the Study ............................................104
8.2.1.2.2
Brain Imaging During the Study............................................104
8.2.1.3
End of Treatment and Follow-up Tumor Imaging...........................105
8.2.1.4
Second Course (Retreatment) Tumor Imaging................................105
8.2.1.4.1
Bone Imaging During Second Course ...................................106
8.2.1.4.2
Brain Imaging During Second Course...................................106
8.2.1.5
RECIST 1.1 Assessment of Disease................................................106
8.2.1.6
iRECIST Assessment of Disease.....................................................108
8.2.2
Patient-reported Outcomes.........................................................................110
8.3
Safety Assessments.............................................................................................111
8.3.1
Physical Examinations...............................................................................111
8.3.2
Vital Signs..................................................................................................111
8.3.3
Electrocardiograms ....................................................................................112
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8.3.4
Echocardiogram or Multiple Gated Acquisition Scan...............................112
8.3.5
Clinical Safety Laboratory Assessments ...................................................113
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Reportable Safety Events ..................................................................................113
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ........................................................114
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events....115
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information.116
8.4.4
Regulatory Reporting Requirements for SAE ...........................................116
8.4.5
Pregnancy and Exposure During Breastfeeding ........................................116
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs..........................................................................................117
8.4.7
Events of Clinical Interest (ECIs)..............................................................117
8.5
Treatment of Overdose......................................................................................117
8.6
Pharmacokinetics...............................................................................................118
8.7
Pharmacodynamics............................................................................................118
8.8
Mismatch Repair................................................................................................118
8.9
Biomarkers .........................................................................................................119
8.9.1
Planned Genetic Analysis Sample Collection............................................119
8.10
Health Economics Medical Resource Utilization and Health Economics.....119
8.11
Visit Requirements.............................................................................................120
8.11.1
Screening....................................................................................................120
8.11.2
Treatment Period........................................................................................120
8.11.3
Post-treatment Visit ...................................................................................121
8.11.3.1
Safety Follow-up..............................................................................121
8.11.3.2
Imaging Follow-up Visits ................................................................121
8.11.3.3
Survival Follow-up ..........................................................................122
8.11.4
Survival Status ...........................................................................................122
9
STATISTICAL ANALYSIS PLAN ...........................................................................122
9.1
Statistical Analysis Plan Summary...................................................................122
9.2
Responsibility for Analyses/In-house Blinding ...............................................125
9.3
Hypotheses/Estimation ......................................................................................125
9.4
Analysis Endpoints.............................................................................................125
9.5
Analysis Populations..........................................................................................126
9.5.1
Efficacy Analysis Populations...................................................................127
9.5.2
Safety Analysis Populations ......................................................................127
9.5.3
PRO Analysis Population ..........................................................................127
9.6
Statistical Methods.............................................................................................127
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9.6.1
Statistical Methods for Efficacy Analyses.................................................127
9.6.1.1
Progression-free Survival (PFS) ......................................................128
9.6.1.2
Overall Survival (OS) ......................................................................129
9.6.1.3
Objective Response Rate (ORR) .....................................................130
9.6.2
Statistical Methods for Safety Analyses ....................................................130
9.6.3
Statistical Methods for PRO Analyses.......................................................132
9.6.4
Summaries of Baseline Characteristics and Demographics.......................132
9.7
Interim Analyses ................................................................................................133
9.7.1
Safety Interim Analyses.............................................................................133
9.7.2
Efficacy Interim Analyses..........................................................................133
9.8
Multiplicity .........................................................................................................134
9.8.1
Efficacy Analyses ......................................................................................135
9.8.1.1
Progression-free Survival.................................................................135
9.8.1.2
Overall Survival...............................................................................136
9.8.1.3
Safety Analyses................................................................................137
9.9
Sample Size and Power Calculations ...............................................................138
9.10
Subgroup Analyses.............................................................................................138
9.11
Compliance (Medication Adherence)...............................................................139
9.12
Extent of Exposure.............................................................................................139
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...................................................................................................140
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations......140
10.1.1
Code of Conduct for Clinical Trials...........................................................140
10.1.2
Financial Disclosure...................................................................................142
10.1.3
Data Protection...........................................................................................142
10.1.3.1
Confidentiality of Data ....................................................................143
10.1.3.2
Confidentiality of Participant Records.............................................143
10.1.3.3
Confidentiality of IRB/IEC Information..........................................143
10.1.4
Committees Structure.................................................................................143
10.1.4.1
Scientific Advisory Committee........................................................143
10.1.4.2
Executive Oversight Committee......................................................143
10.1.4.3
External Data Monitoring Committee .............................................143
10.1.5
Publication Policy......................................................................................144
10.1.6
Compliance with Study Registration and Results Posting Requirements .144
10.1.7
Compliance with Law, Audit, and Debarment ..........................................145
10.1.8
Data Quality Assurance .............................................................................145
10.1.9
Source Documents .....................................................................................146
10.1.10
Study and Site Closure...............................................................................146
08JDYZ


PRODUCT: MK-7902
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PROTOCOL/AMENDMENT NO.: MK-7902-001-07 (E7080-G000-313; ENGOT-EN9)
MK-7902-001-07 FINAL PROTOCOL
13-FEB-2024
10.2
Appendix 2: Clinical Laboratory Tests............................................................148
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................151
10.3.1
Definitions of Medication Error, Misuse, and Abuse................................151
10.3.2
Definition of AE ........................................................................................151
10.3.3
Definition of SAE ......................................................................................152
10.3.4
Additional Events Reported in the Same Manner as SAE.........................153
10.3.5
Recording AE and SAE .............................................................................154
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................157
10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation..................................159
10.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing......................160
10.5.1
Definitions..................................................................................................160
10.5.2
Contraception Requirements......................................................................161
10.5.3
Pregnancy Testing......................................................................................162
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................163
10.7
Appendix 7: Country-specific Requirements..................................................164
10.7.1
Canada........................................................................................................164
10.7.2
Germany.....................................................................................................164
10.8
Appendix 8: Description of the iRECIST Process for Assessment of 
Disease Progression............................................................................................165
10.9
Appendix 9: Carcinoma of the Endometrium – FIGO Staging.....................169
10.10 Appendix 10: New York Heart Association Cardiac Disease Classification170
10.11 Appendix 11: Clinical Studies Evaluating Drug-Drug Interactions With 
Lenvatinib...........................................................................................................171
10.12 Appendix 12: Justification of Non-inferiority Margin ...................................172
10.13 Appendix 13: Abbreviations .............................................................................173
11
REFERENCES.............................................................................................................177
08JDYZ


PRODUCT: MK-7902
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PROTOCOL/AMENDMENT NO.: MK-7902-001-07 (E7080-G000-313; ENGOT-EN9)
MK-7902-001-07 FINAL PROTOCOL
13-FEB-2024
LIST OF TABLES
Table 1
Study Schedule of Activities – Initial Treatment Phase ..................................22
Table 2
Study Schedule of Activities – Second Course Treatment Phase....................37
Table 3
Adequate Organ Function Laboratory Values .................................................67
Table 4
Study Interventions..........................................................................................73
Table 5
Dose Modification Guidelines for Lenvatinib-related Adverse Events (for 
the Lenvatinib-Pembrolizumab Combination) ................................................80
Table 6
Dose Modification and Toxicity Management Guidelines for Immune-
related Adverse Events Associated with Pembrolizumab Monotherapy, 
Coformulations or IO Combinations ...............................................................86
Table 7
Pembrolizumab Infusion Reaction Dose Modification and Treatment 
Guidelines ........................................................................................................90
Table 8
Imaging and Treatment after First Radiologic Evidence of Progressive 
Disease...........................................................................................................109
Table 9
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events...............................................................................115
Table 10
Censoring Rules for Primary and Sensitivity Analyses of Progression-free 
Survival..........................................................................................................129
Table 11
Efficacy Analysis Methods for Key Efficacy Endpoints...............................130
Table 12
Analysis Strategy for Safety Parameters........................................................132
Table 13
Summary of Interim and Final Analyses .......................................................134
Table 14
Efficacy Boundaries and Properties for PFS Analyses in the pMMR 
Participants with Initial Alpha Allocation .....................................................136
Table 15
Efficacy Boundaries and Properties for OS Analysis for pMMR 
Participants with Initial Alpha Allocation .....................................................137
Table 16
Protocol-required Safety Laboratory Assessments........................................149
Table 17
Highly Effective Contraception Methods......................................................161
08JDYZ


PRODUCT: MK-7902
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PROTOCOL/AMENDMENT NO.: MK-7902-001-07 (E7080-G000-313; ENGOT-EN9)
MK-7902-001-07 FINAL PROTOCOL
13-FEB-2024
LIST OF FIGURES
Figure 1
Study Diagram .................................................................................................21
Figure 2
Imaging and Treatment for Clinically Stable Participants After First 
Radiologic Evidence of PD Assessed by the Investigator.............................108
Figure 3
Multiplicity Graph for Type I Error Control of Study Hypotheses ...............135
08JDYZ


PRODUCT: MK-7902
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PROTOCOL/AMENDMENT NO.: MK-7902-001-07 (E7080-G000-313; ENGOT-EN9)
MK-7902-001-07 FINAL PROTOCOL
13-FEB-2024
1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 3 Randomized, Open-Label, Study of Pembrolizumab (MK-3475) 
Plus Lenvatinib (E7080/MK-7902) Versus Chemotherapy for First-line Treatment of 
Advanced or Recurrent Endometrial Carcinoma (LEAP-001)
Short Title: Phase 3 study of pembrolizumab plus lenvatinib in endometrial carcinoma
Acronym: LEAP-001
Hypotheses, Objectives, and Endpoints:
In women with Stage III, Stage IV, or recurrent endometrial carcinoma who have been 
treated with pembrolizumab plus lenvatinib versus chemotherapy:
Primary Objectives
Primary Endpoints
Objective: To compare progression-free 
survival (PFS) per Response Evaluation 
Criteria In Solid Tumors version 1.1 (RECIST 
1.1) by blinded independent central review 
(BICR), modified to follow a maximum of 10 
target lesions and a maximum of 5 target 
lesions per organ (see Section 8.2.1).
Hypothesis 1 (H1): The combination of 
pembrolizumab plus lenvatinib is superior to 
chemotherapy with respect to PFS per 
RECIST 1.1 by BICR in mismatch repair 
proficient (pMMR) participants.
H2: The combination of pembrolizumab plus 
lenvatinib is superior to chemotherapy with 
respect to PFS per RECIST 1.1 by BICR in 
all-comers.
PFS is defined as the time from 
randomization to first documented 
disease progression or death due to any 
cause, whichever occurs first.
Objective: To compare overall survival (OS)
H3: The combination of pembrolizumab plus 
lenvatinib is non-inferior to chemotherapy 
with respect to OS in pMMR participants.
H4: The combination of pembrolizumab plus 
lenvatinib is superior to chemotherapy with 
respect to OS in pMMR participants.
H5: The combination of pembrolizumab plus 
lenvatinib is superior to chemotherapy with 
respect to OS in all-comers.
OS is defined as the time from 
randomization to death due to any cause.
08JDYZ


PRODUCT: MK-7902
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PROTOCOL/AMENDMENT NO.: MK-7902-001-07 (E7080-G000-313; ENGOT-EN9)
MK-7902-001-07 FINAL PROTOCOL
13-FEB-2024
Secondary Objectives
Secondary Endpoints
Objective: To compare objective response rate 
(ORR) per RECIST 1.1 by BICR in pMMR 
participants and in all-comer participants who 
have measurable disease at study entry.
Objective Response (OR) is defined as a 
confirmed complete response (CR) or 
partial response (PR).
Objective: To evaluate the impact of treatment 
on Health-Related Quality-of-Life (HRQoL) 
as assessed by using the global score of the 
European Organization for Research and 
Treatment of Cancer (EORTC) Quality of Life 
Questionnaire Core-30 (QLQ-C30) in pMMR 
and in all-comer participants.
Mean change from baseline in EORTC 
QLQ-C30 global health status/quality of 
life score.
Objective: To compare the safety and 
tolerability of pembrolizumab plus lenvatinib 
versus chemotherapy in all-comer participants.
•
AEs, SAEs and irAEs.
•
Study intervention discontinuations 
due to AEs.
Overall Design:
Study Phase
Phase 3
Primary Purpose
Treatment
Indication
Participants with advanced or recurrent endometrial carcinoma
Population
Participants with Stage III, Stage IV, or recurrent endometrial 
carcinoma
Study Type
Interventional
Intervention Model
Parallel
This is a multi-site study.
Type of Control
Active
Study Blinding
Unblinded Open-label
Masking
Outcomes Assessor
Estimated Duration of 
Study
The Sponsor estimates that the Global study will require 
approximately 51 months from the time the first participant signs 
the informed consent until the last participant’s last study-related 
telephone call or visit.
Extension Portion of the Study in China: The study may 
remain open longer than 51 months to complete an extension 
portion of the study in China
08JDYZ


PRODUCT: MK-7902
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PROTOCOL/AMENDMENT NO.: MK-7902-001-07 (E7080-G000-313; ENGOT-EN9)
MK-7902-001-07 FINAL PROTOCOL
13-FEB-2024
Number of Participants:
Approximately 875 participants will be randomized to the global portion of this study. After 
enrollment of the global portion of the study is complete, the study may remain open to 
enrollment in China alone until the target number of participants from China have been 
enrolled to meet local regulatory requirements.
Intervention Groups and Duration:
Intervention 
Groups
Inter-
vention 
Group 
Name
Drug
Dose
Dose 
Frequency
Route of 
Adminis-
tration
Regimen/ 
Treatment 
Period
Use
Arm 1
Lenvatinib
20 mg
Daily
Oral
Once daily
Test 
Product
Pembrolizumab
200 mg
Every 3 
weeks 
(Q3W)
Intravenous 
(IV) 
Infusion
Day 1 of 
each cycle
Test 
Product
Arm 2
Paclitaxela,b
175 mg/m2
Q3W
IV Infusion
Day 1 of 
each cycle
Comparator
Carboplatina
AUC 
6 mg/mL/
min
Q3W
IV Infusion
Day 1 of 
each cycle
Comparator
Abbreviations: AE=adverse event; IV=intravenous; Q3W=every 3 weeks.
a Lower starting dose of paclitaxel (135 mg/m2) and carboplatin (AUC 5 mg/mL/min) may be 
administered for participants who are at risk for developing toxicities due to prior pelvic/spine 
radiation. An AUC 5 mg/mL/min dose for carboplatin may be administered in accordance with 
local practice. 
b Docetaxel may be considered for participants who experience either a severe hypersensitivity 
reaction to paclitaxel or an AE requiring discontinuation of paclitaxel only after consultation with 
the Sponsor.
Total 
Number
2 treatment groups
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PRODUCT: MK-7902
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PROTOCOL/AMENDMENT NO.: MK-7902-001-07 (E7080-G000-313; ENGOT-EN9)
MK-7902-001-07 FINAL PROTOCOL
13-FEB-2024
Duration of 
Participation
Each participant will participate in the study from the time the participant 
signs the Informed Consent Form through the final protocol-specified 
contact.
After a screening phase of up to 28 days, each participant will be assigned 
to receive study intervention until one of the conditions for discontinuation 
of study intervention is met.
Participants in Arm 1 who stop study intervention after receiving 35 
infusions of pembrolizumab for reasons other than disease progression or 
intolerability, or participants who attain a complete response (CR) and stop 
study intervention after a minimum of 8 infusions of pembrolizumab (and a 
minimum of 2 infusions after the complete response was attained) may be 
eligible for up to an additional 1 year (17 cycles) of pembrolizumab ± 
lenvatinib after experiencing disease progression; if lenvatinib is stopped 
due to unacceptable toxicity, it will not be restarted during second course 
(Second Course Phase; Section 6.6.5).
Note: Participants who discontinue pembrolizumab after receiving 35 
infusions or attaining a CR should continue to receive lenvatinib alone 
until disease progression is verified by BICR or the development of 
unacceptable toxicity.
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 from treatment for reasons other than 
radiographic disease progression will have posttreatment follow-up 
imaging to assess disease status until disease progression is documented 
radiographically per RECIST 1.1 and verified by BICR (and when 
clinically appropriate, confirmed by the site per iRECIST), initiating a new 
anticancer treatment, withdrawing consent, becoming lost to follow-up, 
pregnancy, or death.
All participants will be followed by telephone for overall survival until 
death, withdrawal of consent, or 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, lenvatinib monotherapy, or a combination of 
both pembrolizumab and lenvatinib as received in the parent study, if 
available.
08JDYZ


PRODUCT: MK-7902
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PROTOCOL/AMENDMENT NO.: MK-7902-001-07 (E7080-G000-313; ENGOT-EN9)
MK-7902-001-07 FINAL PROTOCOL
13-FEB-2024
Study Governance Committees:
Steering Committee
No
Executive Oversight Committee
Yes
Data Monitoring Committee
Yes
Clinical Adjudication Committee
No
Study governance considerations are outlined in Appendix 1.
Study Accepts Healthy Volunteers: No
A list of abbreviations used in this document can be found in Appendix 13.
1.2
Schema
The study design is depicted in Figure 1.
08JDYZ


PRODUCT: MK-7902
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PROTOCOL/AMENDMENT NO.: MK-7902-001-07 (E7080-G000-313; ENGOT-EN9)
MK-7902-001-07 FINAL PROTOCOL
13-FEB-2024
Figure 1
Study Diagram
AE=adverse event; AUC=area under the concentration-time curve; dMMR=mismatch repair deficient; 
ECOG=Eastern Cooperative Oncology Group; ICF=informed consent form; pMMR=mismatch repair 
proficient; Q3W=every 3 weeks.
Note: Docetaxel may be considered for participants who experience either a severe hypersensitivity reaction to 
paclitaxel or an AE requiring discontinuation of paclitaxel only after consultation with the Sponsor 
(see Section 4.3.3.1)
08JDYZ


PRODUCT: MK-7902
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PROTOCOL/AMENDMENT NO.:  MK-7902-001-07 (E7080-G000-313; ENGOT-EN9)
MK-7902-001-07 FINAL PROTOCOL
13-FEB-2024
1.3
Schedule of Activities (SoA)
1.3.1
Schedule of Activities – Initial Treatment Phase
Table 1
Study Schedule of Activities – Initial Treatment Phase
Study Period
Screen-
ing
INITIAL Treatment Phase
End of 
Treat-
ment 
Posttreatment
Comments
Treatment Cycle
C1
C2
C3
C4
C5
C6+
Safety 
Follow-
upb,c
Imaging 
Follow-
upd
Survival 
Follow-
up
Cycle Day
1
8
15
1
8
15
1
1
1
1
At time 
of 
discon-
tinuation
30 days 
and 90 
days 
from 
last 
dose 
(+7)
Q9W or 
Q12W
(±7)
Q12W 
(±7)
Scheduled Days
-28 to -
1
-
3a
±3
±3
±3
±3
±3
±3
±3
±3
±3
Administrative Procedures
Informed Consent
X
ICF may be signed at any point 
prior to performing 
protocol-specific screening 
procedures.
If MMR result is unavailable 
within 28 days from when 
original consent was obtained, an 
extension may be granted after 
consultation with the Sponsor as 
long as all other screening 
procedures are performed within 
the protocol-specified timeframe.
If the investigator plans to treat 
beyond the initial radiographic 
disease progression per RECIST 
1.1, additional consent is 
required at initial site-assessed 
radiographic disease progression.
08JDYZ


PRODUCT: MK-7902
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PROTOCOL/AMENDMENT NO.:  MK-7902-001-07 (E7080-G000-313; ENGOT-EN9)
MK-7902-001-07 FINAL PROTOCOL
13-FEB-2024
Study Period
Screen-
ing
INITIAL Treatment Phase
End of 
Treat-
ment 
Posttreatment
Comments
Treatment Cycle
C1
C2
C3
C4
C5
C6+
Safety 
Follow-
upb,c
Imaging 
Follow-
upd
Survival 
Follow-
up
Cycle Day
1
8
15
1
8
15
1
1
1
1
At time 
of 
discon-
tinuation
30 days 
and 90 
days 
from 
last 
dose 
(+7)
Q9W or 
Q12W
(±7)
Q12W 
(±7)
Scheduled Days
-28 to -
1
-
3a
±3
±3
±3
±3
±3
±3
±3
±3
±3
Inclusion/Exclusion 
Criteria
X
Participant 
Identification Card
X
X
Add randomization number at 
C1.
Demographics
X
Medical History
X
Significant medical history to be 
captured for last 10 years.
Endometrial 
Carcinoma History
X
Review prior surgery, radiation 
and oncologic therapy.
FIGO Staging at 
Initial Diagnosis
X
Prior/Concomitant 
Therapy
X
X
X
X
X
X
X
X
X
X
X
X
X
Record medications taken within 
28 days prior to the start of study 
intervention. Concomitant 
medications will be recorded for 
30 days after last dose (or for up 
to 120 days after last dose for 
SAEs).
Randomization and 
Study Intervention 
Assignment
X
Participants may be randomized 
up to 3 days prior to C1D1. All 
C1D1 procedures and 
assessments should be performed 
after randomization.
08JDYZ


PRODUCT: MK-7902
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PROTOCOL/AMENDMENT NO.:  MK-7902-001-07 (E7080-G000-313; ENGOT-EN9)
MK-7902-001-07 FINAL PROTOCOL
13-FEB-2024
Study Period
Screen-
ing
INITIAL Treatment Phase
End of 
Treat-
ment 
Posttreatment
Comments
Treatment Cycle
C1
C2
C3
C4
C5
C6+
Safety 
Follow-
upb,c
Imaging 
Follow-
upd
Survival 
Follow-
up
Cycle Day
1
8
15
1
8
15
1
1
1
1
At time 
of 
discon-
tinuation
30 days 
and 90 
days 
from 
last 
dose 
(+7)
Q9W or 
Q12W
(±7)
Q12W 
(±7)
Scheduled Days
-28 to -
1
-
3a
±3
±3
±3
±3
±3
±3
±3
±3
±3
Telephone Contact
X
X
A phone visit will be scheduled 
to report blood pressure and 
record adverse events. Blood 
pressure will be taken, for 
example, at home or at a local 
pharmacy, and will be reviewed 
with the investigator or designee.
Note: An unscheduled clinic visit 
can occur prior to C1D15 or 
C2D15 if necessary for safety. 
Review New 
Anticancer 
Treatment
X
X
X
X
All anticancer therapy will be 
recorded until time of death or 
termination of survival follow-
up. 
If a clinical visit is not feasible, 
this information may be obtained 
via telephone or e-mail.
Survival Status
X
All participants may be contacted 
for survival status at any time 
during the course of the study.
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PRODUCT: MK-7902
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PROTOCOL/AMENDMENT NO.:  MK-7902-001-07 (E7080-G000-313; ENGOT-EN9)
MK-7902-001-07 FINAL PROTOCOL
13-FEB-2024
Study Period
Screen-
ing
INITIAL Treatment Phase
End of 
Treat-
ment 
Posttreatment
Comments
Treatment Cycle
C1
C2
C3
C4
C5
C6+
Safety 
Follow-
upb,c
Imaging 
Follow-
upd
Survival 
Follow-
up
Cycle Day
1
8
15
1
8
15
1
1
1
1
At time 
of 
discon-
tinuation
30 days 
and 90 
days 
from 
last 
dose 
(+7)
Q9W or 
Q12W
(±7)
Q12W 
(±7)
Scheduled Days
-28 to -
1
-
3a
±3
±3
±3
±3
±3
±3
±3
±3
±3
Clinical Assessments or Procedures
AE/SAE review 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
AEs: monitored up to 90 days 
after last dose or 30 days after 
the last dose if the participant 
initiates new anticancer therapy, 
whichever occurs first.
SAEs: monitored up to 120 days 
after last dose, or 30 days after 
last dose if participant starts a 
new anticancer therapy, 
whichever occurs first. 
Full Physical 
Examination
X
X
Includes evaluation of the head, 
eyes, ears, nose, throat, neck, 
chest (including heart and lungs), 
abdomen, limbs, skin, and a 
complete neurological 
examination.
Directed Physical 
Examination
X
X
X
X
X
X
X
Based on participant’s 
symptoms.
08JDYZ


PRODUCT: MK-7902
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PROTOCOL/AMENDMENT NO.:  MK-7902-001-07 (E7080-G000-313; ENGOT-EN9)
MK-7902-001-07 FINAL PROTOCOL
13-FEB-2024
Study Period
Screen-
ing
INITIAL Treatment Phase
End of 
Treat-
ment 
Posttreatment
Comments
Treatment Cycle
C1
C2
C3
C4
C5
C6+
Safety 
Follow-
upb,c
Imaging 
Follow-
upd
Survival 
Follow-
up
Cycle Day
1
8
15
1
8
15
1
1
1
1
At time 
of 
discon-
tinuation
30 days 
and 90 
days 
from 
last 
dose 
(+7)
Q9W or 
Q12W
(±7)
Q12W 
(±7)
Scheduled Days
-28 to -
1
-
3a
±3
±3
±3
±3
±3
±3
±3
±3
±3
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
Height at screening only. 
Refer to Section 8.3.2 for 
monitoring vital signs and 
Section 6.6.1.1 for hypertension 
management and BP monitoring 
guidelines.
Blood pressure should be taken 
on the day of dosing.
12-lead ECG
X
X
X
X
X
X
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.
08JDYZ


PRODUCT: MK-7902
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PROTOCOL/AMENDMENT NO.:  MK-7902-001-07 (E7080-G000-313; ENGOT-EN9)
MK-7902-001-07 FINAL PROTOCOL
13-FEB-2024
Study Period
Screen-
ing
INITIAL Treatment Phase
End of 
Treat-
ment 
Posttreatment
Comments
Treatment Cycle
C1
C2
C3
C4
C5
C6+
Safety 
Follow-
upb,c
Imaging 
Follow-
upd
Survival 
Follow-
up
Cycle Day
1
8
15
1
8
15
1
1
1
1
At time 
of 
discon-
tinuation
30 days 
and 90 
days 
from 
last 
dose 
(+7)
Q9W or 
Q12W
(±7)
Q12W 
(±7)
Scheduled Days
-28 to -
1
-
3a
±3
±3
±3
±3
±3
±3
±3
±3
±3
MUGA or ECHO
LVEF Assessment
X
X
Additional assessments may be 
performed as clinically indicated.
NYHA Cardiac 
Disease 
Classification
X
See Appendix 10.
Only required for participants 
with cardiovascular impairment 
within 12 months of the first dose 
of study intervention.
ECOG Performance 
Status
X
X
X
X
X
X
X
X
Assess within 7 days prior to first 
dose of study intervention.
Assess prior to treatment during 
subsequent treatment visits.
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PRODUCT: MK-7902
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PROTOCOL/AMENDMENT NO.:  MK-7902-001-07 (E7080-G000-313; ENGOT-EN9)
MK-7902-001-07 FINAL PROTOCOL
13-FEB-2024
Study Period
Screen-
ing
INITIAL Treatment Phase
End of 
Treat-
ment 
Posttreatment
Comments
Treatment Cycle
C1
C2
C3
C4
C5
C6+
Safety 
Follow-
upb,c
Imaging 
Follow-
upd
Survival 
Follow-
up
Cycle Day
1
8
15
1
8
15
1
1
1
1
At time 
of 
discon-
tinuation
30 days 
and 90 
days 
from 
last 
dose 
(+7)
Q9W or 
Q12W
(±7)
Q12W 
(±7)
Scheduled Days
-28 to -
1
-
3a
±3
±3
±3
±3
±3
±3
±3
±3
±3
Laboratory Assessments or Procedures
Pregnancy Test 
(WOCBP only) –
Urine or β-HCG
X
X
X
X
X
X
X
X
X
WOCBP require: 
A negative test prior to 
randomization and within 24 hours 
prior to the first dose of study 
intervention. If less than 24 hours 
have elapsed between the 
randomization test and the first 
dose of study intervention, another 
pregnancy test is not required.
Serum or urine pregnancy tests will 
be performed per Appendix 2.
Pregnancy testing should be 
performed every 30 days during the 
intervention period and for at least 
120 days post pembrolizumab or 
30 days post lenvatinib (up to 180 
days for participants receiving 
chemotherapy) or the start of a new 
anticancer therapy, whichever 
comes first.
In the absence of 12 months of 
amenorrhea, hysterectomy, or 
oophorectomy, confirmation with 2 
FSH measurements in the 
postmenopausal range is required.
08JDYZ


PRODUCT: MK-7902
29
PROTOCOL/AMENDMENT NO.:  MK-7902-001-07 (E7080-G000-313; ENGOT-EN9)
MK-7902-001-07 FINAL PROTOCOL
13-FEB-2024
Study Period
Screen-
ing
INITIAL Treatment Phase
End of 
Treat-
ment 
Posttreatment
Comments
Treatment Cycle
C1
C2
C3
C4
C5
C6+
Safety 
Follow-
upb,c
Imaging 
Follow-
upd
Survival 
Follow-
up
Cycle Day
1
8
15
1
8
15
1
1
1
1
At time 
of 
discon-
tinuation
30 days 
and 90 
days 
from 
last 
dose 
(+7)
Q9W or 
Q12W
(±7)
Q12W 
(±7)
Scheduled Days
-28 to -
1
-
3a
±3
±3
±3
±3
±3
±3
±3
±3
±3
HIV Testing
X
Required prior to enrollment if 
mandated by local health 
authority.
Hepatitis B and C 
Testing
X
Required prior to enrollment if 
mandated by local health 
authority.
PT/INR and 
aPTT/PTT
X
Perform within 7 days prior to 
first dose of study intervention.
Participants receiving 
coumarin-based anticoagulants 
should have more frequent INR 
monitoring as clinically 
indicated.
Chemistry Panel
X
X
X
X
X
X
X
X
X
X
Perform within 7 days prior to 
first dose of study intervention. 
Hematology Panel 
X
X
X
X
X
X
X
X
X
X
Perform within 7 days prior to 
first dose of study intervention. 
Urine Dipstick 
Testing
X
X
X
X
X
X
X
X
X
X
Perform within 7 days prior to 
first dose of study intervention.
Refer to Section 6.6.1.2 for 
management of proteinuria by 
dipstick, UPCR and/or 24-hour 
urinalysis.
08JDYZ


PRODUCT: MK-7902
30
PROTOCOL/AMENDMENT NO.:  MK-7902-001-07 (E7080-G000-313; ENGOT-EN9)
MK-7902-001-07 FINAL PROTOCOL
13-FEB-2024
Study Period
Screen-
ing
INITIAL Treatment Phase
End of 
Treat-
ment 
Posttreatment
Comments
Treatment Cycle
C1
C2
C3
C4
C5
C6+
Safety 
Follow-
upb,c
Imaging 
Follow-
upd
Survival 
Follow-
up
Cycle Day
1
8
15
1
8
15
1
1
1
1
At time 
of 
discon-
tinuation
30 days 
and 90 
days 
from 
last 
dose 
(+7)
Q9W or 
Q12W
(±7)
Q12W 
(±7)
Scheduled Days
-28 to -
1
-
3a
±3
±3
±3
±3
±3
±3
±3
±3
±3
T3, FT4, TSH
X
X
X
X
X
X
Perform within 7 days prior to 
first dose of study intervention.
Perform every other cycle 
starting with Cycle 2 (C2, C4, 
C6,…).
Sample Collection
MMR Status
X
pMMR versus dMMR
Submission of 
Archival or Newly 
Obtained Tumor 
Tissue Blocks or 
Slides 
X
Sample collected for exploring 
biomarkers of response.
Blood for Genetic 
Analysis
X
Predose
Blood for RNA 
Analysis
X
X
X
X
X
Predose on C1D1, C2D1, C3D1, 
C5D1, and at EOT.
Blood for Serum 
Biomarkers 
X
X
X
X
X
X
Predose on C1D1, C1D15, 
C2D1, C3D1, C5D1, and at 
EOT.
08JDYZ


PRODUCT: MK-7902
31
PROTOCOL/AMENDMENT NO.:  MK-7902-001-07 (E7080-G000-313; ENGOT-EN9)
MK-7902-001-07 FINAL PROTOCOL
13-FEB-2024
Study Period
Screen-
ing
INITIAL Treatment Phase
End of 
Treat-
ment 
Posttreatment
Comments
Treatment Cycle
C1
C2
C3
C4
C5
C6+
Safety 
Follow-
upb,c
Imaging 
Follow-
upd
Survival 
Follow-
up
Cycle Day
1
8
15
1
8
15
1
1
1
1
At time 
of 
discon-
tinuation
30 days 
and 90 
days 
from 
last 
dose 
(+7)
Q9W or 
Q12W
(±7)
Q12W 
(±7)
Scheduled Days
-28 to -
1
-
3a
±3
±3
±3
±3
±3
±3
±3
±3
±3
Blood for Plasma 
Biomarkers 
X
X
X
X
X
X
Predose on C1D1, C2D1, C3D1, 
C5D1, on D1 every 3 cycles 
thereafter (C8D1, C11D1, 
C14D1,…) and at EOT.
The collection of blood for 
plasma biomarker samples will 
be discontinued following the 
implementation of Amendment 
07.
Blood for Circulating 
Tumor Nucleic Acids
X
X
X
X
X
X
Predose on C1D1, C2D1, C3D1, 
C5D1, on D1 every 3 cycles 
thereafter (C8D1, C11D1, 
C14D1,…) and at EOT.
The collection of blood for 
circulating tumor nucleic acids 
will be discontinued following 
the implementation of 
Amendment 07.
08JDYZ


PRODUCT: MK-7902
32
PROTOCOL/AMENDMENT NO.:  MK-7902-001-07 (E7080-G000-313; ENGOT-EN9)
MK-7902-001-07 FINAL PROTOCOL
13-FEB-2024
Study Period
Screen-
ing
INITIAL Treatment Phase
End of 
Treat-
ment 
Posttreatment
Comments
Treatment Cycle
C1
C2
C3
C4
C5
C6+
Safety 
Follow-
upb,c
Imaging 
Follow-
upd
Survival 
Follow-
up
Cycle Day
1
8
15
1
8
15
1
1
1
1
At time 
of 
discon-
tinuation
30 days 
and 90 
days 
from 
last 
dose 
(+7)
Q9W or 
Q12W
(±7)
Q12W 
(±7)
Scheduled Days
-28 to -
1
-
3a
±3
±3
±3
±3
±3
±3
±3
±3
±3
Health Related Quality of Life
Perform in this order:
EORTC QLQ-C30
EORTC QLQ-
EN24
EuroQoL EQ-5D-
5L
X
X
X
X
X
X
X
X
Every effort should be made to 
administer HRQoL surveys prior 
to dosing and before other 
assessments and procedures. 
Collect on Day 1 of every cycle 
through Cycle 35, then every 4 
cycles through Cycle 60, at time 
of discontinuation, at the 30-day 
and 90-day Safety Follow-up 
visit. 
The collection of PRO data will 
be discontinued following the 
implementation of Amendment 
07.
Efficacy Measurements
Imaging 
Chest/Abdomen/
Pelvis
X
X
X
Xe
Perform within 28 days prior to 
randomization.
On treatment Q9W (±7 days) 
from randomization through 
Week 54, Q12W (±7 days) 
thereafter.
If imaging was obtained within 
28 days prior to discontinuation, 
an additional scan is not needed 
at discontinuation.
08JDYZ


PRODUCT: MK-7902
33
PROTOCOL/AMENDMENT NO.:  MK-7902-001-07 (E7080-G000-313; ENGOT-EN9)
MK-7902-001-07 FINAL PROTOCOL
13-FEB-2024
Study Period
Screen-
ing
INITIAL Treatment Phase
End of 
Treat-
ment 
Posttreatment
Comments
Treatment Cycle
C1
C2
C3
C4
C5
C6+
Safety 
Follow-
upb,c
Imaging 
Follow-
upd
Survival 
Follow-
up
Cycle Day
1
8
15
1
8
15
1
1
1
1
At time 
of 
discon-
tinuation
30 days 
and 90 
days 
from 
last 
dose 
(+7)
Q9W or 
Q12W
(±7)
Q12W 
(±7)
Scheduled Days
-28 to -
1
-
3a
±3
±3
±3
±3
±3
±3
±3
±3
±3
Imaging 
Bone
X
X
X
Xe
Perform within 42 days prior to 
randomization if known to be 
positive for bone metastases at 
baseline or if clinically 
symptomatic.
If positive for bone metastases at 
baseline, continue imaging at 
W27, W54, and Q24W (±7 days) 
thereafter (W78, W102, 
W126…).
Bone scan is required ≤2 weeks 
after CR for all participants 
positive for bone metastases at 
any point during the study.
If imaging was obtained within 
28 days prior to discontinuation, 
an additional scan is not needed 
at discontinuation.
08JDYZ


PRODUCT: MK-7902
34
PROTOCOL/AMENDMENT NO.:  MK-7902-001-07 (E7080-G000-313; ENGOT-EN9)
MK-7902-001-07 FINAL PROTOCOL
13-FEB-2024
Study Period
Screen-
ing
INITIAL Treatment Phase
End of 
Treat-
ment 
Posttreatment
Comments
Treatment Cycle
C1
C2
C3
C4
C5
C6+
Safety 
Follow-
upb,c
Imaging 
Follow-
upd
Survival 
Follow-
up
Cycle Day
1
8
15
1
8
15
1
1
1
1
At time 
of 
discon-
tinuation
30 days 
and 90 
days 
from 
last 
dose 
(+7)
Q9W or 
Q12W
(±7)
Q12W 
(±7)
Scheduled Days
-28 to -
1
-
3a
±3
±3
±3
±3
±3
±3
±3
±3
±3
Imaging 
Brain
X
X
X
Xe
Perform within 28 days prior to 
randomization if known to have 
brain metastases at baseline or if 
clinically symptomatic.
If positive for brain metastases at 
baseline, continue imaging Q9W 
from randomization through 
Week 54, Q12W (±7 days) 
thereafter.
Brain imaging is required 
≤2 weeks after CR for all 
participants positive for brain 
metastases at any point during 
the study.
If imaging was obtained within 
28 days prior to discontinuation, 
an additional scan is not needed 
at discontinuation.
Dispensing and Administration of Study intervention
Pembrolizumab 
(Arm 1)
X
X
X
X
X
X
200 mg IV Q3W up to 35 
infusions.
Lenvatinib (Arm 1)
X
X
X
X
X
X
20 mg orally QD until disease 
progression or unacceptable 
toxicity.
08JDYZ


PRODUCT: MK-7902
35
PROTOCOL/AMENDMENT NO.:  MK-7902-001-07 (E7080-G000-313; ENGOT-EN9)
MK-7902-001-07 FINAL PROTOCOL
13-FEB-2024
Study Period
Screen-
ing
INITIAL Treatment Phase
End of 
Treat-
ment 
Posttreatment
Comments
Treatment Cycle
C1
C2
C3
C4
C5
C6+
Safety 
Follow-
upb,c
Imaging 
Follow-
upd
Survival 
Follow-
up
Cycle Day
1
8
15
1
8
15
1
1
1
1
At time 
of 
discon-
tinuation
30 days 
and 90 
days 
from 
last 
dose 
(+7)
Q9W or 
Q12W
(±7)
Q12W 
(±7)
Scheduled Days
-28 to -
1
-
3a
±3
±3
±3
±3
±3
±3
±3
±3
±3
Paclitaxel/carboplatin 
(Arm 2)f, g
X
X
X
X
X
X
Paclitaxel: 175 mg/m2 IV Q3W 
up to 7 cycles.
Carboplatin: AUC 6 mg/mL/min 
IV Q3W up to 7 cycles 
(administered immediately after 
paclitaxel).
Abbreviations: AE=adverse event; BICR=blinded independent central review; BP=blood pressure; C1=Cycle 1; C2 = Cycle 2; CR=complete response; CT=computed 
tomography; D1=Day 1; D8=Day 8; D15=Day 15; DC=discontinuation; dMMR=mismatch repair deficient; ECHO=echocardiogram; ECOG=Eastern Cooperative Oncology 
Group; EORTC QLQ=European Organization for Research and Treatment of Cancer Quality of Life Questionnaire; EOT=End of Treatment; EQ-5D-5L=EuroQoL 5-
dimension, 5-level Questionnaire; 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; 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; PFS2=progression-free survival on next-line therapy; pMMR=mismatch repair proficient; 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; 
TSH=thyroid stimulating hormone; WES=whole exome sequencing; WOCBP=women of childbearing potential.
a.
With the exception of ECGs, and blood pressure (which should be performed on the day of dosing), C1D1 assessments can be performed up to 3 days prior to dosing. The 
screening assessment can serve as the C1D1 assessment if performed within 72 hours prior to randomization.
b.
If a discontinuation visit occurs ≥30 days from last dose of study intervention, a Safety Follow-up visit is not required. All procedures for both visits will be performed at 
the discontinuation visit.
c.
The 90-day Safety Follow-up visit is only required for participants who have not yet started new anticancer treatment. If the 90-day Safety Follow-up visit falls within the 
same window as an imaging follow-up visit, the procedures required at both visits may be combined.
d.
Follow-up visits to be scheduled to coincide with follow-up imaging.
e.
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, confirmed by the site per iRECIST when clinically appropriate, initiating a new 
anticancer treatment, withdrawing consent, becoming lost to follow-up, pregnancy or death.
f.
A lower starting dose of paclitaxel (135 mg/m2) and carboplatin (AUC 5 mg/mL/min) may be administered for participants who are at risk for developing toxicities due to 
prior pelvic/spine radiation. An AUC 5 mg/mL/min dose for carboplatin may be administered in accordance with local practice. Docetaxel may be considered for 
08JDYZ


PRODUCT: MK-7902
36
PROTOCOL/AMENDMENT NO.:  MK-7902-001-07 (E7080-G000-313; ENGOT-EN9)
MK-7902-001-07 FINAL PROTOCOL
13-FEB-2024
Study Period
Screen-
ing
INITIAL Treatment Phase
End of 
Treat-
ment 
Posttreatment
Comments
Treatment Cycle
C1
C2
C3
C4
C5
C6+
Safety 
Follow-
upb,c
Imaging 
Follow-
upd
Survival 
Follow-
up
Cycle Day
1
8
15
1
8
15
1
1
1
1
At time 
of 
discon-
tinuation
30 days 
and 90 
days 
from 
last 
dose 
(+7)
Q9W or 
Q12W
(±7)
Q12W 
(±7)
Scheduled Days
-28 to -
1
-
3a
±3
±3
±3
±3
±3
±3
±3
±3
±3
participants who experience either a severe hypersensitivity reaction to paclitaxel or an AE requiring discontinuation of paclitaxel only after consultation with the Sponsor 
(see Section 4.3.3.1).
g.
Chemotherapy treatment beyond 7 cycles may be permitted for participants who continue to derive clinical benefit, with Sponsor approval.
08JDYZ


PRODUCT: MK-7902
37
PROTOCOL/AMENDMENT NO.:  MK-7902-001-07 (E7080-G000-313; ENGOT-EN9)
MK-7902-001-07 FINAL PROTOCOL
13-FEB-2024
1.3.2
Schedule of Activities – Second Course Treatment Phase
Table 2
Study Schedule of Activities – Second Course Treatment Phase
Study Period
SECOND COURSE Treatment Phase
End of 
Treatment 
Post-Treatment
Comments
Treatment Cycle
C1
C2
C3
C4
C5
C6+
Safety 
Follow-
upb,c
Imaging 
Follow-
upd
Survival 
Follow-
up
Cycle Day
1
1
1
1
1
1
At time of 
discon-
tinuation
30 days 
and 90 
days from 
last dose 
(+7)
Q12W
(±7)
Q12W 
(±7)
Scheduled Days
3a
±3
±3
±3
±3
±3
Administrative Procedures
Review Eligibility Criteria
X
Review Concomitant 
Medication
X
X
X
X
X
X
X
X
Record medications taken within 
28 days prior to Second Course 
Cycle 1. Concomitant medications 
will be recorded for 30 days after 
last dose (or for up to 120 days 
after last dose for SAEs).
Review New Anticancer 
Treatment
X
X
X
X
All anticancer therapy will be 
recorded until time of death or 
termination of survival follow-up. 
If a clinical visit is not feasible, this 
information may be obtained via 
telephone or e-mail.
Survival Status
X
All participants may be contacted 
for survival status at any time 
during the course of the study.
08JDYZ


PRODUCT: MK-7902
38
PROTOCOL/AMENDMENT NO.:  MK-7902-001-07 (E7080-G000-313; ENGOT-EN9)
MK-7902-001-07 FINAL PROTOCOL
13-FEB-2024
Study Period
SECOND COURSE Treatment Phase
End of 
Treatment 
Post-Treatment
Comments
Treatment Cycle
C1
C2
C3
C4
C5
C6+
Safety 
Follow-
upb,c
Imaging 
Follow-
upd
Survival 
Follow-
up
Cycle Day
1
1
1
1
1
1
At time of 
discon-
tinuation
30 days 
and 90 
days from 
last dose 
(+7)
Q12W
(±7)
Q12W 
(±7)
Scheduled Days
3a
±3
±3
±3
±3
±3
Clinical Assessments or Procedures
AE/SAE review
X
X
X
X
X
X
X
X
X
AEs: monitored up to 90 days after 
last dose or 30 days after the last 
dose if the participant initiates new 
anticancer therapy, whichever 
occurs first.
SAEs: monitored up to 120 days 
after last dose, or 30 days after last 
dose if participant starts a new 
anticancer therapy, whichever 
occurs first. 
Full Physical Exam
X
X
Includes evaluation of the head, 
eyes, ears, nose, throat, neck, chest 
(including heart and lungs), 
abdomen, limbs, skin, and a 
complete neurological 
examination.
Directed Physical Exam
X
X
X
X
X
X
Exam based on participant’s 
symptoms.
Vital Signs
X
X
X
X
X
X
X
X
Refer to Section 8.3.2 for 
monitoring vital signs and 
Section 6.6.1.1 for hypertension 
management and BP monitoring 
guidelines.
08JDYZ


PRODUCT: MK-7902
39
PROTOCOL/AMENDMENT NO.:  MK-7902-001-07 (E7080-G000-313; ENGOT-EN9)
MK-7902-001-07 FINAL PROTOCOL
13-FEB-2024
Study Period
SECOND COURSE Treatment Phase
End of 
Treatment 
Post-Treatment
Comments
Treatment Cycle
C1
C2
C3
C4
C5
C6+
Safety 
Follow-
upb,c
Imaging 
Follow-
upd
Survival 
Follow-
up
Cycle Day
1
1
1
1
1
1
At time of 
discon-
tinuation
30 days 
and 90 
days from 
last dose 
(+7)
Q12W
(±7)
Q12W 
(±7)
Scheduled Days
3a
±3
±3
±3
±3
±3
12-lead ECG
X
X
X
X
X
Required at C1D1 prior to 
restarting study intervention unless 
it was already completed within 28 
days prior to Second Course Cycle 
1. Also required at C2D1, D1 of 
every 4th cycle (12 weeks) 
thereafter (eg, C6, C10, C14, etc.), 
EOT, and safety follow-up. 
For high-risk participants (as 
defined in Sec. 8.3.3), conduct 
ECG monitoring every cycle (if on 
lenvatinib). If lenvatinib is 
discontinued, ECGs are only 
required at the EOT and Safety 
Follow-up visits.
MUGA or ECHO
LVEF Assessment
X
X
Required prior to restarting study 
intervention only if it was not 
already completed within 28 days 
prior. Additional assessments may 
be performed as clinically 
indicated.
ECOG Performance Status
X
X
X
X
X
X
X
Perform within 3 days prior to 
Second Course Cycle 1.
Assess prior to treatment during 
subsequent treatment visits.
08JDYZ


PRODUCT: MK-7902
40
PROTOCOL/AMENDMENT NO.:  MK-7902-001-07 (E7080-G000-313; ENGOT-EN9)
MK-7902-001-07 FINAL PROTOCOL
13-FEB-2024
Study Period
SECOND COURSE Treatment Phase
End of 
Treatment 
Post-Treatment
Comments
Treatment Cycle
C1
C2
C3
C4
C5
C6+
Safety 
Follow-
upb,c
Imaging 
Follow-
upd
Survival 
Follow-
up
Cycle Day
1
1
1
1
1
1
At time of 
discon-
tinuation
30 days 
and 90 
days from 
last dose 
(+7)
Q12W
(±7)
Q12W 
(±7)
Scheduled Days
3a
±3
±3
±3
±3
±3
Laboratory Assessments or Procedures
Pregnancy Test (WOCBP 
only) - Urine or β-HCG
X
X
X
X
X
X
X
X
X
For WOCBP, perform within 24 
hours prior to Second Course Cycle 
1.
Pregnancy testing should be 
performed every 30 days during the 
intervention period and for at least 
120 days post pembrolizumab or 
30 days post lenvatinib or the start 
of a new anticancer therapy, 
whichever comes first.
PT/INR and aPTT/PTT
X
Perform within 3 days prior to 
Second Course Cycle 1
Participants receiving 
coumarin-based anticoagulants 
should have more frequent INR 
monitoring as clinically indicated.
Chemistry Panel
X
X
X
X
X
X
X
X
Perform within 3 days prior to 
Second Course Cycle 1
Hematology Panel
X
X
X
X
X
X
X
X
Perform within 3 days prior to 
Second Course Cycle 1.
Urine Dipstick Testing
X
X
X
X
X
X
X
X
Perform within 3 days prior to 
Second Course Cycle 1. Refer to 
Section 6.6.1.2 for management of 
proteinuria by dipstick, UPCR 
and/or 24-hour urinalysis.
T3, FT4, TSH
X
X
X
X
X
Perform within 3 days prior to 
Second Course Cycle 1 and every 
other cycle thereafter (C3, C5, 
C7,…).
08JDYZ


PRODUCT: MK-7902
41
PROTOCOL/AMENDMENT NO.:  MK-7902-001-07 (E7080-G000-313; ENGOT-EN9)
MK-7902-001-07 FINAL PROTOCOL
13-FEB-2024
Study Period
SECOND COURSE Treatment Phase
End of 
Treatment 
Post-Treatment
Comments
Treatment Cycle
C1
C2
C3
C4
C5
C6+
Safety 
Follow-
upb,c
Imaging 
Follow-
upd
Survival 
Follow-
up
Cycle Day
1
1
1
1
1
1
At time of 
discon-
tinuation
30 days 
and 90 
days from 
last dose 
(+7)
Q12W
(±7)
Q12W 
(±7)
Scheduled Days
3a
±3
±3
±3
±3
±3
Efficacy Measurements
Imaging 
Chest/Abdomen/Pelvis
X
X
X
Xe
Perform within 28 days prior to 
Second Course Cycle 1.
Q12W (±7 days) from Second 
Course Cycle 1 onwards or more 
frequently as clinically indicated.
If imaging was obtained within 
28 days prior to discontinuation, an 
additional scan is not needed at 
discontinuation.
Imaging
Brain
X
X
X
Xe
Perform within 28 days prior to 
Second Course Cycle 1 for 
participants known to be positive 
for brain metastases or who are 
clinically symptomatic.
If positive for brain metastases at 
the start of Second Course, 
continue imaging Q12W (±7 days) 
from Second Course Cycle 1 
onwards or more frequently as 
clinically indicated.
If imaging was obtained within 
28 days prior to discontinuation, an 
additional scan is not needed at 
discontinuation.
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Study Period
SECOND COURSE Treatment Phase
End of 
Treatment 
Post-Treatment
Comments
Treatment Cycle
C1
C2
C3
C4
C5
C6+
Safety 
Follow-
upb,c
Imaging 
Follow-
upd
Survival 
Follow-
up
Cycle Day
1
1
1
1
1
1
At time of 
discon-
tinuation
30 days 
and 90 
days from 
last dose 
(+7)
Q12W
(±7)
Q12W 
(±7)
Scheduled Days
3a
±3
±3
±3
±3
±3
Imaging 
Bone
X
X
X
Xe
Perform within 42 days prior to 
Second Course Cycle 1 for 
participants known to be positive 
for bone metastases or who are 
clinically symptomatic.
If positive for bone metastases at 
the start of Second Course, 
continue imaging Q24W (±7 days) 
from Second Course Cycle 1 
onwards, or more frequently as 
clinically indicated.
If imaging was obtained within 
28 days prior to discontinuation, an 
additional scan is not needed at 
discontinuation.
Dispensing and Administration of Study intervention
Pembrolizumab
X
X
X
X
X
X
200 mg IV Q3W up to 17 
additional cycles
Lenvatinib
X
X
X
X
X
X
If receiving lenvatinib in Second 
Course, start with the last 
prescribed dose last taken in First 
Course. If lenvatinib is stopped due 
to unacceptable toxicity in First 
Course, it will not be restarted 
during Second Course.
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Study Period
SECOND COURSE Treatment Phase
End of 
Treatment 
Post-Treatment
Comments
Treatment Cycle
C1
C2
C3
C4
C5
C6+
Safety 
Follow-
upb,c
Imaging 
Follow-
upd
Survival 
Follow-
up
Cycle Day
1
1
1
1
1
1
At time of 
discon-
tinuation
30 days 
and 90 
days from 
last dose 
(+7)
Q12W
(±7)
Q12W 
(±7)
Scheduled Days
3a
±3
±3
±3
±3
±3
Abbreviations: AE=adverse event; BICR=blinded independent central review; BP=blood pressure; C1=Cycle 1; C2=Cycle 2; CR=complete response; CT=computed 
tomography; D1=Day 1; D8=Day 8; D15=Day 15; DC=discontinuation; 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; 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; 
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; RNAseq=RNA sequencing; RR=respiratory rate; SAE=serious adverse event; T3=triiodothyronine; TSH=thyroid stimulating hormone; WES=whole exome sequencing; 
WOCBP=women of childbearing potential.
a.
With the exception of ECGs and blood pressure (which should be performed on the day of dosing), C1D1 assessments can be performed up to 3 days prior to dosing. The 
screening assessment can serve as the C1D1 assessment if performed within 72 hours prior to randomization.
b.
If discontinuation visit occurs ≥30 days from last dose of study intervention, a Safety Follow-up visit is not required. All procedures for both visits will be performed at the 
discontinuation visit.
c.
The 90-day Safety Follow-up visit is only required for participants who have not yet started new anticancer treatment. If the 90-day Safety Follow-up visit falls within the 
same window as an imaging follow-up visit, the procedures required at both visits may be combined.
d.
Follow-up visits to be scheduled to coincide with follow-up imaging.
e.
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, confirmed by the site per iRECIST when clinically appropriate, initiating a new 
anticancer treatment, withdrawing consent, becoming lost to follow-up, pregnancy or death.
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2
INTRODUCTION
2.1
Study Rationale
Carcinoma of the uterine corpus is often referred to as endometrial cancer (EC) because the 
vast majority of cases (~92%) occur in the endometrium (lining of the uterus) [American 
Cancer Society 2018]. Most EC cases are identified at an early stage with a 5-year survival 
rate of 94.9% for localized EC [National Cancer Institute 2018]. However, despite early 
detection, approximately 13% of all endometrial carcinomas recur [Fung-Kee-Fung, M., et al 
2006]. Women diagnosed with advanced or recurrent disease have a poor prognosis, with a 
5-year survival rate of 17% [National Cancer Institute 2018] [Makker, V., et al 2017].
The combination of immune checkpoint inhibitor pembrolizumab and lenvatinib (a multi 
receptor tyrosine kinase inhibitor) has emerged as a novel combination with promising 
efficacy in EC. KEYNOTE-146/E7080-A001-111 (Study 111) is an ongoing Phase 1b/2 
study that is being conducted in selected solid tumors, including EC. Promising activity was 
observed in 53 EC participants who had progressed on prior therapy and showed an ORR of 
39%, and response was seen across participants who had both defective mismatch repair and 
proficient mismatch repair. Based on the data from Study 111, the present study has been 
designed to compare the combination of pembrolizumab and lenvatinib (also known as 
E7080 or MK-7902, hereafter referred to as lenvatinib), to paclitaxel and carboplatin in 
patients with newly diagnosed Stage III, Stage IV, or recurrent EC.
2.2
Background
Pembrolizumab is a potent humanized IgG4 mAb with high specificity of binding to the PD-
1 receptor, thus inhibiting its interaction with PD-L1 and PD-L2. Based on preclinical in 
vitro data, pembrolizumab has high affinity and potent receptor blocking activity for PD-1. 
Pembrolizumab has an acceptable preclinical safety profile and is in clinical development as 
an IV immunotherapy for advanced malignancies. Keytruda® (pembrolizumab) is indicated 
for the treatment of patients across a number of indications. For more details on specific 
indications refer to the Investigator’s Brochure.
Lenvatinib (also known as E7080 or MK 7902; hereafter referred to as lenvatinib) inhibits 
the kinase activities of vascular endothelial growth factor (VEGF) receptors (VEGFRs), 
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 (FGFRs), FGFR1, FGFR2, FGFR3, and FGFR4, platelet-derived growth factor 
receptor (PDGFR) α, c-kit, and the RET proto-oncogene. Lenvatinib also showed 
antiproliferative activity in cell lines dependent on activated FGFR signaling with a 
concurrent inhibition of FGFR substrated 2α phosphorylation.
Refer to the Investigator’s Brochures (IBs)/approved labeling for detailed background 
information on pembrolizumab [IB Edition 17 2019] and lenvatinib [IB Edition 16 2019].
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2.2.1
Pharmaceutical and Therapeutic Background
2.2.1.1
Pembrolizumab
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control. The normal function of PD-1, expressed on the cell surface of activated 
T-cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an Ig 
superfamily member related to CD28 and CTLA-4 that has been shown to negatively 
regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2) 
[Greenwald, R. J., et al 2005] [Okazaki, T., et al 2001].
The structure of murine PD-1 has been resolved [Zhang, X., et al 2004]. PD-1 and its family 
members are type I transmembrane glycoproteins containing an IgV-type domain responsible 
for ligand binding and a cytoplasmic tail responsible for the binding of signaling molecules. 
The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an immunoreceptor 
tyrosine-based inhibition motif, and an immunoreceptor tyrosine-based switch motif. After
T-cell stimulation, PD-1 recruits the tyrosine phosphatases, SHP-1 and SHP-2, to the 
immunoreceptor tyrosine-based switch motif within its cytoplasmic tail, leading to the 
dephosphorylation of effector molecules such as CD3ζ, PKCθ, and ZAP70, which are 
involved in the CD3 T-cell signaling cascade [Okazaki, T., et al 2001] [Chemnitz, J. M., et al 
2004] [Sheppard, K-A, et al 2004] [Riley, J. L. 2009]. The mechanism by which PD-1 down-
modulates T-cell responses is similar to, but distinct from, that of CTLA-4, because both 
molecules regulate an overlapping set of signaling proteins [Parry, R. V., et al 2005] 
[Francisco, L. M., et al 2010]. As a consequence, the PD-1/PD-L1 pathway is an attractive 
target for therapeutic intervention in EC.
2.2.1.2
Lenvatinib
Angiogenesis, the formation of new blood vessels from a pre-existing vascular network, is 
essential for tumor growth and metastasis. VEGF and its family of receptors (VEGRs 1-3) 
play a major role in tumor angiogenesis [Ferrara, N., et al 2003] [Ellis, L. M. and Hicklin, D. 
J. 2008] [Tammela, T. and Alitalo, K. 2010]. Accumulated evidence suggests that FGF and 
its receptor tyrosine kinase, FGFR also play important roles for tumor angiogenesis [Cross, 
M. J. and Claesson-Welsh L. 2001] [Lieu, C., et al 2011] [Limaverde-Sousa, G., et al 2014]. 
Lenvatinib is a potent multiple RTK inhibitor that selectively inhibits VEGF receptors, 
VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4), FGFR1-4, PDGFRα, KIT, and 
RET. Among known kinase inhibitors in clinical use, lenvatinib is one of the only inhibitors 
currently labeled with a mechanism of action as an inhibitor of not only VEGFRs, but also 
FGFRs, both of which are currently believed to be very important for tumor angiogenesis.
Lenvatinib inhibited cell free kinase activities for VEGFR1-3 and FGFR1-3 with Ki values 
around 1 nmol/L, and 8-22 nmol/L, respectively. In cell-based assays, lenvatinib inhibited 
VEGF-derived and FGF-derived tube formation of HUVEC with IC50 values of 2.1 and 7.3 
nmol/L, respectively. Analysis of the signal transduction molecules revealed that lenvatinib 
inhibited both the MAPK pathway and the mTOR-S6K-S6 pathway in HUVECs triggered by 
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activated VEGFR and FGFR. Furthermore, lenvatinib (10, 30 mg/kg) significantly inhibited 
both VEGF- and FGF-driven angiogenesis in a murine in vivo model [Yamamoto, Y., et al 
2014]. In vivo, lenvatinib showed antitumor activity against various human tumor xenografts 
in athymic mice including 5 types of thyroid carcinomas (differentiated [papillary and 
follicular], anaplastic, squamous, and medullary thyroid carcinomas), RCC, HCC, melanoma, 
gastric cancer, NSCLC, ovarian cancer, Ewing’s sarcoma, and osteosarcoma. In addition, the 
antitumor activity of lenvatinib in combination with other anticancer agents in several 
xenograft models was greater than that of lenvatinib or the other agents alone.
In summary, lenvatinib inhibited VEGF-driven VEGFR2 phosphorylation and suppressed 
proliferation and tube formation in human umbilical vein endothelial cell (HUVEC) models. 
Antitumor activity of lenvatinib in vivo has been shown in numerous xenograft animals. 
These results suggest that lenvatinib may be a novel anticancer therapy through inhibition of 
angiogenesis and may be useful as either monotherapy or in combination with other 
anticancer drugs.
2.2.1.3
Endometrial Carcinoma: Epidemiology and Current Therapeutic Options
Endometrial cancer is the sixth most common cancer in women worldwide with 
approximately 320,000 new cases diagnosed in 2012 [Ferlay, J., et al 2015] [Torre, L. A., et 
al 2017]. In the United States, the estimated numbers of new cases and deaths occurring in 
2018 are 63,230 and 11,350, respectively [National Cancer Institute 2018]. Chemotherapy 
has been the standard of care in the first-line treatment setting and beyond, with platinum 
compounds, anthracyclines, and taxanes (alone and in combination) being the most 
frequently used treatments for women with advanced or recurrent EC [National 
Comprehensive Cancer Network 2017] [Colombo, N., et al 2013] [Miller, D., et al 2015]. 
While systemic therapy has improved outcomes in the first-line treatment setting [Thigpen, J. 
T., et al 1994] [Thigpen, J. T., et al 2004] [Fleming, G. F., et al 2004], the median 
progression-free survival and overall survival remains at 14 months and 32 to 38 months 
respectively [Miller, D., et al 2015] suggesting an urgent need for newer systemic therapies. 
An interim analysis of 1,381 (69 ineligible) participants who received first-line chemotherapy 
for metastatic or recurrent EC showed that the combination of paclitaxel and carboplatin 
(TC) chemotherapy was not clinically inferior to the combination of doxorubicin, cisplatin, 
and paclitaxel (TAP) chemotherapy with regard to PFS (median TC versus TAP, 14 versus 
14 months; Hazard Ratio [HR] = 1.03) and OS (median TC versus TAP, 32 versus 
38 months; HR = 1.01) [Miller, D., et al 2015]. Overall, the toxicity profile favored TC and
study intervention was discontinued due to toxicity in 18% on TAP and 12% on TC. 
Although TC remains a reasonable first-line treatment option, there is a need for treatment 
that is more efficacious and/or tolerable. 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 (MK-7902-001) will 
compare the efficacy and safety of lenvatinib in combination with pembrolizumab versus 
paclitaxel plus carboplatin in participants with advanced EC.
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2.2.1.4
Scientific Rationale for the Combination of Lenvatinib with Pembrolizumab
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades [Disis, M. L. 2010]. Accumulating evidence 
shows a correlation between tumor-infiltrating lymphocytes in cancer tissue and favorable 
prognosis in various malignancies. In particular, the presence of CD8+ T-cells and the ratio 
of CD8+ effector T-cells/FoxP3+ regulatory T-cells (T-regs) correlates with improved 
prognosis and long-term survival in solid malignancies, such as ovarian, colorectal, and 
pancreatic cancer; hepatocellular carcinoma; malignant melanoma; and renal cell carcinoma. 
Tumor-infiltrating lymphocytes can be expanded ex vivo and reinfused, inducing durable 
objective tumor responses in cancers such as melanoma [Dudley, M. E., et al 2005] [Hunder, 
N. N., et al 2008].
In preclinical models, lenvatinib decreased the tumor-associated macrophage (TAM) 
population, which is known as an immune-regulator in the tumor microenvironment. The 
decrease in TAM population was accompanied by increases in activated cytotoxic T-cell 
populations through stimulation of interferon-gamma signaling, resulting in increased 
immune activation [Kimura, T., et al 2018]. The immune-modulating effect of lenvatinib 
may result in a potent combination effect with PD-1/L1 signal inhibitors. The effect of 
combining lenvatinib with an antihuman PD-1 humanized mAb was investigated in 4 murine 
tumor isograft models, which showed significant tumor growth inhibition compared with
control. In the RAG murine tumor isograft tumor model, survival in the group treated with 
the combination was significantly longer than that of the respective monotherapy groups. In 
the CT26 murine tumor isograft model, treatment with the combination significantly 
increased the population of activated cytotoxic T cells compared with that of the respective 
monotherapy groups [Kato, Y., et al 2019]. All treatments were well tolerated and severe 
body weight loss was not observed
Based on these results, an open-label, Phase 1b/2 study (Study 111) to assess the safety and 
preliminary antitumor activity of the combination of lenvatinib plus pembrolizumab in 
participants with selected solid tumors is currently ongoing. Phase 1b of this study 
determined the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) as 
20 mg lenvatinib once daily (QD) in combination with 200 mg of pembrolizumab given IV 
every 3 weeks (Q3W). The safety and efficacy of the combination at the lenvatinib RP2D is 
being assessed in the Phase 2 portion of the study that includes 6 cohorts (ie, nonsmall cell 
lung cancer (NSCLC), renal cell carcinoma (RCC), EC, urothelial carcinoma, melanoma, and 
squamous cell carcinoma of the head and neck). Based on the tolerable safety profile 
observed, and promising antitumor efficacy seen in both the EC and RCC expansion cohorts 
from Study 111/KEYNOTE-146 [Makker, V., et al 2018], 2 Phase 3 studies are ongoing for 
both of these tumor types, Study E7080-G000-309/KEYNOTE-775 and Study E7080-G000-
307/KEYNOTE-581.
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2.2.1.5
Rationale for Inclusion of Participants Who Have Received Prior Adjuvant 
and/or Neoadjuvant Chemotherapy
After resection of localized or locally advanced high-risk endometrial cancer, platinum-based 
adjuvant chemotherapy is frequently administered to reduce the risk of disease recurrence. 
The adjuvant chemotherapy may be administered in 3 ways:1) chemotherapy alone; 2) as 
part of a concurrent chemoradiation regimen; or 3) as part of a sequential approach such as in 
a regimen involving concurrent chemoradiation followed by chemotherapy. The use of 
adjuvant chemotherapy in the above setting is endorsed by established clinical practice 
guidelines [National Comprehensive Cancer Network 2019] [Colombo, N., et al 2013]. With 
the widespread use of adjuvant chemotherapy, many patients with recurrent disease, who are 
appropriate candidates for first-line systemic treatment for advanced or recurrent disease, 
have received prior adjuvant chemotherapy. 
In the setting of recurrent disease after prior platinum-based adjuvant chemotherapy, 
retreatment with paclitaxel-carboplatin chemotherapy after a platinum-free interval of 
>6 months results in a response rate of 50%, with a median PFS and OS after retreatment of 
10 and 27 months respectively [Rubinstein, M., et al 2019]. These data approximate the 
efficacy for paclitaxel-carboplatin in the GOG 209 study in the first-line setting, which 
included a 51% response rate, and a median PFS and OS of 14 months and 32 months 
respectively [Miller, D., et al 2015]. Accordingly, with the inclusion of these patients, the 
statistical assumptions for this study, which were based on GOG 209, do not change. 
Therefore, it is appropriate to use carboplatin-paclitaxel for recurrent disease after prior 
platinum-based adjuvant chemotherapy, with the expectation of response rates comparable to 
those observed for chemo-naïve disease.
In summary, inclusion of participants with recurrent disease after neo/adjuvant chemotherapy 
is an appropriate adjustment to current practice patterns and is further justified by the high-
expected efficacy of paclitaxel-carboplatin in the newly included population.
2.2.1.6
Clinical Data on Lenvatinib in Combination with Pembrolizumab for 
Treatment of Endometrial Carcinoma
Promising activity was observed in 53 EC participants analyzed for efficacy and safety
during an interim analysis of the Phase 2 Study 111; 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 
65 years, and all had an Eastern Cooperative Oncology Group (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, 8% had microsatellite instability high (MSI-H) tumors, 
and 8% of participants had an unknown MSI status. Thirteen participants (25%) were PD-L1 
positive, 11 (21%) were PD-L1 negative, and 29 (55%) were not tested for PD-L1 status.
The best overall response (BOR) was evaluated per immune-related Response Evaluation 
Criteria in Solid Tumors (iRECIST) by both investigator assessment and independent
radiology review. As of the 15-DEC-2017 data cutoff, the BOR by investigator assessment 
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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 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 iRECIST 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.
2.2.1.7
Clinical Data on Lenvatinib and Pembrolizumab as Single Agents for the 
Treatment of Endometrial Carcinoma
Eisai and the Sponsor have conducted trials 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 after 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 BICR). Per BICR, 19 (14.3%) participants achieved a best overall response of either 
complete response (CR; 1 participant) or PR (18 participants), and 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 AE; 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 frequently 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 
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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 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, NCT02054806). At the time of the data cutoff (17-FEB-2016), the ORR, 
based on RECIST 1.1 by investigator assessment, 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 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].
The Sponsor is further investigating the clinical benefit of pembrolizumab monotherapy 
(200 mg administered IV Q3W) in advanced EC, irrespective of PD-L1 status, in the 
multi-cohort Phase 2 KEYNOTE-158 (NCT02628067) study.
As of 28-APR-2017, 107 EC participants have been treated. Most 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 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 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 intervention by the investigator. Grade 3, 4, or 5 events 
occurred in 57.9% of participants, with 15.9% considered related to the study intervention 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 
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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 is greater than can be accounted for by each of 
these single agents on their own.
2.2.2
Preclinical and Clinical Studies
Refer to the respective IBs for preclinical and clinical study data for pembrolizumab and 
lenvatinib.
2.2.3
Ongoing Clinical Studies
Refer to the respective IBs for ongoing clinical study data for pembrolizumab and lenvatinib.
2.2.4
Information on Other Study-related Therapy
For additional information on paclitaxel and carboplatin (or docetaxel when approved by the 
Sponsor due to either a severe hypersensitivity reaction to paclitaxel or an AE requiring 
discontinuation of paclitaxel, see Section 4.3.3.1), refer to the respective approved product 
labels.
2.3
Benefit/Risk Assessment
It cannot be guaranteed that participants in clinical studies will directly benefit from 
treatment during participation, as clinical studies are designed to provide information about 
the safety and effectiveness of an investigational medicine.
As discussed in Sections 2.2.1.5 and 2.2.1.6, 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 
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 IBs and informed consent documents.
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3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
In women with Stage III, Stage IV, or recurrent endometrial carcinoma who have been 
treated with pembrolizumab plus lenvatinib versus chemotherapy:
Objectives
Endpoints
Primary
•
Objective: To compare progression-free 
survival (PFS) per Response Evaluation 
Criteria in Solid Tumors version 1.1 
(RECIST 1.1) by blinded independent 
central review (BICR), modified to follow 
a maximum of 10 target lesions and a 
maximum of 5 target lesions per organ 
(see Section 8.2.1).
Hypothesis 1 (H1): The combination of 
pembrolizumab plus lenvatinib is superior 
to chemotherapy with respect to PFS per 
RECIST 1.1 by BICR in mismatch repair 
proficient (pMMR) participants.
H2: The combination of pembrolizumab 
plus lenvatinib is superior to chemotherapy 
with respect to PFS per RECIST 1.1 by 
BICR in all-comers.
•
PFS is defined as the time from 
randomization to first documented 
disease progression or death due to 
any cause, whichever occurs first.
•
Objective: To compare overall survival 
(OS)
H3: The combination of pembrolizumab 
plus lenvatinib is non-inferior to 
chemotherapy with respect to OS in 
pMMR participants.
H4: The combination of pembrolizumab 
plus lenvatinib is superior to chemotherapy 
with respect to OS in pMMR participants.
H5: The combination of pembrolizumab 
plus lenvatinib is superior to chemotherapy 
with respect to OS in all-comers.
•
OS is defined as the time from 
randomization to death due to any 
cause.
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Objectives
Endpoints
Secondary
•
Objective: To compare objective response 
rate (ORR) per RECIST 1.1 by BICR in 
pMMR participants and in all-comer 
participants who have measurable disease 
at study entry.
•
Objective Response (OR) is defined 
as a confirmed complete response 
(CR) or partial response (PR).
•
Objective: To evaluate the impact of 
treatment on Health-Related Quality-of-
Life (HRQoL) as assessed by using the 
global score of the European Organization 
for Research and Treatment of Cancer 
(EORTC) Quality of Life Questionnaire 
Core-30 (QLQ-C30) in pMMR and in all-
comer participants.
•
Mean change from baseline in 
EORTC QLQ-C30 global health 
status/quality of life score.
•
Objective: To compare the safety and 
tolerability of pembrolizumab plus 
lenvatinib versus chemotherapy in all-
comer participants.
•
AEs, SAEs and irAEs.
•
Study intervention discontinuations 
due to AEs.
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4
STUDY DESIGN
4.1
Overall Design
This is a Phase 3 randomized, open-label, study of pembrolizumab plus lenvatinib (Arm 1) 
versus chemotherapy (Arm 2) in women at least 18 years of age with a histologically-
confirmed diagnosis of Stage III, Stage IV, or recurrent endometrial carcinoma who have not 
previously been treated with prior systemic chemotherapy (note: prior chemotherapy 
administered in the adjuvant or neoadjuvant setting and/or concurrently with radiation is 
permitted). Participants who are candidates for curative-intent surgery should not be enrolled. 
Accordingly, investigators should assess the appropriateness of study participation with 
careful discretion.
Enrollment will be considered complete when 612 pMMR participants have been enrolled. 
Approximately 875 total participants are expected to be enrolled (612 pMMR participants 
and approximately 263 dMMR participants).
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After enrollment of the global portion of the study is complete, the study may remain open to 
enrollment in China alone until the target number of participants in China has been enrolled 
to meet local regulatory requirements. An extension portion of the study will be identical to 
the global study, (eg, inclusion and exclusion criteria, study endpoints, primary and 
secondary objectives, and study procedures) and details pertaining to the statistical analyses
for participants enrolled in China will be provided in a separate supplemental statistical 
analysis plan (sSAP).
The study includes dual-primary efficacy endpoints: 1) PFS per RECIST 1.1 as assessed by 
BICR and 2) OS. Eligible participants will first be stratified by MMR status (pMMR versus 
dMMR), then only within the pMMR stratum, participants will be further stratified according 
to ECOG (0 versus 1), measurable disease (yes versus no), and prior chemotherapy and/or 
chemoradiation (yes versus no). A total of 9 strata will be used for the study. Participants will 
be randomized centrally to one of 2 treatment arms:
Arm 1:
Lenvatinib 20 mg orally QD plus
Pembrolizumab 200 mg IV infusion Q3W
Arm 2:
Paclitaxel 175 mg/m2 IV infusion Q3W plus
Carboplatin AUC 6 mg/mL/min IV infusion Q3W
A lower starting dose of paclitaxel (135 mg/m2) and carboplatin (AUC 5 mg/mL/min) may 
be administered for participants who are at risk for developing toxicities due to prior 
pelvic/spine radiation. An AUC 5 mg/mL/min dose for carboplatin may be administered in 
accordance with local practice. Note: Docetaxel may be considered for participants who 
experience either a severe hypersensitivity reaction to paclitaxel or an AE requiring 
discontinuation of paclitaxel only after consultation with the Sponsor (see Section 4.3.3.1).
Pembrolizumab (Arm 1) and paclitaxel plus carboplatin (Arm 2) will be administered on 
Day 1 of each 21-day cycle. Lenvatinib (Arm 1) will be taken daily starting on Day 1 of 
Cycle 1. 
The first on-treatment imaging assessment will be performed at 9 weeks (63 days ± 7 days) 
from the date of randomization. Subsequent tumor imaging should be performed Q9W 
(63 days ± 7 days) through Week 54 and Q12W (84 days ± 7 days) thereafter. Progressive 
disease will be verified by BICR per RECIST 1.1 and may be further confirmed by 
subsequent imaging at the site per iRECIST. Refer to Section 8.2.1 for details about tumor 
imaging and assessments.
Participants may receive a maximum of 35 infusions of pembrolizumab; however, in the 
presence of clinical benefit, lenvatinib should continue beyond 35 cycles until disease 
progression or unacceptable toxicity. Participants may receive up to 7 cycles of 
paclitaxel/carboplatin. Chemotherapy treatment beyond 7 cycles may be permitted for 
participants who continue to derive clinical benefit, with Sponsor approval. If needed, 
participants may interrupt or discontinue pembrolizumab and continue with lenvatinib; 
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similarly, participants may interrupt or discontinue lenvatinib and continue with 
pembrolizumab. This protocol does not allow participants to cross over to the 
pembrolizumab plus lenvatinib arm upon experiencing progression with chemotherapy.
Participants in Arm 1 who stop study intervention for reasons other than disease progression 
or intolerability after receiving 35 infusions of pembrolizumab or participants who attain a 
complete response and stop study intervention after a minimum of 8 infusions of 
pembrolizumab (and a minimum of 2 infusions after the complete response was attained)
may be eligible for an additional 17 cycles of pembrolizumab (± lenvatinib) after 
experiencing disease progression; if lenvatinib is stopped due to unacceptable toxicity, it will 
not be restarted during second course (Second Course Phase; Section 6.6.5). Participants who 
discontinue pembrolizumab after receiving 35 infusions or attaining a CR should continue to 
receive lenvatinib alone until disease progression is verified by BICR or the development of 
unacceptable toxicity.
Participants who discontinue from treatment for reasons other than radiographic disease 
progression will have post-treatment follow-up imaging to assess disease status until disease 
progression is documented radiographically per RECIST 1.1 and verified by BICR (and 
when clinically appropriate, confirmed by the site per iRECIST), initiating a new anticancer 
treatment, withdrawing consent, becoming lost to follow-up, pregnancy, or death.
After verification of progression by BICR per RECIST 1.1 and/or initiation of a subsequent 
anticancer treatment, all participants will be followed for survival (by phone contact or clinic 
visit) until death, withdrawal of consent, loss to follow-up, or until the study is concluded or 
terminated early, whichever comes first.
The study will have an independent eDMC to monitor safety during the course of the study, 
evaluate efficacy at the interim analyses, and to provide recommendations for the study in 
accordance with the eDMC charter and the SAP.
Specific procedures to be performed during the study, as well as their prescribed times and 
associated visit windows, are outlined in the SoA in Section 1.3 (Table 1 and Table 2). 
Details of each procedure are provided in Section 8.
4.2
Scientific Rationale for Study Design
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 
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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-high (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 dMMR tumors, including 
EC. To account for the improved efficacy of pembrolizumab in the MSI-H/dMMR EC 
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% to 15% increase in sample 
size). The study will stop recruitment once fully enrolled for pMMR participants (n = 612) 
and it is anticipated that up to 263 dMMR participants will be enrolled.
 
4.2.2
Rationale for Antidrug Antibody (ADA) Assessment
To evaluate the immunogenicity and exposure of pembrolizumab in this indication, sample 
collections for analysis of antidrug antibodies (ADA) were obtained, but discontinued in 
MK-7902-001-04. As part of the clinical development program for pembrolizumab, pre- and 
post-baseline serum samples from participants treated with pembrolizumab have been 
analyzed for ADA, and an integrated immunogenicity evaluation has been performed. Data 
indicates that pembrolizumab has a low potential for eliciting the formation of ADA as 
detailed in the pembrolizumab IB. 
4.2.3
Rationale for Endpoints
4.2.3.1
Efficacy Endpoints
This study will use PFS based on RECIST 1.1 criteria as assessed by BICR, modified to 
follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ and OS 
as dual-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 an iCRO 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 verification of radiologic progression as determined by central review 
will be communicated to the site.
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Overall survival has been recognized as the gold standard for the demonstration of 
superiority of a new antineoplastic therapy in randomized clinical studies.
Objective Response is a secondary endpoint. OR is an acceptable measure of clinical benefit 
for a late stage study that demonstrates superiority of a new antineoplastic therapy, especially 
if the magnitude of the effect is large and the therapy has an acceptable risk/benefit profile. 
Images will be read per RECIST 1.1 by BICR to minimize bias in the response assessments. 
4.2.3.1.1
RECIST 1.1
RECIST 1.1 will be used by the BICR and local site when assessing images for efficacy and 
determining eligibility per 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 will implement a 
modification to RECIST 1.1 to allow a maximum of 10 target lesions in total and 5 per 
organ.
4.2.3.1.2
Modified RECIST 1.1 for Immune-based Therapeutics (iRECIST)
RECIST 1.1 will be adapted to account for the unique tumor response characteristics seen 
after 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 pseudoprogression. 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 
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 has been developed and published by the RECIST Working Group, with input from 
leading experts from industry and academia, along with the US Food and Drug 
Administration and the European Medicines Agency [Seymour, L., et al 2017] participation.
The unidimensional measurement of target lesions, qualitative assessment of nontarget 
lesions, and response categories are identical to RECIST 1.1, until progression is seen by 
RECIST 1.1. However, if a participant is clinically stable, additional imaging will be 
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performed to confirm radiographic progression. iRECIST will be used by investigators to 
assess tumor response and progression 
 
4.2.3.2
Safety Endpoints
Safety parameters frequently used for evaluating investigational systemic anticancer 
treatments are included as safety endpoints including, but not limited to, the incidence of, 
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 4.0.
4.2.3.3
Patient-reported Outcomes
Symptomatic improvement is considered a clinical benefit and accepted by health authorities 
as additional evidence of the risk-benefit profile of any new study intervention. As part of the 
analyses for this study, health-related quality of life (HRQoL) and disease-related symptoms 
will be investigated among all participants via the following assessment tools: EORTC QLQ-
C30, EORTC-QLQ-EN24, and the EuroQoL EQ-5D-5L questionnaires. Health utilities will 
be evaluated using the EQ-5D-5L PRO instrument. PRO instruments will be administered by 
trained site personnel and completed electronically by participants in the following order: 
EORTC QLQ-C30, EORTC-QLQ-EN24, and EQ-5D-5L. These measures are not pure
efficacy or safety endpoints because they are affected by both disease progression and 
treatment tolerability.
4.2.3.3.1
EORTC QLQ-C30
EORTC QLQ-C30 is a psychometrically and clinically validated instrument appropriate for 
assessing HRQoL in oncology studies [Aaronson, N. K., et al 1993]. The EORTC QLQ-C30 
is the most widely used cancer-specific HRQoL instrument, which contains 30 items and 
measures 5 functional dimensions (physical, role, emotional, cognitive and social), 3 
symptom items (fatigue, nausea/vomiting, and pain), 6 single items (dyspnea, sleep 
disturbance, appetite loss, constipation, diarrhea, and financial impact), and a global health 
and QoL scale [Aaronson, N. K., et al 1993]. For the global health status or QoL and function 
scales, a higher value indicates a better level of function; for symptom scales and items, a 
higher value indicates increased severity of symptoms. Mean change from baseline in global 
health status or QoL scale of the EORTC QLQ-C30 will be evaluated as a secondary 
objective.
4.2.3.3.2
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 
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).
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4.2.3.3.3
EuroQoL EQ-5D-5L
The EQ-5D-5L is a standardized instrument for use as a measure of health outcome and will 
provide data to develop health utilities for use in health economic analyses [Rabin, R. and de 
Charro, F. 2001]. The 5 health state dimensions in the EQ-5D-5L include the following: 
mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension 
is rated on a 5 point scale from 1 (no problem) to 5 (unable to/extreme problems). The EQ-
5D-5L also includes a graded (0 to 100) vertical visual analog scale on which the participant 
rates his or her general state of health at the time of the assessment. This instrument has been 
used extensively in cancer studies and published results from these studies support its 
validity and reliability [Pickard, A. S., et al 2007].
4.2.3.4
Pharmacokinetic Endpoints
Based on lenvatinib PK data obtained in this study and from other studies, a population PK 
analysis may be performed to characterize PK parameters of lenvatinib when co-
administered with pembrolizumab to support the proposed dosing regimen.
4.2.3.5
Pharmacodynamic Endpoints
No pharmacodynamic endpoints are planned for this study.
4.2.3.6
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4.2.4
Rationale for the Use of Comparator
Paclitaxel and carboplatin 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 was selected based on the results of the Phase 1b portion of 
Phase 1b/2 Study 111/KEYNOTE 146, the primary endpoint of which was to determine the 
MTD and RP2D for lenvatinib in combination with pembrolizumab 200 mg Q3W. Thirteen 
participants (lenvatinib 24 mg/day + pembrolizumab 200 mg IV Q3W: n=3; lenvatinib 
20 mg/day + pembrolizumab 200 mg: n=10) were enrolled in the Phase 1b portion of the 
study. Eight of the participants had RCC, 2 had NSCLC, 2 had EC, and 1 had melanoma.
There were 2 DLTs at the dose of lenvatinib 24 mg/day + pembrolizumab 200 mg IV Q3W 
(1 participant had Grade 3 arthralgia and another had Grade 3 fatigue); hence, this was 
defined as the toxic dose. No DLTs were reported in the next 10 participants (expansion 
part), all of whom received the lenvatinib 20 mg/day + pembrolizumab 200 mg Q3W dose. 
Based on review of all of the clinical data from these 13 participants, the MTD and RP2D 
were determined to be 20 mg lenvatinib daily in combination with a fixed dose of 200 mg 
pembrolizumab given Q3W.
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 every 2 weeks (Q2W),
•
Clinical data showing meaningful improvement in benefit-risk including overall survival 
at 200 mg Q3W across multiple indications, and
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•
Pharmacology data showing full target saturation in both systemic circulation (inferred 
from PK data) and tumor (inferred from physiologically-based PK (PBPK) analysis) at 
200 mg Q3W.
Among the 8 randomized dose-comparison studies, a total of 2262 participants were enrolled 
with melanoma and NSCLC, covering different disease settings (treatment naïve, previously 
treated, PD-L1 enriched, and all-comers) and different treatment settings (monotherapy and
in combination with chemotherapy). Five studies compared 2 mg/kg Q3W versus 10 mg/kg 
Q3W (KEYNOTE-001 Cohort B2, KEYNOTE-001 Cohort D, KEYNOTE-002, KEYNOTE-
010, and KEYNOTE-021), and 3 studies compared 10 mg/kg Q3W versus 10 mg/kg Q2W 
(KEYNOTE-001 Cohort B3, KEYNOTE-001 Cohort F2 and KEYNOTE-006). All of these 
studies showed 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 dose 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 regardless 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. PK data in 
KEYNOTE-001 evaluating TMDD conclusively showed saturation of PD-1 in systemic 
circulation at doses much lower than 200 mg Q3W. Also, 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
The doses of paclitaxel and carboplatin were selected based on standard clinical practice.
All participants should receive premedication and other supportive care measures, to prevent 
severe hypersensitivity reactions and minimize toxicity, according to the local label and/or 
per local practice.
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4.3.3.1
Paclitaxel
Paclitaxel 175 mg/m2 will be administered as an IV infusion on Day 1 of each 3-week 
treatment cycle according to the local label and/or per local practice.
The paclitaxel dose may be reduced to 135 mg/m2 for participants with a history of 
pelvic/spine radiation.
Docetaxel may be considered for participants who experience either a severe hypersensitivity 
reaction to paclitaxel or an AE requiring discontinuation of paclitaxel only after consultation 
with the Sponsor. Docetaxel 75 mg/m2 would then be administered as an IV infusion on 
Day 1 of each 3-week treatment cycle according to the local label and/or per local practice.
Other starting doses of docetaxel should be discussed with the Sponsor.
4.3.3.2
Carboplatin
Carboplatin AUC 6 mg/mL/min will be administered as an IV infusion on Day 1 of each 
3-week treatment cycle immediately after paclitaxel (or docetaxel for participants who 
experience either a severe hypersensitivity reaction to paclitaxel or an AE requiring 
discontinuation of paclitaxel only after consultation with the Sponsor, see Section 4.3.3.1), 
according to the local label and/or per local practice.
The carboplatin dose may be reduced to AUC 5 mg/mL/min for participants with a history of 
pelvic/spine radiation and in accordance with local practice.
4.3.4
Maximum Dose/Exposure for This Study
The maximum dose/exposure of pembrolizumab allowed in this study is 200 mg Q3W for up 
to 35 infusions; however, participants may be eligible for an additional 17 administrations 
(Section 6.6.5). Participants may receive up to 7 cycles of paclitaxel (or docetaxel for 
participants who experience either a severe hypersensitivity reaction to paclitaxel or an AE 
requiring discontinuation of paclitaxel only after consultation with the Sponsor, see 
Section 4.3.3.1) plus carboplatin. Chemotherapy treatment beyond 7 cycles may be permitted 
for participants who continue to derive clinical benefit, with Sponsor approval. The 
maximum dose/exposure of lenvatinib allowed in this study is 20 mg QD. Participants should 
continue treatment with lenvatinib until disease progression or unacceptable toxicity.
4.4
Beginning and End of Study Definition
The overall study begins when the first participant (or their legally acceptable representative) 
provides documented informed consent. The overall study ends when the last participant 
completes the last study-related contact, withdraws consent, or is lost to follow-up (ie, the 
participant is unable to be contacted by the investigator).
Upon study completion, eligible participants may be enrolled in an extension study in which 
they are administered pembrolizumab monotherapy, lenvatinib monotherapy, or a 
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combination of both pembrolizumab and lenvatinib as received in the parent study, if 
available.
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, 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 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
To be eligible for inclusion in this study, the participant must:
1. Have Stage III, Stage IV, or recurrent, histologically-confirmed endometrial carcinoma 
with disease that is either measurable or nonmeasurable per RECIST 1.1, but 
radiographically apparent, as assessed by BICR.
Notes about prior therapy:
•
May have received 1 prior line of systemic platinum-based adjuvant and/or 
neoadjuvant chemotherapy in the setting of a curative-intent resection, if the 
recurrence occurred ≥6 months after the last dose of chemotherapy. This prior 
chemotherapy may be given as treatment involving chemotherapy alone, concurrent 
chemoradiation, or as part of a sequential approach such as in a regimen involving 
concurrent chemoradiation followed by chemotherapy.
•
If neoadjuvant chemotherapy is used, there must be no evidence of tumor growth 
during this treatment prior to surgical resection.
•
Instances in which both adjuvant and neoadjuvant systemic platinum-based 
chemotherapy are used will be counted as one line of chemotherapy.
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•
May have received prior radiation with or without chemotherapy (see also Section 
5.2).
•
May have received prior hormonal therapy for treatment of endometrial carcinoma, 
provided that it was discontinued ≥1 week prior to randomization.
2. Have provided archival tumor tissue sample or newly obtained core or excisional biopsy 
of a tumor lesion that was not previously irradiated, for determination of MMR status.
Note: FFPE tissue blocks are preferred to slides. Newly obtained biopsies are preferred 
to archived tissue. If submitting unstained cut slides, newly cut slides should be submitted 
to the testing laboratory within 14 days from the date slides are cut (details pertaining to 
tumor tissue submission can be found in the Laboratory Manual).
Demographics
3. Have an ECOG performance status of 0 or 1, as assessed within 7 days prior to the first 
dose of study intervention.
4. Be female and at least 18 years of age on the day of signing consent.
Female Participants
5. A female participant is eligible to participate if she is not pregnant or breastfeeding, and 
at least one of the following conditions applies:
•
Is not a WOCBP
OR
•
Is a WOCBP and using a contraceptive method that is highly effective (with a failure 
rate of <1% per year), with low user dependency, or be abstinent from heterosexual 
intercourse as their preferred and usual lifestyle (abstinent on a long-term and 
persistent basis), as described in Appendix 5 during the intervention period and for at 
least 120 days post pembrolizumab or 30 days post lenvatinib, whichever occurs last,
and 180 days after the last dose of chemotherapy. The investigator should evaluate 
the potential for contraceptive method failure (ie, noncompliance, recently initiated) 
in relationship to the first dose of study intervention.
•
A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as 
required by local regulations) within 24 hours before the first dose of study 
intervention.
•
If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum 
pregnancy test is required. In such cases, the participant must be excluded from 
participation if the serum pregnancy result is positive.
•
Additional requirements for pregnancy testing during and after study intervention are 
in Appendix 2.
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•
The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy.
•
Contraceptive use by women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies. If the 
contraception requirements in the local label for any of the study interventions is 
more stringent than the requirements above, the local label requirements are to be 
followed.
Informed Consent
6. The participant (or legally acceptable representative if applicable) provides written 
informed consent for the study.
Additional Categories
7. Have adequately controlled BP with or without antihypertensive medications, defined as 
BP ≤150/90 mm Hg with no change in antihypertensive medications within 1 week prior 
to randomization.
8. Have adequate organ function as indicated by the following laboratory values (Table 3)
within 7 days prior to the first dose of study intervention:
Table 3
Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
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
≤3 × ULN (≤5 × ULN for participants with liver 
metastases)
Coagulation
INR OR PT
aPTT OR 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
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System
Laboratory Value
Abbreviations: ALP = alkaline phosphatase; ALT (SGPT) = alanine aminotransferase (serum glutamic pyruvic 
transaminase); ANC = absolute neutrophil count; aPTT = activated partial thromboplastin time; AST (SGOT) = aspartate 
aminotransferase (serum glutamic oxaloacetic transaminase); CrCl = creatinine clearance; GFR = glomerular filtration 
rate; INR = International Normalized Ratio; PT = prothrombin time; PTT = partial thromboplastin time; ULN = upper 
limit of normal.
1.
Criteria must be met without erythropoietin dependency and without pRBC transfusion within last 14 days.
2.
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 the local lab is unable to perform aPTT.
5.2
Exclusion Criteria
The participant must be excluded from the study if the participant:
Medical Conditions
1. Has carcinosarcoma (malignant mixed Műllerian tumor), endometrial leiomyosarcoma or
other high grade sarcomas, or endometrial stromal sarcomas.
2. Participants with central nervous system (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. Has a known additional malignancy (other than endometrial carcinoma) that is 
progressing or has required active treatment in the last 3 years.
Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the 
skin, or carcinoma in situ (eg, ductal carcinoma in situ, cervical carcinoma in situ) that 
have undergone potentially curative therapy are not excluded.
4. Has gastrointestinal malabsorption, or any other condition that might affect the 
absorption of lenvatinib. 
5. Has a pre-existing Grade ≥3 gastrointestinal or nongastrointestinal fistula.
6. Has radiographic evidence of major blood vessel invasion/infiltration. The degree of 
tumor invasion/infiltration of major blood vessels should be considered because of the 
potential risk of severe hemorrhage associated with tumor shrinkage/necrosis after
lenvatinib therapy.
7. Has active hemoptysis (bright red blood of at least 0.5 teaspoon) within 3 weeks prior to 
the first dose of study intervention or tumor bleeding within 2 weeks prior to
randomization.
8. Has clinically significant cardiovascular disease within 12 months from first dose of 
study intervention including New York Heart Association Class III or IV congestive heart 
failure, unstable angina, myocardial infarction, cerebral vascular accident, or cardiac 
arrhythmia associated with hemodynamic instability.
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Note: Medically controlled arrhythmia is permitted.
9. Has an active infection (any infection requiring systemic treatment).
10. Has had major surgery within 3 weeks prior to first dose of study interventions. Note: 
Adequate wound healing after major surgery must be assessed clinically, independent of 
time elapsed for eligibility.
11. Has not recovered adequately from any toxicity and/or complications from major surgery 
prior to randomization.
12. Has a known history of human immunodeficiency virus (HIV) infection.
Note: HIV testing is required at screening only when mandated by local health authority.
13. Has a known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg] 
reactive) or known active hepatitis C virus (defined as HCV RNA [qualitative] is 
detected) infection.
Note: Testing for Hepatitis B and Hepatitis C is required at screening only when 
mandated by local health authority.
14. Has a history of (noninfectious) pneumonitis that required treatment with steroids, or has 
current pneumonitis.
15. 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.
16. Has a known psychiatric or substance abuse disorder that would interfere with 
cooperation with the requirements of the study.
17. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in 
dosing exceeding 10 mg daily of prednisone equivalent) or any other form of 
immunosuppressive therapy within 7 days prior to randomization.
18. Has an 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.
Prior/Concomitant Therapy
19. Has received prior systemic chemotherapy in any setting for the treatment of endometrial 
carcinoma (note: prior chemotherapy administered as adjuvant therapy, neoadjuvant 
therapy, and/or concurrently with radiation is permitted).
20. Has received prior radiotherapy within 4 weeks prior to randomization. Participants must 
have recovered from all radiation-related toxicities, not require corticosteroids, and not 
have had radiation pneumonitis. A 2-week washout is permitted for palliative radiation to 
non-CNS disease and vaginal brachytherapy.
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21. Has received prior hormonal therapy for the treatment of endometrial carcinoma within 1 
week of randomization.
22. Has received prior therapy with any treatment targeting VEGF-directed angiogenesis, an 
anti-PD-1, anti-PD-L1, or anti-PD L2 agent, or with an agent directed to another 
stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX 40, CD137).
23. Has received a live or live attenuated vaccine within 30 days prior to the first dose of 
study intervention. Note: Administration of killed vaccines is allowed.
24. Has known intolerance to study intervention (or any of the excipients).
25. Has had an allogenic tissue/solid organ transplant.
Prior/Concurrent Clinical Study Experience
26. Is currently participating in or has participated in a study of an investigational agent or 
has used an investigational device within 4 weeks prior to randomization.
Note: Participants who have entered the Follow-up Phase of an investigational study 
may participate as long as it has been ≥4 weeks from the last dose of the investigational 
agent and randomization.
Diagnostic Assessments
27. Has urine protein ≥1 g/24 hours.
Note: Participants with proteinuria ≥2+ (≥100 mg/dL) on urine dipstick testing 
(urinalysis) will undergo 24-hr urine collection for quantitative assessment of 
proteinuria.
28. Has prolongation of QTcF interval to >480 ms (corrected by Fridericia Formula).
Note: If the QTcF is prolonged to >480 ms in the presence of a pacemaker, contact the 
Sponsor to determine eligibility.
29. Has left ventricular ejection fraction (LVEF) below the institutional normal range as 
determined by multigated acquisition (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
Based on its mechanism of action, lenvatinib can cause fetal harm when administered to a 
pregnant woman. Lenvatinib may also result in reduced fertility in females of reproductive 
potential and may result in damage to male reproductive tissues leading to reduced fertility of 
unknown duration. In animal reproduction studies, oral administration of lenvatinib during 
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organogenesis at doses below the recommended human dose resulted in embryotoxicity, 
fetotoxicity, and teratogenicity in rats and rabbits.
Participants should be informed that taking the study medication may involve unknown risks 
to the fetus (unborn baby) if pregnancy were to occur during the study. To participate in the 
study, participants of childbearing potential must adhere to the contraception requirement 
(Appendix 5) from the day of study medication initiation throughout the study period up to 
120 days after the last dose of pembrolizumab or 30 days post the last dose of lenvatinib, 
whichever comes last, and 180 days after the last dose of chemotherapy. 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 intervention, the participant 
will be immediately discontinued from study intervention. The site will contact the 
participant at least monthly and document the participant’s status until the pregnancy has 
been completed or terminated. The outcome of the pregnancy will be reported to the Sponsor
without delay and within 24 hours if the outcome is a serious adverse experience (eg, death, 
abortion, congenital anomaly, or other disabling or life-threatening complication to the 
mother or newborn). The study investigator will make every effort to obtain permission to 
follow the outcome of the pregnancy and report the condition of the fetus or newborn to the 
Sponsor as described in Section 8.4.1.
5.3.4
Use in Nursing Women
It is unknown whether the study interventions are excreted in human milk. Since many drugs 
are excreted in human milk, and because of the potential for serious adverse reactions in the 
nursing infant, participants who are breastfeeding are not eligible for enrollment.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study, but 
are not subsequently randomized in the study. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any AEs or SAEs meeting reporting 
requirements as outlined in the data entry guidelines.
5.5
Participant Replacement Strategy
A participant who discontinues from study intervention OR withdraws from the study will 
not be replaced.
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6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
“Study intervention” refers to pembrolizumab, lenvatinib, paclitaxel (or docetaxel for 
participants who experience either a severe hypersensitivity reaction to paclitaxel or an AE 
requiring discontinuation of paclitaxel only after consultation with the Sponsor, see 
Section 4.3.3.1) and/or carboplatin.
Clinical supplies will be packaged to support enrollment. Clinical supplies will be affixed 
with a clinical label in accordance with regulatory requirements.
6.1
Study Intervention(s) Administered
The study intervention(s) to be used in this study are outlined in Table 4.
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Table 4
Study Interventions
Arm 
Name
Arm Type
Intervention 
Name
Type
Dose 
Formu-
lation
Unit Dose 
Strength(s)a
Dosage 
Level(s)b, e
Route of 
Adminis-
tration
Regimen/ 
Treatment 
Period
Use 
IMP or 
NIMP/AxMP 
f
Sourcingc, d
Arm 1
Experimental
Lenvatinib
Drug
Capsule
10 mg, 4 mg
20 mg
Oral
Once daily
Test Product
IMP
Central
Arm 1
Experimental
Pembrolizumab
Drug
Vial
25 mg/mL
200 mg
IV Infusion
Day 1 of 
each cycle
Test Product
IMP
Central
Arm 2
Active 
Comparator
Paclitaxel
Drug
Vial
6 mg/mL 
(16.7 mL)
175 mg/
m2
IV Infusion
Day 1 of 
each cycle
Comparator
IMP
Local or 
Central
Arm 2
Active 
Comparator
Carboplatin
Drug
Vial
10 mg/mL 
(60 mL)
AUC 6 mg/ 
mL/min
IV Infusion
Day 1 of 
each cycle
Comparator
IMP
Local or 
Central
a.
Unit dose strength and volume may vary depending on market availability. 
b.
Paclitaxel 175 mg/m2 IV infusion Q3W; carboplatin AUC 6 mg/mL/min IV infusion Q3W. Docetaxel may be considered for participants who experience either a severe 
hypersensitivity reaction to paclitaxel or an AE requiring discontinuation of paclitaxel only after consultation with the Sponsor (see Section 4.3.3.1).
c.
4 mg capsules provided for successive dose reduction of lenvatinib, if needed, as described in Section 6.6.1.
d.
Paclitaxel (or docetaxel for participants who experience either a severe hypersensitivity reaction to paclitaxel or an AE requiring discontinuation of paclitaxel only after 
consultation with the Sponsor, see Section 4.3.3.1) and carboplatin should be provided centrally by the Sponsor or locally by the trial site, subsidiary, or designee. 
Pembrolizumab and lenvatinib should be provided centrally by the Sponsor.
e.
A lower starting dose of paclitaxel (135 mg/m2) and carboplatin (AUC 5 mg/mL/min) may be administered for participants who are at risk for developing toxicities due to 
prior pelvic/spine radiation. An AUC 5 mg/mL/min dose for carboplatin may be administered in accordance with local practice. 
f.
The definition of IMP and NIMP/(AxMP) is based on guidance issued by the European Commission. Regional and/or Country differences of the definition of IMP or 
NIMP/AxMP may exist. In these circumstances, local legislation is followed.
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All study interventions will be administered on an outpatient basis.
All supplies indicated in Table 4 will be provided per the "Sourcing" column depending upon 
local country operational requirements. If local sourcing, 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 intervention.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
Details on preparation and administration of pembrolizumab are provided in the Pharmacy 
Manual. Lenvatinib is a capsule for oral administration and does not require preparation.
Paclitaxel and carboplatin (or docetaxel if used in place of paclitaxel for participants who 
experience either a severe hypersensitivity reaction to paclitaxel or an AE requiring 
discontinuation of paclitaxel only after consultation with the Sponsor, see Section 4.3.3.1)
should be prepared as outlined in the respective approved labeling or institutional guidelines. 
6.2.2
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
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The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment 
Treatment allocation/randomization will occur centrally using an IRT system. There are 
2 study intervention arms. Participants will be assigned randomly in a 1:1 ratio to lenvatinib 
+ pembrolizumab study intervention and paclitaxel + carboplatin study intervention, 
respectively.
6.3.2
Stratification
Treatment allocation/randomization will be stratified according to the following factors:
•
MMR status (pMMR versus dMMR), and if pMMR:
-
ECOG (0 versus 1)
-
Measurable disease (yes versus no)
-
Prior chemotherapy and/or chemoradiation (yes versus no)
Eligible participants will first be stratified by MMR status (pMMR versus dMMR), then only 
within the pMMR stratum, participants will be further stratified according to ECOG (0 versus 
1), measurable disease (yes versus no), and prior chemotherapy and/or chemoradiation (yes 
versus no). A total of 9 strata will be used for the study. 
6.3.3
Blinding
This study is an open-label study; therefore, the Sponsor, investigator and participant will 
know the treatment administered.
6.4
Study Intervention Compliance
If there are interruptions in the study intervention schedule, the details of and reason for any 
interruption of study intervention will be documented in the participant’s medical record. 
Refer to Section 6.6.1 for dose modifications and toxicity management for lenvatinib and to
Section 6.6.2 for dose modification and toxicity management for irAEs associated with 
pembrolizumab and for other allowed dose interruption of pembrolizumab. Refer to 
Section 6.6.3 for dose modifications management for overlapping toxicities.
6.5
Concomitant Therapy
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the treatment period. If there is a clinical indication for any medication or vaccination 
specifically prohibited, discontinuation from study intervention may be required. The 
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investigator is to discuss prohibited medication with the Sponsor’s Clinical Director. The 
final decision on any supportive therapy or vaccination rests with the investigator and/or the 
participant’s primary physician. However, the decision to continue the participant on study 
intervention requires the mutual agreement of the investigator, the Sponsor, and the 
participant.
Any medication (including over-the-counter medications) or therapy administered to the 
participant during the study (starting at the date of informed consent) will be recorded on the 
appropriate CRF. The investigator will record the AE for which the concomitant 
medication/therapy was administered on the appropriate CRF. If the concomitant 
medication/therapy is being administered for a medical condition present at the time of entry 
into the study, the investigator will record the medical condition on the appropriate CRF.
All prior medications (including over-the-counter medications) administered 30 days before 
the first dose of study intervention and any concomitant therapy administered to the 
participant during the course of the study (starting at the date of informed consent) until 
30 days after the final dose of study intervention will be recorded. Additionally, all 
diagnostic, therapeutic, or surgical procedures relating to malignancy should be recorded. 
Any medication that is considered necessary for the participant’s health and that is not 
expected to interfere with the evaluation of or interact with the study medication may be 
continued during the study.
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 antidiarrheal drugs), may be 
given at the discretion of the investigator, unless it is expected to interfere with the evaluation 
of (or to interact with) the study medication. Anti-emetic or any other prophylaxis should be 
considered in accordance with institutional guidelines.
The following concomitant medications are also allowed:
•
Hormone replacement therapy.
•
Thyroid hormone suppressive therapy.
•
Adjuvant hormonal therapy for history of definitively treated breast cancer.
•
Anticoagulants including low molecular weight heparin, 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 of up to 2 pre-existing, nontarget bone metastases will be 
permitted. Palliative radiotherapy of other nontarget lesions may be permitted after 
consultation with the Sponsor.
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Any additional procedural or participant-specific particularities should be discussed with the 
Sponsor.
6.5.2
Prohibited Concomitant Medications
Participants are prohibited from receiving the following therapies during the Screening and 
Treatment Phase of this study:
•
Concurrent anticancer therapies such as chemotherapy, targeted therapies (eg, 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.
•
Immunotherapy not specified in this protocol.
•
Investigational agents other than pembrolizumab, lenvatinib, paclitaxel (or docetaxel for 
participants who experience either a severe hypersensitivity reaction to paclitaxel or an 
AE requiring discontinuation of paclitaxel, only after consultation with the Sponsor, see 
Section 4.3.3.1), and carboplatin.
•
Live or live attenuated vaccines within 30 days prior to the first dose of study 
intervention and while participating in the study. Killed vaccines are allowed.
•
For participants in the lenvatinib plus pembrolizumab arm, systemic glucocorticoids are 
not permitted except for the following purposes:
-
To modulate symptoms of an AE that is suspected to have an immunologic etiology.
-
As needed for the prevention of emesis.
-
Premedication for IV contrast allergies.
-
Short-term oral or IV use in doses >10 mg/day prednisone equivalent for COPD 
exacerbations.
-
For chronic systemic replacement not to exceed 10 mg/day prednisone equivalent.
•
In addition, the following nonsystemic 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 on with the Sponsor.
If participants receive additional anticancer therapies, this will be judged to represent 
evidence of disease progression, and study medication will be discontinued. These 
participants should complete all End of Treatment assessments and continue to be followed 
for survival in the Follow-up Period. All treatments that the investigator considers necessary 
for a participant’s welfare may be administered at the discretion of the investigator in 
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keeping with the community standards of medical care. All concomitant medication will be 
recorded on the eCRF including all prescription, OTC products, herbal supplements, IV 
medications, and fluids. If changes occur during the study period, documentation of drug 
dosage, frequency, route, and date should also be included on the eCRF.
All concomitant medications received within 28 days prior to the first dose of study 
intervention and up to 30 days after the last dose of study intervention should be recorded. 
All concomitant medications administered during SAEs or ECIs are to be recorded. SAEs 
and ECIs are defined in Section 8.4.
For further information on the prohibited concomitant therapies for paclitaxel or carboplatin 
(or docetaxel for participants who experience either a severe hypersensitivity reaction to 
paclitaxel or an AE requiring discontinuation of paclitaxel only after consultation with the 
Sponsor, see Section 4.3.3.1), please refer to their respective prescribing information.
6.5.3
Drug-Drug Interactions
A clinical drug-drug interaction (DDI) study in cancer patients showed that plasma 
concentrations of midazolam (a sensitive CYP3A and Pgp substrate) were not altered in a 
clinically meaningful manner in the presence of lenvatinib. No significant drug-drug 
interaction is therefore expected between lenvatinib and other CYP3A4/Pgp substrates.
Nonclinical studies identify CYP3A4 as the important CYP isozyme responsible for human 
hepatic metabolism of lenvatinib. However, clinical studies conducted showed that co-
administration of lenvatinib with either inducers or inhibitors of CYP3A4/P-glycoprotein 
(Pgp) are not of clinical concern.
There are no DDI-related concomitant medication prohibitions or restrictions. Lenvatinib is 
not expected to clinically meaningfully alter exposure to CYP3A4/ P-glycoprotein (Pgp) 
substrates based on results from a lenvatinib DDI study with midazolam (a sensitive CYP3A 
and Pgp substrate). Clinical studies also showed that co-administration of lenvatinib with 
either inducers or inhibitors of CYP3A4/Pgp are not of clinical concern. No drug interaction 
is expected between pembrolizumab and lenvatinib because of divergent metabolic 
pathways. Pembrolizumab is a monoclonal antibody and is primarily catabolized like other 
proteins, while lenvatinib is metabolized by enzymatic (CYP3A and aldehyde oxidase) and 
nonenzymatic processes (lenvatinib IB).
6.5.4
Rescue Medications and Supportive Care
Participants should receive appropriate supportive care measures as deemed necessary by the 
treating investigator. 
For participants receiving pembrolizumab + lenvatinib, suggested supportive care measures 
for the management of AEs with potential immunologic etiology are outlined in Table 6, 
Section 6.6.2.1, along with the dose modification guidelines in Table 5, in Section 6.6.1.
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Note: If after the evaluation of the event, it is determined not to be related to pembrolizumab, 
the investigator does not need to follow the treatment guidance. Refer to Table 6 in 
Section 6.6.2.1 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)
6.6.1
Lenvatinib Dose Modification
Lenvatinib dose reduction and interruption for participants who experience lenvatinib-
pembrolizumab combination therapy-related toxicity will be in accordance with the dose 
modification guidelines described in Table 5. An interruption of study intervention for more 
than 28 days will require Sponsor approval before treatment can be resumed.
Adverse events will be graded using NCI CTCAE Version 4.0. Investigators will decide the 
probability of the event being related to one or both drugs as to whether dose modification of 
one or both drugs is required.
The starting dose of lenvatinib is 20 mg/day for participants enrolled in Arm 1. Dose 
reductions of lenvatinib occur in succession based on the previous dose level (14, 10, and 
8 mg/day). Any dose reduction below 8 mg/day must be discussed with the Sponsor. Once 
the lenvatinib dose has been reduced, it may not be increased at a later date, unless the dose 
has been mistakenly decreased; in this situation, the Sponsor’s approval is required to 
increase the dose.
Refer to the subsections below for management of hypertension (Section 6.6.1.1), 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), PRES/RPLS (Section 6.6.1.6), hypocalcemia 
(Section 6.6.1.7), hemorrhage (Section 6.6.1.8), gastrointestinal perforation or fistula 
formation (Section 6.6.1.9), QT prolongation (Section 6.6.1.10) , and osteonecrosis of the 
jaw (Section 6.6.1.11)  as appropriate, before consulting the dose modification table 
(Table 5). For overlapping toxicities of pembrolizumab and lenvatinib, please refer to 
Section 6.6.3.
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Table 5
Dose Modification Guidelines for Lenvatinib-related Adverse Events (for the 
Lenvatinib-Pembrolizumab Combination)
Treatment-Related Toxicitya,b
Management
Dose Adjustment
Grade 1 or Tolerable Grade 2
Continue treatment
No change
Intolerable Grade 2c, d or Grade 3e,g
First occurrence
Interrupt lenvatinib until resolved 
to Grade 0-1, or tolerable Grade 2
Reduce lenvatinib dose to 14 mg once a 
day (1-level reduction) 
Second occurrence (same toxicity or 
new toxicity)
Interrupt lenvatinib until resolved 
to Grade 0-1, or tolerable Grade 2
Reduce lenvatinib dose to 10 mg once a 
day (1-level reduction) 
Third occurrence (same toxicity or 
new toxicity)
Interrupt lenvatinib until resolved 
to Grade 0-1, or tolerable Grade 2
Reduce lenvatinib dose to 8 mg orally once 
a day (1-level reduction) 
Fourth occurrence (same toxicity or 
new toxicity)
Interrupt lenvatinib 
Discuss with Sponsor
Grade 4f: Discontinue Study Treatment
Abbreviations: AE = adverse event; BMI = body mass index; CTCAE = Common Terminology Criteria for Adverse 
Events.
Note: For grading see CTCAE version 4.0. Collect all AE grades (ie, decreasing and increasing CTCAE grade). 
a.
An interruption of study treatment for more than 28 days will require Sponsor approval before treatment can be 
resumed.
b.
Initiate optimal medical management for nausea, vomiting, hypertension, hypothyroidism and/or diarrhea prior to 
any lenvatinib interruption or dose reduction. 
c.
Applicable only to Grade 2 toxicities judged by the participant and/or physician to be intolerable.
d.
Obese participants (BMI ≥30) with weight loss do not need to return to their baseline weight or within 10% of their 
baseline weight (ie, Grade 1 weight loss). These participants may restart study intervention at a lower dose once 
their weight remains stable for at least 1 week and they reach at least a BMI of 25. The new stable weight should be 
used as the new baseline for further dose reductions.
e.
For asymptomatic laboratory abnormalities, such as Grade ≥3 elevations of amylase and lipase that are not 
considered clinically relevant by the investigator, continuation of treatment should be discussed with Sponsor.
f.
Excluding laboratory abnormalities judged to be nonlife-threatening, in which case manage as Grade 3.
g.
For Grade 3 thromboembolic event, permanently discontinue lenvatinib. See Section 6.6.1.5.
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 v4.0, based on BP measurements only (and 
not on the number of antihypertensive medications).
If the participant’s initial BP measurement is elevated (ie, systolic BP ≥140 mm Hg or 
diastolic BP ≥90 mm Hg), the BP measurement should be repeated at least 5 minutes later. 
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One BP assessment is defined as the mean value of 2 measurements at least 5 minutes apart. 
If the BP assessment (ie, the mean of the 2 BP measurements obtained at least 5 minutes 
apart) is elevated (systolic BP ≥140 mm Hg or diastolic BP ≥90 mm Hg), a confirmatory 
assessment should be obtained at least 30 minutes later by performing 2 measurements (at 
least 5 minutes apart) to yield a mean value.
Antihypertensive agents should be started as soon as elevated BP (systolic BP ≥140 mm Hg 
or diastolic BP ≥90 mm Hg) is confirmed on 2 assessments at least 30 minutes apart. The 
choice of antihypertensive treatment should be individualized to the participant’s clinical 
circumstances and follow standard medical practice. For previously normotensive 
participants, appropriate antihypertensive therapy should be started when systolic BP 
≥140 mm Hg or diastolic BP ≥90 mm Hg is first observed on 2 assessments at least 
30 minutes apart. For those participants already on antihypertensive medication, treatment 
modification may be necessary if hypertension persists.
Lenvatinib should be withheld in any instance where a participant is at imminent risk to 
develop a hypertensive crisis or has significant risk factors for severe complications of 
uncontrolled hypertension (eg, BP ≥160/100 mm Hg, significant risk factors for cardiac 
disease, intracerebral hemorrhage, or other significant comorbidities). Once the participant 
has been on the same antihypertensive medications for at least 48 hours and the BP is 
controlled, lenvatinib should be resumed as described below.
Participants who have had systolic BP ≥160 mm Hg or diastolic BP ≥100 mm Hg must have 
their BP monitored on Day 15 (or more frequently as clinically indicated) until systolic BP 
has been ≤150 mm Hg and diastolic BP has been ≤95 mm Hg for 2 consecutive treatment 
cycles. If a repeat event of systolic BP ≥160 mm Hg or diastolic BP ≥100 mm Hg occurs, the 
participant must resume the Day 15 evaluation until systolic BP has been ≤150 mm Hg and 
diastolic BP has been ≤95 mm Hg for 2 consecutive treatment cycles. 
The following guidelines should be followed for the management of systolic BP 
≥160 mm Hg or diastolic BP ≥100 mm Hg confirmed on 2 BP assessments at least 
30 minutes apart:
1. Continue study intervention and institute antihypertensive therapy for participants not 
already receiving this.
2. For those participants already on antihypertensive medication, the dose of the current 
agent may be increased, if appropriate, or 1 or more agents of a different class of 
antihypertensive should be added. Study intervention can be continued without dose 
modification.
3. If systolic BP ≥160 mm Hg or diastolic BP ≥100 mm Hg persists despite maximal 
antihypertensive therapy, then lenvatinib administration should be interrupted and 
restarted at 1 dose level reduction only when systolic BP ≤150 mm Hg and diastolic BP 
≤95 mm Hg and the participant has been on a stable dose of antihypertensive medication 
for at least 48 hours.
•
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 
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medications (either by dose increase or the addition of a different class of 
antihypertensive), then lenvatinib administration should be interrupted and restarted 
at an additional dose reduction only when systolic BP ≤150 mm Hg and diastolic BP 
≤95 mm Hg and the participant has been on a stable dose of antihypertensive 
medication for at least 48 hours.
•
If systolic BP ≥160 mm Hg or diastolic BP ≥100 mm Hg recurs on the second dose 
reduction despite optimal management of hypertension with antihypertensive 
medications (either by dose increase or the addition of a different class of 
antihypertensive), then lenvatinib administration should be interrupted and restarted 
at a third dose reduction only when systolic BP ≤150 mm Hg and diastolic BP 
≤95 mm Hg and the participant has been on a stable dose of antihypertensive 
medication for at least 48 hours.
•
Additional dose reduction should be discussed with the Sponsor.
The following guidelines should be followed for the management of Grade 4 hypertension 
(life-threatening consequences):
1. Institute appropriate medical management
2. Discontinue study intervention
6.6.1.2
Management of Proteinuria
Regular assessment of proteinuria should be conducted as detailed in the SoA (Section 1.3.1 
and Section 1.3.2). Guidelines for assessment and management of proteinuria are as follows:
Detection and Confirmation
1. Perform urine dipstick testing or urinalysis per the SoA (Section 1.3.1 and 1.3.2). Urine 
dipstick testing is the preferred method for testing for urinary protein; however, urinalysis 
may be used if the use of urine dipsticks is not feasible.
2. A 24-hour urine collection initiated as soon as possible and at least within 72 hours (or an 
immediate spot urine protein-to-creatinine ratio [UPCR] test is required in the following 
situations):
•
The first (initial) occurrence of ≥2+ (≥100 mg/dL) proteinuria on urine dipstick (or 
urinalysis) while on study intervention.
•
A subsequent increase in severity of urine dipstick or urinalysis proteinuria occurring 
on the same lenvatinib dose level.
•
When there has been a lenvatinib dose reduction and at the new dose level the urine 
protein dipstick result is ≥2+ (≥100 mg/dL).
3. A 24-hour urine collection (initiated as soon as possible and at least within 72 hours) to 
verify the grade of proteinuria is required when UPCR is ≥2.4.
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Grading of Proteinuria
1. Grading according to NCI CTCAE v4.0 will be based on the 24-hour urinary protein 
result if one has been obtained. If the participant has 4+ proteinuria by dipstick (≥1000 
mg/dL by urinalysis), a 24-hour urinary protein result is required to confirm Grade 3 
proteinuria. Management of lenvatinib administration will be based on the grade of 
proteinuria according to Table 5.
Monitoring
a.
Urine dipstick or urinalysis testing for participants with proteinuria ≥2+ (≥100 mg/dL) 
should be performed on Day 15 (or more frequently as clinically indicated) until the 
results have been 1+ (30 mg/dL) or negative for 2 consecutive treatment cycles.
b. Proteinuria monitoring can be performed at the local laboratory or investigator site, but 
must be managed by the site physician.
c.
In the event of nephrotic syndrome, lenvatinib must be discontinued.
6.6.1.3
Management of Diarrhea
An antidiarrheal agent should be recommended to the participant at the start of study 
intervention and participants should be instructed and educated to initiate antidiarrheal
treatment at the first onset of soft bowel movements. The choice of antidiarrheal agent should 
be individualized to the participant’s clinical circumstances and follow standard medical 
practice. If signs/symptoms of diarrhea persist despite optimal medical management, 
instructions contained in Table 5 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 5 should be followed. Appropriate supportive care should be provided together with 
close monitoring. If hepatic failure (any grade per CTCAE v4) occurs, lenvatinib 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 that 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. If any of these symptoms appear, participants 
should be instructed to report such symptoms promptly to the treating physician. If a 
thromboembolic event is confirmed, instructions contained in Table 5 should be followed. 
Appropriate supportive care should be provided together with close monitoring. If a 
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participant experiences a Grade 3 or a life-threatening (Grade 4) thromboembolic reaction, 
including pulmonary embolism, lenvatinib must be discontinued.
Arterial thromboembolic events (eg, new onset, worsening, or unstable angina, myocardial 
infarction, transient ischemic attack, and cerebrovascular accident) of any grade require study 
intervention 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 5 should be followed.
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 v4.0, using 
the following formula:
Corrected calcium = ([4 – serum albumin in g/dL] × 0.8 + serum calcium)
The formula is not applicable when serum albumin concentration is normal (˃4 g/dL); in 
such situations, the total (uncorrected) serum calcium should be used instead.
Hypocalcemia should be treated per institutional guidelines (eg, using appropriate calcium, 
magnesium, and vitamin D supplementation) until resolution.
6.6.1.8
Management of Hemorrhage
Instructions in Table 5 should be followed for the management of hemorrhage. Either resume 
at a reduced dose or discontinue lenvatinib 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 Grade 4 fistula.
6.6.1.10
Management of QT Prolongation
Lenvatinib should be withheld in the event of development of QT interval prolongation 
greater than 500 msec. Lenvatinib should be resumed at a reduced dose when QTc 
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prolongation is resolved to <480 msec or baseline. Monitor potassium, calcium and 
magnesium, and replenish as appropriate.
6.6.1.11
Management of Osteonecrosis of the Jaw
Perform an oral examination prior to treatment with lenvatinib and periodically during 
lenvatinib treatment. Advise participants regarding good oral hygiene practices. Avoid 
invasive dental procedures, if possible, while on lenvatinib treatment, particularly in 
participants at higher risk. For participants requiring invasive dental procedures, 
discontinuation of bisphosphonate treatment may reduce the risk of ONJ. Withhold 
lenvatinib if ONJ develops and restart based on clinical judgement of adequate resolution 
(See Section 6.6.4).
6.6.2
Pembrolizumab Dose Modification
6.6.2.1
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue)
Dose Modification and Toxicity Management for Immune-related AEs Associated with 
Pembrolizumab
AEs associated with pembrolizumab exposure may represent an immune-related response. 
These irAEs may occur shortly after the first dose or several months after the last dose of 
pembrolizumab treatment and may affect more than one body system simultaneously. 
Therefore, early recognition and initiation of treatment is critical to reduce complications. 
Based on existing clinical study data, most irAEs were reversible and could be managed with 
interruptions of pembrolizumab, administration of corticosteroids and/or other supportive 
care. For suspected irAEs, ensure adequate evaluation to confirm etiology or exclude other 
causes. Additional procedures or tests such as bronchoscopy, endoscopy, skin biopsy may be 
included as part of the evaluation. Based on the severity of irAEs, withhold or permanently 
discontinue pembrolizumab and administer corticosteroids. 
Dose Modification and Toxicity Management Guidelines for irAEs associated with 
pembrolizumab monotherapy, coformulations, or IO combinations are provided in Table 6.
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Table 6
Dose Modification and Toxicity Management Guidelines for Immune-related Adverse Events Associated with 
Pembrolizumab Monotherapy, Coformulations or IO Combinations
General instructions:
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 7.
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Table 7
Pembrolizumab Infusion Reaction Dose Modification and Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at Subsequent Dosing
Grade 1
Mild reaction; infusion interruption not 
indicated; intervention not indicated.
Increase monitoring of vital signs as medically indicated until the participant is 
deemed medically stable in the opinion of the investigator.
None.
Grade 2
Requires therapy or infusion 
interruption, but responds promptly to 
symptomatic treatment (eg, 
antihistamines, NSAIDs, narcotics, IV 
fluids); prophylactic medications 
indicated for ≤24 hrs.
Stop Infusion.
Additional appropriate medical therapy may include, but is not limited to:

IV fluids

Antihistamines

NSAIDs

Acetaminophen

Narcotics
Increase monitoring of vital signs as medically indicated until the participant is 
deemed medically stable in the opinion of the investigator.
If symptoms resolve within 1 hour of stopping drug infusion, the infusion may be 
restarted at 50% of the original infusion rate (eg, from 100 mL/hr to 50 mL/hr). 
Otherwise dosing will be held until symptoms resolve and the participant should be 
premedicated for the next scheduled dose.
Participants who develop Grade 2 toxicity despite adequate premedication should 
be permanently discontinued from further study intervention.
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 to 1000 mg PO (or 
equivalent dose of analgesic).
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NCI CTCAE Grade
Treatment
Premedication at Subsequent Dosing
Grades 3 or 4
Grade 3:
Prolonged (ie, not rapidly responsive 
to symptomatic medication and/or 
brief interruption of infusion); 
recurrence of symptoms after initial 
improvement; hospitalization indicated 
for other clinical sequelae (eg, renal 
impairment, pulmonary infiltrates).
Grade 4:
Life-threatening; pressor or ventilatory 
support indicated.
Stop Infusion.
Additional appropriate medical therapy may include, but is not limited to:

Epinephrine**

IV fluids

Antihistamines

NSAIDs

Acetaminophen

Narcotics

Oxygen

Pressors

Corticosteroids
Increase monitoring of vital signs as medically indicated until the participant is 
deemed medically stable in the opinion of the investigator.
Hospitalization may be indicated.
**In cases of anaphylaxis, epinephrine should be used immediately.
Participant is permanently discontinued from further study intervention.
No subsequent dosing.
CTCAE = Common Terminology Criteria for Adverse Events; 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 v4.0 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 intervention. Therefore, evaluation of 
attribution is important for determining the study intervention most likely related to the AE, 
or an alternative etiology, and subsequently proper clinical management. The following 
aspects should be considered: 
1. Timing of AE onset 
Since lenvatinib is dosed daily and continuously due to a relatively short half-life (28 hours), 
and pembrolizumab is dosed Q3W due to a long half-life, lenvatinib can be interrupted to 
assess whether an AE improves/resolves with dechallenge (ie, interruption of treatment) 
based on the following 2 scenarios:
•
If an AE is identified during a treatment cycle (ie, between 2 pembrolizumab doses), only 
lenvatinib dose interruption is needed. 
•
If an AE is identified at the beginning of a treatment cycle, lenvatinib can be interrupted 
and dosing of pembrolizumab should be held.
If the participant recovers from an AE in response to lenvatinib interruption (ie, positive 
dechallenge), the event is more likely to be related to lenvatinib. Otherwise, after excluding 
other alternative explanations, an immune-related AE should be considered. 
2. Severity of AE
If an AE is suspected to be treatment related and is severe/life threatening at the time of onset 
or is rapidly worsened, action including interrupting both drugs and initiating treatment with 
a corticosteroid (with exception of hypothyroidism, T1DM) and other supportive care should 
be taken promptly.
Participants receiving the combination therapy (pembrolizumab + lenvatinib) must 
discontinue study therapy if any of the following occur: 
•
ALT or AST >5 X ULN for more than 2 weeks
Pembrolizumab will have already been permanently discontinued per Table 6, but 
lenvatinib may be administered at a reduced dose by the time this criterion is met and 
must be permanently discontinued immediately. 
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•
ALT or AST >3 X ULN and (TBL >2 X ULN or INR >1.5)
Although Table 6 advises pembrolizumab to be withheld (interrupted), and Table 5
advises lenvatinib to have no dose modification or a reduction, if this criterion is met, 
both drugs must be permanently discontinued immediately.
•
ALT or AST >3 X ULN with appearance of at least 1 of the following: fatigue, nausea, 
vomiting, RUQ pain/tenderness, fever, rash, and/or eosinophilia (>5%).
Although Table 6 advises pembrolizumab to be withheld (interrupted), and Table 5
advises lenvatinib to have no dose modification or a reduction, if this criterion is met, 
both drugs must be permanently discontinued immediately.
6.6.4
Other Allowed Dose Interruptions 
If the participant is receiving treatment with lenvatinib and requires surgery during the study, 
the stop time and restart time of lenvatinib should be as follows:
•
For minor procedures: stop lenvatinib at least 2 days before the procedure and restart it at 
least 2 days after, once there is evidence of adequate healing and no risk of bleeding.
•
For major procedures: stop lenvatinib at least 1 week (5 half-lives) prior to surgery and 
then restart it at least 2 weeks after, once there is evidence of adequate healing and no 
risk of bleeding.
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as 
medical/surgical events and/or unforeseen circumstances not related to study intervention. 
However, study intervention is to be restarted within 3 weeks (21 days) of the originally 
scheduled dose and within 42 days of the previously administered dose, unless otherwise 
discussed with the Sponsor. The reason for interruption is to be documented in the 
participant’s study record.
Pembrolizumab may be interrupted for treatment-related AEs for up to 12 weeks. Resuming 
pembrolizumab after an interruption >12 weeks requires Sponsor consultation.
Resuming lenvatinib after an interruption from the protocol-specified treatment plan for 
>28 consecutive days requires Sponsor consultation.
Resuming paclitaxel (or docetaxel for participants who experience either a severe 
hypersensitivity reaction to paclitaxel or an AE requiring discontinuation of paclitaxel only 
after consultation with the Sponsor, see Section 4.3.3.1)/carboplatin after an interruption 
from the protocol-specified treatment plan for >6 weeks requires Sponsor consultation.
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) with or without lenvatinib if they progress after stopping study treatment from the 
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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:
•
Experienced an investigator-determined radiographic disease progression by RECIST 1.1 
after stopping initial treatment with pembrolizumab, and
•
No new anticancer treatment was administered after the last dose of study intervention, 
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.
AND EITHER
•
Stopped initial treatment with pembrolizumab with or without stopping of lenvatinib, 
after attaining an investigator-determined confirmed CR according to RECIST 1.1.
-
Was treated for at least 8 infusions of pembrolizumab before discontinuing therapy, 
and 
-
Received at least 2 infusions of pembrolizumab beyond the date when the initial CR 
was declared.
OR
•
Had SD, PR or CR and stopped pembrolizumab treatment after completion of 
35 infusions (approximately 2 years) of study intervention for reasons other than disease 
progression or intolerability.
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.
Visit requirements for the Second Course Phase are outlined in Section 1.3.2.
6.6.6
Paclitaxel and Carboplatin Chemotherapy
Management for participants who experience paclitaxel-related or carboplatin-related toxicity 
will be in accordance with the respective paclitaxel or carboplatin prescribing information in 
each country/region or local institutional guidelines.
Prophylactic use of granulocyte colony stimulating factors may be used to treat treatment-
emergent neutropenia per local guidelines.
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For participants who have transitioned to docetaxel due to a severe hypersensitivity reaction 
or an AE requiring discontinuation of paclitaxel (after Sponsor consultation), management of 
the docetaxel-related toxicity will be in accordance with the respective docetaxel prescribing 
information in each country/region or local institutional guidelines (see Section 4.3.3.1).
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, lenvatinib 
monotherapy, or a combination of both pembrolizumab and lenvatinib as received 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, 
and/or designee are not blinded. Study intervention (name, strength or potency) is included in 
the label text; random code/disclosure envelopes or lists are not provided.
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
Discontinuation of study intervention does not represent withdrawal from the study.
As certain data on clinical events beyond study intervention discontinuation may be 
important to the study, they must be collected through the participant’s last scheduled follow-
up, even if the participant has discontinued study intervention. Therefore, all participants 
who discontinue study intervention prior to completion of the protocol-specified treatment 
period will still continue to participate in the study as specified in Section 1.3 and 
Section 8.11.3.
Participants may discontinue study intervention at any time for any reason or be discontinued 
from the study intervention at the discretion of the investigator should any untoward effect 
occur. In addition, a participant may be discontinued from study intervention by the 
investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or 
for administrative and/or other safety reasons. Specific details regarding procedures to be 
performed at study intervention discontinuation are provided in Section 8.1.9 and 
Section 8.11.3.
A participant must be discontinued from study intervention but continue to be monitored in 
the study for any of the following reasons:
•
The participant or participant’s legally acceptable representative requests to discontinue 
study intervention.
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•
The participant has a medical condition or personal circumstance which, in the opinion of 
the investigator and/or Sponsor, places the participant at unnecessary risk from continued 
administration of study intervention.
•
The participant has a confirmed positive serum pregnancy test.
•
Confirmed radiographic disease progression (iCPD) outlined in Section 8.2.1.6 
(exception if after obtaining informed consent addendum and Sponsor communication, 
the investigator may elect to continue treatment beyond confirmed disease progression).
•
Any progression or recurrence of any malignancy, or occurrence of another malignancy 
that requires active treatment.
•
Unacceptable toxicity as described in Section 6.6 and Table 5 and Table 6.
•
ALT or AST elevation meeting the following criteria:
-
ALT or AST >5 X ULN for more than 2 weeks
Pembrolizumab will have already been permanently discontinued per Table 6, but 
lenvatinib may be administered at a reduced dose by the time this criterion is met and 
must be permanently discontinued immediately.
-
ALT or AST >3 X ULN and (TBL >2 X ULN or INR >1.5)
Although Table 6 advises pembrolizumab to be withheld (interrupted), and Table 5
advises lenvatinib to have no dose modification or a reduction, if this criterion is met, 
both drugs must be permanently discontinued immediately.
-
ALT or AST >3 X ULN with appearance of at least 1 of the following: fatigue, 
nausea, vomiting, right upper quadrant (RUQ) pain/tenderness, fever, rash, and/or 
eosinophilia (>5%)
Although Table 6 advises pembrolizumab to be withheld (interrupted), and Table 5
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.
•
The study is terminated by the Sponsor.
•
The study is terminated by the local health authority, IRB, or IEC.
•
Completion of 35 infusions of pembrolizumab or up to 7 cycles of paclitaxel (or 
docetaxel for participants who experience either a severe hypersensitivity reaction to 
paclitaxel or an AE requiring discontinuation of paclitaxel only after consultation with 
the Sponsor, see Section 4.3.3.1) plus carboplatin. Note: If a participant in Arm 1
completes 35 infusions of pembrolizumab, she should continue with lenvatinib alone until 
disease progression or unacceptable toxicity.
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7.2
Participant Withdrawal From the Study
It has been well-documented that a higher rate of withdrawal can render a study 
uninterpretable; therefore, unnecessary withdrawal of participants should be avoided.
As clinical event data are important study endpoints, participants who discontinue study 
intervention prior to completion of the treatment period should be encouraged to continue all 
remaining study visits for follow-up and vital status assessment as outlined in the SoA and
Section 8.11.3.
The investigator is to inform the participants that:
•
They may discontinue from study intervention at any time during the study, and
•
They are encouraged to continue visits in the study for follow-up, imaging, and vital 
status assessment
If participants elect to stop study procedures, they are encouraged to continue to be followed, 
which allows periodic survival follow-up and vital status data to be collected.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
•
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
•
The investigator or designee must make every effort to regain contact with the participant 
at each missed visit (eg, telephone calls and/or a certified letter to the participant’s last 
known mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
•
Note: A participant is not considered lost to follow-up until the last scheduled visit for the 
individual participant. The missing data for the participant will be managed via the 
prespecified statistical data handling and analysis guidelines.
8
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and their timing are summarized in the SoA.
•
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
•
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified or trained staff. Delegation of study site personnel responsibilities 
will be documented in the Investigator Trial File Binder (or equivalent).
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•
All study-related medical or dental decisions must be made by an investigator who is a 
qualified physician.
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of ICF may be utilized for screening or baseline 
purposes provided the procedure met the protocol-specified criteria and were performed 
within the time frame defined in the SoA.
•
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, Hepatitis C), and thus local regulations 
may require that additional informed consent be obtained from the participant. In these 
cases, such evaluations/testing will be performed in accordance with those regulations.
8.1
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented consent from each potential participant or each participant’s legally 
acceptable representative prior to participating in a clinical study. If there are changes to the 
participant’s status during the study (eg, health or age of majority requirements), the 
investigator or medically qualified designee must ensure the appropriate consent is in place.
Rescreened participants do not need to be reconsented if original consent was obtained 
greater than 28 days prior to Cycle 1.
8.1.1.1
General Informed Consent
Consent must be documented by the participant’s dated signature or by the participant’s 
legally acceptable representative’s dated signature on a consent form along with the dated 
signature of the person conducting the consent discussion.
A copy of the signed and dated consent form should be given to the participant before 
participation in the study.
The initial ICF, any subsequent revised written ICF, and any written information provided to 
the participant must receive the Institutional Review Board/Independent Ethics Committee’s 
(IRB/IEC’s) approval/favorable opinion in advance of use. The participant or his/her legally 
acceptable representative should be informed in a timely manner if new information becomes 
available that may be relevant to the participant’s willingness to continue participation in the 
study. The communication of this information will be provided and documented via a revised 
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consent form or addendum to the original consent form that captures the participant’s dated 
signature or by the participant’s legally acceptable representative’s dated signature.
The participant or legally acceptable representative will be asked to sign consent at the point 
of initial radiographic disease progression if the investigator recommends continuation of 
study intervention.
Specifics about a study and the study population will be added to the consent form template 
at the protocol level.
The informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, 
and Sponsor requirements.
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator who is a qualified 
physician to ensure that the participant qualifies for the study.
8.1.3
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant provides written informed consent. At the time of intervention 
allocation/randomization, site personnel will add the treatment/randomization number to the 
participant identification card.
The participant identification card also contains contact information for the emergency 
unblinding call center so that a healthcare provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
8.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee. The medical 
history will collect all active conditions and any condition diagnosed within the prior 
10 years that the investigator considers to be clinically important.
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 International 
Federation of Gynecology and Obstetrics (FIGO) stage at initial diagnosis (see Appendix 9), 
histopathology, location(s) of tumor burden, and all prior treatment (including prior radiation, 
prior chemotherapy, and prior surgery).
Participants will have disease that is either measurable or nonmeasurable per RECIST 1.1, 
but radiographically apparent, as assessed by BICR and defined in the eligibility criteria.
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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 28 days before first dose of study intervention.
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study. This also includes new medications started during the Second Course Phase 
through the Second Course Safety Follow-up Visit.
8.1.6
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur prior to randomization. Each participant 
will be assigned only 1 screening number. Screening numbers must not be re-used for 
different participants.
Any participant who is screened multiple times will retain the original screening number 
assigned at the initial screening visit.
Specific details on the screening visit requirements (screening/rescreening) are provided in 
Section 8.11.1.
8.1.7
Assignment of Treatment/Randomization Number
All eligible participants will be randomly allocated and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment allocation/randomization. Once a 
treatment/randomization number is assigned to a participant, it can never be re-assigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
8.1.8
Study Intervention Administration
Study interventions 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 and Day 15 of Cycle 1 and Day 1 of Cycle 2. Please refer to Section 
8.1.8.1.1 for further detail.
Study intervention should begin within 3 days of randomization.
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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. 
Participants will be instructed to bring their lenvatinib bottles with them to each study visit. 
Drug accountability should be evaluated and documented by site personnel, and appropriate 
steps should be taken to optimize compliance, if needed. 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.
8.1.8.1.3
Chemotherapy
Chemotherapy consists of paclitaxel (or docetaxel for participants who experience either a 
severe hypersensitivity reaction to paclitaxel or an AE requiring discontinuation of paclitaxel
only after consultation with the Sponsor, see Section 4.3.3.1) plus carboplatin. 
Paclitaxel will be administered IV as a 1-hour infusion (or per institutional guidelines) at a 
dose of 175 mg/m2 administered on Day 1 of each 21-day cycle.
Carboplatin will be administered IV as a 1-hour infusion (or per institutional guidelines) at 
AUC 6 mg/mL/min on Day 1 of each 21-day cycle. 
A lower starting dose of paclitaxel (135 mg/m2) and carboplatin (AUC 5 mg/mL/min) may 
be administered for participants who are at risk for developing toxicities due to prior 
pelvic/spine radiation. An AUC 5 mg/mL/min dose for carboplatin may be administered in 
accordance with local practice.
The administration procedure should follow the approved prescribing information for 
paclitaxel or carboplatin (or docetaxel for participants who experience either a severe 
hypersensitivity reaction to paclitaxel or an AE requiring discontinuation of paclitaxel only 
after consultation with the Sponsor, see Section 4.3.3.1) in each country/region or 
institutional guidelines.
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8.1.9
Discontinuation and Withdrawal
Participants who withdraw consent from the study should be encouraged to complete all 
applicable activities scheduled for the final study visit at the time of withdrawal.
If discontinuation occurs ≥30 days after the last dose of study treatment, a Safety Follow-up 
Visit (Section 8.11.3.1) 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.
8.2
Efficacy/Immunogenicity Assessments
8.2.1
Tumor Imaging and Assessment of Disease
The process for image collection and transmission to the iCRO 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 
imaging (MRI) is the preferred modality; however, CT with iodinated contrast may be used 
when contrast-enhanced MRI is contraindicated, or when necessary 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 to confirm radiographically apparent disease will be assessed by BICR. 
For stratification prior to randomization, measurable disease (yes versus no) will be assessed 
by BICR per RECIST 1.1. Participants with fluid-only disease (eg, pleural effusion or 
ascites, and no other radiographically apparent lesions), must have cytologic confirmation of 
malignancy.
All scheduled images for all study participants from the sites will be submitted to the central 
imaging vendor. In addition, images (including via other modalities) that are obtained at an 
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unscheduled time point to determine disease progression, as well as imaging obtained for 
other reasons, but which demonstrates radiologic progression, should also be submitted to the 
central imaging vendor.
Sites will follow RECIST 1.1 to assess response and progression.
When the investigator identifies radiographic progression per RECIST 1.1, the central 
imaging vendor will perform expedited verification of radiologic PD and communicate the 
results to the study site and Sponsor (see Section 8.2.1.5 and Figure 2). Treatment should 
continue until PD has been verified. Regardless of whether PD is verified, if the investigator 
considers the participant has progressed, but elects to implement iRECIST, the investigator 
will assess for confirmation of progression by iRECIST at subsequent time points. Images 
should continue to be submitted to the central imaging vendor.
8.2.1.1
Initial Tumor Imaging
The screening images must be submitted to the central imaging vendor for prospective
review.
Tumor imaging performed as part of routine clinical management is acceptable for use as 
screening tumor imaging if it is of diagnostic quality and performed within 28 days prior to 
the date of randomization and can be assessed by the central imaging vendor.
Bone scans performed as part of routine clinical management are acceptable for use as 
screening imaging if they are of diagnostic quality and performed within 42 days prior to the 
date of randomization and can be assessed by the central imaging vendor.
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
8.2.1.2
Tumor Imaging During the Study
The first on-study imaging assessment should be performed at 9 weeks (63 days ±7 days]) 
from the date of randomization. Subsequent tumor imaging should be performed every
9 weeks (63 days ±7 days) or more frequently if clinically indicated. After 54 weeks (378 
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days ±7 days]), participants who remain on treatment will have imaging performed every 12 
weeks (84 days ±7 days). Imaging timing should follow calendar days and should not be 
adjusted for delays in cycle starts. Imaging should continue to be performed until disease 
progression is identified by the investigator and verified by the central imaging vendor 
(unless the investigator elects to continue treatment and follow iRECIST), the start of new 
anticancer treatment, withdrawal of consent, or death, whichever occurs first. All 
supplemental imaging must be submitted to the central imaging vendor.
Objective response should be confirmed by a repeat imaging assessment. Tumor imaging to 
confirm PR or CR should be performed at least 4 weeks after the first indication of a 
response is observed. Participants will then return to regular scheduled imaging, starting with 
the next scheduled imaging time point. Participants who receive additional imaging for 
confirmation do not need to undergo the next scheduled tumor imaging if it is less than 4 
weeks later; tumor imaging may resume at the subsequent scheduled imaging time point. 
Note: Response does not typically need to be verified in real time by the central imaging 
vendor.
Per iRECIST (Section 8.2.1.6), 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 intervention. Exceptions are detailed in 
Section 8.2.1.6.
8.2.1.2.1
Bone Imaging During the Study
A bone scan at screening will only be performed in participants who have a history of bone 
metastases or are clinically symptomatic. The screening bone scan should be performed 
within 42 days prior to randomization (historical is acceptable). Subsequent bone scans in 
these participants with bone metastases at baseline will be performed at W27, and W54 after 
randomization, and every 24 weeks (±7 days) thereafter, or as clinically indicated, and ≤2 
weeks after a CR as assessed by the investigator.
8.2.1.2.2
Brain Imaging During the Study
A brain scan at screening will only be performed in participants who have a history of 
protocol-eligible brain metastases or are clinically symptomatic. The screening brain scan 
should be performed within 28 days prior to randomization. Subsequent brain scans in these 
participants with brain metastases at baseline will be performed every 9 weeks (±7 days) 
after randomization through W54 and Q12W thereafter, or as clinically indicated thereafter, 
and ≤2 weeks after achievement of a CR as assessed by the investigator.
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8.2.1.3
End of Treatment and Follow-up Tumor Imaging
For participants who discontinue study intervention, tumor imaging should be performed at 
the time of treatment discontinuation (±4 week window). If previous imaging was obtained 
within 4 weeks prior to the date of discontinuation, then imaging at treatment discontinuation 
is not mandatory. For participants who discontinue study intervention due to documented 
disease progression, this is the final required tumor imaging if the investigator elects not to 
implement iRECIST.
For participants who discontinue study intervention without documented disease progression, 
every effort should be made to continue monitoring disease status by tumor imaging using 
the same imaging schedule used while on treatment (every 9 or 12 weeks) until the start of a 
new anticancer treatment, disease progression, pregnancy, death, withdrawal of consent, or 
the end of the study, whichever occurs first.
8.2.1.4
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 iCRO for quality control, storage, and possible retrospective review.
The first on-study imaging assessment should be performed at 12 weeks (84 days ±7 days) 
after the restart of treatment. Subsequent tumor imaging should be performed every 12 weeks 
(84 days ±7 days) or more frequently, if clinically indicated. Participants who remain on 
treatment will have imaging performed as determined by the treating physician per the local 
standard of care, but not less frequently than every 12 weeks (84 days ±7 days).
Per iRECIST (Section 8.2.1.6), if tumor imaging shows initial PD, tumor assessment should 
be repeated 4 to 8 weeks later 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 the Sponsor, 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.
For participants who discontinue Second Course study intervention, tumor imaging should be 
performed at the time of treatment discontinuation (±4 week window). If previous imaging 
was obtained within 4 weeks prior to the date of discontinuation, then imaging at treatment 
discontinuation is not mandatory. For participants who discontinue study intervention due to 
documented disease progression, this is the final required tumor imaging.
For participants who discontinue Second Course study intervention without documented 
disease progression, every effort should be made to continue monitoring their disease status 
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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 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 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 12 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 intervention). Although RECIST 1.1 references a maximum of 
5 target lesions in total and 2 per organ, this protocol allows a maximum of 10 target lesions 
in total and 5 per organ, if clinically relevant to enable a broader sampling of tumor burden.
Investigator-assessed scans are to be submitted immediately to the iCRO for BICR 
verification of progression. After submission of scans, the iCRO will email the assessment to 
the site and Sponsor.
If disease progression is not verified, the process continues as follows:
•
If participant is clinically stable, continue study intervention per protocol at investigator 
discretion
-
resume imaging per protocol schedule (≥4 weeks to next scan)
-
send scans to iCRO
-
continue local assessment
-
do not change investigator assessment of progression
-
if subsequent scan(s) indicate progression, submit scan(s) to iCRO to request 
verification
•
If the participant is not clinically stable, best medical practice is to be applied
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If disease progression is verified, the process continues as follows:
•
Investigator judgment will determine action
•
If the participant is clinically stable and study intervention is to continue, a reconsent 
addendum must be signed
•
Obtain scans locally per original protocol schedule
•
Do not send scans to iCRO
Figure 2 illustrates the study intervention decision process involving verification of disease 
progression for participants.
•
For the purpose of this decision process, lack of clinical stability is defined as:
-
unacceptable toxicity
-
clinical signs or symptoms indicating clinically significant disease progression
-
decline in performance status
-
rapid disease progression or threat to vital organs or critical anatomical sites (eg, CNS 
metastasis, respiratory failure due to tumor compression, spinal cord compression) 
requiring urgent alternative medical intervention
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Figure 2
Imaging and Treatment for Clinically Stable Participants After First Radiologic 
Evidence of PD Assessed by the Investigator
Abbreviations: iCR=immune-related complete response; iCRO=imaging contract research organization; 
iPR=immune-related partial response; iRECIST=Response Evaluation Criteria in Solid Tumors 1.1 for 
immune-based therapeutics; iUPD=immune-related unconfirmed progressive disease; PD=progressive disease; 
RECIST=Response Evaluation Criteria in Solid Tumors.
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 8. This allowance to continue 
treatment despite initial radiologic PD takes into account the observation that some 
participants can have a transient tumor flare in the first few months after the start of 
immunotherapy, and then experience subsequent disease response. This data will be captured 
in the clinical database.
Clinical stability is defined as the following:
•
Absence of symptoms and signs indicating clinically significant progression of disease.
•
No decline in ECOG performance status.
Site submits all required imaging to 
imaging CRO (iCRO) with VOP request
Does iCRO 
verify PD per 
RECIST 1.1?
Does 
Investigator 
confirm PD 
per iRECIST?
YES: PD is verified.
NO: PD is not verified.
YES: confirms PD 
by iRECIST
NO: does not confirm 
PD by iRECIST
1. Participant may remain on study drug at Investigator discretion.
2.If iUPD: repeat imaging in 4-8 weeks, assess for confirmation of PD
3. If iSD/iPR/iCR: return to regular imaging schedule
4.Future imaging and participant management per iRECIST. Continue 
to submit imaging to iCRO until PD by RECIST 1.1 verified.
1. Participant discontinues trial 
treatment
2. Exception possible upon sponsor 
consultation.
3. Tumor imaging done only if needed 
for follow-up.
iRECIST
RECIST 1.1 PD identified by Investigator, participant is clinically stable: 
May continue study treatment at investigator discretion and after 
obtaining participant’s consent
Repeat imaging at 4-8 
weeks, assess per iRECIST. 
No additional VOP requests 
needed
Repeat imaging at 4-8 weeks, assess per 
iRECIST.
Submit VOP requests until PD verified
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•
No requirements for intensified management, including increased analgesia, radiation, or 
other palliative care.
Any participant deemed clinically unstable should be discontinued from study intervention at 
central verification of site-assessed first radiologic evidence of PD, and is not required to 
have repeat tumor imaging for confirmation of PD by iRECIST.
If the investigator decides to continue treatment, the participant may continue to receive 
study intervention and the tumor assessment should be repeated 4 to 8 weeks later to confirm 
PD by iRECIST, per investigator assessment. Images should continue to be sent in to the 
central imaging vendor for potential retrospective BICR.
If repeat imaging does not confirm PD per iRECIST, as assessed by the investigator, and the 
participant continues to be clinically stable, study intervention may continue and follow the 
regular imaging schedule. If PD is confirmed, participants will be discontinued from study 
intervention.
If a participant has confirmed radiographic progression (iCPD) as defined in Appendix 8, 
study intervention should be discontinued; however, if the participant is achieving a 
clinically meaningful benefit, an exception to continue study intervention may be considered 
after consultation with the Sponsor. In this case, if study intervention is continued, tumor 
imaging should continue to be performed after the intervals as outlined in Section1.3 and 
submitted to the central imaging vendor.
A description of the adaptations and iRECIST process is provided in Appendix 8, with 
additional details in the iRECIST publication [Seymour, L., et al 2017]. A summary of 
imaging and treatment requirements after first radiologic evidence of progression is provided 
in Table 8 and illustrated as a flowchart in Figure 2.
Table 8
Imaging and Treatment after First Radiologic Evidence of Progressive Disease
Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
First radiologic 
evidence of PD by 
RECIST 1.1 per 
investigator 
assessment
Submit the imaging 
to BICR for 
verification. Repeat 
imaging at 4 to 
8 weeks to confirm 
PD.
May continue study 
treatment at the 
assessment of the 
investigator and after 
the participant’s 
consent.
Submit the imaging to 
BICR for verification. 
Repeat imaging at 4 to 
8 weeks to confirm PD 
per investigator’s 
discretion only.
Discontinue 
treatment
First radiologic 
evidence of PD by 
RECIST 1.1 which 
has been verified 
by the central 
imaging vendor
Repeat imaging at 
4 to 8 weeks to 
confirm PD.
May continue study 
intervention at the 
investigator’s discretion 
while awaiting 
confirmatory tumor 
imaging by site by 
iRECIST.
Repeat imaging at 4 to 
8 weeks to confirm PD 
per investigator’s 
discretion only.
Discontinue 
treatment
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Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
Repeat tumor 
imaging confirms 
PD (iCPD) by 
iRECIST per 
investigator 
assessment
No additional 
imaging required.
Discontinue treatment 
(exception is possible 
upon consultation with 
Sponsor).
No additional imaging 
required.
Not applicable
Repeat tumor 
imaging shows 
iUPD by iRECIST 
per investigator 
assessment
Repeat imaging at 
4 to 8 weeks to 
confirm PD. May 
occur at next 
regularly scheduled 
imaging visit.
Continue study 
intervention at the 
investigator’s 
discretion.
Repeat imaging at 4 to 
8 weeks to confirm PD 
per investigator’s 
discretion only.
Discontinue 
treatment
Repeat tumor 
imaging shows 
iSD, iPR, or iCR 
by iRECIST per 
investigator 
assessment.
Continue regularly 
scheduled imaging 
assessments.
Continue study 
treatment at the 
investigator’s 
discretion.
Continue regularly 
scheduled imaging 
assessments.
May restart study 
treatment if 
condition has 
improved and/or 
clinically stable per 
investigator’s 
discretion. Next 
tumor imaging 
should occur 
according to the 
regular imaging 
schedule.
Abbreviations: BICR = blinded independent central review; iCPD = iRECIST confirmed progressive disease; 
iCR = iRECIST complete response; iPR = iRECIST partial response; iRECIST = 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 iCRO, but no rapid review will occur. If RECIST 1.1 disease progression has not 
been centrally verified, the site should continue treatment. Whether treatment continues, imaging should be collected and 
submitted to the iCRO with VOP request until RECIST 1.1 progression is verified by BICR.
8.2.2
Patient-reported Outcomes
The EORTC QLQ-C30, EORTC QLQ-EN24, and EQ-5D-5L, questionnaires will be 
administered by trained site personnel and completed electronically by participants in the 
following order: 1) EORTC QLQ-C30, 2) EORTC QLQ-EN24, then 3) EuroQoL EQ-5D-5L.
HRQoL will be assessed at on Day 1 of every cycle through Cycle 35, then every 4 cycles 
through Cycle 60, at time of discontinuation, at the 30 day and 90 day Safety Follow-up visit.
It is best practice and strongly recommended that electronic patient-reported outcomes 
(ePROs) are administered to randomized participants prior to drug administration, AE 
evaluation, and disease status notification. If the participant does not complete the ePROs at a
scheduled time point, the MISS_MODE form must be completed to capture the reason the 
assessment was not performed.
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NOTE: For some sites, the translated EORTC QLQ-C30 and/or 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-C30 and/or EORTC QLQ-EN24 translation 
might not be available for the entire duration of the study.
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.
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided. The total amount of blood to be drawn/collected over the course of the study, 
including approximate blood volume drawn/collected by visit and by sample type per 
participant, can be found in the Procedures Manual.
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
Physical examinations including oral examination (comprehensive or symptom-directed) will 
be performed as specified in the SoA (Section 1.3.1 and Section 1.3.2). A comprehensive 
physical examination will include evaluations of the head, eyes, ears, mouth, 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], heart rate [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.
•
BP and heart rate will be measured after the participant has been resting for 5 minutes. 
All BP measurements should be performed on the same arm, preferably by the same 
person.
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•
Only 1 BP measurement is needed for participants with systolic BP <140 mm Hg and 
diastolic BP <90 mm Hg. If the participant’s initial BP measurement is elevated (ie, 
systolic BP ≥140 mm Hg or diastolic BP ≥90 mm Hg), the BP measurement should be 
repeated at least 5 minutes later. One BP assessment is defined as the mean value of 2 
measurements at least 5 minutes apart. If the BP assessment (ie, the mean of the 2 BP 
measurements obtained at least 5 minutes apart) is elevated (systolic BP ≥140 mm Hg or 
diastolic BP ≥90 mm Hg), a confirmatory assessment should be obtained at least 30 
minutes later by performing 2 measurements (at least 5 minutes apart) to yield a mean 
value.
•
Under exceptional circumstances, for Day 15 blood pressure monitoring (Cycle 3 
onwards, if applicable), participants will have the option of having BP measured between 
visits 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.
See Section 10.7, Appendix 7 for Country-specific Requirements.
8.3.3
Electrocardiograms
•
Electrocardiograms (ECGs) will be obtained as designated in the SoA (Section 1.3). 
Complete, standardized, 12-lead ECG recordings that permit all 12 leads to be displayed 
on a single page with an accompanying lead II rhythm strip below the customary 3 × 4 
lead format are to be used. In addition to a rhythm strip, a minimum of 3 full complexes 
should be recorded from each lead simultaneously. Participants must be in the recumbent
position for a period of 5 minutes prior to the ECG. The Fridericia correction method for 
calculating QTc will be used.
•
QTc prolongation has been seen in some lenvatinib studies. Monitor ECGs every cycle 
(as specified in the Schedule of Assessments) 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. Please refer 
to the lenvatinib IB.
•
An ECG abnormality may meet the criteria of an AE as described in this protocol (see 
Appendix 3) and the CRF Completion Guidelines. In these instances, the AE 
corresponding to the ECG abnormality will be recorded on the appropriate CRF.
8.3.4
Echocardiogram or Multiple Gated Acquisition Scan 
A MUGA scan (using technetium-based tracer) or an ECHO will be performed to assess 
LVEF as designated in the SoA (Section 1.3). MUGA or eECHO 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 
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assessed by the institution will be entered onto the CRF. Investigator assessment will be 
based on institutional reports.
8.3.5
Clinical Safety Laboratory Assessments
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency.
•
The investigator or medically qualified designee (consistent with local requirements) 
must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the case report form 
(CRF). The laboratory reports must be filed with the source documents. Clinically 
significant abnormal laboratory findings are those which are not associated with the 
underlying disease, unless judged by the investigator to be more severe than expected for 
the participant's condition.
•
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the Laboratory Manual and the SoA.
•
If laboratory values from nonprotocol specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).
•
For any laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 30 days after the last dose of study intervention, every 
attempt should be made to perform repeat assessments until the values return to normal or 
baseline or if a new baseline is established as determined by the investigator.
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 8.4.6 
and Appendix 3.
Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant's legally authorized 
representative).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators need to document if an SAE was associated with a medication error, misuse, or 
abuse. Investigators remain responsible for following up AEs, SAEs, and other reportable 
safety events for outcome according to Section 8.4.3.
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The investigator, who is a qualified physician, will assess events that meet the definition of 
an AE or SAE as well as other reportable safety events with respect to seriousness, 
intensity/toxicity and causality.
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
All AEs, SAEs, and other reportable safety events that occur after the consent form is signed, 
but before intervention allocation/randomization must be reported by the investigator if the 
participant is receiving placebo run-in or other run-in treatment, if the event cause the 
participant to be excluded from the study, or is the result of a protocol-specified intervention, 
including, but not limited to washout or discontinuation of usual therapy, diet, or a procedure.
•
All AEs from the time of intervention allocation/randomization through 90 days, or 
30 days after cessation of study intervention if the participant initiates new anticancer 
therapy, must be reported by the investigator.
•
All AEs meeting serious criteria, from the time of intervention allocation/randomization 
through 120 days after cessation of study intervention or 30 days after cessation of study 
intervention if the participant initiates new anticancer therapy, whichever is earlier, must 
be reported by the investigator.
•
All pregnancies and exposure during breastfeeding, from the time of intervention
allocation/randomization through 120 days after cessation of study intervention, or 30 
days after cessation of study intervention if the participant initiates new anticancer 
therapy must be reported by the investigator.
•
Additionally, any SAE brought to the attention of an investigator at any time outside the 
time period specified above must be reported immediately to the Sponsor if the event is 
considered drug-related.
Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
Participants who Enter the Extension Study:
From the time of intervention randomization up to the signing of consent to the extension 
study, all AEs, SAEs, and other reportable safety events must be reported by the investigator 
in this protocol (parent study). Laboratory values that meet criteria for reporting as AEs 
performed during the parent study will be collected in the parent study.
Note: Once consented to the extension study, safety events, including those considered 
related to study intervention, will be collected as instructed in the extension study.
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All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 9.
Table 9
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation through 
Protocol-specified 
Follow-up Period
Reporting Time 
Period:
After the Protocol-
specified Follow-up 
Period
Time Frame to 
Report Event 
and Follow-up 
Information to 
Sponsor:
NSAE
Report if:
- due to protocol-specified 
intervention
- causes exclusion
- participant is receiving 
placebo run-in or other run-
in treatment
Report all
Not required
Per data entry 
guidelines
SAE including 
Cancer and 
Overdose
Report if:
- due to protocol-specified 
intervention
- causes exclusion
- participant is receiving 
placebo run-in or other run-
in treatment
Report all
Report if:
- drug/vaccine 
related.
(Follow ongoing to 
outcome)
Within 24 hours 
of learning of 
event
Pregnancy/
Lactation 
Exposure
Report if:
-  participant has been 
exposed to any protocol-
specified intervention (eg, 
procedure, washout or run-
in treatment including 
placebo run-in)
Exception: A positive 
pregnancy test at the time 
of initial screening is not a 
reportable event.
Report all
Previously reported –
Follow to 
completion/
termination; report 
outcome
Within 24 hours 
of learning of 
event
ECI (require 
regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report
- potential DILI
- require regulatory 
reporting
Not required
Within 24 hours 
of learning of 
event
ECI (do not 
require 
regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report
- non-DILI ECIs and 
those not requiring 
regulatory reporting
Not required
Within 5 calendar 
days of learning 
of event
DILI=drug-induced liver injury; ECI=event of clinical interest; NSAE=nonserious adverse event; SAE=serious adverse 
event.
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other 
reportable safety events. Open-ended and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE occurrence.
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8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs, SAEs, and other reportable safety events 
including pregnancy and exposure during breastfeeding, 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 the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and Sponsor policy and 
forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.4.5
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to 
the investigator or their designee) that occurs during the study are reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy.
Any pregnancy complication will be reported as an AE or SAE.
The medical reason (example: maternal health or fetal disease) for an elective termination of 
a pregnancy will be reported as an AE or SAE. Prenatal testing showing fetus will be born 
with severe abnormalities/congenital anomalies that leads to an elective termination of a 
pregnancy will be reported as an SAE for the fetus.
Pregnancy outcomes of ectopic pregnancy, spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth 
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must be reported as serious events (Important Medical Events). If the pregnancy continues to 
term, the outcome (health of infant) must also be reported.
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
Efficacy endpoints as outlined in this section will not be reported to the Sponsor as described 
in Section 8.4.1.
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study.
The Sponsor will ensure that unblinded aggregated efficacy endpoint events and safety data 
are monitored to safeguard the participants in the study.
8.4.7
Events of Clinical Interest (ECIs)
Selected nonserious and SAEs are also known as ECIs and must be reported to the Sponsor. 
Events of clinical interest for this study include: 
•
An overdose of Sponsor's product, as defined in Section 8.5, that is not associated with 
clinical symptoms or abnormal laboratory results.
•
An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less 
than 2X the upper limit of normal, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.* 
*Note: These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may 
require an additional evaluation for an underlying etiology. The study site guidance 
for assessment and follow up of these criteria can be found in the Investigator Study 
File Binder (or equivalent).
8.5
Treatment of Overdose
For purposes of this study, an overdose will be defined as any dose exceeding the prescribed 
dose for:
•
Pembrolizumab: ≥5 times the protocol-specified dose.
•
lenvatinib: any dose above the protocol-prescribed dose if associated with an adverse 
event
•
chemotherapy: any dose ≥20% over the prescribed dose described in the protocol
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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 participants 
receiving single doses of lenvatinib as high as 40 mg were similar to those in clinical studies 
at the recommended dose for differentiated thyroid cancer and RCC.
No specific information is available on the treatment of overdose of pembrolizumab, 
lenvatinib or chemotherapy. In the event of overdose, the participant should be observed 
closely for signs of toxicity. Appropriate supportive treatment should be provided if 
clinically indicated.
All reports of pembrolizumab overdose with and without an AE and all reports of lenvatinib 
overdose with an AE must be reported by the investigator within 24 hours to the Sponsor,
either by electronic media or paper. Reports of pembrolizumab overdose without any 
associated clinical symptoms or abnormal laboratory results should be reported using the 
terminology “accidental or intentional overdose without adverse effect”.
8.6
Pharmacokinetics
To evaluate the immunogenicity and exposure of pembrolizumab in this indication, sample 
collections for analysis of ADA and PK were obtained, but are discontinued in MK-7902-
001-04. Blood samples for PK and ADA collected may be stored only at this time. Further 
analysis may be performed if required and reported separately if conducted. 
To evaluate the exposure of lenvatinib in combination with pembrolizumab, blood samples 
were collected from all participants, but are discontinued in Amendment 4. 
Plasma concentrations of lenvatinib when co-administered with pembrolizumab may be 
measured. If performed, lenvatinib will be quantified by use of validated High Performance 
Liquid Chromatography-tandem mass spectroscopy method and data will be analyzed using a 
population PK approach.
8.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
8.8
Mismatch Repair
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.
If the MMR result is not available within 28 days from when the original consent was 
obtained, an extension may be granted after consultation with the Sponsor as long as all other 
screening procedures are performed within the correct timeframe.
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8.9
 
8.9.1
Planned Genetic Analysis Sample Collection
Samples should be collected for planned analysis of associations between genetic variants in 
germline/tumor DNA and drug response. If a documented law or regulation prohibits (or 
local IRB/Independent Ethics Committee [IEC] does not approve) sample collection for these 
purposes, then such samples should not be collected at the corresponding sites.
If providing slides, it is requested that the remainder of the tissue block be maintained at the 
site until the end of the study if a bridging study is required for development of the MMR 
assay.
8.10
Health Economics Medical Resource Utilization and Health Economics
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8.11
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.11.1
Screening
Approximately 28 days prior to intervention allocation/randomization, potential participants 
will be evaluated to determine that they fulfill the entry requirements as set forth in 
Section 5. Screening procedures may be repeated after consultation with the Sponsor.
Written consent must be obtained prior to performing any protocol-specific procedure.
Results of a test performed prior to the participant signing consent as part of routine clinical 
management are acceptable in lieu of a screening test if performed within the specified time 
frame. Screening procedures are to be completed within 28 days prior to the first dose of 
study treatment except for the following:
•
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 performed up to 28 
days 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 the Sponsor.
•
Evaluation of ECOG is to be performed within 7 days prior to the date of first dose of 
study treatment.
•
For women of reproductive potential, a urine or serum pregnancy test will be performed 
prior to randomization and within 24 hours prior to first dose of study intervention. If less 
than 24 hours have elapsed between the randomization test and first dose a second test is 
not required. If urine pregnancy results cannot be confirmed as negative, a serum 
pregnancy test will be required (performed by the local trial site laboratory).
•
Newly or recently obtained tumor tissue must have been obtained prior to randomization 
and preferably after the latest systemic treatment for EC.
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. Rescreened participants do not need to be reconsented if original consent 
was obtained greater than 28 days prior to Cycle 1.
8.11.2
Treatment Period
Visit requirements are outlined in the SoA (Section 1.3.1 and Section 1.3.2).
Assessments/procedures are to be performed prior to the administration of study treatment.
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8.11.3
Post-treatment Visit
8.11.3.1
Safety Follow-up
Safety Follow-up will occur during 2 separate visits: 30 days and 90 days after last dose. One 
mandatory Safety Follow-up visit should be conducted approximately 30 days after the last 
dose of study intervention or before the initiation of a new anticancer treatment, whichever 
comes first. 
The 90-day Safety Follow-up visit is only required for participants who have not yet started 
new anticancer treatment. If the 90-day Safety Follow-up visit falls within the same window 
as an imaging follow-up visit, the procedures required at both visits may be combined.
Follow-up visits to be scheduled to coincide with follow-up imaging. For participants 
continuing with imaging follow-up, if their 90-day Safety Follow-up visit falls within the 
same window as their imaging follow-up visit, these visits may be combined. All procedures 
required at the Safety Follow-up visit at 90 days will be performed at the imaging follow-up.
Participants who are eligible for retreatment with pembrolizumab (with or without 
lenvatinib) may have up to 4 safety follow-up visits, 2 after the Initial Treatment Period and 
2 after the Second Course Treatment.
8.11.3.2
Imaging Follow-up Visits
Participants who discontinue study treatment for a reason other than disease progression will 
move into the Follow-up Phase and should be assessed by every 9 or 12 weeks according to 
the imaging schedule (or more frequently as needed) by clinic visit to monitor disease status.
Every effort should be made to collect information regarding disease status until the start of 
new anticancer therapy, disease progression, death, end of study or if the participant begins 
retreatment with pembrolizumab as detailed in Section 6.6.5. Information regarding 
poststudy anticancer treatment will be collected if new treatment is initiated. Participants will 
also be asked to complete HRQoL questionnaires as outlined in Section 8.2.2.
All participants who discontinue study intervention prior to disease progression will continue 
to undergo tumor assessments every 9 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. After 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 (with or without 
lenvatinib) according to the criteria in Section 6.6.5 will move from the Follow-up Phase to 
the Second Course Phase when they experience disease progression. Details are provided in 
the SoA (Section 1.3.2) for retreatment.
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8.11.3.3
Survival Follow-up
Participants who experience confirmed disease progression or start a new anticancer therapy, 
will move into the Survival Follow-up Phase and should be contacted by telephone 
approximately every 12 weeks to assess for survival status until death, withdrawal of 
consent, or the end of the study, whichever occurs first.
8.11.4
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)
 
 
 
9.1
Statistical Analysis Plan Summary
Key elements of the SAP are summarized here. The comprehensive plan is provided in 
Sections 9.2 through 9.12.
Study Design
Overview
A Phase 3 Randomized, Open-Label, Study of Pembrolizumab 
(MK-3475) Plus Lenvatinib (E7080/MK-7902) Versus 
Chemotherapy for First-line Treatment of Advanced or Recurrent 
Endometrial Carcinoma (LEAP-001)
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Treatment
Assignment
Approximately 875 eligible participants (612 pMMR participants 
and approximately 263 dMMR participants) will be randomized 
to one of the following 2 treatment arms in a 1:1 ratio:

Arm 1:  pembrolizumab plus lenvatinib

Arm 2:  paclitaxel (or docetaxel for participants who 
experience either a severe hypersensitivity reaction to 
paclitaxel or an AE requiring discontinuation of paclitaxel, 
see Section 4.3.3.1) and carboplatin
Randomization stratification factors include:

MMR status (pMMR versus dMMR), and if pMMR:
-
ECOG (0 versus 1)
-
Measurable disease (yes versus no)
-
Prior chemotherapy and/or chemoradiation (yes versus no)
Eligible participants will first be stratified by MMR status 
(pMMR versus dMMR), then only within the pMMR stratum, 
participants will be further stratified according to ECOG (0 versus 
1), measurable disease (yes versus no) and prior chemotherapy 
and/or chemoradiation (yes versus no). A total of 9 strata will be 
used for the study.
Analysis Populations

Efficacy: Intent to Treat (ITT)

Safety: All Participants as Treated (APaT)
Primary Endpoints

PFS based on RECIST 1.1 as assessed by BICR, modified to 
follow a maximum of 10 target lesions and a maximum of 5 
target lesions per organ

OS
Secondary Endpoints

OR by BICR using RECIST 1.1

Patient reported quality of life assessed by mean change 
from baseline of EORTC QLQ-C30

Safety and tolerability of the 2 treatment arms
Statistical Methods
for Key Efficacy
Analyses
The primary hypotheses will be evaluated by comparing PFS and 
OS using a stratified log-rank test. The hazard ratio 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.
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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% CIs provided for between-group comparison; 
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 [Miettinen, O. and Nurminen, M. 1985].
Interim Analyses
Multiplicity
 
 
 
 
 
 The graphical approach of 
Maurer and Bretz [Maurer, W. and Bretz, F. 2013] will be applied
to re-allocate alpha among the hypotheses of PFS and OS.
 
 
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Sample Size and
Power
The planned sample size is approximately 875 participants 
(612 pMMR participants and approximately 
263 dMMR participants). 
 
 
 
 
 
 
 
 
 
 
9.2
Responsibility for Analyses/In-house Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
The Sponsor will generate the randomized allocation schedule for study intervention
assignment for this protocol and the randomization will be implemented in IVRS/IWRS.
Although the study is open label, analyses or summaries generated by randomized treatment 
assignment, or actual treatment received status will be limited and documented. Further 
documentation will be provided in the sSAP. In addition, the independent radiologist(s) will 
perform the central imaging review without knowledge of treatment group assignment.
Blinding issues related to the planned interim analyses are described in Section 9.7.
9.3
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.
9.4
Analysis Endpoints
Efficacy, safety and PRO endpoints that will be evaluated for within- and/or between-
treatment differences are listed below. Other endpoints will be described in the sSAP.
Primary
PFS is defined as the time from randomization to the first documented disease progression 
per RECIST 1.1 as assessed by BICR, modified to follow a maximum of 10 target lesions 
and a maximum of 5 target lesions per organ or death due to any cause, whichever occurs 
first.
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OS is defined as the time from randomization to death due to any cause.
Secondary
OR is defined as a confirmed CR or PR per RECIST 1.1 as assessed by BICR.
PRO endpoints will be assessed by mean change from baseline of the global score of the 
EORTC QLQ-C30.
Safety will be assessed by the number of AEs, SAEs, and irAEs and the number of 
participants discontinuing study intervention due to AEs
9.5
Analysis Populations
Extension Portion of the Study in China
After the sample size required for the Global Cohort is reached, the study will continue to
randomize participants in China until the sample size for the Chinese participants meets the 
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target for China. The Chinese subjects randomized after the enrollment of the Global Cohort 
is closed will not be included in the primary analysis population which is based on the Global 
Cohort. The China Cohort may also be analyzed separately per local regulatory requirement.
9.5.1
Efficacy Analysis Populations
The 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 arm to which they are randomized.
9.5.2
Safety Analysis Populations
The APaT population will be used for the analysis of safety data in this study. The APaT 
population consists of all randomized/allocated participants who received at least 1 dose of 
study intervention. Participants will be included in the treatment group corresponding to the 
study intervention they actually received for the analysis of safety data using the APaT 
population. This will be the treatment group to which they are randomized except for 
participants who take incorrect study intervention for the entire treatment period; such 
participants will be included in the treatment group corresponding to the study intervention 
actually received.
At least 1 laboratory, vital sign, or ECG measurement obtained after at least 1 dose of study 
intervention is required for inclusion in the analysis of the respective safety parameter. To 
assess change from baseline, a baseline measurement is also required.
Details on the approach to handling safety analyses are provided in Section 9.6.2.
9.5.3
PRO Analysis Population
The PRO analyses are based on the PRO FAS population, defined as participants who have at 
least 1 PRO assessment available and have received at least 1 dose of study intervention.
9.6
Statistical Methods
9.6.1
Statistical Methods for Efficacy Analyses
This section describes the statistical methods that address the primary and secondary
objectives. 
 
Statistical testing and inference for safety analyses are described in Section 9.6.2. Efficacy 
results that will be deemed to be statistically significant after consideration of the Type I 
error control strategy are described in Section 9.8. Nominal p-values will be computed for 
other efficacy analyses, but should be interpreted with caution due to potential issues of 
multiplicity.
The stratification factors used for randomization (see Section 6.3.2) will be applied to all 
stratified analyses, in particular, the stratified log-rank test, stratified Cox model, and 
stratified Miettinen and Nurminen method [Miettinen, O. and Nurminen, M. 1985]. If there 
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are small strata, for the purpose of analysis, strata will be combined to ensure sufficient 
number of participants, responses and events in each stratum. Details regarding the pooling 
strategy will be prespecified in the sSAP prior to the database lock for the first analysis when 
each applicable endpoint will be analyzed, and decisions regarding the pooling will be based 
on a blinded review of response and event counts by stratum.
9.6.1.1
Progression-free Survival (PFS)
The nonparametric 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. 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 6.3.2) will be applied to both the stratified log-rank test and the 
stratified Cox model.
Since disease progression is assessed periodically, PD can occur any time in the time interval 
between the last assessment where PD was not documented and the assessment when PD is 
documented. The true date of disease progression will be approximated by the date of the 
first assessment at which PD is objectively documented per RECIST 1.1 (based on BICR). 
Death is always considered as a PD event. Participants who do not experience a PFS event 
will be censored at the last disease assessment. Sensitivity analyses will be performed for 
comparison of PFS based on investigator’s assessment.
To evaluate the robustness of the PFS endpoint per RECIST 1.1 based on BICR, one primary 
and 2 sensitivity analyses with a different set of censoring rules will be performed. For the 
primary analysis, if the events (PD or death) are immediately after more than one missed 
disease assessment, the data are censored at the last disease assessment prior to missing 
visits. Also data after new anticancer therapy are censored at the last disease assessment prior 
to the initiation of new anticancer therapy. The first sensitivity analysis follows the complete 
follow-up intention-to-treat principle. PDs/deaths are counted as events regardless of missed 
study visits or initiation of new anticancer therapy. The second sensitivity analysis, it 
considers discontinuation of treatment or initiation of an anticancer treatment after
discontinuation of study-specified treatments, whichever occurs later, to be a PD event for 
participants without documented PD or death. If a participant meets multiple criteria for 
censoring, the censoring criterion that occurs earliest will be applied. The censoring rules for 
primary and sensitivity analyses are summarized in Table 10.
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Table 10
Censoring Rules for Primary and Sensitivity Analyses of Progression-free 
Survival
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 intervention.
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
An analysis of PFS2, defined as the time from randomization to subsequent disease 
progression after initiation of new anticancer therapy, or death from any cause, whichever 
first, will be performed. Participants alive and for whom a disease progression after initiation 
of new anticancer treatment has not been observed will be censored at the last time the 
participant was known to be alive and without disease progression. The same stratified Cox 
proportional hazard model will be used to estimate the HR and its 95% CI.
9.6.1.2
Overall Survival (OS)
The nonparametric 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 6.3.2). 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 6.3.2) 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. The Restricted Mean Survival Time (RMST) method may be 
conducted for OS to account for the possible nonproportional hazards effect.
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9.6.1.3
Objective Response Rate (ORR)
Stratified Miettinen and Nurminen’s method will be used for comparison of the objective 
response rate (ORR) between 2 treatment groups [Miettinen, O. and Nurminen, M. 1985]. 
The difference in ORR and its 95% confidence interval (CI) 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 6.3.2) will be applied to the analysis.
A summary of the primary analysis strategy for the key efficacy endpoints is provided in 
Table 11.
Table 11
Efficacy Analysis Methods for Key Efficacy Endpoints
Endpoint/Variable
Statistical Method
Analysis 
Population
Missing Data Approach
Primary Analyses:
PFS (RECIST 1.1) by 
BICR
Testing: Stratified Log-rank Test 
Estimation: Stratified Cox model 
with Efron’s tie handling method.
ITT
Censored according to rules in 
Table 10.
OS
Testing: Stratified Log-rank Test 
Estimation: Stratified Cox model 
with Efron’s tie handling method.
ITT
Censored at last known alive date.
Secondary Analyses:
ORR (RECIST 1.1) by 
BICR
Testing: Stratified Miettinen and 
Nurminen method [Miettinen, O. 
and Nurminen, M. 1985a].
ITT with 
measurable 
disease at 
baseline
Participants with missing data are 
considered nonresponders.
Sensitivity analyses will be performed for PFS, and ORR based on investigator’s assessment.
9.6.2
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, laboratory tests, vital signs, and ECG measurements.
The analysis of safety results will follow a tiered approach (Table 12). 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 
classified as belonging to “Tier 2” or “Tier 3” based on the observed proportions of 
participants with an event.
Tier 1 Events
Safety parameters or adverse events of special interest (AEOSIs) that are identified a priori
constitute “Tier 1” safety endpoints that will be subject to inferential testing for statistical 
significance. AEOSIs that are immune-mediated or potentially immune-mediated are well 
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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 plus lenvatinib included in this study has not been found to 
impact safety. 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 (via the Miettinen and Nurminen method 
[Miettinen, O. and Nurminen, M. 1985]).
Membership in Tier 2 requires that at least 10% of participants in any treatment group show
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 for Tier 2 events may 
be provided without adjustment for multiplicity, the CIs should be regarded as a helpful 
descriptive measure to be used in review, not a formal method for assessing the statistical 
significance of the between-group differences.
Tier 3 Events
Safety endpoints that are not Tier 1 or 2 events are considered Tier 3 events. 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 to 5 AE, a drug-related 
Grade 3 to 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.
Continuous Safety Measures
For continuous measures such as changes from baseline in laboratory, vital signs, and ECG 
parameters, summary statistics for baseline, on-treatment, and change from baseline values 
will be provided by treatment group in table format.
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Table 12
Analysis Strategy for Safety Parameters
Safety 
Tier
Safety Endpoint
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
Any AE leading to death
X
Specific AEs, SOCs (incidence <10% 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 Methods for PRO Analyses
This section describes the planned analyses for the PRO endpoints.
To evaluate the treatment effect on the health-related QoL outcomes at prespecified time 
points, a constrained longitudinal data analysis (cLDA) model will be applied, with the PRO 
score as the response variable, and the treatment by time interaction and stratification factors 
as covariates. Least square mean (LS mean) change from baseline will be summarized.
Group-wise comparisons will be performed, and model-based LS mean score will be 
provided by treatment group and study visit.
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 randomized, and the primary 
reason for discontinuation will be displayed. Demographic variables (such as age) and 
baseline characteristics will be summarized by treatment either by descriptive statistics or 
categorical tables. The reasons for exclusion from the ITT population (if any) will be 
summarized.
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9.7
Interim Analyses
An eDMC will serve as the primary reviewer of the results of the interim analyses of the 
study and will make recommendations for discontinuation of the study or protocol 
modifications to an Executive Oversight Committee of the Sponsor. If the eDMC 
recommends modifications to the design of the protocol or discontinuation of the study, this 
Executive Oversight Committee (and potentially other limited Sponsor personnel) may be 
unblinded to results at the treatment level to act on these recommendations. The extent to 
which individuals are unblinded with respect to results of interim analyses will be 
documented by the unblinded statistician. Additional logistical details will be provided in the 
eDMC Charter. Key aspects of the interim analyses are described in Section 9.7.2.
Treatment-level results from the interim analysis will be provided to the eDMC by the 
unblinded statistician. Prior to final study unblinding, the unblinded statistician will not be 
involved in any discussions regarding modifications to the protocol, statistical methods, 
identification of protocol deviations, or data validation efforts after the interim analyses.
9.7.1
Safety Interim Analyses
The eDMC will conduct regular safety interim analyses. The timing of these safety interim 
analyses will be specified in the eDMC charter.
9.7.2
Efficacy Interim Analyses
CCI
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9.8
Multiplicity
The study uses the graphical method of Maurer and Bretz [Maurer, W. and Bretz, F. 2013] to 
control multiplicity for multiple hypotheses as well as interim analyses. 
 
 
CCI
CCI
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9.8.1
Efficacy Analyses
9.8.1.1
Progression-free Survival
CCI
CCI
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9.8.1.2
Overall Survival
CCI
CCI
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9.8.1.3
Safety Analyses
The eDMC has responsibility for assessment of overall risk: benefit. When prompted by 
safety concerns, the eDMC can request corresponding efficacy data. eDMC review of 
efficacy data to assess the overall risk: benefit to study participants will not require a 
multiplicity adjustment typically associated with a planned efficacy IA. However, to account 
for any multiplicity concerns raised by the eDMC review of unplanned efficacy data when 
CCI
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prompted by safety concerns, a sensitivity analysis for OS adopting a conservative 
multiplicity adjustment will be prespecified in the sSAP.
9.9
Sample Size and Power Calculations
The sample size is estimated based on the primary endpoints PFS and OS. Approximately 
875 participants (including approximately 612 pMMR participants and approximately 
263 dMMR participants) will be randomized in a 1:1 ratio for the global study.
The study will be considered to be fully enrolled when 612 pMMR participants have
enrolled. 
Sample size and power calculations are based on pMMR participants:
9.10
Subgroup Analyses
To determine whether the treatment effect is consistent across various subgroups, the 
between-group treatment effect for PFS and OS (with a nominal 95% CI) will be estimated 
and plotted by treatment group within each category of the following classification variables:
•
Stratification factors
MMR status (pMMR versus dMMR)
-
If pMMR
◦
ECOG (0 versus 1)
◦
Measurable disease (yes versus no)
◦
Prior chemotherapy and/or chemoradiation (yes versus no)
CCI
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•
Age group (<65 years versus ≥65 years)
•
Race (white, non-white)
The consistency of the treatment effect will be assessed descriptively via summary statistics 
by category for the classification variables listed above. If the number of participants in a 
category of a subgroup variable is less than 10% of the ITT population, the subgroup analysis 
will not be performed for this category of the subgroup variable, and this subgroup variable 
will not be displayed in the forest plot.
9.11
Compliance (Medication Adherence)
Drug accountability data for study intervention will be collected during the study. Any 
deviation from protocol-directed administration will be reported.
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.
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
10.1.1
Code of Conduct for Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing and reporting these trials 
in compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design of clinical trials. In all cases, MSD clinical trials will be conducted in compliance 
with local and/or national regulations (eg, International Council for Harmonisation Good Clinical Practice [ICH-
GCP]) and in accordance with the ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD irrespective of the party (parties) employed for their execution (eg, contract research organizations, 
collaborative research efforts). This Code is not intended to apply to trials that are observational in nature, or 
which are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the 
full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, 
efficacy, and/or pharmacokinetic or pharmacodynamic indices of MSD or comparator products. 
Alternatively, MSD may conduct outcomes research trials, trials to assess or validate various endpoint 
measures, or trials to determine patient preferences, etc.
The design (ie, participant population, duration, statistical power) must be adequate to address the specific
purpose of the trial. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
MSD selects investigative sites based on medical expertise, access to appropriate participants, adequacy of 
facilities and staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial 
initiation, sites are evaluated by MSD personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and general principles of
Good Clinical Practice (GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data 
are verified versus source documentation according to standard operating procedures. Per MSD policies and 
procedures, if fraud, scientific/research misconduct, or serious GCP-noncompliance is suspected, the issues 
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are investigated. When necessary, the clinical site will be closed, the responsible regulatory authorities and 
ethics review committees notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the prespecified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important 
to patients, physicians, and payers. Some early phase or pilot trials are intended to be hypothesis-generating rather 
than hypothesis testing, in such cases, publication of results may not be appropriate since the trial may be 
underpowered and the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). In summary, authorship should reflect significant contribution to the design and 
conduct of the trial, performance or interpretation of the analysis, and/or writing of the manuscript. All named 
authors must be able to defend the trial results and conclusions. MSD funding of a trial will be acknowledged in 
publications.
III. Participant Protection
A. Ethics Committee Review (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.
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B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may 
wish to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (eg, to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
10.1.2
Financial Disclosure
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required. It is the investigator's/subinvestigator's 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
10.1.3
Data Protection
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information that would make the participant identifiable will not be transferred.
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
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10.1.3.1
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the IRB, IEC, or similar or expert committee; affiliated institution and 
employees, only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution and employees. Data generated by this study will be 
considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol.
10.1.3.2
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF data. By signing the consent form, the participant agrees to this 
process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules 
and regulations.
10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
10.1.4
Committees Structure
10.1.4.1
Scientific Advisory Committee
The Scientific Advisory Committee 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.
10.1.4.2
Executive Oversight Committee
The EOC is comprised of members of Sponsor Senior Management. The EOC will receive 
and decide upon any recommendations made by the DMC regarding the study.
10.1.4.3
External Data Monitoring Committee
To supplement the routine study monitoring outlined in this protocol, an external DMC will 
monitor the interim data from this study. The voting members of the committee are external 
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to the Sponsor. The members of the DMC must not be involved with the study in any other 
way (eg, they cannot be study investigators) and must have no competing interests that could 
affect their roles with respect to the study.
The DMC will make recommendations to the EOC regarding steps to ensure both participant 
safety and the continued ethical integrity of the study. Also, the DMC will review interim 
study results, consider the overall risk and benefit to study participants (Section 9.7 Interim 
Analysis) and recommend to the EOC whether the study should continue in accordance with 
the protocol.
Specific details regarding composition, responsibilities, and governance, including the roles 
and responsibilities of the various members and the Sponsor protocol team; meeting 
facilitation; the study governance structure; and requirements for and proper documentation 
of DMC reports, minutes, and recommendations will be described in the DMC charter that is 
reviewed and approved by all the DMC members.
10.1.5
Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments.
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
10.1.6
Compliance with Study Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Amendments Act (FDAAA) of 2007 
and the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, the Sponsor 
of the study is solely responsible for determining whether the study and its results are subject
to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries. MSD, as Sponsor of this study, will 
review this protocol and submit the information necessary to fulfill these requirements. MSD 
entries are not limited to FDAAA or the EMA clinical trial directive mandated trials. 
Information posted will allow participants to identify potentially appropriate studies for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate study locations and study site contact information.
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 
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Sponsor and agrees not to submit any information about this study or its results to those 
registries.
10.1.7
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of GCP
(eg, International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals for Human Use GCP: Consolidated Guideline and other generally 
accepted standards of GCP); and all applicable federal, state and local laws, rules and 
regulations relating to the conduct of the clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Studies.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority. 
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
10.1.8
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
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The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including signed ICF, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the Sponsor. No records may be 
transferred to another location or party without written notification to the Sponsor.
10.1.9
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
of the site’s participants. Source documents and data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained if necessary (eg, via 
an audit trail). Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.
10.1.10
Study and Site Closure
The Sponsor or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
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In the event the Sponsor prematurely terminates a particular study site, the Sponsor will 
promptly notify that study site’s IRB/IEC.
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10.2
Appendix 2: Clinical Laboratory Tests
•
The tests detailed in Table 16 will be performed by the local lab.
•
Pregnancy testing:
-
Pregnancy testing requirements for study inclusion are described in Section 5.1.
-
Pregnancy testing (urine or serum as required by local regulations) should be 
conducted at monthly intervals during intervention.
-
Pregnancy testing (urine or serum as required by local regulations) should be 
conducted at the end of relevant systemic exposure and correspond with the time 
frame for female participant contraception in Section 5.1.
-
Additional serum or urine pregnancy tests may be performed, as determined 
necessary by the investigator or required by local regulation, to establish the absence 
of pregnancy at any time during the participant’s participation in the study.
•
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5.1 and Section 5.2 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.
•
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.
•
Additional laboratory assessments required per standard of care for the chemotherapy 
arm, but not included here, should be obtained per local guidance.
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Table 16
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 
hormone (TSH)c
Free thyroxine (FT4)c
Albumin
Cholesterol
Glucose
Triiodothyronine (T3)c
Total protein
Amylase
Lipased
Lactate 
dehydrogenase
Urinalysis/Urine 
dipstick testinge
Specific gravity
Glucose, hemoglobin or blood, ketones, pH, proteinf, by dipstick
Other Tests
PT/INR and aPTT/PTTg
Serum or urine β human chorionic gonadotropin (β hCG) pregnancy test (as needed for WOCBP)h
Serology (HIV antibody, hepatitis B surface antigen [HBsAg], and hepatitis C virus antibody)] if 
required by local health authority
Abbreviations: aPTT = activated partial thromboplastin time; 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 C1, retrospective review of thyroid function testing results is allowed when the results are not available prior to 
dosing.
d.
After Cycle 1 Day 1, retrospective review of lipase and amylase results is allowed when the results are not available prior to dosing.
e.
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.
f.
If urine protein is ≥2+ (first occurrence or a subsequent increase in severity of urine dipstick proteinuria occurring on the same 
lenvatinib dose level), then a 24-hour urine collection should be performed to quantify the 24-hour urine protein excretion.
g.
Performed as part of the screening assessment and as clinically indicated for participants taking anticoagulation therapy.
h.
WOCBP require negative test prior to randomization and within 24 hours prior to first dose. If less than 24 hours have elapsed 
between the randomization test and the first dose of study intervention, another pregnancy test is not required prior to starting study 
intervention.
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The investigator (or medically qualified designee) must document their review of each 
laboratory safety report.
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definitions of Medication Error, Misuse, and Abuse
Medication Error
This is an unintended failure in the drug treatment process that leads to or has the potential to 
lead to harm to the patient.
Misuse
This refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the terms of the product information.
Abuse
This corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product for a perceived psychological or physiological reward or desired non-therapeutic 
effect.
10.3.2
Definition of AE
AE definition
•
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.
•
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.
•
NOTE: For purposes of AE definition, study intervention (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, diagnostic 
agent, or protocol specified procedure whether investigational or marketed (including 
placebo, active comparator product, or run-in intervention), manufactured by, licensed 
by, provided by, or distributed by the Sponsor for human use in this study.
Events meeting the AE definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.
•
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.
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•
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.
•
For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”
•
Any new cancer (that is not a condition of the study). Progression of the cancer under 
study is not a reportable event. Refer to Section 8.4.6 for additional details.
Events NOT meeting the AE definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
•
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
•
Surgery planned prior to informed consent to treat a pre-existing condition that has not 
worsened.
•
Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.3
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
•
The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
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 
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worsened is not an SAE. A pre-existing condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
d.
Results in persistent or significant disability/incapacity
•
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
•
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
•
In offspring of participant taking the product regardless of time to diagnosis.
f.
Other important medical events
•
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.
•
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.3.4
Additional Events Reported in the Same Manner as SAE
Additional events that require reporting in the same manner as SAE
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor in the same time frame as SAEs to 
meet certain local requirements. Therefore, these events are considered serious by the 
Sponsor for collection purposes.
•
Is a new cancer (that is not a condition of the study)
•
Is associated with an overdose
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10.3.5
Recording AE and SAE
AE and SAE recording
•
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.
•
The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.
•
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
•
There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.
•
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity/toxicity
•
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
•
The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) according to the NCI Common Terminology for Adverse Events 
(CTCAE), version v. 4.0. Any AE that changes CTCAE grade over the course of a given 
episode will have each change of grade recorded on the AE CRFs/worksheets.
-
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated.
-
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (ADL).
-
Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care ADL.
-
Grade 4: Life threatening consequences; urgent intervention indicated.
-
Grade 5: Death related to AE.
Assessment of causality
•
Did the Sponsor’s product cause the AE?
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•
The determination of the likelihood that the Sponsor’s product caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed 
document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test product and the AE based upon the available information.
•
The following components are to be used to assess the relationship between the 
Sponsor’s product and the AE; the greater the correlation with the components and their 
respective elements (in number and/or intensity), the more likely the Sponsor’s product 
caused the AE:
-
Exposure: Is there evidence that the participant was actually exposed to the 
Sponsor’s product such as: reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite 
in bodily specimen?
-
Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the Sponsor’s product? Is the time of onset of the AE compatible 
with a drug-induced effect (applies to studies with investigational medicinal product)?
-
Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors.
-
Dechallenge: Was the Sponsor’s product discontinued or dose/exposure/frequency 
reduced?
-
If yes, did the AE resolve or improve?
-
If yes, this is a positive dechallenge.
-
If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent 
disability; (2) the AE resolved/improved despite continuation of the Sponsor’s 
product; (3) the study is a single-dose drug study; or (4) Sponsor’s product(s) is/are 
only used 1 time.)
-
Rechallenge: Was the participant re-exposed to the Sponsor’s product in this study?
-
If yes, did the AE recur or worsen?
-
If yes, this is a positive rechallenge.
-
If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or 
permanent disability, or (2) the study is a single-dose drug study; or (3) Sponsor’s 
product(s) is/are used only 1 time.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE SPONSOR’S PRODUCT, OR IF RE-EXPOSURE 
TO THE SPONSOR’S PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR AS PER DOSE 
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MODIFICATION GUIDELINES IN THE PROTOCOL, AND IF REQUIRED, THE 
INIRB/IEC.
•
Consistency with study intervention profile: Is the clinical/pathological presentation of 
the AE consistent with previous knowledge regarding the Sponsor’s product or drug class 
pharmacology or toxicology?
•
The assessment of relationship will be reported on the case report forms/worksheets by 
an investigator who is a qualified physician according to his/her best clinical judgment, 
including consideration of the above elements.
•
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Sponsor’s product relationship).
-
Yes, there is a reasonable possibility of Sponsor’s product relationship:
-
There is evidence of exposure to the Sponsor’s product. The temporal sequence of the 
AE onset relative to the administration of the Sponsor’s product is reasonable. The 
AE is more likely explained by the Sponsor’s product than by another cause.
-
No, there is not a reasonable possibility of Sponsor's product relationship:
-
Participant did not receive the Sponsor’s product OR temporal sequence of the AE 
onset relative to administration of the Sponsor’s product is not reasonable OR the AE 
is more likely explained by another cause than the Sponsor’s product. (Also entered 
for a participant with overdose without an associated AE.)
•
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.
•
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.
•
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.
•
For studies in which multiple agents are administered as part of a combination regimen, 
the investigator may attribute each AE causality to the combination regimen or to a single 
agent of the combination. In general, causality attribution should be assigned to the 
combination regimen (ie, to all agents in the regimen). However, causality attribution 
may be assigned to a single agent if in the investigator’s opinion, there is sufficient data 
to support full attribution of the AE to the single agent.
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Follow-up of AE and SAE
•
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
•
New or updated information will be recorded in the CRF.
•
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool
•
The primary mechanism for reporting to the Sponsor will be the electronic data collection 
(EDC) tool.
•
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
•
If the electronic system is unavailable for more than 24 hours, then the site will use the 
paper AE Reporting form.
•
Reference Section 8.4.1 for reporting time requirements.
•
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
•
After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.
•
If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).
•
Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
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SAE reporting to the Sponsor via paper CRF
•
If the EDC tool is not operational, facsimile transmission or secure e-mail of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.
•
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
•
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
•
Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
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10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation
Not applicable.
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10.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing
10.5.1
Definitions
Women of Childbearing Potential (WOCBP)
A woman is considered fertile after menarche and until becoming postmenopausal unless 
permanently sterile (see below):
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
•
Premenarchal
•
Premenopausal female with 1 of the following:
-
Documented hysterectomy
-
Documented bilateral salpingectomy
-
Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Műllerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.
•
Postmenopausal female
-
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
◦
A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. 
However, in the absence of 12 months of amenorrhea, confirmation with 2 FSH 
measurements in the postmenopausal range is required.
-
Females on HRT and whose menopausal status is in doubt will be required to use one 
of the nonhormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
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10.5.2
Contraception Requirements
Female Participants
Female participants of childbearing potential are eligible to participate if they agree to 
consistent and correct use of a highly effective method of contraception as described in 
Table 17 during the protocol-defined time frame in Section 5.1.
Table 17
Highly Effective Contraception Methods
Contraceptives allowed during the study includea:
Highly Effective Contraceptive Methods That Have Low User Dependency
Failure rate of <1% per year when used consistently and correctly
•
Progestogen-only subdermal contraceptive implantb,c
•
IUSc,
•
IUD
•
Bilateral tubal occlusion
•
Azoospermic partner (vasectomized or secondary to medical cause)
This is a highly effective contraception method provided that the partner is the sole male sexual partner of the 
WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used. A spermatogenesis cycle is approximately 90 days.
Note: Documentation of azoospermia can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.
Sexual Abstinence
•
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the 
participant.
a.
Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive 
methods for participants of clinical studies.
b.
If locally required, in accordance with CTFG guidelines, acceptable contraceptive implants are limited to those 
which inhibit ovulation.
c.
IUS is a progestin releasing IUD.
Note: The following are not acceptable methods of contraception:
•
Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides 
only, and LAM.
•
Male condom with cap, diaphragm, or sponge with spermicide.
•
Male and female condom should not be used together (due to risk of failure with friction).
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10.5.3
Pregnancy Testing
All women who are being considered for participation in the study, and who are not 
surgically sterilized or postmenopausal, must be tested for pregnancy within 24 hours or the 
first dose of study intervention.
WOCBP should only be included after a negative highly sensitive urine or serum pregnancy 
test and in accordance with local requirements. 
After initiation of treatment, additional pregnancy testing will be performed at monthly 
intervals during the treatment period and at least every 30 days up to 120 days post last dose 
of pembrolizumab or 30 days post the last dose of lenvatinib, whichever comes last, (up to 
180 days for participants receiving chemotherapy), and as required locally.
Pregnancy testing will be performed whenever an expected menstrual cycle is missed or 
when pregnancy is otherwise suspected.
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
Not Applicable. 
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10.7
Appendix 7: Country-specific Requirements
10.7.1
Canada
Please refer to the current lenvatinib product monograph for management of AEs associated 
with lenvatinib administration.
Section 6.6.1.9
Management of Gastrointestinal Perforation or Fistula Formation
Lenvatinib should be discontinued in any participant who develops gastrointestinal 
perforation of any grade or ≥ Grade 3 fistula. 
10.7.2
Germany
Laboratory Testing
HIV, hepatitis B/C, and tuberculosis testing are required evaluations for study entry and need 
to be performed to evaluate eligibility. This testing can be performed at any time during the 
Screening period.
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10.8
Appendix 8: Description of the iRECIST Process for Assessment of Disease 
Progression 
Assessment at Screening and Prior to RECIST 1.1 Progression
Until radiographic disease progression based on RECIST 1.1, there is no distinct iRECIST 
assessment.
Assessment and Decision at RECIST 1.1 Progression
For participants who show evidence of radiological PD by RECIST 1.1 as determined by the 
investigator, the investigator will decide whether to continue a participant on study 
intervention until repeat imaging is obtained (using iRECIST for participant management)
(see Table 8 and Figure 2). This decision by the investigator should be based on the 
participant’s overall clinical condition.
Clinical stability is defined as the following:
•
Absence of symptoms and signs indicating clinically significant progression of disease
•
No decline in ECOG performance status
•
No requirements for intensified management, including increased analgesia, radiation, or 
other palliative care
Any participant deemed clinically unstable should be discontinued from study intervention at 
central verification of site-assessed first radiologic evidence of PD, and is not required to 
have repeat tumor imaging for confirmation of PD by iRECIST.
If the investigator decides to continue treatment, the participant may continue to receive 
study intervention and the tumor assessment should be repeated 4 to 8 weeks later to confirm 
PD by iRECIST, per investigator assessment. Images should continue to be sent in to the 
central imaging vendor for potential retrospective BICR.
Tumor flare may manifest as any factor causing radiographic progression per RECIST 1.1, 
including:
Increase in the sum of diameters of target lesion(s) identified at baseline to ≥20% and ≥5 mm 
from nadir
Note: The iRECIST publication uses the terminology “sum of measurements,”, but “sum of 
diameters” will be used in this protocol, consistent with the original RECIST 1.1 
terminology.
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Unequivocal progression of nontarget lesion(s) identified at baseline
Development of new lesion(s)
iRECIST defines new response categories, including iUPD (unconfirmed progressive 
disease) and iCPD (confirmed progressive disease). For purposes of iRECIST assessment, 
the first visit showing progression according to RECIST 1.1 will be assigned a visit (overall) 
response of iUPD, regardless of which factors caused the progression.
At this visit, target and nontarget lesions identified at baseline by RECIST 1.1 will be 
assessed as usual.
New lesions will be classified as measurable or nonmeasurable, using the same size 
thresholds and rules as for baseline lesion assessment in RECIST 1.1. From measurable new 
lesions, up to 5 lesions total (up to 2 per organ), may be selected as New Lesions – Target. 
The sum of diameters of these lesions will be calculated, and kept distinct from the sum of 
diameters for target lesions at baseline. All other new lesions will be followed qualitatively 
as New Lesions – Nontarget.
Assessment at the Confirmatory Imaging
On the confirmatory imaging, the participant will be classified as progression confirmed 
(with an overall response of iCPD), or as showing persistent unconfirmed progression (with 
an overall response of iUPD), or as showing disease stability or response (iSD/iPR/iCR).
Confirmation of Progression
Progression is considered confirmed, and the overall response will be iCPD, if ANY of the 
following occurs:
Any of the factors that were the basis for the iUPD at the previous visit show worsening
For target lesions, worsening is a further increase in the sum of diameters of ≥5 mm, 
compared with any prior iUPD time point
For nontarget lesions, worsening is any significant growth in lesions overall, compared with
a prior iUPD time point; this does not have to meet the “unequivocal” standard of RECIST 
1.1
For new lesions, worsening is any of these:
An increase in the new lesion sum of diameters by ≥5 mm from a prior iUPD time point
Visible growth of new nontarget lesions
The appearance of additional new lesions
Any new factor appears that would have triggered PD by RECIST 1.1
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Persistent iUPD
Progression is considered not confirmed, and the overall response remains iUPD, if:
None of the progression-confirming factors identified above occurs AND
The target lesion sum of diameters (initial target lesions) remains above the initial PD 
threshold (by RECIST 1.1)
Additional imaging for confirmation should be scheduled 4 to 8 weeks from the imaging on 
which iUPD is seen. This may correspond to the next visit in the original visit schedule. The 
assessment of the subsequent confirmation imaging proceeds in an identical manner, with 
possible outcomes of iCPD, iUPD, and iSD/iPR/iCR.
Resolution of iUPD
Progression is considered not confirmed, and the overall response becomes iSD/iPR/iCR, if:
None of the progression-confirming factors identified above occurs, AND
The target lesion sum of diameters (initial target lesions) is not above the initial PD 
threshold.
The response is classified as iSD or iPR (depending on the sum of diameters of the target 
lesions), or iCR if all lesions resolve.
In this case, the initial iUPD is considered to be pseudoprogression, and the level of 
suspicion for progression is “reset.” This means that the next visit that shows radiographic 
progression, whenever it occurs, is again classified as iUPD by iRECIST, and the 
confirmation process is repeated before a response of iCPD can be assigned.
Management After the Confirmatory Imaging
If repeat imaging does not confirm PD per iRECIST, as assessed by the investigator, and the 
participant continues to be clinically stable, study treatment may continue and follow the 
regular imaging schedule. If PD is confirmed, participants will be discontinued from study 
treatment.
NOTE: If a participant has confirmed radiographic progression (iCPD) as defined above, but 
the participant is achieving a clinically meaningful benefit or if RECIST 1.1 PD has not been 
verified centrally, an exception to continue study intervention may be considered after
consultation with the Sponsor. In this case, if study intervention is continued, tumor imaging 
should continue to be performed after the intervals as outlined in Section 1.3 and submitted
to the central imaging vendor.
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Detection of Progression at Visits After Pseudoprogression Resolves
After resolution of pseudoprogression (ie, achievement of iSD/iPR/iCR), iUPD is indicated 
by any of the following events:
Target lesions
Sum of diameters reaches the PD threshold (≥20% and ≥5 mm increase from nadir) either for 
the first time, or after resolution of previous pseudoprogression. The nadir is always the 
smallest sum of diameters seen during the entire study, either before or after an instance of 
pseudoprogression.
Nontarget lesions
If nontarget lesions have never shown unequivocal progression, their doing so for the first 
time results in iUPD.
If nontarget lesions have shown previous unequivocal progression, and this progression has 
not resolved, iUPD results from any significant further growth of nontarget lesions, taken as 
a whole.
New lesions
New lesions appear for the first time
Additional new lesions appear
Previously identified new target lesions show an increase of ≥5 mm in the new lesion sum of 
diameters, from the nadir value of that sum
Previously identified nontarget lesions show any significant growth
If any of the events above occur, the overall response for that visit is iUPD, and the iUPD 
evaluation process (see Assessment at the Confirmatory Imaging above) is repeated. 
Progression must be confirmed before iCPD can occur.
The decision process is identical to the iUPD confirmation process for the initial PD, with 
one exception: If new lesions occurred at a prior instance of iUPD, and at the Confirmatory 
Imaging, the burden of new lesions has increased from its smallest value (for new target 
lesions, the sum of diameters is ≥5 mm increased from its nadir), then iUPD cannot resolve 
to iSD or iPR. It will remain iUPD until either a decrease in the new lesion burden allows 
resolution to iSD or iPR, or until a confirmatory factor causes iCPD.
Additional details about iRECIST are provided in the iRECIST publication [Seymour, L., et 
al 2017].
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10.9
Appendix 9: 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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10.10 Appendix 10: 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 1994a].
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10.11 Appendix 11: Clinical Studies Evaluating Drug-Drug Interactions With 
Lenvatinib
Nonclinical studies identify CYP3A4 as a potentially important Cytochrome P450 isozyme 
responsible for metabolism of lenvatinib. Clinical studies were conducted to test these 
findings. 
Simultaneous CYP3A4/P-glycoprotein (Pgp) inhibition by ketoconazole slightly (15% to 
19%) increases systemic exposure to lenvatinib [Shumaker, R., et al 2015]. Since no change 
was observed in half-life, tmax, or lag time (tlag), the slight increase in systemic exposure is 
probably related to a decrease in first pass metabolism. However, since the magnitude of 
change is small, co-administration of lenvatinib with CYP3A4/Pgp inhibitors is not of 
clinical concern. 
The influence of Pgp inhibition on lenvatinib PK has been investigated. Pgp inhibition was 
accomplished by co-administering a single dose of rifampin with a single dose of lenvatinib. 
Preliminary results suggest Pgp inhibition increases systemic exposure to lenvatinib 26% to 
32%. Thus, co-administration of lenvatinib with Pgp inhibitors only causes a small increase 
in lenvatinib exposure. 
The influence of simultaneous Pgp and CYP3A4 induction on lenvatinib PK has been 
investigated. Examination of simultaneous Pgp and CYP3A4 induction on lenvatinib PK was 
accomplished by administering rifampin QD for 21 days [Shumaker, R. C., et al 2014]. A 
single dose of lenvatinib was co-administered with the 15th dose of rifampin. Based on 
preliminary data, simultaneous Pgp and CYP3A4 induction minimally altered lenvatinib 
exposure as mean Cmax increased about 8% while AUC decreased about 7%. 
Co-administration of lenvatinib with CYP3A4/Pgp inducers is not of clinical concern.
The main metabolic pathways for lenvatinib in humans were identified as enzymatic 
(CYP3A and aldehyde oxidase) and nonenzymatic processes (Lenvima Product Information).
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10.12 Appendix 12: Justification of Non-inferiority Margin
The Sponsor conducted a systematic literature review (SLR) to gather clinical trial evidence 
on the efficacy and safety of carboplatin and paclitaxel combination therapy for the first line 
(1L) treatment of patients with advanced (unresectable and/or metastatic) or recurrent 
endometrial carcinoma to justify a NI margin for hypothesis H3 (the combination of 
pembrolizumab plus lenvatinib is non-inferior to chemotherapy with respect to OS in pMMR 
participants) in LEAP-001/ENGOT-EN9. The SLR focused on studies evaluating the 
efficacy and safety of treatments for patients with advanced or metastatic endometrial 
carcinoma.
A total of 3,217 abstracts were identified from a literature search of MEDLINE, EMBASE, 
and Cochrane databases, and no additional records were identified through other sources 
such as the ASCO, ESMO, ISPOR conference proceedings and the US clinical trial 
registries. After excluding 599 duplicate citations, a total of 2,618 abstracts were screened to 
257 full texts for the following reasons: duplicate publication (n = 47), study design (n = 
571), population (n = 1,119), intervention (n = 27), other (n = 597). Of the 257 full text 
articles screened, 45 were excluded: 3 due to study design; 24 due to population not of 
interest; 2 due to interventions not of interest; 1 due to other reasons (such as reviews, 
editorials, comments, etc.); 3 due to duplicate publication; and 12 that did not provide 
outcomes for the population of interest to this review. A final number of 212 citations, testing 
interventions for treatment naïve and previously treated advanced endometrial patient 
populations, were retained. These publications were screened independently by 2 reviewers 
and decisions were reconciled. Of these, 7 primary publications (5 were single-arm studies 
and 2 were randomized controlled trials) were included in the evidence synthesis (see 
Table 8: Trial characteristics, study identifier in the SLR), reflecting the state of the evidence 
on the treatment of patients with previously untreated advanced (unresectable and/or 
metastatic) or recurrent endometrial carcinoma. 
Of the 7 primary publications included in the evidence synthesis, carboplatin + paclitaxel was 
used in the randomized controlled setting in only 2 studies, Miller 2012 (vs doxorubicin + 
cisplatin + paclitaxel), and Matei 2017 (vs cisplatin + irradiation + carboplatin + paclitaxel)
[Matei, D., et al 2017]. The median OS was only reported in Miller (2012) (32 months for 
paclitaxel + carboplatin and 38 months for doxorubicin + cisplatin + paclitaxel, HR = 1.01, 
90% upper confidence limit = 1.16) [Miller, D., et al 2015]. Therefore, it is not feasible to 
derive a NI margin based on a meta-analysis of existing studies. 
Nevertheless, with use of a NI margin of 1.1 in LEAP-001/ENGOT-EN-9, the HR boundary 
for H3 is 0.83 based on retaining 50% of the assumed effect of chemotherapy versus placebo. 
This margin is lower than the 90% upper confidence limit from the Miller 2012 publication. 
The margin of 1.1 is also the lower bound of the range of margins for non-inferiority cancer 
trials that used time-to-event primary outcomes [Riechelmann, R. P., et al 2013].
Therefore, based on this information, the Sponsor believes the prespecified NI margin of 1.1 
in LEAP-001/ENGOT-EN9 represents a meaningful measure for testing the non-inferiority 
hypotheses in this study.
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10.13 Appendix 13: Abbreviations
Abbreviation
Expanded Term
ADA
antidrug antibodies
ADL
activities of daily living
AE
adverse event 
AEOSI
adverse events of special interest
ALT
alanine transaminase
APaT
All Participants as Treated
aPTT
activated partial thromboplastin time
AST
aspartate transaminase
AUC
area under the concentration-time curve
AxIMP
auxiliary medicinal product
BCG
Bacillus Calmette–Guérin
BICR
blinded independent central review
BOR
best overall response
BP
blood pressure
CB
clinical benefit
CBR
clinical benefit rate
CD
cluster of differentiation
CHMP
Committee for Medicinal Products for Human Use
CI
Confidence Interval(s)
cLDA
constrained longitudinal data analysis
CNS
central nervous system
CONSORT
Consolidated Standards of Reporting Trials
CPMP
Committee for Proprietary Medicinal Products
CR
complete response
CRF
Case Report Form
CSR
Clinical Study Report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTFG
Clinical Trial Facilitation Group
CTLA-4
cytotoxic T-lymphocyte-associated protein 4
CYP 
Cytochrome P450
CYP3A4
Cytochrome P450 3A4
DC
disease control
DCR
disease control rate
DDI
drug-drug interaction
DILI
drug-induced liver injury
DLT
dose-limiting toxicity
DMC
Data Monitoring Committee
dMMR
mismatch repair deficient
DNA
deoxyribonucleic acid
DOR
duration of response
DVT
deep vein thrombosis
EC
endometrial carcinoma (or cancer)
ECG
electrocardiogram
ECHO
echocardiogram
ECI
event(s) of clinical interest
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
EDC
electronic data collection
eDMC
external Data Monitoring Committee
ELISA
enzyme-linked immunosorbent assay
EMA
European Medicines Agency
EOC
Executive Oversight Committee
EORTC
European Organization for Research and Treatment of Cancer
EORTC-QLG
EORTC Quality of Life Group
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Abbreviation
Expanded Term
EORTC-QLQ-C30
EORTC Quality of Life Questionnaire Core 30
EORTC-QLQ-EN24
EORTC Quality of Life Questionnaire Endometrial Cancer Module
EOT
End of treatment
ePRO
electronic patient-report outcomes
EuroQoL EQ-5D-5L
European Quality of Life eEuroQol-5 Dimensions 5-Level
FA
final analysis
FAS
full analysis set
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FFPE
formalin-fixed, paraffin-embedded
FGF
fibroblast growth factor
FIGO
International Federation of Gynecology and Obstetrics
FSH
follicle stimulating hormone
FT3
free T3
FT4
free T4
GCP
Good Clinical Practice 
H
hypothesis
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCC
Hurthle cell cancer
HCG
human chorionic gonadotropin
HCV
hepatitis C virus
HIV
Human Immunodeficiency Virus
HR
hazard ratio
HRQoL
health-related quality of life
HRT
hormone replacement therapy
HUVEC
human umbilical vein endothelial cell
IA
interim analysis
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonization
iCPD
immune-related confirmed radiographic disease progression
iCR
immune-related complete response
iCRO
imaging contract research organization
ID
identification 
IEC
Independent Ethics Committee
Ig
immunoglobulin
IgG4
immunoglobulin G4
IgV
Ig-variable
IHC
immunohistochemistry
IMP
Investigational Medicinal Product
IND
Investigational New Drug
INR
International Normalized Ratio
iPD
immune-related progressive disease
iPR
immune-related partial response
irAEs
immune-related adverse events
IRB
Institutional Review Board
iRECIST
modified RECIST 1.1 for immune-based therapeutics
IRR
independent radiologic review
IRT
interactive response technology
iSD
immune-related stable disease
ITT
Intention-to-Treat
IUD
intrauterine device
iUPD
Immune-related unconfirmed progressive disease
IUS
intrauterine hormone-releasing system
IV
intravenous
IVD
in vitro diagnostic
IVRS
Interactive Voice Response System
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Abbreviation
Expanded Term
IWRS
Integrated Web Response System
LS mean
least square mean
LVEF
left ventricular ejection fraction
MMR
mismatch repair
mRECIST
modified RECIST
MRI
magnetic resonance imaging
mRNA
messenger RNA
MSI
microsatellite instability
MSI-H
MSI-high
MSS
microsatellite stable
MTD
maximum tolerated dose 
MUGA
multigated acquisition
nAb
neutralizing antibodies
NCI
National Cancer Institute
NDA
New Drug Application 
NIMP
Non Investigational Medicinal Product
NSCLC
non-small cell lung cancer
ONJ
Osteonecrosis of the jaw
OR
objective response
ORR
objective response rate
OS
overall survival
PBPK
physiologically-based PK
PD
progressive disease
PD-1
programmed cell death 1
PD-L1
programmed cell death ligand 1
PD-L2
programmed cell death ligand 2
PDGF
platelet-derived growth factor
PDLC
predefined limits of change
PFS
progression-free survival
PFS2
progression-free survival on next line therapy
Pgp
P-glycoprotein
PK
pharmacokinetic(s)
PKCθ
protein kinase C-theta
pMMR
mismatch repair proficient
PR
partial response
PRES
Posterior Reversible Encephalopathy Syndrome
PRO
Patient-reported Outcomes
PT
prothrombin time
PTT
partial thromboplastin time
Q2W
every 2 weeks
Q3W
every 3 weeks
Q9W
every 9 weeks
Q12W
every 12 weeks
QD
once daily
QoL
quality-of-life
QP2
Department of Quantitative Pharmacology and Pharmacometrics
QTc
QT interval corrected
QTcF
QTc Fridericia formula
RCC
renal cell carcinoma
RECIST 1.1
Response Evaluation Criteria in Solid Tumors version 1.1
RMST
Restricted Mean Survival Time
RNA
ribonucleic acid
RP2D
recommended Phase 2 dose
RPLS
Reversible Encephalopathy Syndrome/Reversible Posterior Leukoencephalopathy Syndrome
RR
respiratory rate
RTK
receptor tyrosine kinase
RUQ
right upper quadrant
SAC
Scientific Advisory Committee
08JDYZ


PRODUCT:  MK-7902
176
PROTOCOL/AMENDMENT NO.: MK-7902-001-07 (E7080-G000-313; ENGOT-EN9)
MK-7902-001-07 FINAL PROTOCOL
13-FEB-2024
Abbreviation
Expanded Term
SAE
serious adverse event 
SAP
Statistical Analysis Plan
SD
stable disease
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
SIM
Site Imaging Manual
SNP
single nucleotide polymorphisms
SoA
Schedule of Activities
SOC
System Organ Class
sSAP
supplemental Statistical Analysis Plan
SUSAR
suspected unexpected serious adverse reaction
T3
triiodothyronine
T4
thyroxine
TAM
tumor associated macrophage
TAP
doxorubicin, cisplatin, and paclitaxel
TB
tuberculosis
TBL
total bilirubin
TC
paclitaxel and carboplatin
TEAE
treatment emergent adverse events
TMDD
target-mediated drug disposition
T-regs
regulatory T-cells
TSH
thyroid stimulating hormone
ULN
upper limit of normal
UPCR
urine protein-to-creatinine ratio
US
United States
VEGF
vascular endothelial growth factor
W27
Week 27
W54
Week 54
WBRT
whole brain radiation therapy
WES
whole exome sequencing
WOCBP
woman/women of childbearing potential 
ZAP70
zeta-chain-associated protein kinase
08JDYZ


PRODUCT:  MK-7902
177
PROTOCOL/AMENDMENT NO.: MK-7902-001-07 (E7080-G000-313; ENGOT-EN9)
MK-7902-001-07 FINAL PROTOCOL
13-FEB-2024
11
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MK-7902-001-07 FINAL PROTOCOL
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08JDYZ


PRODUCT:  MK-7902
179
PROTOCOL/AMENDMENT NO.: MK-7902-001-07 (E7080-G000-313; ENGOT-EN9)
MK-7902-001-07 FINAL PROTOCOL
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[057JXY]
08JDYZ


PRODUCT:  MK-7902
180
PROTOCOL/AMENDMENT NO.: MK-7902-001-07 (E7080-G000-313; ENGOT-EN9)
MK-7902-001-07 FINAL PROTOCOL
13-FEB-2024
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PRODUCT:  MK-7902
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PROTOCOL/AMENDMENT NO.: MK-7902-001-07 (E7080-G000-313; ENGOT-EN9)
MK-7902-001-07 FINAL PROTOCOL
13-FEB-2024
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PRODUCT:  MK-7902
182
PROTOCOL/AMENDMENT NO.: MK-7902-001-07 (E7080-G000-313; ENGOT-EN9)
MK-7902-001-07 FINAL PROTOCOL
13-FEB-2024
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PRODUCT:  MK-7902
183
PROTOCOL/AMENDMENT NO.: MK-7902-001-07 (E7080-G000-313; ENGOT-EN9)
MK-7902-001-07 FINAL PROTOCOL
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PRODUCT:  MK-7902
184
PROTOCOL/AMENDMENT NO.: MK-7902-001-07 (E7080-G000-313; ENGOT-EN9)
MK-7902-001-07 FINAL PROTOCOL
13-FEB-2024
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