Phase 3, Randomized Study to Evaluate the Efficacy and Safety of Lenvatinib (E7080/MK-7902) Plus Pembrolizumab (MK-3475) Plus Chemotherapy Compared With Standard of Care Therapy as First-line Intervention in Participants With Advanced/Metastatic Gastroesophageal Adenocarcinoma (LEAP-015)
Phase: PHASE3
Conditions: Advanced/Metastatic Gastroesophageal Adenocarcinoma
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title:
NCT Number:               NCT04662710
Document Date:           10-Jun-2025
A Phase 3, Randomized Study to Evaluate the Efficacy 
and Safety of Lenvatinib (E7080/MK-7902) plus 
Pembrolizumab (MK-3475) plus Chemotherapy 
Compared with Standard of Care Therapy as First-line 
Intervention in Participants with Advanced/Metastatic 
Gastroesophageal Adenocarcinoma (LEAP-015)

PRODUCT: MK-7902
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TITLE PAGE
THIS PROTOCOL AND ALL OF THE INFORMATION RELATING TO IT ARE 
CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK SHARP & 
DOHME LLC, RAHWAY, NJ, USA (MSD).
Protocol Title: A Phase 3, Randomized Study to Evaluate the Efficacy and Safety of 
Lenvatinib (E7080/MK-7902) plus Pembrolizumab (MK-3475) plus Chemotherapy 
Compared with Standard of Care Therapy as First-line Intervention in Participants with 
Advanced/Metastatic Gastroesophageal Adenocarcinoma (LEAP-015)
Protocol Number: 015-08 (E7080-G000-321)
Compound Number: MK-7902
Sponsor Name: Merck Sharp & Dohme LLC (hereafter called the Sponsor or MSD)
The study is part of a collaboration between MSD and Eisai
Legal Registered Address:
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Regulatory Agency Identifying Number(s):
NCT
Not applicable
EU CT
2023-504834-23
EudraCT
2020-001990-53
JRCT
2051200127
WHO
U1111-1288-1010
UTN
U1111-1288-1010
IND
140284
Approval Date: 10 June 2025
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study 
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 8
10-JUN-2025
This change was made to include an extension 
study option and remove the option for starting 
Second Course Treatment Phase. Second Course 
Treatment Phase is removed due to study close-out 
activities and transitioning participants to extension 
study.
Amendment 7
29-JUN-2024
Revisions to align with Regulation (EU) 536/2014.
Amendment 6
11-AUG-2023
Amendment 5
07-OCT-2022
Amendment 4 –
Country-specific
22-DEC-2021
To address request from Peru National Institute of 
Health related to justification of inclusion of 
esophageal adenocarcinoma participants.
Amendment 3
29-JUN-2021
To address Health Authority requests and to 
include updates based on pembrolizumab and 
lenvatinib template revisions, including to update 
the pembrolizumab dose modification and toxicity 
management guidelines for irAEs.
Amendment 2
23-FEB-2021
Update protocol in response to recently presented 
data from CM649, ATTRACTION-4 and KN590 
studies, and make updates in response to 
Regulatory Authority input. Revise lenvatinib dose 
in consolidation. Alignment of dose modification 
table with global program standards.
Amendment 1
03-FEB-2021
Update protocol in response to recently presented 
data from CM649, ATTRACTION-4 and KN590 
studies, and make updates in response to 
Regulatory Authority input. Revise lenvatinib dose 
in consolidation.
Original 
Protocol
11-SEP-2020
Not applicable
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 08
Overall Rationale for the Amendment:
This change was made to include an extension study option and remove the option for 
starting Second Course Treatment Phase. Second Course Treatment Phase is removed due to 
study close-out activities and transitioning participants to extension study. 
Summary of Changes Table
Section Number 
and Name
Description of Change
Brief Rationale
Primary Reason for Amendment
Section 1.1, 
Synopsis 
Added text describing the inclusion of an 
extension study option and removal of Second 
Course Treatment Phase.
This change was made to include an extension 
study option and remove the option for starting 
Second Course Treatment Phase. Second Course 
Treatment Phase is removed due to study close-
out activities and transitioning participants to 
extension study.
Section Number and 
Name
Description of Change
Brief Rationale
Additional Changes
Section 1.1, Synopsis
Added note about changes to imaging 
requirements .
To provide new information for 
performing imaging per local standard of 
care.
Section 1.2, Schema
Added note that the Second Course 
Treatment Phase (Figure 3) will no longer be 
offered.
See rationale for Section 1.1 under primary 
reason.
Added note about changes to imaging 
requirements.
See rationale for Section 1.1 under 
additional changes.
Section 1.3, Schedule of 
Activities
Simplified Schedule of Activities (SoA) for 
ePROs to show only the required. 
assessments for participants active on 
treatment.
In accordance with the overall rationale for 
the amendment, assessments/procedures 
are simplified.
Simplified Schedule of Activities (SoA) for 
blood for RNA analysis to show only the 
required assessments for participants active 
on treatment.
See rationale for Section 1.3.
Simplified Schedule of Activities (SoA) for 
blood for serum biomarkers to show only the 
required assessments for participants active 
on treatment.
See rationale for Section 1.3.
Simplified Schedule of Activities (SoA) for 
ctDNA analysis to show only the required 
assessments for participants active on 
treatment.
See rationale for Section 1.3.
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Section Number and 
Name
Description of Change
Brief Rationale
Simplified Schedule of Activities (SoA) for 
tumor imaging to show only the required 
assessments for participants active on 
treatment.
See rationale for Section 1.3.
Section 1.3.5, Second 
Course (Part 1 and Part 2)
Updated Second Course Treatment Phase.
See rationale for Section 1.1 under the 
primary reason.
Section 4.1, Overall 
Design
Where deletion of text could cause 
confusion, due to the design of the study to 
date, the text has been left unchanged, and a 
note has been added regarding the removal 
of the Second Course Treatment Phase.
See rationale for Section 1.1.under the 
primary reason.
Where deletion of text could cause 
confusion, due to the design of the study to 
date, the text has been left unchanged, and a 
note has been added regarding the safety, 
efficacy, and survival follow-up after 
discontinuation.
See rationale for Section 1.1 under the 
primary reason.
Where deletion of text could cause 
confusion, due to the design of the study to 
date, the text has been left unchanged, and a 
note has been added regarding the inclusion 
of extension study.
See rationale for Section 1.1 under the 
primary reason.
Added note about changes to imaging 
requirements.
See rationale for Section 1.1. under the 
additional changes.
Section 4.2.1.3, Patient-
reported Outcomes
Added note regarding updates to ePROs.
Removed ePROs assessments at C>18, 
EOT, and Safety Follow-up.
Section 6, Study 
Intervention 
Added text for reporting requirements of 
clinical supply complaints and/or 
temperature excursions.
To align language with new Online 
Clinical Supply Incident Reporting Form 
to report clinical supply complaints, site 
temperature excursions, and dosing past 
expiry.
Section 6.6.6, Second 
Course
Option for Second Course Treatment Phase 
is removed due to study close-out activities 
and transitioning participants to extension 
study.
See rationale for Section 1.1 under the 
primary reason.
Section 8.2.1.2, Tumor 
Scans During the Study
Added note about changes to imaging
requirements.
See rationale for Section 1.1 under the 
additional changes.
Section 8.2.1.3, End-of-
treatment and Follow-up 
Tumor Scans
Added note about changes to the collection 
of tumor scans during follow-up. 
See rationale for Section 1.1 under the 
additional changes.
Section 8.2.1.4, Second 
Course (Retreatment) 
Tumor Scans
Added note about changes to imaging 
requirements.
See rationale for Section 1.1 under the 
additional changes.
Section 8.2.1.5, RECIST 
1.1 Assessment of Disease
Added note about changes to imaging 
requirements.
See rationale for Section 1.1 under the 
additional changes.
Section 8.2.2.1, Patient-
Reported Outcomes
Added note regarding updates to ePROs.
See rationale for Section 4.2.1.3.
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Section Number and 
Name
Description of Change
Brief Rationale
Section 8.4 1, Reporting 
Periods and Time Frames 
for Adverse Events and 
Other Reportable Safety 
Events
Added text regarding safety assessments 
during the extension study.
To align safety assessments with the 
Amendment 8.
Table 13: Updated periods and duration for 
potential DILI events meeting biochemical 
criteria of Hy’s Law. 
To maintain continued regulatory reporting 
compliance in alignment with new Health 
Authority DILI reporting requirements.
Section 8.4.3, Follow -up 
of AE, SAE, and other 
Reportable Safety Event 
Information
Added potential DILI events meeting 
biochemical criteria of Hy’s Law to list of 
reportable safety events.
See rationale for Section 8.4 1, DILI 
reporting.
Section 8.4.7, Events of 
Clinical Interest
ECI updated to include potential DILI 
meeting biochemical criteria of Hy’s Law, 
with associated reporting requirements.
See rationale for Section 8.4 1, DILI 
reporting.
Section 8.11.5.2, Efficacy 
Follow-up Visit(s)
Where deletion of text could cause 
confusion, due to the design of the study to 
date, the text has been left unchanged, and a 
note has been added regarding changes to 
imaging requirements.
See rationale for Section 1.1. under the 
additional changes.
Section 8.11.5.3, Survival
Follow-up Contacts
Where deletion of text could cause 
confusion, due to the design of the study to 
date, the text has been left unchanged, and a 
note has been added regarding the survival 
follow-up.
See rationale for Section 1.1 under the 
primary reason..
Section 10.3.3, Definition 
of SAE
Added potential DILI events meeting 
biochemical criteria of Hy’s Law to 
definition of SAE. 
Refer to rationale for Section 8.4.1, DILI 
reporting.
Section 10.7.2.10, Japan
Country-specific text describing background 
chemotherapy. 
Due to 5-FU shortage, locally sourced 5-
FU will be supplied as 1,000 mg/20 mL 
vials.
Throughout
Minor administrative, formatting, 
grammatical, and/or typographical changes 
were made throughout the document.
To ensure clarity and accurate 
interpretation of the intent of the protocol.
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TABLE OF CONTENTS
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................17
1.1
Synopsis.................................................................................................................17
1.2
Schema ..................................................................................................................23
1.3
Schedule of Activities...........................................................................................26
1.3.1
Initial Treatment Phase: Lenvatinib Plus Pembrolizumab Plus CAPOX 
(Safety Run-in [Part 1] and Main Study [Part 2])........................................26
1.3.2
Initial Treatment Phase: Lenvatinib Plus Pembrolizumab Plus 
mFOLFOX6 (Safety Run-in [Part 1] and Main Study [Part 2])..................38
1.3.3
CAPOX Only (Main Study [Part 2]) ...........................................................47
1.3.4
mFOLFOX6 Only (Main Study [Part 2]) ....................................................51
1.3.5
Second Course (Part 1 and Part 2)...............................................................55
2
INTRODUCTION..........................................................................................................61
2.1
Study Rationale....................................................................................................61
2.2
Background ..........................................................................................................63
2.2.1
Pharmaceutical and Therapeutic Background .............................................63
2.2.1.1
Pembrolizumab ..................................................................................63
2.2.1.2
Lenvatinib ..........................................................................................63
2.2.1.3
Lenvatinib Plus Pembrolizumab........................................................65
2.2.1.4
Chemotherapy....................................................................................65
2.2.1.5
Lenvatinib in Combination With Chemotherapy in Other 
Indications..........................................................................................67
2.2.2
Preclinical and Clinical Studies ...................................................................67
2.2.2.1
Clinical Activity of Pembrolizumab in Advanced Gastric Cancer....67
2.2.2.2
Clinical Activity of Pembrolizumab in Combination Therapy..........68
2.2.2.3
Clinical Activity of VEGF TKI in Gastric Cancer ............................69
2.2.3
Ongoing Clinical Studies.............................................................................69
2.3
Benefit/Risk Assessment......................................................................................70
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................72
4
STUDY DESIGN............................................................................................................75
4.1
Overall Design......................................................................................................75
4.2
Scientific Rationale for Study Design.................................................................77
4.2.1
Rationale for Endpoints ...............................................................................77
4.2.1.1
.............................................................................77
4.2.1.2
Safety Endpoints................................................................................78
4.2.1.3
.................................................................78
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4.2.1.3.1
.................................................78
4.2.1.3.2
.................................................79
4.2.1.3.3
.................................................79
4.2.1.4
.........................79
4.2.1.5
.........................79
4.2.2
Rationale for Use of CAPOX and mFOLFOX6..........................................81
4.3
Justification for Dose...........................................................................................82
4.3.1
Pembrolizumab ............................................................................................82
4.3.2
Lenvatinib ....................................................................................................83
4.3.3
Maximum Dose/Exposure of Lenvatinib and Pembrolizumab for This 
Study ............................................................................................................84
4.3.4
Background Chemotherapy .........................................................................84
4.3.4.1
CAPOX..............................................................................................84
4.3.4.2
mFOLFOX6.......................................................................................85
4.4
Beginning and End-of-Study Definition ............................................................85
4.4.1
Clinical Criteria for Early Study Termination .............................................86
5
STUDY POPULATION ................................................................................................87
5.1
Inclusion Criteria.................................................................................................87
5.2
Exclusion Criteria................................................................................................91
5.3
Lifestyle Considerations......................................................................................94
5.3.1
Meals and Dietary Restrictions....................................................................94
5.3.2
Photosensitivity............................................................................................94
5.3.3
Caffeine, Alcohol, and Tobacco Restrictions ..............................................94
5.4
Screen Failures.....................................................................................................95
5.5
Participant Replacement Strategy......................................................................95
6
STUDY INTERVENTION............................................................................................96
6.1
Study Intervention(s) Administered...................................................................96
6.2
Preparation/Handling/Storage/Accountability .................................................99
6.2.1
Dose Preparation..........................................................................................99
6.2.2
Handling, Storage, and Accountability........................................................99
6.3
Measures to Minimize Bias: Randomization and Blinding............................100
6.3.1
Intervention Assignment............................................................................100
6.3.2
Stratification...............................................................................................100
6.3.3
Blinding......................................................................................................100
6.4
Study Intervention Compliance........................................................................100
6.5
Concomitant Therapy........................................................................................101
6.5.1
Rescue Medications and Supportive Care .................................................103
6.5.1.1
Supportive Care Guidelines for Capecitabine..................................104
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6.5.1.2
Supportive Care Guidelines for Oxaliplatin ....................................104
6.5.1.3
Supportive Care Guidelines for 5-FU..............................................104
6.5.2
Drug Interactions .......................................................................................104
6.5.3
Concomitant Surgery .................................................................................104
6.6
Dose Modification (Escalation/Titration/Other).............................................105
6.6.1
Initial Treatment or First Course................................................................105
6.6.2
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue)...............................................................................................105
6.6.3
Lenvatinib Dose Modification and Toxicity Management........................111
6.6.3.1
.........111
6.6.3.2
.........113
6.6.3.3
Management of QT Prolongation ....................................................116
6.6.3.4
Management of Hypertension..........................................................116
6.6.3.5
Management of Proteinuria..............................................................118
6.6.3.6
Management of Diarrhea .................................................................118
6.6.3.7
Management of Hepatotoxicity........................................................119
6.6.3.8
Management of Thromboembolic Events........................................119
6.6.3.9
Management of Posterior Reversible Encephalopathy 
Syndrome/Reversible Encephalopathy Syndrome/ Reversible 
Posterior Leukoencephalopathy Syndrome .....................................119
6.6.3.10
Management of Hypocalcemia ........................................................119
6.6.3.11
Management of Hemorrhage ...........................................................120
6.6.3.12
Management of Gastrointestinal Perforation or Fistula Formation.120
6.6.3.13
Management of Palmar-plantar Erythrodysesthesia Syndrome.......120
6.6.3.14
Management of Osteonecrosis of the Jaw .......................................121
6.6.3.15
Other Allowed Dose Interruptions for Lenvatinib...........................122
6.6.4
Dose Modifications for Overlapping Toxicities ........................................122
6.6.4.1
Lenvatinib and Pembrolizumab .......................................................122
6.6.4.2
Chemotherapy..................................................................................123
6.6.4.3
........124
6.6.5
Chemotherapy Dose Modification.............................................................125
6.6.5.1
CAPOX (Capecitabine/Oxaliplatin) ................................................125
6.6.5.2
mFOLFOX6.....................................................................................128
6.6.6
Second Course ...........................................................................................130
6.7
Intervention After the End of the Study..........................................................131
6.8
Clinical Supplies Disclosure..............................................................................131
6.9
Standard Policies................................................................................................131
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7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL..........................................................................................................132
7.1
Discontinuation of Study Intervention.............................................................132
7.2
Participant Withdrawal From the Study.........................................................133
7.3
Lost to Follow-up ...............................................................................................133
8
STUDY ASSESSMENTS AND PROCEDURES......................................................134
8.1
Administrative and General Procedures .........................................................134
8.1.1
Informed Consent.......................................................................................134
8.1.1.1
General Informed Consent...............................................................134
8.1.2
Inclusion/Exclusion Criteria ......................................................................135
8.1.3
Participant Identification Card...................................................................135
8.1.4
Medical History .........................................................................................136
8.1.4.1
General Medical History..................................................................136
8.1.4.2
Oncologic Disease Details...............................................................136
8.1.5
Prior and Concomitant Medications Review.............................................136
8.1.5.1
Prior Medications.............................................................................136
8.1.5.2
Prior Oncologic Treatment ..............................................................136
8.1.5.3
Concomitant Medications................................................................136
8.1.6
Assignment of Screening Number.............................................................137
8.1.7
Assignment of Treatment/Randomization Number...................................137
8.1.8
Study Intervention Administration ............................................................137
8.1.8.1
Timing of Dose Administration.......................................................137
8.1.8.1.1
Pembrolizumab ......................................................................138
8.1.8.1.2
Lenvatinib ..............................................................................138
8.1.8.1.3
CAPOX..................................................................................138
8.1.8.1.4
mFOLFOX6...........................................................................139
8.1.8.2
Treatment Compliance.....................................................................139
8.1.8.2.1
Lenvatinib ..............................................................................139
8.1.8.2.2
Pembrolizumab/CAPOX/mFOLFOX6..................................140
8.1.9
Discontinuation and Withdrawal ...............................................................140
8.1.10
Participant Blinding/Unblinding................................................................140
8.1.11
Calibration of Equipment...........................................................................140
8.2
Efficacy/Immunogenicity Assessments ............................................................140
8.2.1
Tumor Imaging and Assessment of Disease..............................................140
8.2.1.1
Initial Tumor Scans..........................................................................141
8.2.1.2
Tumor Scans During the Study........................................................141
8.2.1.3
End-of-treatment and Follow-up Tumor Scans ...............................142
8.2.1.4
Second Course (Retreatment) Tumor Scans....................................142
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8.2.1.5
RECIST 1.1 Assessment of Disease................................................143
8.2.2
.....................................................................145
8.2.2.1
.............................................................145
8.3
Safety Assessments.............................................................................................145
8.3.1
Physical Examinations...............................................................................146
8.3.2
Vital Signs..................................................................................................146
8.3.3
Electrocardiograms ....................................................................................147
8.3.4
Echocardiogram or Multiple Gated Acquisition Scan...............................147
8.3.5
Clinical Safety Laboratory Assessments (Hematology, Chemistry, and 
Urinalysis)..................................................................................................147
8.3.6
Pregnancy Testing......................................................................................148
8.3.7
Eastern Cooperative Oncology Group Performance Scale........................148
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events..................................................................................................................149
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ........................................................149
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events....152
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information.152
8.4.4
Regulatory Reporting Requirements for SAE ...........................................153
8.4.5
Pregnancy and Exposure During Breastfeeding ........................................153
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs..........................................................................................153
8.4.7
Events of Clinical Interest..........................................................................154
8.5
Treatment of Overdose......................................................................................154
8.6
Pharmacokinetics...............................................................................................155
8.6.1
Plasma Collection for Lenvatinib ..............................................................155
8.6.2
Serum Collection for Pembrolizumab .......................................................155
8.7
Pharmacodynamics............................................................................................156
8.8
.........................................................................................................156
8.8.1
............................................156
8.9
....156
8.10
....156
8.11
Visit Requirements.............................................................................................157
8.11.1
Screening....................................................................................................157
8.11.2
Safety Run-in .............................................................................................157
8.11.3
Treatment Period Visit...............................................................................158
8.11.4
Discontinued Participants Continuing to be Monitored in the Study ........159
8.11.5
Posttreatment..............................................................................................159
8.11.5.1
Safety Follow-up Visit.....................................................................159
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8.11.5.2
Efficacy Follow-up Visit(s) .............................................................159
8.11.5.3
Survival Follow-up Contacts ...........................................................160
8.11.6
Vital Status.................................................................................................160
9
STATISTICAL ANALYSIS PLAN ...........................................................................161
9.1
Statistical Analysis Plan Summary...................................................................161
9.2
Responsibility for Analyses/In-house Blinding ...............................................163
9.3
Hypotheses/Estimation ......................................................................................163
9.4
Analysis Endpoints.............................................................................................163
9.4.1
Efficacy/Immunogenicity/Pharmacokinetics Endpoints............................164
9.4.1.1
Primary.............................................................................................164
9.4.1.2
Secondary.........................................................................................164
9.4.1.3
Exploratory ......................................................................................164
9.4.2
Safety Endpoint..........................................................................................164
9.4.3
Patient-reported Outcome (PRO) Endpoint ...............................................164
9.5
Analysis Populations..........................................................................................164
9.5.1
Efficacy Analysis Populations...................................................................164
9.5.2
Safety Analysis Populations ......................................................................165
9.5.3
PRO Analysis Populations.........................................................................165
9.6
Statistical Methods.............................................................................................165
9.6.1
Statistical Methods for Efficacy Analyses.................................................166
9.6.1.1
Overall Survival...............................................................................166
9.6.1.2
Progression-free Survival.................................................................166
9.6.1.3
Objective Response Rate .................................................................168
9.6.1.4
Duration of Response.......................................................................168
9.6.1.5
Analysis Strategy for Key Efficacy Endpoints................................169
9.6.2
Statistical Methods for Safety Analyses ....................................................170
9.6.2.1
Overall Safety Assessment ..............................................................170
9.6.2.2
Assessment of Safety Topics of Special Interest .............................171
9.6.3
Statistical Methods for Patient-Reported Outcome Analyses....................172
9.6.4
Summaries of Demographic and Baseline Characteristics ........................172
9.7
Interim Analyses ................................................................................................172
9.7.1
Efficacy Interim Analysis ..........................................................................173
9.7.2
Safety Interim Analysis..............................................................................173
9.8
Multiplicity .........................................................................................................174
9.8.1
OS Hypotheses...........................................................................................175
9.8.2
PFS Hypotheses .........................................................................................178
9.8.3
ORR Hypotheses........................................................................................180
9.8.4
Safety Analyses..........................................................................................180
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9.9
Sample Size and Power Calculations ...............................................................181
9.9.1
Overall Survival.........................................................................................181
9.9.2
Progression-free Survival...........................................................................181
9.9.3
Objective Response Rate ...........................................................................182
9.10
Subgroup Analyses.............................................................................................182
9.11
Compliance (Medication Adherence)...............................................................183
9.12
Extent of Exposure.............................................................................................183
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...................................................................................................184
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations......184
10.1.1
Code of Conduct for Clinical Trials...........................................................184
10.1.2
Financial Disclosure...................................................................................187
10.1.3
Data Protection...........................................................................................188
10.1.3.1
Confidentiality of Data ....................................................................188
10.1.3.2
Confidentiality of Participant Records.............................................188
10.1.3.3
Confidentiality of IRB/IEC Information..........................................189
10.1.4
.................................................................................189
10.1.4.1
.........................................189
10.1.4.2
........................................189
10.1.4.3
........................................189
10.1.5
Publication Policy......................................................................................189
10.1.6
Compliance with Study Registration and Results Posting Requirements .190
10.1.7
Compliance with Law, Audit, and Debarment ..........................................190
10.1.8
Data Quality Assurance .............................................................................191
10.1.9
Source Documents .....................................................................................192
10.1.10
Study and Site Closure...............................................................................192
10.2
Appendix 2: Clinical Laboratory Tests............................................................193
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................194
10.3.1
Definitions of Medication Error, Misuse, and Abuse................................194
10.3.2
Definition of AE ........................................................................................194
10.3.3
Definition of SAE ......................................................................................195
10.3.4
Additional Events Reported.......................................................................196
10.3.5
Recording AE and SAE .............................................................................196
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................200
10.4
Appendix 4: Medical Device and Drug–Device Combination Products: 
Product Quality Complaints/Malfunctions: Definitions, Recording, and 
Follow-up ............................................................................................................202
CCI
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10.5
Appendix 5: Contraceptive Guidance..............................................................203
10.5.1
Definitions..................................................................................................203
10.5.2
Contraceptive Requirements......................................................................204
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................205
10.7
Appendix 7: Country-specific Requirements..................................................206
10.7.1
Laboratory Testing.....................................................................................206
10.7.2
Country-Specific Requirements.................................................................206
10.7.2.1
France...............................................................................................206
10.7.2.2
Argentina..........................................................................................207
10.7.2.3
Germany...........................................................................................207
10.7.2.4
United Kingdom...............................................................................208
10.7.2.5
Italy ..................................................................................................208
10.7.2.6
Peru ..................................................................................................209
10.7.2.7
Ireland ..............................................................................................209
10.7.2.8
Russia...............................................................................................209
10.7.2.9
China................................................................................................210
10.7.2.10
Japan ................................................................................................210
10.8
Appendix 8: Management of Hypertension.....................................................211
10.9
Appendix 9: Abbreviations ...............................................................................212
11
REFERENCES.............................................................................................................219
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LIST OF TABLES
Table 1
Ongoing Clinical Studies With Pembrolizumab in Gastric Cancer.............70
Table 2
Dose-Limiting Toxicities.............................................................................75
Table 3
Adequate Organ Function Laboratory Values .............................................90
Table 4
Study Interventions......................................................................................97
Table 5
Dose Modification and Toxicity Management Guidelines for Immune-
related Adverse Events Associated With Pembrolizumab Monotherapy, 
Coformulations, or IO Combinations ........................................................................106
Table 6
Pembrolizumab Infusion Reaction Dose Modification and Treatment 
Guidelines ..................................................................................................................110
Table 7
 
....................................................................................................................112
Table 8
 
........................................................................................113
Table 9
 
................................................................................115
Table 10
Recommended Dose Modification (Reduction) Guidelines for CAPOX 
Drug-Related Adverse Events....................................................................................125
Table 11
Recommended Dose Modification Guidelines for CAPOX Drug-
Related Adverse Events .............................................................................................126
Table 12
Recommended Dose Modification Guidelines for mFOLFOX6 Drug-
related Adverse Events ..............................................................................................128
Table 13
Reporting Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events...........................................................................................150
Table 14
Censoring Rules for Primary and Sensitivity Analyses of PFS.................167
Table 15
Censoring Rules for Duration of Response ...............................................169
Table 16
Analysis Strategy for Key Efficacy Endpoints ..........................................169
Table 17
Analysis Strategy for Safety Parameters....................................................171
Table 18
Summary of Interim and Final Analyses Strategy for Efficacy.................173
Table 19
Efficacy Boundaries and Properties for OS Analysis in CPS ≥1 
Participants.................................................................................................................177
Table 20
Efficacy Boundaries and Properties for OS Analysis in All Participants..178
Table 21
Efficacy Boundaries and Properties for PFS Analysis in CPS ≥1 
Participants.................................................................................................................179
Table 22
Efficacy Boundaries and Properties for PFS Analysis in All Participants 179
Table 23
Statistical Power and Approximate ORR Difference Required to Show 
Efficacy for ORR at IA ..............................................................................................180
Table 24
Protocol-Required Safety Laboratory Assessments...................................193
CCI
CCI
CCI
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LIST OF FIGURES
Figure 1
Study Schema (Part 1: Safety Run-in).........................................................23
Figure 2
Study Schema (Part 2: Main Study).............................................................24
Figure 3
Second Course Treatment Phase..................................................................25
Figure 4
 
...................................................................................................114
Figure 5
Treatment Algorithm for Palmar-Plantar Erythrodysesthesia ...................121
Figure 6
Decision-making Process When Progression Observed by Investigator...145
Figure 7
Multiplicity Graph for Type I Error Control of Study Hypotheses ...........175
Figure 8
Management of Hypertension – INDUCTION..........................................211
Figure 9
Management of Hypertension – CONSOLIDATION ...............................211
CCI
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 3, Randomized Study to Evaluate the Efficacy and Safety of 
Lenvatinib (E7080/MK-7902) plus Pembrolizumab (MK-3475) plus Chemotherapy 
Compared with Standard of Care Therapy as First-line Intervention in Participants with 
Advanced/Metastatic Gastroesophageal Adenocarcinoma (LEAP-015)
Short Title: Lenvatinib plus Pembrolizumab plus Chemotherapy for the Treatment of 
Advanced/Metastatic Gastroesophageal Adenocarcinoma
Acronym: LEAP-015
Hypotheses, Objectives, and Endpoints:
Male and female adults, at least 18 years of age with previously untreated, locally advanced 
unresectable or metastatic gastric, gastroesophageal junction, or esophageal adenocarcinoma 
will be enrolled, and the following objectives and endpoints will be assessed (there are dual 
primary endpoints):
Primary Objective
Primary Endpoint
- Objective (Part 1): To evaluate the safety 
and tolerability of treatment with lenvatinib 
plus pembrolizumab plus chemotherapy.
- Dose-limiting toxicities, adverse events 
and study intervention discontinuations due 
to adverse events.
- Objective (Part 2): To compare the overall 
survival between treatment groups
- Hypothesis (H1): Lenvatinib plus 
pembrolizumab plus chemotherapy is 
superior to chemotherapy for OS in 
participants with programmed cell death 
ligand 1 combined positive score ≥1.
- Hypothesis (H3): Lenvatinib plus 
pembrolizumab plus chemotherapy is 
superior to chemotherapy for OS in all 
participants.
- Overall Survival: The time from 
randomization to death due to any cause
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- Objective (Part 2): To compare the PFS 
between treatment groups
- Hypothesis (H2): Lenvatinib plus 
pembrolizumab plus chemotherapy is 
superior to chemotherapy alone for PFS per 
RECIST 1.1 as assessed by BICR in 
participants with programmed cell death 
ligand 1 combined positive score ≥1.
- Hypothesis (H4): Lenvatinib plus 
pembrolizumab plus chemotherapy is 
superior to chemotherapy for PFS per 
RECIST 1.1 as assessed by BICR in all 
participants.
- Progression-free Survival: The time from 
randomization to the first documented 
disease progression or death due to any 
cause, whichever occurs first.
Secondary Objectives
Secondary Endpoints
- Objective (Part 2): To compare ORR 
between treatment groups.
- Hypothesis (H5): Lenvatinib plus 
pembrolizumab plus chemotherapy is 
superior to chemotherapy for ORR per 
RECIST 1.1 as assessed by BICR in 
participants with programmed cell death 
ligand 1 positive tumors defined by 
combined positive score ≥1.
- Hypothesis (H6): Lenvatinib plus 
pembrolizumab plus chemotherapy is 
superior to chemotherapy for ORR per 
RECIST 1.1 as assessed by BICR in all 
participants.
- Objective Response: Complete response or 
partial response
- Objective (Part 2): To estimate DOR, per 
RECIST 1.1 as assessed by BICR for each 
treatment group in participants with 
programmed cell death ligand 1 combined 
positive score ≥1 and in all participants.
- Duration of Response: The time from first 
response (complete response or partial 
response) to subsequent disease 
progression, or death from any cause, 
whichever occurs first
- Objective (Part 2): To evaluate the safety 
and tolerability of lenvatinib plus 
pembrolizumab plus chemotherapy versus 
chemotherapy
- Adverse events 
- Study intervention discontinuation due to 
adverse events
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Overall Design:
Study Phase
Phase 3
Primary Purpose
Treatment
Indication
Gastrooesophageal cancer
Population
Male and female participants with first-line 
gastroesophageal adenocarcinoma
Study Type
Interventional
Intervention Model
Parallel
This is a multi site study.
Type of Control
Active Control Without Placebo 
Study Blinding
Unblinded open-label 
Blinding Roles
No blinding 
Estimated Duration of Study
The Sponsor estimates that the study will 
require approximately 5 years from the time 
the first participant (or their legally 
acceptable representative) provides 
documented informed consent until the last 
participant’s last study-related contact.
Number of Participants:
The planned sample size for Part 1 (Safety Run-in) is approximately 12 participants. The 
planned sample size for Part 2 (Main Study) is approximately 878 participants who will be 
randomized as described in Section 9.9. 
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Intervention Groups and Duration:
Arm Name
Intervention 
Name
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen/
Treatment 
Period/
Vaccination 
Regimen
Use
Arm 1
Pembrolizumab
25 mg/mL
400 mg
IV Infusion
Q6W
Test Product
Arm 1
Lenvatinib
10 mg/
4 mg / 1mg
8 mg induction/
20 mg 
consolidation
Oral
Once daily
Test Product
Arm 1
Capecitabine
(CAPOX)
150 mg tablet
or
500 mg tablet
1000 mg/m2
Oral
BID for 14 
days Q3W for 
4 cycles 
Test Product
Arm 1
Oxaliplatin
(CAPOX)
100 mg/ 20 mL 
vial or 50 mg 
vial
130 mg/m2
IV Infusion
Once Q3W for 
4 cycles
Test Product
Arm 1
Oxaliplatin
(mFOLFOX)
100 mg/ 20 mL 
vial or 50 mg 
vial
85 mg/m2
IV Infusion
Once Q2W for 
6 cycles
Test Product
Arm 1
5-FU 
(mFOLFOX)
500 mg/ 10 mL 
vial or
250 mg/ 10 mL 
vial
400 mg/m2
(bolus) plus 2400 
mg/m2
(continuous)
IV Infusion
Q2W for 6 
cycles
Test Product
Arm 1
Leucovorin or 
Levoleucovorin 
(mFOLFOX)
100 mg vial or 
300 mg vial
400 mg/m² (or 
200 mg/m² for 
levoleucovorin)
IV Infusion
Q2W for 6 
cycles
Test Product
Arm 2
Capecitabine
(CAPOX)
150 mg tablet
or
500 mg tablet
1000 mg/m2
Oral
bid for 14 days 
q3w
Comparator
Arm 2
Oxaliplatin
(CAPOX)
100 mg/ 20 mL 
vial or 50 mg 
vial
130 mg/m2
IV Infusion
q3w
Comparator
Arm 2
Oxaliplatin
(mFOLFOX)
100 mg/ 20 mL 
vial or 50 mg 
vial
85 mg/m2
IV Infusion
q2w
Comparator
Arm 2
5-FU 
(mFOLFOX)
500 mg/ 10 mL 
vial or
250 mg/ 10 mL 
vial
400 mg/m2
(bolus) plus 2400 
mg/m2
(continuous)
IV Infusion
q2w
Comparator
Arm 2
Leucovorin or 
Levoleucovorin 
(mFOLFOX)
100 mg vial or 
300 mg vial
400 mg/m² (or
200 mg/m² for 
levoleucovorin)
IV Infusion
q2w
Comparator
AxMP=auxiliary medical product; IMP=investigational medicinal product; IV=intravenous.; NIMP=noninvestigational medical product
The classification of IMP in this table is based on guidance issued by the European Commission and applies to countries in the European 
Economic Area (EEA). Country differences with respect to the definition/classification of IMP/NIMP may exist. In these 
circumstances, local legislation is followed. 
Investigator decision regarding the type of backbone chemotherapy (CAPOX or mFOLFOX6) should be determined prior to 
allocation/randomization. Participants should continue on the type of backbone chemotherapy chosen prior to randomization 
throughout the study.
Lenvatinib capsules may be added without breaking or crushing them to a tablespoon of water or apple juice in a small glass to produce a 
suspension (please refer to Pharmacy Manual).
Clinical supply concentration and formulation of chemotherapy may vary by local source.
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Total Number of 
Intervention Groups/Arms
2 intervention groups
Duration of Participation
Each participant will participate in the study from the time 
the participant provides documented informed consent 
through the final contact. After a Screening Phase of up to 
28 days, each participant will be assigned to receive study 
treatment until one of the conditions for discontinuation of 
study intervention is met. Participants may continue 
treatment with lenvatinib beyond 2 years if they experience 
clinical benefit according to the PI, with Sponsor 
consultation and approval. 
Participants treated with pembrolizumab who complete 18 
cycles (2 years) of treatment with stable disease or better or 
participants who attain an investigator-determined complete 
response and have received at least 4 cycles of 
pembrolizumab may be eligible for retreatment with up to 
an additional 9 cycles (approximately 1 year) of 
pembrolizumab if they experience radiographic disease 
progression verified by blinded independent central review 
after stopping treatment in the initial treatment phase. This 
retreatment is termed Second Course Treatment. 
Participants may continue treatment with pembrolizumab 
with or without lenvatinib during Second Course Treatment 
at the discretion of the investigator until meeting one of the 
criteria for treatment discontinuation.
Note: As of Amendment 8, Second Course will no longer be 
offered. Any participant currently receiving Second Course 
retreatment will be able to continue treatment as planned. 
Imaging will be performed per local standard of care.
Participants may be permitted to continue study intervention 
beyond Response Evaluation Criteria in Solid Tumors 1.1 
defined disease progression as long as the treating 
investigator considers that the participant may experience 
clinical benefit with continued treatment, and the participant 
is tolerating study intervention. Request to validate 
progression by BICR must be submitted on disease 
progression assessed by investigator. Imaging should 
continue to be performed and submitted to the iCRO until 
any of the conditions for discontinuation of imaging are 
met. All decisions to continue treatment beyond BICR 
verified disease progression must be approved by the 
Sponsor.
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After study intervention completion/discontinuation, each 
participant will be followed for safety as described in 
Section 8.4. In addition, all participants will be followed for 
overall survival until death, withdrawal of consent, the end 
of the study, or enrollment into an extension study (if 
applicable).
Participants who complete or discontinue study intervention 
in the absence of radiographic disease progression will have 
posttreatment follow-up imaging for disease status every 6 
weeks until any of the conditions for discontinuation of 
imaging are met.
Participants in Part 1 are expected to be treated with the full 
course of study treatment as depicted in Figure 1. The 
duration of the study for participants in Part 1 (Safety Run-
in) and Part 2 (Main Study) is anticipated to be the same 
provided that the study passes Part 1 and moves to Part 2 
(as detailed in Section 4.1, Figure 1 and Figure 2).
Study Governance Committees:
Executive Oversight Committee
Yes 
Data Monitoring Committee
Yes 
Clinical Adjudication Committee
No 
Steering Committee
No
Study governance considerations are outlined in Appendix 1.
Study Accepts Healthy Participants: No
A list of abbreviations is in Appendix 9.
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1.2
Schema
The study design is depicted in Figure 1 (Part 1: Safety Run-in), Figure 2 (Part 2: Main Study) and Figure 3 (Second Course 
Treatment Phase). Note: As of Amendment 8, Second Course (Figure 3)will no longer be offered. Any participant currently receiving 
Second Course retreatment will be able to continue treatment as planned. Imaging will be performed per local standard of care.
Figure 1
Study Schema (Part 1: Safety Run-in)
CAPOX=capecitabine + oxaliplatin; ECOG=Eastern Cooperative Oncology Group; mFOLFOX6=folinic acid, fluorouracil, and oxaliplatin; HER-2=human epidermal growth 
factor receptor 2; po=per oral; qd=once daily; QW6=dosing every 6 weeks.
a. HER-2 positive participants are excluded.   
b. Selection of chemotherapy backbone by the investigator must be determined prior to allocation.
c. If 3 or more DLTs occur in either chemotherapy backbone treatment group during this Safety Run-in, enrollment to Part 2 may be delayed to further examine safety data and 
consider study design changes.
Note: After the last cycle of the Induction Phase, lenvatinib will be maintained at the current dose until the start of the Consolidation Phase. The Consolidation Phase, will begin 
3 weeks after the last dose of oxaliplatin induction for CAPOX and 3 weeks after C2D29 of mFOLFOX6, when the dose will be escalated to 20 mg in participants who 
tolerated 8 mg. Participants who have had lenvatinib-related dose reductions during induction for hematologic toxicity may have dose escalation per Figure 2
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Figure 2
Study Schema (Part 2: Main Study)
CAPOX=capecitabine + oxaliplatin; DOR = duration of response; ECOG=Eastern Cooperative Oncology Group; mFOLFOX6=folinic acid, fluorouracil, and oxaliplatin; HER-
2=human epidermal growth factor receptor 2; ORR = objective response rate; OS=overall survival; PFS=progression-free survival; po=per oral; qd=once daily; QW6=dosing 
every 6 weeks.
a. HER-2 positive participants are excluded.  
Note: After the last cycle of the Induction Phase, lenvatinib will be maintained at the current dose until the start of the Consolidation Phase. The Consolidation Phase, will begin 
3 weeks after the last dose of oxaliplatin induction for CAPOX and 3 weeks after C2D29 of mFOLFOX6, when the dose will be escalated to 20 mg in participants who 
tolerated 8 mg. Participants who have had lenvatinib-related dose reductions during induction for hematologic toxicity will have dose escalation per Table 7. 
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Figure 3
Second Course Treatment Phase 
IV=intravenous; po=orally; Q6W=dosing every 6 weeks; qd=once daily.
Second Course is for eligible participants in both Part 1 and Part 2.
a. Second Course is up to 9 cycles of pembrolizumab (approximately 1 year), or meeting discontinuation criteria are listed in Section 7.1. Lenvatinib may continue beyond a year, 
per investigator’s discretion.
b. Lenvatinib administration in the Second Course is at the discretion of the investigator. Lenvatinib may be restarted if the participant did not discontinue lenvatinib in the First 
Course due to lenvatinib-related AEs (Section 7.1). Lenvatinib will continue until meeting at least 1 of the discontinuation criteria listed in Section 7.1. Participants may begin 
the Second Course with lenvatinib at the highest tolerable dose received during the Consolidation Phase, per investigator’s decision.
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1.3
Schedule of Activities
1.3.1
Initial Treatment Phase: Lenvatinib Plus Pembrolizumab Plus CAPOX (Safety Run-in [Part 1] and Main Study 
[Part 2])
Study Perioda
Screeningb
Induction Phase (Cycles) 
Consolidation Phase (Cycles) 
EOT
Posttreatment
Notes
Treatment Cycles
Screening
C1
C2
C3
C4 to 
18
C>18
DC
Safety 
FU
FU 
Visits
Survival 
FU
Cycle Day
-28 to -1
1
8
15
22
29
36
1 to 
36
1
8
15
22
29
36
1 to 
36
1 to 36
Study Week
1
2
3
4
5
6
7 to 
12
13
14
15
16
17
18
DC
30 
Days 
Post 
Last 
Dose
Every 
6 
Weeks 
Post 
DC
Every 
12 
Weeks
Scheduled Window (days):
3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±7
Administrative Procedures
Informed Consent
X
Section 8.1.1.1 
Reconsent at the first indication of 
radiographic recurrence/progression
Assessed by the 
investigator before 
the next cycle 
starts.
Inclusion/Exclusion Criteria
X
Participant Identification Card
X
X
Update at C1D1
Medical History 
X
Prior/Concomitant Medication Review
X
X
X
X
X
X
X
X
X
X
Will be assessed 
on Day 1 and Day 
22 of C2-C18. See 
Section 6.5
Treatment Randomization/allocationc
X
Survival Status
<---------------------------------------------------------------------------------------------------------------------------------------------------->
X
Updated survival 
status may be 
requested by the 
Sponsor at any 
time during the 
course of the 
study.
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Study Perioda
Screeningb
Induction Phase (Cycles) 
Consolidation Phase (Cycles) 
EOT
Posttreatment
Notes
Treatment Cycles
Screening
C1
C2
C3
C4 to 
18
C>18
DC
Safety 
FU
FU 
Visits
Survival 
FU
Cycle Day
-28 to -1
1
8
15
22
29
36
1 to 
36
1
8
15
22
29
36
1 to 
36
1 to 36
Study Week
1
2
3
4
5
6
7 to 
12
13
14
15
16
17
18
DC
30 
Days 
Post 
Last 
Dose
Every 
6 
Weeks 
Post 
DC
Every 
12 
Weeks
Scheduled Window (days):
3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±7
Study Treatment Administration
Pembrolizumab Administration
X
X
X
X
18 cycles, Q6W
Lenvatinib
Lenvatinib Dispense
X
X
X
X
X 
X
X
Will be dispensed 
at Day 1 and 
Day 22 of all 
cycles after C2.
Lenvatinib Administration
<---------------------------------->
<---------------------------------------------------->
See Sections 
6.6.3.1, 6.6.3.2, 
and 8.1.8.1 
regarding dosing 
during Induction 
and Consolidation.
CAPOX 
administration
Oxaliplatin
X
X
X
130 mg/m2 over 
~2 hours
At C2 will be 
administered at 
Day 1 and Day 22.
Capecitabine
Capecitabine 
Dispense
X
X
X
At C2 will be 
dispensed at Day 1 
and Day 22.
Capecitabine 
Administration
<------>
<----->
X
1000 mg/m2 BID 
on C1 and C2 
Day 1 to 14 and 
Day 22 to 35 
Clinical procedure and events
Adverse Events Monitoring
X
Xd
X
X
Xd
X
X
X
Xd
X
X
X
X
X
X
X
Will be recorded 
on Day 1 and 
Day 22 of C2, and 
C4-C18, and at 
every clinic 
visit. AE reporting 
will be continuous 
throughout the 
study as detailed in 
Section 8.4.
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Study Perioda
Screeningb
Induction Phase (Cycles) 
Consolidation Phase (Cycles) 
EOT
Posttreatment
Notes
Treatment Cycles
Screening
C1
C2
C3
C4 to 
18
C>18
DC
Safety 
FU
FU 
Visits
Survival 
FU
Cycle Day
-28 to -1
1
8
15
22
29
36
1 to 
36
1
8
15
22
29
36
1 to 
36
1 to 36
Study Week
1
2
3
4
5
6
7 to 
12
13
14
15
16
17
18
DC
30 
Days 
Post 
Last 
Dose
Every 
6 
Weeks 
Post 
DC
Every 
12 
Weeks
Scheduled Window (days):
3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±7
Full physical examination
X
X
X
At Screening, 
perform within 
7 days prior to 
C1D1. If full 
physical 
examination is 
performed within 
3 days before 
C1D1, directed 
physical 
examination for 
C1D1 could be 
skipped.
Directed physical examination
X
X
X
X
X
X
X
X
X
Will be performed 
on Day 1 and 
Day 22 of C2 and 
C4-C18.
Height
X
Weight and Vital Signs (including blood 
pressure) 
X
X
Xd
X
X
Xd
X
X
X
Xd
X
X
X
X
X
Will be performed 
on Day 1 and 
Day 22 of C2 and 
C4-C18
Telephone or virtual contact
X
X
X
Participant check 
of blood pressure 
and review of AEs
12-lead ECG with QTc measurement e
X
X
X
X
X
X
X
X
X
X
For 
country-specific 
requirements see 
Appendix 7.
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Study Perioda
Screeningb
Induction Phase (Cycles) 
Consolidation Phase (Cycles) 
EOT
Posttreatment
Notes
Treatment Cycles
Screening
C1
C2
C3
C4 to 
18
C>18
DC
Safety 
FU
FU 
Visits
Survival 
FU
Cycle Day
-28 to -1
1
8
15
22
29
36
1 to 
36
1
8
15
22
29
36
1 to 
36
1 to 36
Study Week
1
2
3
4
5
6
7 to 
12
13
14
15
16
17
18
DC
30 
Days 
Post 
Last 
Dose
Every 
6 
Weeks 
Post 
DC
Every 
12 
Weeks
Scheduled Window (days):
3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±7
ECHO/MUGA
X
X
A 14-day window 
for the assessment 
is allowed at EOT. 
Additional 
assessments may 
be performed as 
clinically 
indicated.
ECOG Performance Status
X
X
X
X
X
X
X
X
X
Will be assessed at 
Day 1 and Day 22 
at C2-C18. ECOG 
status must be 
performed within 
3 days of the 
beginning of 
Cycle 1 and prior 
to each systemic 
treatment 
administration.
Poststudy Anticancer Therapy Status
X
X
X
X
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10-JUN-2025
Study Perioda
Screeningb
Induction Phase (Cycles) 
Consolidation Phase (Cycles) 
EOT
Posttreatment
Notes
Treatment Cycles
Screening
C1
C2
C3
C4 to 
18
C>18
DC
Safety 
FU
FU 
Visits
Survival 
FU
Cycle Day
-28 to -1
1
8
15
22
29
36
1 to 
36
1
8
15
22
29
36
1 to 
36
1 to 36
Study Week
1
2
3
4
5
6
7 to 
12
13
14
15
16
17
18
DC
30 
Days 
Post 
Last 
Dose
Every 
6 
Weeks 
Post 
DC
Every 
12 
Weeks
Scheduled Window (days):
3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±7
Patient-reported Outcomes
CCI
08ZFCS

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10-JUN-2025
Study Perioda
Screeningb
Induction Phase (Cycles) 
Consolidation Phase (Cycles) 
EOT
Posttreatment
Notes
Treatment Cycles
Screening
C1
C2
C3
C4 to 
18
C>18
DC
Safety 
FU
FU 
Visits
Survival 
FU
Cycle Day
-28 to -1
1
8
15
22
29
36
1 to 
36
1
8
15
22
29
36
1 to 
36
1 to 36
Study Week
1
2
3
4
5
6
7 to 
12
13
14
15
16
17
18
DC
30 
Days 
Post 
Last 
Dose
Every 
6 
Weeks 
Post 
DC
Every 
12 
Weeks
Scheduled Window (days):
3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±7
Tumor Tissue Collection
Tumor Blocks or Slides
X
To include PD-L1 
and MSI analysis. 
Central PD-L1 
result will be 
masked to the site. 
A repeat sample 
will be required if 
submitted sample 
is inadequate. The 
planned MSI 
sample should be 
obtained at 
screening but may 
be collected post-
randomization if 
needed.
Laboratory Assessments
Pregnancy Test – Urine or Serum 
X
X
X
X
X
X
X
X
X
Xh
Will be performed 
on Day 1 and Day 
22 of C2 -C18. See 
Section 8.3.6.
WOCBP require a 
negative 
pregnancy test 
within either 
24 hours (urine) or 
72 hours (serum) 
before the first 
dose of study 
intervention and 
before each 
subsequent testing 
day as indicated.
FSH (in WONCBP only)
X
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Study Perioda
Screeningb
Induction Phase (Cycles) 
Consolidation Phase (Cycles) 
EOT
Posttreatment
Notes
Treatment Cycles
Screening
C1
C2
C3
C4 to 
18
C>18
DC
Safety 
FU
FU 
Visits
Survival 
FU
Cycle Day
-28 to -1
1
8
15
22
29
36
1 to 
36
1
8
15
22
29
36
1 to 
36
1 to 36
Study Week
1
2
3
4
5
6
7 to 
12
13
14
15
16
17
18
DC
30 
Days 
Post 
Last 
Dose
Every 
6 
Weeks 
Post 
DC
Every 
12 
Weeks
Scheduled Window (days):
3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±7
PT/INR and aPTTf
X
After baseline, 
PT/INR should be 
tested as needed 
for participants on 
warfarin-based 
anticoagulation 
therapy.
CBC with Differentialf 
X
X
X
X
X
X
X
X
X
Will be assessed 
on Day 1 and Day 
22 of C2-C18. 
Starting from C19 
it will be assessed 
on Day 1 of every 
cycle.
Chemistry Panelf
X
X
X
X
X
X
X
X
X
X
X
X
Will be assessed 
on Day 1 and Day 
22 of C2 and every 
cycle from C4 
onwards.
C-reactive proteinf
X
X
Screening and 
Cycle 3 only
Urine Dipstick (Urinalysis)f, g
X
X
X
X
X
X
X
X
X
X
X
At C2 will be 
assessed at Day 1 
and Day 22. After 
Cycle 3, urine 
dipstick testing for 
protein will be 
performed within 3 
days before Day 1 
and Day 22 of 
every cycle while 
participants are 
taking lenvatinib.
08ZFCS

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10-JUN-2025
Study Perioda
Screeningb
Induction Phase (Cycles) 
Consolidation Phase (Cycles) 
EOT
Posttreatment
Notes
Treatment Cycles
Screening
C1
C2
C3
C4 to 
18
C>18
DC
Safety 
FU
FU 
Visits
Survival 
FU
Cycle Day
-28 to -1
1
8
15
22
29
36
1 to 
36
1
8
15
22
29
36
1 to 
36
1 to 36
Study Week
1
2
3
4
5
6
7 to 
12
13
14
15
16
17
18
DC
30 
Days 
Post 
Last 
Dose
Every 
6 
Weeks 
Post 
DC
Every 
12 
Weeks
Scheduled Window (days):
3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±7
HIV, Hepatitis B and C screen
X
Required at 
baseline. only if 
mandated by local 
health authority or 
as clinically 
indicated (see 
Appendix 7).
Thyroid function (T3, T4, and TSH)
X
X
X
X
X
X
X
Should be 
performed at 
Day 1 of every 
Cycle. Free T3 and 
Free T4 are 
acceptable. 
Participants may 
be dosed while 
thyroid function 
tests are pending.
Plasma Sample for Lenvatinib PK
X
X
X
C1D1: 0.5 to 4 and 
6 to 10 hours post 
dose
C1D22: predose, 
and 2 to 12 hours 
postdose
C3D1: predose, 0.5 
to 4 and 6 to 
10 hours postdose.
All predose 
samples should be 
collected within 
2 hours of 
lenvatinib 
administration.
Postdose samples 
are not needed if
lenvatinib 
administration is 
skipped.
08ZFCS

PRODUCT: MK-7902
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10-JUN-2025
Study Perioda
Screeningb
Induction Phase (Cycles) 
Consolidation Phase (Cycles) 
EOT
Posttreatment
Notes
Treatment Cycles
Screening
C1
C2
C3
C4 to 
18
C>18
DC
Safety 
FU
FU 
Visits
Survival 
FU
Cycle Day
-28 to -1
1
8
15
22
29
36
1 to 
36
1
8
15
22
29
36
1 to 
36
1 to 36
Study Week
1
2
3
4
5
6
7 to 
12
13
14
15
16
17
18
DC
30 
Days 
Post 
Last 
Dose
Every 
6 
Weeks 
Post 
DC
Every 
12 
Weeks
Scheduled Window (days):
3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±7
Serum for Pembrolizumab PK
X
X
Prior to 
pembrolizumab 
infusion on C1D1 
and C3D1.
Antipembrolizumab Antibodies
X
X
Prior to 
pembrolizumab 
infusion on C1D1 
and C3D1.
CCI
08ZFCS

PRODUCT: MK-7902
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PROTOCOL/AMENDMENT NO.: 015-08
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10-JUN-2025
Study Perioda
Screeningb
Induction Phase (Cycles) 
Consolidation Phase (Cycles) 
EOT
Posttreatment
Notes
Treatment Cycles
Screening
C1
C2
C3
C4 to 
18
C>18
DC
Safety 
FU
FU 
Visits
Survival 
FU
Cycle Day
-28 to -1
1
8
15
22
29
36
1 to 
36
1
8
15
22
29
36
1 to 
36
1 to 36
Study Week
1
2
3
4
5
6
7 to 
12
13
14
15
16
17
18
DC
30 
Days 
Post 
Last 
Dose
Every 
6 
Weeks 
Post 
DC
Every 
12 
Weeks
Scheduled Window (days):
3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±7
CCI
08ZFCS

PRODUCT: MK-7902
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10-JUN-2025
Study Perioda
Screeningb
Induction Phase (Cycles) 
Consolidation Phase (Cycles) 
EOT
Posttreatment
Notes
Treatment Cycles
Screening
C1
C2
C3
C4 to 
18
C>18
DC
Safety 
FU
FU 
Visits
Survival 
FU
Cycle Day
-28 to -1
1
8
15
22
29
36
1 to 
36
1
8
15
22
29
36
1 to 
36
1 to 36
Study Week
1
2
3
4
5
6
7 to 
12
13
14
15
16
17
18
DC
30 
Days 
Post 
Last 
Dose
Every 
6 
Weeks 
Post 
DC
Every 
12 
Weeks
Scheduled Window (days):
3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±7
Efficacy Assessment
Tumor Imaging (CT/MRI) 
X
See note for tumor imaging schedule
The initial imaging 
must be performed 
within 28 days of 
randomization. 
The first on-study 
imaging 
assessment should 
be performed 
6 weeks (42 days 
+7 days) from the 
date of 
randomization. 
Subsequent tumor 
imaging should be 
performed every 
6 weeks (42 days 
±7 days) or more 
frequently if 
clinically 
indicated. If 
imaging was 
obtained within 
4 weeks prior to 
EOT, a scan at 
EOT is not 
mandatory. As of 
Amendment 8, on-
study imaging is 
no longer required 
and should be 
performed per 
local standard of 
care.
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10-JUN-2025
aPTT/PTT=activated partial thromboplastin time/partial thromboplastin time; BID=twice daily; CBC=complete blood count; CAPOX=capecitabine + oxaliplatin; CT=computed tomography; 
ctDNA=circulating tumor deoxyribonucleic acid; D=day; DC=discontinuation; DNA=deoxyribonucleic acid; ECG=electrocardiograph, ECHO/MUGA=echocardiogram/multiple gated acquisition 
scan; ECOG=Eastern Cooperative Oncology Group; EDTA=ethylenediamine tetraacetic acid; EQ-5D 5L=EuroQoL 5 Dimension Questionnaire; EORTC QLQ C30=European Organization for 
Research & Treatment of Cancer Quality-of-Life Questionnaire global health status; EORTC QLQ-ST022=European Organization for Research & Treatment of Cancer Quality-of-Life 
Questionnaire (Symptom Score for ST022); EOT=end of treatment; FSH=follicle-stimulating hormone; FT3=free T3 thyroid hormone; FT4=free thyroxine; FU=Follow-up; HBV= hepatitis B 
virus; HCV=hepatitis C virus; HIV=human immunodeficiency virus; INR=international normalized ratio; IRT=interactive response technology; MRI=magnetic resonance imaging; 
MSI=microsatellite instability; PD-L1=programmed death-ligand 1; PET=positron emission tomography; PK=pharmacokinetic; ePRO=electronic patient-reported outcomes; PT=prothrombin 
time; QW3=dosing every 3 weeks; QW6=dosing every 6 weeks; RECIST=Response Evaluation Criteria in Solid Tumors 1.1; RNA=ribonucleic acid; SAE=serious adverse event; T3=T3 thyroid 
hormone; TSH=thyroid-stimulating hormone; WOCBP=woman of childbearing potential; WONCBP=woman of nonchild-bearing potential.
a. No stratification in Part 1 (Safety-Run-in).
b. Screening procedures may be performed on the day of randomization; participant eligibility must be confirmed before randomization.
c. Dose within 3 days of randomization.
d. A phone or virtual visit by investigator or designee will be scheduled to report blood pressure and record adverse events. Full vital signs assessment is not required. Blood pressure will be 
taken, for example, at home or at a local pharmacy, and will be reviewed with the investigator or designee.
e. 6-lead ECG is allowed per institutional standard. Induction Phase (CAPOX): ECG at Screening, C1D1, C1D22. C2D1, and C2D22. ECGs in the Induction Phase should be performed 
approximately 2 hours post lenvatinib dose. Consolidation Phase (CAPOX): C3D1 and C3D22, and starting from C5, an ECG should be performed every 2 cycles (12 weeks). For high-risk 
participants (as defined in Section 8.3.3), conduct ECG monitoring every cycle. If lenvatinib is discontinued, an ECG is only required at EOT and Safety Follow-up Visits.
f. Screening laboratory assessments (PT/INR and aPTT, CBC, chemistry, C-reactive protein and urine dipstick) MUST be performed within 10 days of C1D1 or on C1D1 as long as results are 
available prior to administration of study intervention. Results from the most recent laboratory tests must be used to assess participant eligibility. After C1, predose laboratory procedures can be 
conducted up to 72 hours prior to dosing. 
g. Dipstick is preferred but urinalysis may be used if the use of urine dipstick is not feasible. If a urine dipstick is abnormal follow Section 6.6.3.5. If lenvatinib is discontinued, urine dipstick is 
only required at EOT visit.
h. Pregnancy testing is required at the Safety Follow-up visit and at the end of relevant systemic exposure
08ZFCS

PRODUCT: MK-7902
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10-JUN-2025
1.3.2
Initial Treatment Phase: Lenvatinib Plus Pembrolizumab Plus mFOLFOX6 (Safety Run-in [Part 1] and Main Study 
[Part 2])
Study Perioda
Screening Induction Phase (Cycles) 
Consolidation Phase (Cycles) 
EOT
Posttreatment
Notes
Treatment Cycles
Screeningb
C1
C2
C3
C4 
to 
18
C>18
DC
Safety 
FU
FU 
Visits
Survival 
FU
Cycle Day
-28 to -1
1
8
15 22 29 36 1 to 
36
1
8
15
22
29
36
1 to 
36
1 to 36
Study Week
1
2
3
4
5
6
7 to 
13
14
15
16
17
18
19
DC
30 Days 
Post Last 
Dose
Every 6 
Weeks 
Post DC
Every 
12 
Weeks
Scheduled Window (days):
3
±3 ±3 ±3 ±3 ±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±7
Administrative Procedures 
Informed Consent
X
Section 8.1.1.1 
Reconsent at the first indication of 
radiographic recurrence/progression
Assessed by the 
investigator before the 
next cycle starts
Inclusion/Exclusion Criteria
X
Participant Identification Card
X
X
Update at C1D1
Medical History 
X
Prior/Concomitant Medication Review
X
X
X
X
X
X
X
X
X
X
X
At C2 will be assessed on 
Day 1, Day 15, and 
Day 29. Will be assessed 
on Day 1 and Day 22 of 
C4-C18.
See Section 6.5
Treatment Randomizationc
X
Survival Status
<----------------------------------------------------------------------------------------------------------------------------------->
X
Updated survival status 
may be requested by the 
Sponsor at any time 
during the course of the 
study.
Study Treatment Administration
Pembrolizumab Administration 
X
X
X
X
18 cycles, Q6W
Lenvatinib
Lenvatinib Dispense 
X
X
X
X
X
X
X
X
At C2 will be dispensed 
on Day 1, Day 15, and 
Day 29. Will be dispensed 
on Day 1 and Day 22 of 
C3-C18.
Lenvatinib 
Administration
<----------------------------------------------> <----------------------------------------->
X
See Sections 6.6.3.1, 
6.6.3.2, and 8.1.8.1 
regarding dosing during 
Induction and 
Consolidation.
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Study Perioda
Screening Induction Phase (Cycles) 
Consolidation Phase (Cycles) 
EOT
Posttreatment
Notes
Treatment Cycles
Screeningb
C1
C2
C3
C4 
to 
18
C>18
DC
Safety 
FU
FU 
Visits
Survival 
FU
Cycle Day
-28 to -1
1
8
15 22 29 36 1 to 
36
1
8
15
22
29
36
1 to 
36
1 to 36
Study Week
1
2
3
4
5
6
7 to 
13
14
15
16
17
18
19
DC
30 Days 
Post Last 
Dose
Every 6 
Weeks 
Post DC
Every 
12 
Weeks
Scheduled Window (days):
3
±3 ±3 ±3 ±3 ±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±7
mFOLFOX6 
administration
Oxaliplatin
X
X
X
X
Oxaliplatin administration 
85 mg/m2 over ~2 hours. 
Consolidation C3D1 
should start 3 weeks after 
C2D29 (ie, 3 weeks after 
last dose of oxaliplatin)
Leucovorin/
levoleucovorin
X
X
X
X
5-FU Bolus
X
X
X
X
400 mg/m2 IV
5-FU
X
X
X
X
2400 mg/m2 continuous 
IV 
Clinical procedure and events
Adverse Events Monitoring
X Xd
X
X
X 
X
Xd
X
X
X
X
X
X
X
At C2 will be recorded on 
Day 1, Day 15, and 
Day 29. Will also be 
recorded on Day 1 and 
Day 22 of C4-C18. AE 
reporting will be 
continuous throughout the 
study as detailed in 
Section 8.4.
Full physical examination
X
X
X
At Screening, perform 
within 7 days prior to 
C1D1. If full physical 
examination is performed 
within 3 days before 
C1D1, directed physical 
examination for C1D1 
could be skipped.
Directed physical examination
X
X
X
X
X
X
X
X
At C2 will be assessed at 
Day 1, Day 15, and 
Day 29. Will also be 
assessed on Day 1 and 
Day 22 of C4-C18.
Height
X
08ZFCS

PRODUCT: MK-7902
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10-JUN-2025
Study Perioda
Screening Induction Phase (Cycles) 
Consolidation Phase (Cycles) 
EOT
Posttreatment
Notes
Treatment Cycles
Screeningb
C1
C2
C3
C4 
to 
18
C>18
DC
Safety 
FU
FU 
Visits
Survival 
FU
Cycle Day
-28 to -1
1
8
15 22 29 36 1 to 
36
1
8
15
22
29
36
1 to 
36
1 to 36
Study Week
1
2
3
4
5
6
7 to 
13
14
15
16
17
18
19
DC
30 Days 
Post Last 
Dose
Every 6 
Weeks 
Post DC
Every 
12 
Weeks
Scheduled Window (days):
3
±3 ±3 ±3 ±3 ±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±7
Weight and Vital Signs (including blood 
pressure)
X
X
Xd X
X
X 
X
Xd
X
X
X
X
X
At C2 will be assessed on 
Day1, Day 15, and 
Day 29. Will also be 
assessed on Day 1 and 
Day 22 of C4-C18.
Telephone or virtual contact
X
X
Participant check of blood 
pressure and review of 
AEs
12-lead ECG with QTc measurement e
X
X
X
X
X
X
X
X
X
X
See Appendix 7 for 
country-specific 
requirements.
ECHO/MUGA
X
X
A 14-day window for the 
assessment is allowed at 
EOT. Additional 
assessments may be 
performed as clinically 
indicated.
ECOG Performance Status
X
X
X
X
X
X
X
X
X
X
At C2 will be performed 
on Day 1, Day 15, and 
Day 29. Will be 
performed on Day 1 and 
Day 22 of C4-C18.
ECOG Status must be 
performed within 3 days 
of beginning of Cycle 1 
and prior to each systemic 
treatment administration.
Poststudy Anticancer Therapy Status
X
X
X
X
08ZFCS

PRODUCT: MK-7902
41
PROTOCOL/AMENDMENT NO.: 015-08
MK-7902-015-08 FINAL PROTOCOL
10-JUN-2025
Study Perioda
Screening Induction Phase (Cycles) 
Consolidation Phase (Cycles) 
EOT
Posttreatment
Notes
Treatment Cycles
Screeningb
C1
C2
C3
C4 
to 
18
C>18
DC
Safety 
FU
FU 
Visits
Survival 
FU
Cycle Day
-28 to -1
1
8
15 22 29 36 1 to 
36
1
8
15
22
29
36
1 to 
36
1 to 36
Study Week
1
2
3
4
5
6
7 to 
13
14
15
16
17
18
19
DC
30 Days 
Post Last 
Dose
Every 6 
Weeks 
Post DC
Every 
12 
Weeks
Scheduled Window (days):
3
±3 ±3 ±3 ±3 ±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±7
Patient-reported Outcomes
Tumor Tissue Collection
Tumor Blocks or Slide
X
To include PD-L1 and 
MSI analysis. Central 
PD-L1 result will be 
masked to the site. A 
repeat sample will be 
required if submitted 
sample is inadequate. The 
planned MSI sample 
should be obtained at 
screening but may be 
collected post-
randomization if needed.
CCI
08ZFCS

PRODUCT: MK-7902
42
PROTOCOL/AMENDMENT NO.: 015-08
MK-7902-015-08 FINAL PROTOCOL
10-JUN-2025
Study Perioda
Screening Induction Phase (Cycles) 
Consolidation Phase (Cycles) 
EOT
Posttreatment
Notes
Treatment Cycles
Screeningb
C1
C2
C3
C4 
to 
18
C>18
DC
Safety 
FU
FU 
Visits
Survival 
FU
Cycle Day
-28 to -1
1
8
15 22 29 36 1 to 
36
1
8
15
22
29
36
1 to 
36
1 to 36
Study Week
1
2
3
4
5
6
7 to 
13
14
15
16
17
18
19
DC
30 Days 
Post Last 
Dose
Every 6 
Weeks 
Post DC
Every 
12 
Weeks
Scheduled Window (days):
3
±3 ±3 ±3 ±3 ±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±7
Laboratory Assessments
Pregnancy Test – Urine or Serum 
X
X
X
X
X
X
X
X
X
X
Xh
At C2 will be assessed on 
Day 1, Day 15, and Day 
29. Will also be assessed 
on Day 1 and Day 22 of 
C4-C18.
WOCBP require a 
negative pregnancy test 
within either 24 hours 
(urine) or 72 hours 
(serum) before the first 
dose of study intervention 
and before each 
subsequent testing day as 
indicated. See Section 
8.3.6.
FSH (WONCBP only)
X
PT/INR and aPTTf
X
After baseline, PT/INR 
should be tested as needed 
for participants on 
warfarin-based 
anticoagulation therapy.
CBC with Differentialf
X
X
X
X
X
X
X
X
X
X
At C2 will be assessed on 
Day 1, Day 15, and Day 
29. Will also be assessed 
on Day 1 and Day 22 of 
C4-C18. Starting from 
C19 it will be assessed on 
Day 1 of every cycle. 
Chemistry Panelf
X
X
X
X
X
X
X
X
X
X
X
At C2 will be assessed at 
Day 1, Day 15, and Day 
29. Will be assessed on 
Day 1 and Day 22 of 
every cycle from C4 
onwards.
C-reactive proteinf
X
X
Screening and Cycle 3 
only
08ZFCS

PRODUCT: MK-7902
43
PROTOCOL/AMENDMENT NO.: 015-08
MK-7902-015-08 FINAL PROTOCOL
10-JUN-2025
Study Perioda
Screening Induction Phase (Cycles) 
Consolidation Phase (Cycles) 
EOT
Posttreatment
Notes
Treatment Cycles
Screeningb
C1
C2
C3
C4 
to 
18
C>18
DC
Safety 
FU
FU 
Visits
Survival 
FU
Cycle Day
-28 to -1
1
8
15 22 29 36 1 to 
36
1
8
15
22
29
36
1 to 
36
1 to 36
Study Week
1
2
3
4
5
6
7 to 
13
14
15
16
17
18
19
DC
30 Days 
Post Last 
Dose
Every 6 
Weeks 
Post DC
Every 
12 
Weeks
Scheduled Window (days):
3
±3 ±3 ±3 ±3 ±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±7
Urine Dipstick (Urinalysis)f, g
X
X
X
X
X
X
X
X
X
X
At C2 will be assessed at 
Day 1, Day 15, and Day 
29. After Cycle 3, urine 
dipstick testing for protein 
will be performed within 
3 days before Day 1 and 
Day 22 of every cycle 
while participants are 
taking lenvatinib.
HIV, Hepatitis B and C screen
X
Required at baseline only 
if mandated by local 
health authority or as 
clinically indicated 
(Appendix 7).
Thyroid function (T3, T4, and TSH)
X
X
X
X
X
X
X
Should be performed on 
Day 1 of every Cycle. 
Free T3 and Free T4 are 
acceptable. Participants 
may be dosed while 
thyroid function tests are 
pending.
Plasma Sample for Lenvatinib PK
X
X
X
C1D1: 0.5 to 4 and 6 to 
10 hours postdose
C1D15: predose, and 2 to 
12 hours postdose
C3D1: predose, 0.5 to 4 
and 6 to 10 hours 
postdose.
All predose samples 
should be collected within 
2 hours of lenvatinib 
administration.
Postdose samples are not 
needed if
lenvatinib administration 
is skipped.
08ZFCS

PRODUCT: MK-7902
44
PROTOCOL/AMENDMENT NO.: 015-08
MK-7902-015-08 FINAL PROTOCOL
10-JUN-2025
Study Perioda
Screening Induction Phase (Cycles) 
Consolidation Phase (Cycles) 
EOT
Posttreatment
Notes
Treatment Cycles
Screeningb
C1
C2
C3
C4 
to 
18
C>18
DC
Safety 
FU
FU 
Visits
Survival 
FU
Cycle Day
-28 to -1
1
8
15 22 29 36 1 to 
36
1
8
15
22
29
36
1 to 
36
1 to 36
Study Week
1
2
3
4
5
6
7 to 
13
14
15
16
17
18
19
DC
30 Days 
Post Last 
Dose
Every 6 
Weeks 
Post DC
Every 
12 
Weeks
Scheduled Window (days):
3
±3 ±3 ±3 ±3 ±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±7
Serum for Pembrolizumab PK
X
X
Prior to pembrolizumab 
infusion on C1D1 and 
C3D1.
Antipembrolizumab Antibodies
X
X
Prior to pembrolizumab 
infusion on C1D1 and 
C3D1.
 
 
CCI
08ZFCS

PRODUCT: MK-7902
45
PROTOCOL/AMENDMENT NO.: 015-08
MK-7902-015-08 FINAL PROTOCOL
10-JUN-2025
Study Perioda
Screening Induction Phase (Cycles) 
Consolidation Phase (Cycles) 
EOT
Posttreatment
Notes
Treatment Cycles
Screeningb
C1
C2
C3
C4 
to 
18
C>18
DC
Safety 
FU
FU 
Visits
Survival 
FU
Cycle Day
-28 to -1
1
8
15 22 29 36 1 to 
36
1
8
15
22
29
36
1 to 
36
1 to 36
Study Week
1
2
3
4
5
6
7 to 
13
14
15
16
17
18
19
DC
30 Days 
Post Last 
Dose
Every 6 
Weeks 
Post DC
Every 
12 
Weeks
Scheduled Window (days):
3
±3 ±3 ±3 ±3 ±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±7
Efficacy Assessment
Tumor Imaging (CT/MRI) 
X
See note for tumor imaging schedule
Tumor Imaging 
(CT/MRI) The initial 
imaging must be 
performed within 28 days 
of randomization. The 
first on-study imaging 
assessment should be 
performed 6 weeks 
(42 days +7 days) from 
the date of randomization. 
Subsequent tumor 
imaging should be 
performed every 6 weeks 
(42 days ±7 days) or more 
frequently if clinically 
indicated. If imaging was 
obtained within 4 weeks 
prior to EOT, a scan at 
EOT is not mandatory.
As of Amendment 8, on-
study imaging is no 
longer required and 
should be performed per 
local standard of care.
08ZFCS

PRODUCT: MK-7902
46
PROTOCOL/AMENDMENT NO.: 015-08
MK-7902-015-08 FINAL PROTOCOL
10-JUN-2025
5-FU=5-fluoruracil; aPTT/PTT=activated partial thromboplastin time/partial thromboplastin time; BID=twice daily; CBC=complete blood count; CT=computed tomography; ctDNA=circulating 
tumor deoxyribonucleic acid; D=day; DC=discontinuation; DNA=deoxyribonucleic acid; ECG=electrocardiograph, ECHO/MUGA=echocardiogram/multiple gated acquisition scan; 
ECOG=Eastern Cooperative Oncology Group; EDTA= ethylenediamine tetraacetic acid; EQ-5D 5L=EuroQoL 5 Dimension Questionnaire; EORTC QLQ C30=European Organization for 
Research & Treatment of Cancer Quality-of-Life Questionnaire global health status; EORTC QLQ-ST022=European Organization for Research & Treatment of Cancer Quality-of-Life 
Questionnaire (Symptom Score for ST022); EOT=end of treatment; mFOLFOX6=folinic acid, fluorouracil, and oxaliplatin; FSH=follicle-stimulating hormone; FT3=free T3 thyroid hormone; 
FT4=free thyroxine; FU=Follow-up; HBV= hepatitis B virus; HCV=hepatitis C virus; HIV=human immunodeficiency virus; INR=international normalized ratio; IRT=interactive response 
technology; MRI=magnetic resonance imaging; MSI= microsatellite instability; PD-L1=programmed death-ligand 1; PET=positron emission tomography; PK=pharmacokinetic; ePRO= electronic 
patient-reported outcomes; PT=prothrombin time; QW3=dosing every 3 weeks; QW6=dosing every 6 weeks; RECIST=Response Evaluation Criteria in Solid Tumors 1.1; RNA=ribonucleic acid; 
SAE=serious adverse event; T3=T3 thyroid hormone; TSH=thyroid-stimulating hormone; WOCBP=woman of childbearing potential; WONCBP=woman of nonchild-bearing potential.
a. No stratification in Part 1 (Safety-Run-in).
b. Screening procedures may be performed on the day of randomization; participant eligibility must be confirmed before randomization.
c. Dose within 3 days of randomization.
d. A phone or virtual visit will be scheduled to report blood pressure and record adverse events. Full vital signs assessment is not required blood pressure will be taken, for example, at home or at 
a local pharmacy, and will be reviewed with the investigator or designee.
e. 6-lead ECG is allowed per institutional standard. Induction Phase (mFOLFOX6): ECG at Screening, C1D1, C1D15, C2D1, and C2D15. ECGs in induction should be performed approximately 
2 hours post lenvatinib dose. Consolidation Phase (mFOLFOX6): C3D1 and C3D22; and starting from C5, ECG should be performed every second cycle (12 weeks). For high-risk participants 
(as defined in Section 8.3.3), conduct ECG monitoring every Cycle. If lenvatinib is discontinued, an ECG is only required at EOT and Safety Follow-up Visits.
f. Screening laboratory assessments (PT/INR and aPTT, CBC, C-reactive protein, chemistry and urine dipstick) MUST be performed within 10 days of C1D1 or on C1D1 as long as results are 
available prior to administration of study intervention. Results from the most recent laboratory tests must be used to assess participant eligibility. After C1, predose laboratory procedures can be 
conducted up to 72 hours prior to dosing. 
g. Dipstick is preferred but urinalysis may be used if the use of urine dipstick is not feasible. If lenvatinib is discontinued, urine dipstick is only required at EOT visits.
h. Pregnancy testing is required at the Safety Follow-up visit and at the end of relevant systemic exposure.
08ZFCS

PRODUCT: MK-7902
47
PROTOCOL/AMENDMENT NO.: 015-08
MK-7902-015-08 FINAL PROTOCOL
10-JUN-2025
1.3.3
CAPOX Only (Main Study [Part 2])
Study Period
Screening 
Treatment Phase
EOT
Posttreatment
Notes
Treatment Cycles
Screeninga
C1
C2 
to 
18b
DC
Safety 
FU
FU Visits Survival 
FU
Cycle Day
-28 to -1
1
8
15
22
29
36
1 to 
36
Study Week
1
2
3
4
5
6
DC
30 Days 
post Last 
Dose
Every 6 
Weeks 
Post DC
Every 12 
weeks
Scheduled Window (days):
3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±7
Administrative Procedures 
Informed Consent
X
Section 8.1.1.1 
Reconsent at the first indication of 
radiographic recurrence/progression
Assessed by the investigator
Inclusion/Exclusion Criteria
X
Participant Identification Card
X
X
Update at C1D1
Medical History 
X
Prior/Concomitant Medication Review
X
X
X
X
X
X
At C2-C18 will be assessed at Day 1 and Day 22.
See Section 6.5
Treatment Randomizationc
X
Survival Status
<----------------------------------------------------------------------------------------------->
X
Updated survival status may be requested by the 
Sponsor at any time during the course of the study.
Study Treatment Administration
CAPOX 
Oxaliplatin
X
X
X
Capecitabine
Capecitabine 
Dispense
X
X
X
At C2-C18 will be dispensed at Day 1 and Day 22.
Capecitabine 
Administration
<------------>
<---------->
X
1000 mg/m2 BID on Day 1 to 14 and Day 22 to 35 
of every cycle
Clinical Procedures/Assessments
Adverse Events Monitoring
X
X
X
X
X
X
At C2-C18 will be recorded at Day 1 and Day 22. 
AE reporting will be continuous throughout the 
study as detailed in Section 8.4.
Full Physical Examination
X
X
At Screening, perform within 7 days prior to 
C1D1. If full physical examination is performed 
within 3 days before C1D1, directed physical 
examination for C1D1 could be skipped.
Directed Physical Examination
X
X
X
At C2-C18 will be assessed at Day 1 and Day 22. 
Height
X
Weight and Vital Signs
X
X
X
X
X
At C2-C18 will be assessed at Day 1 and Day 22. 
12-lead ECG with QTc measurement d
X
X
X
For country-specific requirements see Appendix 7.
ECHO/MUGA
X
Additional assessments may be performed as 
clinically indicated.
08ZFCS

PRODUCT: MK-7902
48
PROTOCOL/AMENDMENT NO.: 015-08
MK-7902-015-08 FINAL PROTOCOL
10-JUN-2025
Study Period
Screening 
Treatment Phase
EOT
Posttreatment
Notes
Treatment Cycles
Screeninga
C1
C2 
to 
18b
DC
Safety 
FU
FU Visits Survival 
FU
Cycle Day
-28 to -1
1
8
15
22
29
36
1 to 
36
Study Week
1
2
3
4
5
6
DC
30 Days 
post Last 
Dose
Every 6 
Weeks 
Post DC
Every 12 
weeks
Scheduled Window (days):
3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±7
ECOG Performance Status
X
X
X
X
X
Will be assessed on Day 1 and Day 22 of C2-C18. 
ECOG Status must be performed within 3 days of 
beginning of Cycle 1 and prior to each systemic 
treatment administration.
Poststudy Anticancer Therapy Status
X
X
X
X
Patient-reported Outcomes
Tumor Tissue Collection
Tumor Blocks or Slides
X
To include PD-L1 and MSI analysis Central PD-
L1 result will be masked to the site. A repeat 
sample will be required if submitted sample is 
inadequate. 
The planned MSI sample should be obtained at 
screening but may be collected post-randomization 
if needed.
Laboratory Assessments
Pregnancy Test – Urine or Serum 
X
X
X
X
X
Xg
Will be assessed on Day 1 and Day 22 of C2-C18.
WOCBP require a negative pregnancy test within 
either 24 hours (urine) or 72 hours (serum) before 
the first dose of study intervention and before each 
subsequent testing day as indicated. See Section 
8.3.6.
FSH (WONCBP only)
X
PT/INR and aPTTe
X
After baseline, PT/INR should be tested as needed 
for participants on warfarin-based anticoagulation 
therapy.
CBC with Differentiale
X
X
X
X
X
Will be assessed on Day 1 and Day 22 of C2-C18.
Chemistry Panele
X
X
X
X
X
Will be assessed on Day 1 and Day 22 of C2-C18.
C-reactive proteine
X
X
Screening and Cycle 3 only
Urine dipstick (Urinalysis)e, f
X
X
CCI
08ZFCS

PRODUCT: MK-7902
49
PROTOCOL/AMENDMENT NO.: 015-08
MK-7902-015-08 FINAL PROTOCOL
10-JUN-2025
Study Period
Screening 
Treatment Phase
EOT
Posttreatment
Notes
Treatment Cycles
Screeninga
C1
C2 
to 
18b
DC
Safety 
FU
FU Visits Survival 
FU
Cycle Day
-28 to -1
1
8
15
22
29
36
1 to 
36
Study Week
1
2
3
4
5
6
DC
30 Days 
post Last 
Dose
Every 6 
Weeks 
Post DC
Every 12 
weeks
Scheduled Window (days):
3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±7
HIV, Hepatitis B and C screen
X
Required at baseline. only if mandated by local 
health authority or as clinically indicated (see 
Appendix 7).
Thyroid function (T3, T4, and TSH)
X
X
X
X
Should be performed at Day 1 of every Cycle. 
Free T3 and Free T4 are acceptable. Participants 
may be dosed while thyroid function tests are 
pending.
Efficacy Assessment
Tumor Imaging (CT/MRI) 
X
See note for tumor imaging schedule
Tumor Imaging (CT/MRI) The initial imaging 
must be performed within 28 days of 
randomization. The first on-study imaging 
assessment should be performed 6 weeks (42 days 
+7 days) from the date of randomization. 
Subsequent tumor imaging should be performed 
every 6 weeks (42 days ±7 days) or more 
frequently if clinically indicated. If imaging was 
obtained within 4 weeks prior to EOT, a scan at 
EOT is not mandatory. As of Amendment 8, on-
study imaging is no longer required and should be 
performed per local standard of care.
CCI
08ZFCS

PRODUCT: MK-7902
50
PROTOCOL/AMENDMENT NO.: 015-08
MK-7902-015-08 FINAL PROTOCOL
10-JUN-2025
aPTT/PTT=activated partial thromboplastin time/partial thromboplastin time; BID=twice daily; CBC=complete blood count; CAPOX= capecitabine + oxaliplatin; CT=computed tomography; 
ctDNA=circulating tumor deoxyribonucleic acid; D=day; DC=discontinuation; DNA=deoxyribonucleic acid; ECG=electrocardiograph; ECHO/MUGA=echocardiogram/multiple gated acquisition 
scan; ECOG=Eastern Cooperative Oncology Group; EDTA= ethylenediamine tetraacetic acid; EQ-5D 5L=EuroQoL 5 Dimension Questionnaire; EORTC QLQ C30=European Organization for 
Research & Treatment of Cancer Quality-of-Life Questionnaire global health status; EORTC QLQ-ST022=European Organization for Research & Treatment of Cancer Quality-of-Life 
Questionnaire (Symptom Score for ST022); EOT=end of treatment; FSH=follicle-stimulating hormone; FT3=free T3 thyroid hormone; FT4=free thyroxine; FU=Follow-up; HBV= hepatitis B 
virus; HCV=hepatitis C virus; HIV=human immunodeficiency virus; INR=international normalized ratio; IRT=interactive response technology; MRI=magnetic resonance imaging; MSI= 
microsatellite instability; PD-L1=programmed death-ligand 1; PET=positron emission tomography; PK=pharmacokinetic; ePRO= electronic patient-reported outcomes; PT=prothrombin time; 
QW3=dosing every 3 weeks; QW6=dosing every 6 weeks; RECIST=Response Evaluation Criteria in Solid Tumors 1.1; RNA=ribonucleic acid; SAE=serious adverse event; T3=T3 thyroid 
hormone; TSH=thyroid-stimulating hormone; WOCBP=woman of childbearing potential; WONCBP=woman of nonchild-bearing potential.
a. Screening procedures may be performed on the day of randomization; participant eligibility must be confirmed before randomization.
b. C2-C18 should have the same visits as C1.
c. Dose within 3 days of randomization.
d. 6-lead ECG is allowed per institutional standard. 
e. Screening laboratory assessments (PT/INR and aPTT, CBC, chemistry, C-reactive protein and urine dipstick) MUST be performed within 10 days of C1D1 or on C1D1 as long as results are 
available prior to administration of study intervention. Results from the most recent laboratory tests must be used to assess participant eligibility. After C1, pre dose laboratory procedures can 
be conducted up to 72 hours prior to dosing.
f. Dipstick is preferred but urinalysis may be used if the use of urine dipstick is not feasible.
g. Pregnancy testing is required at the Safety Follow-up visit and at the end of relevant systemic exposure
08ZFCS

PRODUCT: MK-7902
51
PROTOCOL/AMENDMENT NO.: 015-08
MK-7902-015-08 FINAL PROTOCOL
10-JUN-2025
1.3.4
mFOLFOX6 Only (Main Study [Part 2]) 
Study Period
Screening 
Treatment Phase
EOT
Posttreatment
Notes
Treatment Cycles
Screeninga
C1
C2 
to 
18b
DC Safety FU FU Visits
Survival 
FU
Cycle Day
-28 to -1
1
8
15 22 29 36 1 to 
36
Study Week
1
2
3
4
5
6
DC
30 Days 
post Last 
Dose
Every 6 
Weeks 
Post DC
Every 12 
weeks
Scheduled Window (days):
3
±3 ±3 ±3 ±3 ±3
±3
±3
±7
±7
±7
Administrative Procedures
Informed Consent
X
Section 8.1.1 
Reconsent at the first indication of radiographic 
recurrence/progression
As assessed by the investigator
Inclusion/Exclusion Criteria
X
Participant Identification Card
X
X
Update at C1D1
Medical History 
X
Prior/Concomitant Medication Review
X
X
X
X
X
X
X
At C2-C18 will be assessed on Day 1, Day 15, and Day 29.
See Section 6.5
Treatment Randomizationc
X
Survival Status
<--------------------------------------------------------------------------------->
X
Updated survival status may be requested by the Sponsor at 
any time during the course of the study.
Study Treatment Administration
mFOLFOX6 
administration
Oxaliplatin
X
X
X
X
Leucovorin/levoleucovorin
X
X
X
X
5-FU Bolus
X
X
X
X
400 mg/m2 IV 
5-FU
X
X
X
X
2400 mg/m2 continuous IV
Clinical Procedures/Assessments
Adverse Events Monitoring
X
X
X
X
X
X
X
At C2-C18 will be recorded on Day 1, Day 15, and Day 29. 
AE reporting will be continuous throughout the study as 
detailed in Section 8.4.
Full physical examination
X
X
At Screening, perform within 7 days prior to C1D1. If full 
physical examination is performed within 3 days before 
C1D1, directed physical examination for C1D1 could be 
skipped.
Directed physical examination
X
X
X
X
At C2-C18 will be assessed on Day 1, Day 15, and Day 29.
Height
X
Weight and Vital Signs
X
X
X
X
X
X
At C2-C18 will be assessed on Day 1, Day 15, and Day 29.
12-lead ECG with QTc measurement d
X
X
X
For country-specific requirements see Appendix 7.
ECHO/MUGA
X
Additional assessments may be performed as clinically 
indicated.
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Study Period
Screening 
Treatment Phase
EOT
Posttreatment
Notes
Treatment Cycles
Screeninga
C1
C2 
to 
18b
DC Safety FU FU Visits
Survival 
FU
Cycle Day
-28 to -1
1
8
15 22 29 36 1 to 
36
Study Week
1
2
3
4
5
6
DC
30 Days 
post Last 
Dose
Every 6 
Weeks 
Post DC
Every 12 
weeks
Scheduled Window (days):
3
±3 ±3 ±3 ±3 ±3
±3
±3
±7
±7
±7
ECOG Performance Status
X
X
X
X
X
X
Will be assessed on Day 1, Day 15, and Day 29 of C2-C18. 
ECOG Status must be performed within 3 days of beginning 
of Cycle 1 and prior to each systemic treatment 
administration.
Poststudy Anticancer Therapy Status
X
X
X
X
Patient-reported Outcomes
Tumor Tissue Collection
Tumor Blocks or Slides
X
To include PD-L1 and MSI analysis. Central PD-L1 result 
will be masked to the site. A repeat sample will be required 
if submitted sample is inadequate. The planned MSI sample 
should be obtained at screening but may be collected post-
randomization if needed.
Laboratory Assessments
Pregnancy Test – Urine or Serum 
X
X
X
X
X
X
Xg
Will be assessed on Days 1, 15 and 29 of C2 to C18
WOCBP require a negative pregnancy test within either 
24 hours (urine) or 72 hours (serum) before the first dose of 
study intervention and before each subsequent testing day as 
indicated. See Section 8.3.6.
FSH (WONCBP only)
X
PT/INR and aPTTe
X
After baseline, PT/INR should be tested as needed for 
participants on warfarin-based anticoagulation therapy.
CBC with Differentiale
X
X
X
X
X
X
Will be assessed on Days 1, 15 and 29 of C2 to C18.
Chemistry Panele
X
X
X
X
X
X
Will be assessed on Days 1, 15 and 29 of C2 to C18.
C-reactive proteine
X
X
Screening and Cycle 3 only
Urine dipstick (Urinalysis)e, f
X
X
HIV, Hepatitis B and C screen
X
Required at baseline only if mandated by local health 
authority or as clinically indicated (Appendix 7).
Thyroid function (T3, T4, and TSH)
X
X
X
X
Should be performed at Day 1 of every Cycle. Free T3 and 
Free T4 are acceptable. Participants may be dosed while 
thyroid function tests are pending.
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Study Period
Screening 
Treatment Phase
EOT
Posttreatment
Notes
Treatment Cycles
Screeninga
C1
C2 
to 
18b
DC Safety FU FU Visits
Survival 
FU
Cycle Day
-28 to -1
1
8
15 22 29 36 1 to 
36
Study Week
1
2
3
4
5
6
DC
30 Days 
post Last 
Dose
Every 6 
Weeks 
Post DC
Every 12 
weeks
Scheduled Window (days):
3
±3 ±3 ±3 ±3 ±3
±3
±3
±7
±7
±7
Efficacy Assessment
Tumor Imaging (CT/MRI)
X
See note for tumor imaging 
schedule
Tumor Imaging (CT/MRI) The initial imaging must be 
performed within 28 days of randomization. The first on-
study imaging assessment should be performed 6 weeks (42 
days +7 days) from the date of randomization. Subsequent 
tumor imaging should be performed every 6 weeks (42 days 
±7 days) or more frequently if clinically indicated. If 
imaging was obtained within 4 weeks prior to EOT, a scan at 
EOT is not mandatory. As of Amendment 8, on-study 
imaging is no longer required and should be performed per 
local standard of care.
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aPTT/PTT=activated partial thromboplastin time/partial thromboplastin time; BID=twice daily; CBC=complete blood count; CT=computed tomography; ctDNA=circulating tumor deoxyribonucleic 
acid; D=day; DC=discontinuation; DNA=deoxyribonucleic acid; ECG=electrocardiograph, ECHO/MUGA= echocardiogram/multiple gated acquisition scan; ECOG=Eastern Cooperative 
Oncology Group; EDTA= ethylenediamine tetraacetic acid; EQ-5D 5L=EuroQoL 5 Dimension Questionnaire; EORTC QLQ C30=European Organization for Research & Treatment of Cancer 
Quality-of-Life Questionnaire global health status; EORTC QLQ-ST022=European Organization for Research & Treatment of Cancer Quality-of-Life Questionnaire (Symptom Score for ST022); 
EOT=end of treatment; mFOLFOX6= folinic acid, fluorouracil, and oxaliplatin; FSH=follicle-stimulating hormone; FT3=free T3 thyroid hormone; FT4=free thyroxine; FU=Follow-up; HBV= 
hepatitis B virus; HCV=hepatitis C virus; HIV=human immunodeficiency virus; INR=international normalized ratio; IRT=interactive response technology; MRI=magnetic resonance imaging; 
MSI= microsatellite instability; PD-L1=programmed death-ligand 1; PET=positron emission tomography; PK=pharmacokinetic; ePRO= electronic patient-reported outcomes; PT=prothrombin 
time; QW3=dosing every 3 weeks; QW6=dosing every 6 weeks; RECIST=Response Evaluation Criteria in Solid Tumors 1.1; RNA=ribonucleic acid; SAE=serious adverse event; T3=T3 thyroid 
hormone; TSH=thyroid-stimulating hormone; WOCBP=woman of childbearing potential; WONCBP=woman of nonchild-bearing potential.
a. Screening procedures may be performed on the day of randomization; participant eligibility must be confirmed before randomization.
b. C2-C18 should have the same visits as C1.
c. Dose within 3 days of randomization. 
d. 6-lead ECG is allowed per institutional standard.
e. Screening laboratory assessments (PT/INR and aPTT, CBC, C-reactive protein, chemistry and urine dipstick) MUST be performed within 10 days of C1D1 or on C1D1 as long as results are 
available prior to administration of study intervention. Results from the most recent laboratory tests must be used to assess participant eligibility. After C1, predose laboratory procedures can be 
conducted up to 72 hours prior to dosing.
f. Dipstick is preferred but urinalysis may be used if the use of urine dipstick is not feasible. 
g. Pregnancy testing is required at the Safety Follow-up visit and at the end of relevant systemic exposure.
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1.3.5
Second Course (Part 1 and Part 2)
Note: As of Amendment 8, Second Course will no longer be offered. Any participant currently receiving Second Course treatment 
will be able to continue treatment as planned. Imaging will be performed per local standard of care. Participants who either complete 
18 cycles of pembrolizumab or discontinue pembrolizumab will be discontinued from the study following the Safety Follow-up visit. 
AE, SAE, and other reportable safety events will be reported and followed as described under Section 8.4. All participants in Efficacy 
Follow-up prior to initiation of Amendment 8 will stop efficacy assessments and be discontinued from the study. All participants in 
Survival Follow-up are considered to have completed the study and should have a final survival contact; these participants will no 
longer be contacted for survival information. The SoA has been amended to only show the required assessments.
Trial Period
Treatment
Cycle =6 weeks
EOT
Posttreatment
Notes
Safety
Follow-
upa
Follow-upb
Survival
Follow-
up
All procedures are to be 
performed before 
administration of study 
intervention unless otherwise 
indicated
Visit Timing/
Cycle Number
1c
2
3 to 9
>9 
(lenvatinib 
only)
At
DC
30 Days 
After
Last 
Dose
Every
12 weeks
Every
12 
weeks
Scheduling Window (days)
+3
±3
±3
±3
+7
±7
±14
Administrative and General Procedures
Second Course informed 
consent obtained
X
New documented informed 
consent must be obtained before 
entering Second Course
Inclusion/exclusion criteria
X
Concomitant medications
X
X
X
X
X
X
X
Prior medications need to be 
collected as detailed in 
Section 6.5.
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Trial Period
Treatment
Cycle =6 weeks
EOT
Posttreatment
Notes
Safety
Follow-
upa
Follow-upb
Survival
Follow-
up
All procedures are to be 
performed before 
administration of study 
intervention unless otherwise 
indicated
Visit Timing/
Cycle Number
1c
2
3 to 9
>9 
(lenvatinib 
only)
At
DC
30 Days 
After
Last 
Dose
Every
12 weeks
Every
12 
weeks
Scheduling Window (days)
+3
±3
±3
±3
+7
±7
±14
Study Intervention Administration
Lenvatinib dispensed
X
X
X
X
Lenvatinib will be dispensed on 
Day 1 and Day 22 of every 
cycle. The decision to continue 
lenvatinib during SC will be at 
the discretion of the investigator.
Lenvatinib treatment will 
continue until meeting at least 
1 of the DC criteria listed in 
Section 7.1.
Dose for lenvatinib at Second 
Course should not exceed the 
last tolerable dose during the 
Consolidation Phase.
Lenvatinib administration
<-------------------------------------------------->
Lenvatinib 20 mg orally qd.
Pembrolizumab 
administration
X
X
X
Pembrolizumab 400 mg IV 
Q6W.
Participants who are eligible for 
SC may receive up to an 
additional 9 cycles of treatment 
with pembrolizumab.
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Trial Period
Treatment
Cycle =6 weeks
EOT
Posttreatment
Notes
Safety
Follow-
upa
Follow-upb
Survival
Follow-
up
All procedures are to be 
performed before 
administration of study 
intervention unless otherwise 
indicated
Visit Timing/
Cycle Number
1c
2
3 to 9
>9 
(lenvatinib 
only)
At
DC
30 Days 
After
Last 
Dose
Every
12 weeks
Every
12 
weeks
Scheduling Window (days)
+3
±3
±3
±3
+7
±7
±14
Efficacy Procedures
Tumor imaging 
SC baseline imaging should be 
performed within 28 days before 
SC C1.
Perform imaging Q12W 
(84 ± 7 days) from SC C1. 
Schedule should be followed 
regardless of treatment delays.
-If imaging was obtained within 
4 weeks before DC, scan at DC 
is not mandatory.
*Follow-up visits may be 
scheduled to coincide with 
Follow-up imaging.
As of Amendment 8 on-study 
imaging is no longer required 
and should be performed per 
local standard of care.
Subsequent antineoplastic 
therapy status
X
X
X
X
All anticancer therapy will be 
recorded until time of death or 
termination of survival 
follow-up. If a clinic visit is not 
feasible, follow-up information 
may be obtained via telephone 
or email.
Survival status
<--------------------------------------------------------------------------------------------------------->
X
Participants may be contacted 
for survival status at any time 
during the course of the study.
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Trial Period
Treatment
Cycle =6 weeks
EOT
Posttreatment
Notes
Safety
Follow-
upa
Follow-upb
Survival
Follow-
up
All procedures are to be 
performed before 
administration of study 
intervention unless otherwise 
indicated
Visit Timing/
Cycle Number
1c
2
3 to 9
>9 
(lenvatinib 
only)
At
DC
30 Days 
After
Last 
Dose
Every
12 weeks
Every
12 
weeks
Scheduling Window (days)
+3
±3
±3
±3
+7
±7
±14
Clinical Procedures/Assessments
Adverse event monitoring
X
X
X
X
X
X
X
Will be assessed on Day 1 and 
Day 22 of every cycle.
Report AEs occurring within 
30 days after the last dose of 
study intervention.
Report SAEs occurring within 
90 days after the last dose of 
study intervention, or 30 days 
after the last dose of study 
intervention if a new anticancer 
therapy is initiated, whichever is 
earlier.
Telephone or virtual visit
X
At C1D8 only, 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.
Full physical examination
X
X
To be performed within 7 days 
before SC C1.
Directed physical 
examination
X
X
X
X
Will be assessed on Day 1 and 
Day 22 of every cycle.
Vital signs, weight
X
X
X
X
X
X
Vital signs must be taken in the 
clinic. Will be assessed on Day 
1 and Day 22 of every cycle.
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Trial Period
Treatment
Cycle =6 weeks
EOT
Posttreatment
Notes
Safety
Follow-
upa
Follow-upb
Survival
Follow-
up
All procedures are to be 
performed before 
administration of study 
intervention unless otherwise 
indicated
Visit Timing/
Cycle Number
1c
2
3 to 9
>9 
(lenvatinib 
only)
At
DC
30 Days 
After
Last 
Dose
Every
12 weeks
Every
12 
weeks
Scheduling Window (days)
+3
±3
±3
±3
+7
±7
±14
12-lead ECG with QTc 
measurement
X
X
X
X
X
ECG is performed every other 
cycle in SC. 
For high-risk participants (as 
defined in Section 8.3.3), 
conduct ECG monitoring every 
cycle. If lenvatinib is 
discontinued, ECGs are only 
required at the EOT and Safety 
Follow-up Visits. For country-
specific requirements see 
Appendix 7.
ECOG performance status
X
X
X
X
Perform within 3 days before SC 
C1.
ECOG is reviewed every other 
cycle in SC.
Laboratory Procedures/Assessments: Analysis Performed by Local Laboratory
Pregnancy test (WOCBP 
only)
X
X
X
X
X
X
Will be assessed on Day 1 and 
Day 22 of every cycle.
WOCBP require a negative 
pregnancy test within either 
24 hours (urine) or 72 hours 
(serum) before the first dose of 
study intervention and before 
each subsequent testing day as 
indicated. See Section 8.3.6.
CBC with Differential
X
X
X
X
X
X
Will be assessed on Day 1 of 
every Cycle.
Chemistry Panel
X
X
X
X
X
X
Perform within 10 days before 
SC C1. After SC C1, collect 
within 3 days before dosing. 
Will be assessed on Day 1 and 
Day 22 of every cycle.
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Trial Period
Treatment
Cycle =6 weeks
EOT
Posttreatment
Notes
Safety
Follow-
upa
Follow-upb
Survival
Follow-
up
All procedures are to be 
performed before 
administration of study 
intervention unless otherwise 
indicated
Visit Timing/
Cycle Number
1c
2
3 to 9
>9 
(lenvatinib 
only)
At
DC
30 Days 
After
Last 
Dose
Every
12 weeks
Every
12 
weeks
Scheduling Window (days)
+3
±3
±3
±3
+7
±7
±14
Urine dipstick (Urinalysis)
X
X
X 
X
X
X
Urine dipstick testing for protein 
will be performed within 3 days 
before Day 1 of every cycle while 
participants are taking lenvatinib. 
If lenvatinib is discontinued, urine 
dipstick is only required at EOT 
and Safety Follow-up Visits.
PT/INR and aPTT/PTT
X
Perform within 10 days before SC 
C1. 
Additional testing to be conducted 
as clinically indicated for 
participants taking anticoagulant 
therapy.
Thyroid function (T3, T4, and 
TSH)
X*
X
X
X
X
X
*Thyroid function tests will be 
performed at C1 and then on Day 
1 at every cycle thereafter.
-Perform within 10 days before SC 
C1. After SC C1, collect within 
3 days before dosing. 
-Participants may be dosed in 
subsequent cycles after SC C1 
while thyroid function tests are 
pending.
-May use central laboratory only if 
local laboratory is not capable.
AE=adverse event; aPTT=activated partial thromboplastin time; β-HCG=beta-human chorionic gonadotropin; CBC=complete blood count; CXDY=Cycle X Day Y; DC=discontinuation; 
ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; EOT=end of treatment; FT4=free thyroxine; hr/H=hours; INR=international normalized ratio; PD=progressive disease; 
PT=prothrombin time; PTT=partial thromboplastin time; QXW=every X weeks; qd=once daily; QTc=corrected QT interval; SAE=serious adverse event; SC=Second Course; T3=triiodothyronine; 
T4=thyroxine;; TSH=thyroid-stimulating hormone; UA=urine analysis; WOCBP=woman of childbearing potential.
Note: Second Course will be for eligible participants from Part 1 and Part 2.
a. If DC Visit occurs ≥30 days from last dose of study intervention, a Safety Follow-up Visit is not required.
b. For participants discontinuing SC for reasons other than PD, Follow-up Visits and imaging continue until PD or initiation of a new antineoplastic therapy. Participants discontinuing SC 
treatment with PD proceed directly to Survival Follow-up.
c. C1D1 procedures should be completed within 28 days of radiographic BICR verified disease progression.
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2
INTRODUCTION
Gastric cancer remains a major health problem worldwide. Gastric cancer is the fifth most 
common cancer in the world and is a major cause of cancer-related death [Bray, F., et al 
2018]. There were over 1 million new cases of gastric cancer worldwide in 2018 (683,754 
men, 349,947 women). There were 783,000 deaths (513,555 men, 269,130 women), making 
it the third-leading cause of cancer death globally in both sexes [Bray, F., et al 2018]. Age-
standardized incidence rates are about twice as high in men as in women. Gastric cancer 
incidence varies markedly by geographic region. More than 70% of cases occur in 
developing countries, and half the world total occurs in Eastern Asia. In the European Union, 
incidence and mortality for gastric cancer were estimated at 82,000 (51,000 in males and 
31,000 in females) and 58,000 (35, 000 in males and 23,000 in females), respectively in 2012 
[Ferlay, J., et al 2014]. In the United States, incidence and mortality estimated at 21,000 
(13,000 in males and 8,000 in females) and 12,000 (7,000 in males and 5,000 in females), 
respectively in 2012 [Ferlay, J., et al 2014].
Although a subset of gastric cancers overexpress or amplify HER-2, ErbB2 and benefit from 
HER-2-targeted agents such as trastuzumab, the majority of gastric cancers (80% to 90%) are 
HER-2 negative [Bang, Y. J., et al 2010]. Promising activity with immunotherapy has been 
shown in recurrent, refractory gastric cancer, although the overall benefit of immunotherapy 
in gastric cancer has been modest, and the majority of patients succumb to their disease about 
1 year after initial diagnosis [Fuchs, C. S., et al 2018] [Shitara, K., et al 2018] [Tabernero, J., 
et al 2019]. As such, new therapeutics, as well as novel combinations, are needed to improve 
outcomes. This study is designed to evaluate the safety and efficacy of combination therapy 
with lenvatinib (also known as E7080 or MK-7902), pembrolizumab, and chemotherapy as a 
first-line treatment in adult participants with advanced unresectable or metastatic HER-2 
negative gastric cancer.
2.1
Study Rationale
This study will explore the potentially synergistic combination of lenvatinib and 
pembrolizumab with the standard and currently recommended preferred chemotherapy 
regimens for the treatment of advanced and metastatic gastric cancer. Chemotherapy doses 
will be limited to 4 cycles of CAPOX or 6 cycles of mFOLFOX6, which is a significant 
cumulative dose reduction compared with standard chemotherapy regimens and intended to 
control tumor burden and clinical disease during the Induction Phase. After discontinuation 
of chemotherapy, participants will continue lenvatinib and pembrolizumab for up to 2 years 
of total therapy. However, participants can continue lenvatinib beyond 2 years, at the 
investigator’s discretion. This study design leverages data from known established treatment 
standards, as well as recently completed Phase 3 clinical studies and highly encouraging 
Phase 2 efficacy studies.
Lenvatinib in Combination with Pembrolizumab in Gastric Cancer
Lenvatinib in combination with pembrolizumab has been studied in an open-label Phase 2 
study in first-line and second-line advanced gastric cancer. This study was a single arm study 
that included 29 participants treated with initial dose of lenvatinib 20 mg daily and 
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pembrolizumab 200 mg IV Q3W. The ORR was 69% (95% CI: 49, 85) with a DCR of 100% 
(95% CI: 88, 100), and a median PFS of 7.1 months (95%CI: 4.2, 10.0); the median OS was 
not reached. This response rate is remarkable considering the expected response rate of 
pembrolizumab monotherapy is 15% and <5% for lenvatinib, thus suggesting promising 
potential synergy with this combination therapy for advanced gastric cancer [Kawazoe, A., et 
al 2020]. 
With regard to safety, the combination therapy had manageable safety profiles. Reported 
Grade ≥3 TRAEs were hypertension (38%), proteinuria (17%), and platelet count decreased 
(7%). The majority of participants required a reduction of the initial lenvatinib 20-mg dose, 
with many participants showing a response at 14 mg and 10 mg dosing [Kawazoe, A., et al 
2020].
The strategy to combine a PD-1 inhibitor with chemotherapy and VEGF TKI is being studied 
in a single arm Phase 2 study (currently ongoing; NCT03472365). In this study, 
camrelizumab (PD-1 inhibitor) was combined with capecitabine and oxaliplatin for 4 to 6 
cycles followed by camrelizumab and apatinib (VEGF TKI). Of 46 evaluable participants, 
there was 1 CR, and 31 PR, for an ORR of 69.6% and DCR of 89.1%. Confirmed ORR was 
58.7% and DCR was 78.3%. Overall, the treatment strategy was well tolerated with 
cutaneous reactive capillary endothelial proliferation (64.6%) and expected hematologic 
toxicities being most prevalent [Shen, L., et al 2019]. The skin toxicities described are likely 
attributed to camrelizumab and are not expected with pembrolizumab.
LEAP-005 is an ongoing Phase 2 study in advanced solid tumors for which there is a third 
line gastric cohort. In this study, the combination of lenvatinib and pembrolizumab has been 
shown to be safe and tolerable (MSD internal data). 
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2.2
Background
2.2.1
Pharmaceutical and Therapeutic Background
2.2.1.1
Pembrolizumab
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. Pembrolizumab is indicated for the 
treatment of patients across a number of indications. For more details on specific indications 
refer to the IB.
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 on engagement of its ligands (PD-L1 and/or PD-L2) 
[Greenwald, R. J., et al 2005] [Okazaki, T., et al 2001].
The structure of murine PD-1 has been resolved [Zhang, X., et al 2004]. PD-1 and its family 
members are type I transmembrane glycoproteins containing an IgV–type domain 
responsible for ligand binding and a cytoplasmic tail responsible for the binding of signaling 
molecules. The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an 
immunoreceptor tyrosine-based inhibition motif, and an immunoreceptor tyrosine-based 
switch motif. After T-cell stimulation, PD-1 recruits the tyrosine phosphatases, SHP-1 and 
SHP-2, to the immunoreceptor tyrosine-based switch motif within its cytoplasmic tail, 
leading to the dephosphorylation of effector molecules such as CD3ζ, PKCθ, and ZAP70, 
which are involved in the CD3 T-cell signaling cascade [Okazaki, T., et al 2001] [Chemnitz, 
J. M., et al 2004] [Sheppard, K-A, et al 2004] [Riley, J. L. 2009]. The mechanism by which 
PD-1 down-modulates T-cell responses is similar to, but distinct from, that of CTLA-4, 
because both molecules regulate an overlapping set of signaling proteins [Parry, R. V., et al 
2005] [Francisco, L. M., et al 2010]. As a consequence, the PD-1/PD-L1 pathway is an 
attractive target for therapeutic intervention in gastric cancer.
2.2.1.2
Lenvatinib
Angiogenesis, the formation of new blood vessels from a preexisting vascular network, is 
essential for tumor growth and metastasis. VEGF and its family of receptors (VEGFRs 1-3) 
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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 in 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 RTKi that selectively inhibits VEGF receptors, VEGFR1 
(FLT1), VEGFR2 (KDR), VEGFR3 (FLT4), FGFR1-4, PDGFRα, c-KIT, and RET. Among 
known kinase inhibitors in clinical use, lenvatinib is one of the only inhibitors currently 
labeled with a mechanism of action as an inhibitor of not only VEGFRs but also FGFRs, 
both of which are currently believed to be very important for tumor angiogenesis.
Lenvatinib inhibited cell free kinase activities for VEGFR1-3 and FGFR1-3 with Ki values 
around 1 nmol/L, and 8-22 nmol/L, respectively. In cell-based assays, lenvatinib inhibited 
VEGF derived and FGF-derived tube formation of HUVEC with IC50 values of 2.1 and 7.3 
nmol/L, respectively. Analysis of the signal transduction molecules revealed that lenvatinib 
inhibited both the MAPK pathway and the mTOR-S6K-S6 pathway in HUVECs triggered by 
activated VEGFR and FGFR. Furthermore, lenvatinib (10 mg/kg and 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 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.
Lenvatinib has shown clinical efficacy in several tumor types. In the US, as of 2021, 
lenvatinib is indicated in the treatment of locally recurrent or metastatic progressive, 
radioactive iodine-refractory differentiated thyroid cancer, in combination with everolimus 
for advanced renal cell carcinoma after 1 prior antiangiogenic therapy, and for the first-line 
treatment of unresectable hepatocellular carcinoma (see lenvatinib package insert). In 
addition, as part of postmarketing request, the safety and efficacy of lenvatinib dosing was 
evaluated in 2 postmarketing studies in differentiated thyroid cancer and renal cell carcinoma 
respectively. In the DTC study, the lenvatinib dose of 18 mg/day failed to show 
noninferiority versus the approved lenvatinib 24 mg/day starting dose, as measured by ORR. 
In the RCC study, the lenvatinib dose of 14 mg/day failed to show noninferiority versus the 
approved 18 mg/day dose. These 2 studies suggest that maximizing the dose of lenvatinib 
may be important for best long-term outcomes[Brose, M. S., et al 2020] [Pal, S., et al 2020].
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2.2.1.3
Lenvatinib Plus 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; HCC; 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 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.
There are a number of ongoing clinical studies investigating the combination of lenvatinib 
plus pembrolizumab in a variety of solid tumors in LEAP studies. Additionally, in 
KEYNOTE-146, a Phase 1b/2 study in participants with solid tumors, the lenvatinib and 
pembrolizumab combination was safe and tolerable, leading to US regulatory approval of the 
lenvatinib and pembrolizumab regimen for treatment of endometrial carcinoma. Based on 
safety data from these studies, it is anticipated that the combination of lenvatinib and 
pembrolizumab with chemotherapy will have an acceptable overlapping safety profile. 
2.2.1.4
Chemotherapy
Despite a large number of randomized studies, there is no globally accepted standard first-
line chemotherapy regimen in HER-2 negative, advanced, unresectable and/or metastatic 
gastric and GEJ adenocarcinoma. In general, combination chemotherapy regimens provide 
higher response rates than do single agents. Many patients are recommended to receive a 
fluoropyrimidine-platinum doublet over more toxic triplet chemotherapeutic regimens.
There is accumulating evidence demonstrating that chemotherapy agents including 5-FU and 
oxaliplatin that are frequently used to treat malignancies may modulate the intrinsic 
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immunogenicity of tumor and sensitize tumors to immunotherapy agents [Pfirschke, C., et al
2016] [Zhou, J., et al 2017]. Preclinical and clinical evidence suggest that conventional 
chemotherapies reactivate antitumor immune responses by increasing immunogenic cell 
death and antigen release, and/or by inhibiting immunosuppressive factors in the tumor 
microenvironment [Emens, L. A. and Middleton, G. 2015] [Galluzzi, L., et al 2015] 
[Vincent, J., et al 2010]. Further, chemotherapies can enhance tumor antigen presentation by 
upregulating the expression of tumor TCR themselves, or of the MHC1 molecules to which 
the TCRs bind [Emens, L. A. and Middleton, G. 2015].
The fluoropyrimidine/platinum doublet combination is a common first-line therapy for 
metastatic gastric cancer, and it is considered “preferred” by the NCCN Gastric Cancer 
Guideline committee [National Comprehensive Cancer Network 2020] [Smyth, E. C., et al 
2016]. Fluoropyrimidine-platinum doublet regimens containing 5-FU or capecitabine and 
cisplatin or oxaliplatin are recognized worldwide as standard first-line chemotherapy 
regimens for patients with metastatic gastric and GEJ adenocarcinoma.
The ML17032 study was a randomized, Phase 3 study that compared the combination of 
cisplatin and capecitabine (XP) to the combination of cisplatin and 5-FU (FP) as first-line 
treatment in patients with previously untreated advanced gastric cancer [Ryu, M. H. and 
Kang, Y. K. 2009]. No difference was seen in median PFS and the results of this study 
suggest that capecitabine is at least as effective as 5-FU in the treatment of patients with 
advanced gastroesophageal cancers.
The REAL-2 study was a randomized, multicenter, Phase 3 study comparing capecitabine 
with 5-FU and oxaliplatin with cisplatin in 1002 patients with advanced esophagogastric 
cancer [Cunningham, D., et al 2008]. Results from this study suggest that capecitabine and 
oxaliplatin are as effective as 5-FU and cisplatin, respectively, in patients with previously 
untreated esophagogastric cancer.
A meta-analysis of the REAL-2 and ML17032 studies suggested that OS was superior in the 
654 patients treated with capecitabine-based combinations compared with the 664 patients 
treated with fluorouracil-based combinations, although no statistically significant difference 
in PFS between the treatment groups was seen [Okines, A. F., et al 2009].
Most frequently used doublet regimens are XP, FP, CAPOX, and FOLFOX. Choices among 
these regimens are typically based on patients’ general medical condition and comorbidities 
in consideration of the different toxicity profiles of the regimens as well as regional 
preferences. This practice pattern is supported by global consensus guidelines for treatment 
of advanced gastric cancer, which recommend use of any of the doublet regimen discussed 
above [National Comprehensive Cancer Network 2020] [Cunningham, D., et al 2008].
FOLFOX and CAPOX have been studied extensively in advanced gastric cancer and are 
routinely used in clinical practice globally. In general, FOLFOX and CAPOX are expected to 
have a similar profile of adverse events, with the most common adverse events being
gastrointestinal (ie, diarrhea, nausea, vomiting and stomatitis) and neurosensory toxicities (ie, 
paresthesia and peripheral neuropathy). However, there are differences between the rates at 
which key events may occur. FOLFOX is anticipated to be associated with more Grade 3/4 
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neutropenia and febrile neutropenia than CAPOX. Conversely, CAPOX is expected to be 
associated with more hand-foot syndrome and diarrhea. Rates of Grade 3/4 neurosensory 
toxicity and cardiac disorders are anticipated to be similar [Cassidy, J., et al 2011]. In 
summary, these 2 regimens are expected to have similar efficacy and will allow investigators 
a choice based on each participant’s medical condition.
2.2.1.5
Lenvatinib in Combination With Chemotherapy in Other Indications
In the ongoing Phase 3 LEAP-006 study, which is a randomized, double-blind study of first-
line pembrolizumab plus platinum doublet chemotherapy (pemetrexed and platinum) +/-
lenvatinib (8 mg qd) in participants with metastatic NSCLC (NCT 03829319) [Hui, R., et al 
2019]. The Safety Run-in (Part 1) portion of this study is complete, and this regimen was 
generally tolerable.
In an ongoing study of patients with rectal cancer, the first 9 participants have received up to 
24 mg qd lenvatinib plus capecitabine (800 mg/m2 BID) and it was well tolerated [Frakes, J., 
et al 2019].
2.2.2
Preclinical and Clinical Studies
Preclinical studies for lenvatinib and pembrolizumab are described in the respective IBs.
2.2.2.1
Clinical Activity of Pembrolizumab in Advanced Gastric Cancer 
Immune checkpoint inhibitors such as pembrolizumab have showed durable immune-
mediated antitumor activity in participants with advanced gastric cancer. Clinical proof of 
concept for pembrolizumab in these participants was shown in Cohort D of the Phase 1b 
study, KEYNOTE-012, which enrolled 39 participants with gastric or GEJ tumors expressing 
PD-L1 assessed using a prototype PD-L1 IHC assay [Muro, K., et al 2016]. Eight of 39 
participants had an OR by RECIST 1.1 using central radiologic review for an ORR of 22% 
(95% CI: 10, 39). 
The Phase 2 study, KEYNOTE-059, tested pembrolizumab monotherapy in a larger cohort 
(Cohort 1) of participants whose tumors had progressed on 2 or more lines of systemic 
therapy (third line + participants). In this study, pembrolizumab monotherapy showed 
clinically meaningful ORR in this heavily treated population for whom there are no other 
effective agents. Durable objective responses were observed in the all-comer population 
regardless of PD-L1 status with ORR of 12%, while a higher response rate (16%) was 
observed in the PD-L1 positive population [Wainberg, Z. A., et al 2017]. Based on data from 
KEYNOTE-059, pembrolizumab received accelerated approval by the US FDA in 
September 2017 for treatment of third line plus participants with tumors expressing PD-L1 
(CPS ≥1) assessed by an FDA-approved test. KEYNOTE-059 included 2 additional cohorts 
where pembrolizumab was tested in first-line gastric cancer participants either as 
monotherapy (Cohort 3) or in combination with a fluoropyrimidine and cisplatin (Cohort 2).
Cohort 3 enrolled 31 participants whose tumors expressed PD-L1 (CPS ≥1). Cohort 2 
enrolled participants irrespective of PD-L1 expression (all-comers). In both cohorts, ORR 
was assessed according to RECIST 1.1 by independent central radiological review. The 
combination of pembrolizumab with cisplatin and 5-FU or capecitabine in Cohort 2 (n=25) 
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yielded an ORR of 60% (95% CI: 39%, 79%) and a DCR of 80% (95% CI: 59%, 93%). 
Responses were observed regardless of PD-L1 status. Median OS in Cohort 2 was 13.8 
months (95% CI: 8.6, NR). Monotherapy in PD-L1 positive first-line participants (Cohort 3) 
yielded an ORR of 26% (95% CI: 12, 45); median OS was 20.7 months (95% CI; 9.2, 20.7) 
[Fuchs, C. S., et al 2018].
KEYNOTE-061 (NCT02370498) was a global Phase 3 study of pembrolizumab versus 
paclitaxel for previously treated advanced gastric/GEJ cancer. Pembrolizumab reduced the 
risk of death by 18% versus paclitaxel in participants with PD-L1 CPS ≥1, although this 
difference was not statistically significant. Durable benefit of pembrolizumab was shown in 
this study. After a median follow-up of 8 months, 7.8% of participants completed or 
remained on pembrolizumab, versus 0% with paclitaxel. Median OS was 9.1 months with 
pembrolizumab versus 8.3 months with paclitaxel; the difference did not reach statistical 
significance (HR 0.82, one-sided p=0.042). Twelve-month OS rates were 39.8% with 
pembrolizumab versus 27.1% with paclitaxel; 18-month OS rates were 25.7% versus 14.8%, 
respectively. There was no difference in PFS or ORR, but pembrolizumab responses were 
more durable: median duration of response was 18 months and 5.2 months for 
pembrolizumab and paclitaxel, respectively [Shitara, K., et al 2018].
KEYNOTE-062 (NCT02494583) was a global Phase 3 study of pembrolizumab as first-line 
monotherapy and combination therapy versus SOC chemotherapy (at the time of the study) 
for advanced gastric or GEJ adenocarcinoma. In this study, in participants with CPS ≥1, the 
OS for pembrolizumab monotherapy was found to be noninferior compared with 
chemotherapy with a median OS of 10.6 months (95% CI: 7.7, 13.8) compared with 11.1 
months (95% CI: 9.2, 12.8) with an HR of 0.91 (95% CI: 0.69, 1.18). In participants selected 
for CPS ≥10, participants treated with pembrolizumab monotherapy showed an improved 
median OS of 17.4 months (95% CI: 9.1, 23.1) compared with 10.8 months (95% CI: 8.5, 
13.8) HR of 0.69 (95% CI: 0.49, 0.97) with chemotherapy, although not formally tested 
based on the study statistical design. When pembrolizumab was combined with 
chemotherapy, the effect was more modest showing a 12.5 month (95% CI: 10.8, 13.9) 
median OS compared with 11.1 month (95% CI: 9.2, 12.8) with an HR 0.85 (95% CI: 0.70, 
1.03) in participants with CPS ≥1. Similarly, in the CPS ≥10 selected participants the median 
OS for pembrolizumab combined with chemotherapy was 12.3 months (95% CI: 9.5, 14.8) 
compared with 10.8 months (95% CI: 8.5, 13.8) with an HR of 0.85 (95% CI: 0.62,1.17). 
Although these differences were not significant, pembrolizumab responses were more 
durable [Tabernero, J., et al 2019].  
Taken together, the data show that pembrolizumab showed durable clinical benefit and 
favorable tolerability in advanced gastric cancer populations. In the context of the proposed 
study, it is important to note that pembrolizumab was safe in combination with 
chemotherapy, and it has showed promising activity, particularly in subsets of PD-L1 
selected participants. 
2.2.2.2
Clinical Activity of Pembrolizumab in Combination Therapy
Results from clinical studies combining PD-L1 agents and chemotherapies have had variable 
outcomes. These studies have showed that chemotherapies can be safely combined with PD-
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L1 agents and many of them have showed promising anticancer activity [Gadgeel, S., et al
2016] [Gadgeel, S., et al 2020] [Wallin, J. J., et al 2016] [Wallin, J., et al 2016]. Various 
chemotherapies were combined with pembrolizumab and produced promising activity. In 
KEYNOTE-189, addition of pembrolizumab to pemetrexed and a platinum-based drug with 
first-line metastatic nonsquamous NSCLC showed significantly longer OS and PFS 
compared with placebo in combination with pemetrexed and a platinum-based drug 
[Gadgeel, S., et al 2020]. In colorectal cancer, FOLFOX plus bevacizumab was combined 
with atezolizumab and showed an acceptable safety profile and promising activity (ORR, 
52%; median PFS, 14.1 months; DOR, 11.4 months) [Wallin, J., et al 2016]. In this study, 
there was a clear demonstration of increased PD-L1 expression, enhanced intra tumoral 
infiltration of CD8+ T-cells, and upregulation of an immune gene signature in tumor by use 
of FOLFOX alone or in combination with atezolizumab [Wallin, J., et al 2016]. Further, 
there was an association between an increase in immune gene signature and durability of 
clinical benefit.
2.2.2.3
Clinical Activity of VEGF TKI in Gastric Cancer
VEGF is a potent angiogenic factor which is upregulated in many tumors and is a marker for 
gastric cancer. VEGF levels are elevated in the presence of gastric cancer and decrease after 
tumor regression suggesting that VEGF levels could be a predictor of recurrence. In addition, 
high VEGF levels were correlated with poor prognosis and lower survival rates [Macedo, F., 
et al 2017].  
When evaluated as monotherapy, the activity of VEGF TKI is modest in gastric cancer, 
although there appears to be some improvement in PFS and OS rates when compared with 
placebo. The ORR after treatment with sunitinib, sorafenib, apatinib, regorafenib, and 
ramucirumab ranged between 2.6% to 3.0%. However, in clinical studies with apatinib, 
regorafenib, and ramucirumab for which there was a placebo control, there was trend toward 
improvement in PFS and OS [Bang, Y. J., et al 2011] [Janjigian, Y. Y., et al 2015] [Li, J., et 
al 2016] [Pavlakis, N., et al 2016] [Fuchs, C. S., et al 2014]. When VEGF TKI were used in 
combination therapy, one study showed that the combination of ramucirumab and paclitaxel 
resulted in ORR 28%, and PFS of 9.6 months compared with 7.4 months for paclitaxel (HR: 
0.807) leading to a new SOC option for second-line gastric cancer [Wilke, H., et al 2014]. 
Lenvatinib, as a multi-targeted VEGF TKI has been evaluated as monotherapy in a subset of 
gastric cancer participants in the Phase 1 study of advanced solid tumors. Of the 6 
participants with advanced gastric cancer, there were no responders suggesting that 
combination therapy with lenvatinib is required for maximum efficacy and potential synergy 
[Boss, D. S., et al 2012].
2.2.3
Ongoing Clinical Studies
Several clinical studies involving pembrolizumab are currently ongoing in participants with 
gastric/GEJ cancer as presented in Table 1.
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Table 1
Ongoing Clinical Studies With Pembrolizumab in Gastric Cancer
Study
Phase
Study Population
Study Intervention
KN-585
3
Previously untreated, locally advanced 
resectable gastric or GEJ adenocarcinoma
Pembrolizumab plus chemotherapy 
versus
Placebo plus chemotherapy
KN-811
3
HER-2 positive with advanced gastric or GEJ 
adenocarcinoma
Pembrolizumab plus trastuzumab 
plus chemotherapy 
versus 
Placebo plus trastuzumab plus 
chemotherapy
KN-859
3
Previously untreated, HER-2 negative, 
advanced gastric or GEJ adenocarcinoma
Pembrolizumab plus chemotherapy 
versus 
Placebo plus chemotherapy
LEAP-005
2
Relapsed/refractory TNBC, ovarian cancer, 
gastric cancer, colorectal cancer, GBM, or 
biliary tract cancers
Open-label lenvatinib plus 
pembrolizumab
KN-659
2b
First-line participants with advanced 
gastric/GEJ tumor  
Nonrandomized
SOX + pembrolizumab or 
SP + pembrolizumab. 
KN-059
2
Recurrent or metastatic gastric or GEJ 
adenocarcinoma
Pembrolizumab monotherapy 
or
Pembrolizumab with 
cisplatin+5-fluorouracil
KN-061
3
Advanced gastric or GEJ adenocarcinoma 
who progressed after first-line therapy with 
platinum and fluoropyrimidine
Pembrolizumab
Versus
Paclitaxel
KN-062
3
Advanced Gastric or GEJ Adenocarcinoma
Pembrolizumab monotherapy 
or
Pembrolizumab in combination with 
cisplatin+5-fluorouracil 
versus 
Placebo+cisplatin+5-fluorouracil 
KN-063
3
Asian participants with advanced gastric or 
GEJ adenocarcinoma who progressed after 
first-line therapy with platinum and 
fluoropyrimidine
Pembrolizumab
Versus
Paclitaxel
GBM=glioblastoma; GEJ=gastroesophageal junction; HER-2=human epidermal growth factor receptor 2; 
KN=KEYNOTE; SOX=s1 oxaliplatin; SP=s1 cisplatin; TNBC=triple negative breast cancer
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.
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Proposed study-specific benefits of the treatment combination of lenvatinib/pembrolizumab 
include: 
•
The potential for improved PFS/OS
•
The potential for decreased cytotoxic side effects due to the reduced cumulative exposure 
to cytotoxic chemotherapy.
Proposed study-specific risks of the treatment combination of lenvatinib/pembrolizumab 
include: 
•
Mean decreased survival due to shorter duration of exposure to chemotherapy
•
Additional toxicities from the addition of lenvatinib and/or pembrolizumab to 
chemotherapy regimen
•
Lenvatinib and/or pembrolizumab specific side effects
•
Unanticipated side effects 
Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the accompanying IB and informed consent documents.
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3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
Male and female adults, at least 18 years of age with previously untreated, locally advanced 
unresectable or metastatic gastric, gastroesophageal junction, or esophageal adenocarcinoma 
will be enrolled, and the following objectives and endpoints will be assessed (there are dual 
primary endpoints):
Primary Objective
Primary Endpoint
- Objective (Part 1): To evaluate the safety 
and tolerability of treatment with lenvatinib 
plus pembrolizumab plus chemotherapy.
- Dose-limiting toxicities, adverse events 
and study intervention discontinuations due 
to adverse events.
- Objective (Part 2): To compare the overall 
survival between treatment groups
- Overall Survival: The time from 
randomization to death due to any cause
- Objective (Part 2): To compare the PFS 
between treatment groups
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Secondary Objectives
Secondary Endpoints
- Objective (Part 2): To compare ORR 
between treatment groups.
- Objective Response: Complete response or 
partial response
- Objective (Part 2): To estimate DOR, per 
RECIST 1.1 as assessed by BICR for each 
treatment group in participants with 
programmed cell death ligand 1 combined 
positive score ≥1 and in all participants.
- Duration of Response: The time from first 
response (complete response or partial 
response) to subsequent disease 
progression, or death from any cause, 
whichever occurs first
- Objective (Part 2): To evaluate the safety 
and tolerability of lenvatinib plus 
pembrolizumab plus chemotherapy versus 
chemotherapy
- Adverse events 
- Study intervention discontinuation due to 
adverse events
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The study will be considered to have met its primary objective if at least 1 primary 
hypothesis test is statistically significant.
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4
STUDY DESIGN
4.1
Overall Design
This is a randomized, active-controlled, parallel-group, multisite, open-label, study of 
lenvatinib plus pembrolizumab plus chemotherapy compared with chemotherapy only in 
participants with locally advanced unresectable/metastatic gastroesophageal adenocarcinoma.
There will be 2 parts to the study: a Safety Run-in (Part 1) and the Main Study (Part 2). In 
Part 1 (Safety Run-in), approximately 12 participants will be treated with lenvatinib in 
combination with pembrolizumab and chemotherapy (CAPOX or mFOLFOX6) to ensure 
that ~6 participants will be treated with lenvatinib in combination with pembrolizumab, 
capecitabine, and oxaliplatin (CAPOX), and ~6 participants will be treated with lenvatinib in 
combination with pembrolizumab, 5-FU, Leucovorin, and oxaliplatin (mFOLFOX6). 
Participants will be closely followed for unacceptable toxicities for 21 days after the first 
dose of study intervention (the DLT evaluation period) for the occurrence of specific AEs 
that are deemed dose limiting according to Table 2. If 3 or more DLTs occur in either 
oxaliplatin-containing cohort during this Safety Run-in, enrollment to Part 2 may be delayed 
to further examine safety data and consider study design changes. Participants in Part 1 will 
continue to receive study intervention and be followed in the posttreatment period as 
applicable. Safety Run-in data will be evaluated before enrollment for Part 2 commences. 
Participants in the Safety Run-in will be treated with full study treatment per SoA, which 
includes induction, consolidation and follow-up. Safety Run-in participants will not be 
included in the efficacy/safety analysis of randomized portion of the study (Part 2).  
Table 2
Dose-Limiting Toxicities
Toxicity Category
Toxicity CTCAE Grade
Hematologic
Grade 4 neutropenia lasting for ≥7 days
Grade 3 or Grade 4 febrile neutropeniaa
Grade 3 thrombocytopenia with bleeding; Grade 4 thrombocytopenia 
Grade 4 anemia
Other nonhematologic 
toxicity
Any other Grade 4 or a Grade 5 toxicity
Grade 3 toxicities lasting >3 days excluding:
o
Nausea, vomiting, and diarrhea controlled by medical intervention 
within 72 hours
o
Grade 3 rash in the absence of desquamation, no mucosal 
involvement, does not require steroids, and resolves to Grade 1 by the 
next scheduled dose of pembrolizumab
Grade 3 hypertension not able to be controlled by medication
Grade 3 or above gastrointestinal perforation
Grade 3 or above wound dehiscence requiring medical or surgical 
intervention
Any grade thromboembolic event
Any Grade 3 nonhematologic laboratory value if:
Medical intervention is required to treat the participant, or
The abnormality leads to hospitalization
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Toxicity Category
Toxicity CTCAE Grade
ANC=absolute neutrophil count; CTCAE=Common Terminology Criteria for Adverse Events v5.0.
a
Febrile neutropenia Grade 3 or Grade 4
•
Grade 3 is defined as ANC <1000/mm3 with a single temperature of >38.3 ºC (101 ºF) or a sustained 
temperature of ≥38 ºC (100.4 ºF) for more than 1 hour.
•
Grade 4 is defined as ANC <1000/mm3 with a single temperature of >38.3 ºC (101 ºF) or a sustained 
temperature of ≥38 ºC (100.4 ºF) for more than 1 hour, with life-threatening consequences and urgent 
intervention indicated.
In Part 2, approximately 878 eligible participants (not to include those participating in Part 1) 
with be randomly assigned in a 1:1 ratio to one of the following treatment arms:
1. Induction with lenvatinib 8 mg qd plus pembrolizumab (400 mg Q6W for 2 cycles) 
plus chemotherapy (CAPOX or mFOLFOX6) followed by consolidation with 
lenvatinib 20 mg qd plus pembrolizumab (400 mg Q6W for 16 cycles)
2. Chemotherapy only (control arm):
•
CAPOX Q3W: capecitabine 1000 mg/m2 BID for 14 days (oral) and 
oxaliplatin 130 mg/m2 (IV) 
OR
•
mFOLFOX6 Q2W: oxaliplatin 85 mg/m2 (IV), 5-FU 400 mg/m2 (bolus IV) 
plus 2400 mg/m2 (continuous IV), and leucovorin 400mg/m2 (IV) or 
levoleucovorin 200 mg/m2 (IV)
Note: As of Amendment 8, participants who either completed lenvatinib plus 
pembrolizumab or chemotherapy administration or discontinued lenvatinib plus 
pembrolizumab or chemotherapy will discontinue from the study following the 
Safety Follow-up visit (Section 8.11.5.1). AE, SAE, and other reportable safety 
events will be reported and followed as described under Section 8.4. All participants 
in Efficacy Follow-up prior to initiation of Amendment 8 will stop efficacy 
assessments and be discontinued from the study and should continue with tumor 
imaging per local standard of care. All participants in Survival Follow-up prior to 
initiation of Amendment 8 are considered to have completed the study and should 
have a final survival contact; these participants will no longer be contacted for 
survival information.
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Specific procedures to be performed during the study, including prescribed times and 
associated visit windows, are outlined in Section 1.3 of the SoA. Details of each procedure 
are provided in Section 8.
The study design is depicted in Figure 1 (Safety Run-in), Figure 2 (Main Study) and Figure 3
(Second Course Treatment Phase).
In Part 2, this study will use a group sequential design, using an eDMC to monitor safety and 
efficacy during the course of the study. 
 
Participants treated with pembrolizumab who complete 18 cycles (2 years) of treatment with 
SD or better, or participants who attain an investigator-determined CR and have received at 
least 4 cycles of pembrolizumab may be eligible for retreatment with up to an additional 
9 cycles (approximately 1 year) of pembrolizumab if they experience radiographic disease 
progression confirmed by BICR after stopping treatment in the initial treatment phase. This 
retreatment is termed the Second Course Treatment Phase and is only available if the study 
remains open and the participant meets the criteria specified in Section 7.1. The decision of 
whether to continue lenvatinib treatment during the Second Course Treatment Phase will be 
at the discretion of the investigator. If continued, participants will be retreated at the same 
dose level and frequency as when they last received the combination of lenvatinib plus 
pembrolizumab. Note: As of Amendment 8, Second Course will no longer be offered. 
Any participant receiving Second Course retreatment prior to the initiation of Amendment 8 
will be able to continue treatment as planned.
After the final analysis, participants may be transitioned to an extension study, if available.
4.2
Scientific Rationale for Study Design
Study and scientific rationale are described in Section 2.1.
4.2.1
Rationale for Endpoints
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RECIST 1.1
RECIST 1.1 will be used by the BICR when assessing images for efficacy measures and by 
the local site when determining eligibility (Section 8.1.2). Although traditional RECIST 1.1 
references a maximum of 5 target lesions in total and 2 per organ, this protocol has 
implemented a modification to RECIST 1.1 to allow a maximum of 10 target lesions in total 
and 5 per organ, if a larger number of target lesions is needed to adequately represent the 
tumor burden. Refer to Section 8.2.1.5 for additional details.
4.2.1.2
Safety Endpoints
Safety parameters frequently used for evaluating investigational-systemic anticancer 
treatments are included as safety endpoints including, but not limited to, the incidence of, 
causality, and outcome of AEs/SAEs, and changes in vital signs and laboratory values. AEs 
will be assessed as defined by CTCAE, Version 5.0.
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4.2.2
Rationale for Use of CAPOX and mFOLFOX6
Systemic chemotherapy is the mainstay of treatment for advanced and metastatic gastric 
cancer as evidenced by treatment guidelines issued by the NCCN and ESMO [National 
Comprehensive Cancer Network 2020] [Smyth, E. C., et al 2016].
Despite a large number of randomized studies, there is no globally accepted standard first-
line chemotherapy regimen in HER-2 negative, advanced, unresectable and/or metastatic 
gastric and GEJ adenocarcinoma. In general, combination chemotherapy regimens provide 
higher response rates than do single agents. Many patients are recommended to receive a 
fluoropyrimidine-platinum doublet over more toxic triplet chemotherapeutic regimens.
Platinum/fluoropyrimidine doublet regimens containing cisplatin or oxaliplatin and 5-FU or 
capecitabine are recognized worldwide as first-line chemotherapy regimens for advanced, 
unresectable, and/or metastatic gastric and GEJ adenocarcinoma. These 
platinum/fluoropyrimidine doublet regimens are considered “preferred” by the NCCN 
Gastric Cancer Guideline committee [National Comprehensive Cancer Network 2020]. 
Most frequently used doublet regimens are XP, FP, CAPOX, and FOLFOX. Choices among 
these regimens are based on a patient’s general medical condition and comorbidities in 
consideration of the different toxicity profiles of the regimens. This practice pattern is 
supported by global consensus guidelines regarding the treatment of advanced gastric cancer, 
which recommend use of any of the doublets discussed above [National Comprehensive 
Cancer Network 2020] [Smyth, E. C., et al 2016].
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The current study will use CAPOX or mFOLFOX6 as the chemotherapy backbone regimens. 
Investigators will have a choice between CAPOX and mFOLFOX6. Use of infusional 5-FU 
in this study provides an alternative fluoropyrimidine treatment to those participants unable 
to take oral capecitabine.
4.3
Justification for Dose
4.3.1
Pembrolizumab
Based on the totality of data generated in the KEYTRUDA® development program, 200 mg 
Q3W is considered the appropriate dose of pembrolizumab for adults across all indications 
and regardless of tumor type.
The planned dose of pembrolizumab for this study is 400 mg Q6W [Lala, M., et al 2020]. 
This regimen has been approved by US FDA, across all adult indications, including 
monotherapy and combination therapy. A 400 mg Q6W dosing regimen of pembrolizumab is 
expected to have a similar benefit-risk profile as 200 mg Q3W, in all treatment settings in 
which 200 mg Q3W pembrolizumab is currently appropriate [Lala, M., et al 2018]. 
Specifically, the dosing regimen of 400 mg Q6W for pembrolizumab is considered adequate 
based on M&S analyses, given the following rationale: 
PK simulations demonstrating that in terms of pembrolizumab exposures: 
•
Cavg (or AUC) at 400 mg Q6W is similar to the approved 200 mg Q3W dose, thus 
bridging efficacy between dosing regimens.
•
Cmin at 400 mg Q6W are generally within the range of those achieved with 2 mg/kg or 
200 mg Q3W in the majority (>99%) of patients. 
•
Cmax at 400 mg Q6W are well below the Cmax for the highest clinically tested dose of 10 
mg/kg Q2W, supporting that the safety profile for 400 mg Q6W should be comparable to 
the established safety profile of pembrolizumab.
•
Exposure-response for pembrolizumab has been shown to be flat across indications, and 
OS predictions in melanoma and NSCLC show that efficacy at 400 mg Q6W is expected 
to be similar to 200 mg or 2 mg/kg Q3W, given the similar exposures; thus, 400 mg Q6W 
is expected to be efficacious across indications.
Safety at the Q6W dosing schedule was bridged based on an established exposure-safety 
analysis anchored on the maximum clinically administered and well tolerated dose (10 mg/kg 
Q2W). The safety of pembrolizumab at doses of 2 mg/kg Q3W and 10 mg/kg Q3W in 
combination with chemotherapy was assessed in KEYNOTE-021 Cohorts A, B, and C in 
NSCLC participants. Based on limited data from approximately 37 participants at each dose 
level, the frequency of various AE categories was generally consistent between 
pembrolizumab 2 mg/kg Q3W in combination with chemotherapy and pembrolizumab 10 
mg/kg Q3W in combination with chemotherapy, and no new safety concerns were identified 
in these cohorts. Because exposures of 400 mg Q6W fall within the range of exposures 
between 2 and 10 mg/kg Q3W, the safety profile of pembrolizumab 400 mg Q6W dose in 
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combination with chemotherapy is expected to be consistent with the safety of 
pembrolizumab 200 mg Q3W dose in combination with chemotherapy.
4.3.2
Lenvatinib
In this protocol, lenvatinib at 8 mg daily dose will be combined with pembrolizumab and 
either CAPOX or mFOLFOX6. Lenvatinib has been studied in combination with 
chemotherapy in NSCLC. In the Phase 1 dose-escalation study, lenvatinib was combined 
with paclitaxel (200 mg/m2) followed by 1-hour infusion of carboplatin (AUC 6.0 min 
mg/mL). Twenty-eight patients were treated for which there were 2 DLTs. A MTD was 
defined as 4 mg BID (equivalent to 8 mg daily). Even at the 4 mg BID dosing, efficacy 
remained impressive with an ORR 68.2% (95% CI 45.1-86.1), and DCR of 90.9% (95% CI 
70.8-98.9) [Nishio, M., et al 2013].
LEAP-006 is an ongoing Phase 3, randomized, double-blind study of first-line 
pembrolizumab plus platinum doublet chemotherapy (pemetrexed and platinum) +/-
lenvatinib (8 mg qd) in participants with metastatic NSCLC. In this study, the regimen was 
tolerable with fewer than 3 DLTs occurring in each platinum-containing arm. The ORR was 
69.2% [Nishio, M., et al 2020]. Part 2 randomized portion of the study is ongoing. Based on 
the data from the LEAP-006 study, 8 mg is likely to be safe and effective when used in 
combination with pembrolizumab and chemotherapy. 
During the Consolidation Phase, lenvatinib at 20 mg oral daily will be given in combination 
with pembrolizumab without chemotherapy. In the KEYNOTE-146/Study 111 
(NCT02501096) Phase 1b/2 study of lenvatinib plus pembrolizumab in solid tumors, TRAEs 
were reported in 97% of patients. Treatment-related AEs resulted in lenvatinib dose 
reduction and/or interruption in 85%, lenvatinib discontinuation in 13%, pembrolizumab 
dose interruption (45%) and pembrolizumab discontinuation (15%). The most common AEs 
reported as reasons for lenvatinib dose reduction and/or interruption were fatigue (26%), 
diarrhea (23%), hypertension (17%), decreased appetite (16%), and proteinuria (11%) 
[Taylor, M. H., et al 2020]. 
In an open-label Phase 1b/2 study of lenvatinib plus pembrolizumab in participants with 
advanced gastric cancer many patients were treated with the combination therapy at 20 mg 
daily dose of lenvatinib. TRAE led to dose interruptions in 28 patients (97%) and at least 1 
dose reduction of lenvatinib in 29 patients (100%); 1 level dose reduction (14 mg) in 9 
patients (31%), 2 level (10 mg) in 14 patients (48%), 3 level (8 mg) in 5 patients (17%) and 4 
level (4 mg) in 1 patient (3%) [Kawazoe, A., et al 2020a]. As described in the background, 
noninferiority of lower dose lenvatinib has been studied in approved indications of DTC and 
RCC, showing that lower dosages of lenvatinib have failed to show noninferiority to higher 
approved dosing. These studies suggest that maximizing the dose of lenvatinib may be 
important for best long-term outcomes [Brose, M. S., et al 2020] [Pal, S., et al 2020]. Based 
on these data, during Consolidation Phase, the starting dose of lenvatinib will be 20 mg oral 
daily combined with pembrolizumab 400 mg every 6 weeks. Dose escalation schema in this 
study is defined such that only patients who tolerate 8-mg dose during induction would be 
eligible to escalate the lenvatinib dose. We expect that some participants will subsequently 
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need dose reduction due to toxicity but understand that maximizing the lenvatinib the dose 
may confer better long-term outcomes.
A 21-day Safety Run-in in Part 1 will include approximately 12 participants, and these 
participants will start on an 8 mg dose of lenvatinib (see Section 4.1 for details). For those 
participants who do not tolerate 8 mg during the Induction Phase or 20 mg during the 
Consolidation Phase due to severe hypersensitivity and/or Grade 3 or higher ongoing AEs, 
dose reduction/discontinuation/dose escalation/dose reescalation will occur as described in 
detail in Section 6.6.3.
4.3.3
Maximum Dose/Exposure of Lenvatinib and Pembrolizumab for This Study
The maximum dose/exposure of lenvatinib in this study is lenvatinib 8 mg qd for 12 weeks in 
the Induction Phase, followed by lenvatinib 20 mg qd during the Consolidation Phase for up 
to 2 years. The maximum dose/exposure of pembrolizumab allowed in this study is 400 mg 
Q6W for 18 infusions in the First Course (approximately 2 years), and 9 infusions 
(approximately 1 year) in the Second Course.
Participants may continue treatment with lenvatinib if they experience clinical benefit 
according to the PI with Sponsor consultation until disease progression or unacceptable 
toxicity.
4.3.4
Background Chemotherapy
Participants randomized to the lenvatinib plus pembrolizumab plus chemotherapy arm will 
receive either 4 cycles of CAPOX OR 6 cycles of mFOLFOX6 given concurrently with 
lenvatinib and pembrolizumab concurrently during the Induction Phase. Participants 
randomized to this treatment arm will receive lenvatinib and pembrolizumab in the 
Consolidation Phase unless either drug is discontinued according to dose modification 
criteria due to AEs. Participants will NOT receive chemotherapy during the Consolidation 
Phase if randomized to this arm of therapy. Participants who are randomized to the 
chemotherapy arm will continue chemotherapy with either CAPOX or mFOLFOX6 per local 
SOC, consistent with NCCN guidelines for the treatment of first-line advanced/metastatic 
gastric cancer. The decision to treat with CAPOX or mFOLFOX6 is per investigator 
judgment and made on a participant-by-participant basis. For any treatment regimen, once 
the participant is randomized, the chemotherapy (backbone) cannot be changed. Country-
specific requirements are noted in Appendix 7.
4.3.4.1
CAPOX
Dose determination for capecitabine and oxaliplatin in the CAPOX regimen is in accordance 
with prescribing information for gastric cancer as described in their package inserts. 
In this protocol, the dose regimen will be oxaliplatin (130 mg/m2 IV) on Day 1 and Day 22 
of each treatment cycle plus capecitabine (1000 mg/m2 orally twice daily) on Days 1 to 14, 
and Days 22 to 35 of each treatment cycle (Q3W).
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The combination of capecitabine, oxaliplatin, and pembrolizumab is currently being 
evaluated in an investigator-initiated study in the United States. This study is a single arm, 
Phase 2 study investigating the combination of pembrolizumab, oxaliplatin, and capecitabine 
in the first-line treatment of metastatic/recurrent adenocarcinoma of the esophagus or 
stomach and is being conducted at Duke University (KeyLargo study). Enrollment began in 
January 2018. The doses of capecitabine, oxaliplatin, and pembrolizumab used are identical 
to those used in this protocol.
4.3.4.2
mFOLFOX6
Dose determination for oxaliplatin, leucovorin, 5-FU in the mFOLFOX6 regimen is in 
accordance with prescribing information for gastric cancer as described in their package 
inserts. 
In this protocol, the dose regimen will be oxaliplatin (85 mg/m2 IV) plus leucovorin 400 
mg/m2 IV) plus 5-FU (400 mg/m2) IV bolus and 5-FU (2400 mg/m2) IV on Day 1 of each 
chemotherapy cycle (Q2W).
The choice of the platinum agent used for treatment for gastric cancer in first-line therapy has 
changed during the last 2 to 3 years in the Group of 7 countries (US, Germany, UK, France, 
Spain, Italy, Japan) and other countries. Oxaliplatin combinations are now the broad SOC in 
most countries (mFOLFOX6: 5-FU plus oxaliplatin plus leucovorin), moving away from the 
nephrotoxicity of cisplatin-based regimens (predominantly cisplatin + 5-FU). The advantages 
of mFOLFOX6 regimen include elimination of several hours of IV hydration needed to avoid 
cisplatin nephrotoxicity, and less nausea, vomiting, thromboembolic events and anemia. The 
SOC chemotherapy predominantly used in the US is mFOLFOX6 (leucovorin plus 5-FU plus 
oxaliplatin) in first-line gastric cancer.
In a Phase 2 study (HCRN GI14-186), pembrolizumab has been combined with mFOLFOX6 
in colorectal cancer using the dose regimen described in this current protocol and was found 
to show tolerable toxicity. The rate of Grade 3/4 toxicity associated with 
mFOLFOX6/pembrolizumab was 36.7%. No Grade 5 toxicity was seen on study. The DMC 
recommended modification of the chemotherapy regimen to oxaliplatin 68 mg/m2, 
leucovorin 400 mg/m2, 5-FU 320 mg/m2, 5-FU infusion of 1920 mg/m2 over 46 hours based 
on initial findings that suggested increased neutropenia [Shahda, S., et al 2017]. 
However, in a subsequent KEYNOTE-651 study, investigating pembrolizumab plus 
mFOLFOX (Cohort B) in participants with metastatic colorectal cancer, the same regimen 
without any dose reduction was determined to be safe and tolerable, with the most common 
Grade 3 TRAEs being anemia and neutrophil count decreased (13% each) [Kim, R., et al 
2019]. 
4.4
Beginning and End-of-Study Definition
The overall study begins when the first participant (or their legally acceptable representative) 
provides documented informed consent. The overall study ends when the last participant 
completes the last study-related contact, withdraws consent, or is lost to follow-up (Section 
7.3). For purposes of analysis and reporting, the overall study ends when the Sponsor 
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receives the last laboratory test result or at the time of final contact with the last participant, 
whichever comes last.
If the study includes countries in the European Economic Area (EEA), the local start of the 
study in the EEA is defined as First Site Ready (FSR) in any Member State.
The Sponsor estimates that the maximum duration of the study from first participant entered 
through long-term follow-up will be 5 years (~1 year after study intervention has been 
completed) to attain the final assessment of the study (eg, to evaluate safety and/or long-term 
efficacy) for all evaluable participants. Refer to the Synopsis, Section 1.1, for the duration of 
participation of participants.
4.4.1
Clinical Criteria for Early Study Termination
The clinical study may be terminated early if the extent (incidence and/or severity) of 
emerging effects/clinical endpoints is such that the risk/benefit ratio to the study population 
as a whole is unacceptable. In addition, further recruitment in the study or at (a) particular 
study site(s) may be stopped due to insufficient compliance with the protocol, GCP, and/or 
other applicable regulatory requirements, procedure-related problems or the number of 
discontinuations for administrative reasons is too high.
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5
STUDY POPULATION
As stated in the Code of Conduct for Clinical Trials (Appendix 1.1), this study includes 
participants of varying age (as applicable), race, ethnicity, and sex (as applicable). The 
collection and use of these demographic data will follow all local laws and participant 
confidentiality guidelines while supporting the study of the disease, its related factors, and 
the IMP under investigation.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
An individual is eligible for inclusion in the study if the individual meets all of the following 
criteria:
Type of Participant and Disease Characteristics
1. Has histologically and/or cytologically confirmed diagnosis of previously untreated, 
locally advanced unresectable or metastatic gastroesophageal adenocarcinoma.
Note: Participants who are eligible for radiotherapy or neoadjuvant therapy are not 
eligible.
2. Is not expected to require tumor resection during the treatment course.
3. Has gastroesophageal adenocarcinoma that is not HER-2/neu positive. 
Note: Participants with gastroesophageal adenocarcinoma that is known to be HER-2/neu 
positive are not eligible. If HER-2/neu status is unknown, site should follow local 
standards if HER-2/neu testing is required as SOC.
Country-specific requirements are provided in Appendix 7.
4. Has measurable disease as defined by RECIST 1.1 by scan with IV contrast as 
determined by the local site investigator. Lesions situated in a previously irradiated area 
are considered measurable if progression has been showed in such lesions since the 
completion of radiation (by scans with contrast).
Demographics
5. Is male or female at least 18 years of age inclusive at the time of signing the informed 
consent.
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Male Participants
6. Male participants are eligible to participate if they agree to the following during the 
intervention period and for at least 7 days after last dose of lenvatinib or 90 days after last 
dose of chemotherapy, whichever comes last:
•
Refrain from donating sperm
PLUS either:
•
Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent 
on a long-term and persistent basis) and agree to remain abstinent
OR
•
Must agree to use contraception as detailed below unless confirmed to be azoospermic 
(vasectomized or secondary to medical cause [Appendix 5]):
•
Agree to use a male condom plus partner use of an additional contraceptive method when 
having penile-vaginal intercourse with a WOCBP who is not currently pregnant. Note: 
Men with a pregnant or breastfeeding partner must agree to remain abstinent from penile-
vaginal intercourse or use a male condom during each episode of penile-vaginal 
penetration.
Please note that 7 days after lenvatinib is stopped, if the participant is on pembrolizumab 
only, no male contraception measures are needed.
Contraceptive use by men 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 drugs is more stringent than the requirements above, the 
local label requirements should be followed.
Country-specific requirements are listed in Appendix 7.
Female Participants
7. 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
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•
Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate 
of <1% per year), with 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 through 120 days after 
last dose of pembrolizumab, 30 days after last dose of lenvatinib, or 180 days after last 
dose of chemotherapy, whichever occurs last, or not to donate eggs (ova, oocytes) to 
others or freeze/store for her own use for the purpose of reproduction during this period. 
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 for urine or 72 hours for serum 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.
•
Abstains from breastfeeding during the study intervention period and for at least 120 days 
after pembrolizumab or 30 days after cessation of lenvatinib, or 180 days after 
chemotherapy, whichever occurs last.
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 drugs is more stringent than the 
requirements above, the local label requirements should be followed.
Informed Consent
8. The participant (or legally acceptable representative) has provided documented informed 
consent/assent for the study.
Additional Categories
9. Has a performance status of 0 or 1 on the ECOG Performance Scale within 3 days prior 
to the first dose of study treatment.
10. Has provided a tumor tissue sample for PD-L1 and MSI biomarker analysis. If the initial 
tissue is inadequate for the analysis, an additional specimen will need to be provided.
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11. Has adequately controlled BP with or without antihypertensive medications, defined as 
BP ≤150/90 mm Hg and no change in antihypertensive medications within 1 week prior
to randomization.
12. Has adequate organ function as defined in the following table (Table 3). Specimens must 
be collected within 10 days prior to the start of study intervention.
Table 3
Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
≥1500 /mcL
Platelets
≥100,000 /mcL
Hemoglobin
≥9 g/dL or ≥5.6 mmol/La
Renal
Calculatedb creatinine clearance
≥50 mL/min 
Hepatic
Total bilirubin
≤1.5 X ULN OR
Direct bilirubin ≤ ULN for participants with total bilirubin 
levels >1.5 ULN
AST (SGOT) and ALT (SGPT)
≤2.5 X ULN OR
≤5 X ULN for participants with liver metastases
Albuminc
≥3.0 g/dL
Coagulation
International Normalized Ratio (INR) or 
Prothrombin Time (PT)
Activated Partial Thromboplastin Time (aPTT)
≤1.5 X ULN unless participant is receiving anticoagulant 
therapy as long as PT or PTT is within therapeutic range 
of intended use of anticoagulants
≤1.5 X ULN unless participant is receiving anticoagulant 
therapy as long as PT or PTT is within therapeutic range 
of intended use of anticoagulants
ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT)=aspartate aminotransferase 
(serum glutamic oxaloacetic transaminase); GFR=glomerular filtration rate; ULN=upper limit of normal.
a Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last 
2 weeks and G-SCF and thrombopoietin within last 3 weeks. 
b Estimated creatinine clearance using Cockcroft-Gault:
(140-age [years] × weight [kg])
(× F)*
Serum creatinine (mg/dL) × 72
*where F = 0.85 for females and F = 1 for males
c Criteria must be met without albumin supplementation within the last 72 hours.
Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value requirements 
should be adapted according to local regulations and guidelines for the administration of specific chemotherapies.
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5.2
Exclusion Criteria
The participant must be excluded from the study if the participant meets any of the following 
criteria:
Medical Conditions
1. Has had previous therapy for locally advanced unresectable or metastatic 
gastric/GEJ/esophageal adenocarcinoma. 
Note: Participants may have received prior neoadjuvant or adjuvant therapy as long as it 
was completed at least 6 months prior to randomization and progression occurred at least 
6 months after completion of therapy.
2. Has had major surgery within 28 days prior to first dose of study interventions. 
Note: Adequate wound healing after major surgery must be assessed clinically, 
independent of time elapsed for eligibility
Note: If participant received major surgery, they must have recovered adequately from 
the toxicity and/or complications from the intervention prior to starting study 
intervention. 
3. Has had radiotherapy within 14 days of randomization. Participants must have recovered 
from all radiation-related toxicities, not require corticosteroids, and not have had 
radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks 
of radiotherapy) to non-CNS disease.
4. Has a known additional malignancy that is progressing or has required active treatment 
within the past 5 years. Exceptions include basal cell carcinoma of the skin, squamous 
cell carcinoma of the skin that has undergone potentially curative therapy or in situ 
cervical cancer.
5. Has known CNS metastases and/or carcinomatous meningitis. 
6. Has severe hypersensitivity (≥Grade 3) to treatment with an mAb or known sensitivity or 
intolerance to any component of lenvatinib, pembrolizumab, study chemotherapy agents 
and/or to any excipients, murine proteins, or platinum-containing products.
7. Has had an allogeneic tissue/solid organ transplant.
8. Has perforation risks or significant GI bleeding, such as:

Has had a serious nonhealing wound, peptic ulcer, or bone fracture within 28 days 
prior to randomization.

Has preexisting ≥Grade 3 GI or non-GI fistula.
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
Has significant bleeding disorders, vasculitis, or has had a significant bleeding 
episode from the GI tract within 12 weeks prior to randomization.
9. Has GI obstruction, poor oral intake (CAPOX participants), or difficulty in taking oral 
medication (CAPOX participants). G-tubes, J-tubes and nasogastric tubes will not be 
permitted for treatment administration of capecitabine. Participants with existing 
esophageal stent are not eligible. Also, participants with known gastrointestinal 
malabsorption, gastrointestinal anastomosis or any other condition that may affect the 
absorption of lenvatinib.
Prior/Concomitant Therapy
10. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an
agent directed to another stimulatory or coinhibitory TCR (eg, CTLA-4, OX40, CD137).
11. Has received prior therapy with anti-VEGF TKI or anti-VEGF mAb.
12. Has received a live or live-attenuated vaccine within 30 days before the first dose of 
study drug. Note: Killed vaccines are allowed. 
Note: See Section 6.5 for information on COVID-19 vaccines.
Prior/Concurrent Clinical Study Experience
13. Is currently participating in or has participated in a study of an investigational agent or 
has used an investigational device within 4 weeks prior to the first dose of study 
intervention.
Note: Participants who have entered the follow-up phase of an investigational study may 
participate as long as it has been 4 weeks after the last dose of the previous 
investigational agent.
Diagnostic Assessments
14. Has an active autoimmune disease that has required systemic treatment in past 2 years 
(ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs). 
Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic 
treatment and is allowed.
15. Has radiographic evidence of encasement or invasion of a major blood vessel, or of 
intratumoral cavitation. 
Note: The degree of proximity to major blood vessels should be considered because of 
the potential risk of severe hemorrhage associated with tumor shrinkage/necrosis after 
lenvatinib therapy
16. Has inadequate cardiac function assessed as: 
•
LVEF below the institutional normal range as determined by a MUGA or ECHO.
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•
QTcF value >470 msec for males and >480 msec for females (mean of 3 measurements 
corrected for heart rate using Fridericia’s formula).
Cardiac function will be assessed using 12-lead ECG scan and ECHO performed by the 
investigator or other qualified person prior to enrollment in the study. For country specific 
requirements, see Appendix 7.
17. Has urine protein ≥1 g/24 hours.
Note: Participants with proteinuria ≥2+ (≥100 mg/dL) on urine dipstick testing 
(urinalysis) will undergo 24-hour urine collection for quantitative assessment of 
proteinuria. Participants may be eligible if 24 hour urine protein ≤1 g.
18. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in 
dosing exceeding 10 mg daily of prednisone equivalent) or any other form of 
immunosuppressive therapy within 7 days prior to the first dose of study intervention.
19. Has a history of (noninfectious) pneumonitis/interstitial lung disease that required 
steroids or has current pneumonitis/interstitial lung disease.
20. Has a known history of active TB (Mycobacterium tuberculosis). No testing for TB is 
required unless mandated by local health authority. Refer to Appendix 7 for 
country-specific requirements.
21. Has an active infection requiring systemic therapy.
22. Has poorly controlled diarrhea (eg, watery stool, uncontrollable bowel movement with 
supportive medication, Grade ≥2 and number of defecations, ≥5/day).
23. Has accumulation of pleural, ascitic, or pericardial fluid requiring drainage or diuretic 
drugs within 2 weeks prior to enrollment. If the participant is receiving diuretic drugs for 
other reasons, it is acceptable. Consult with the Sponsor if the participant has more than 
trivial/trace fluid accumulation.
24. Has a history or current evidence of any condition (eg, but not limited to, known 
deficiency of the enzyme DPD, etc.), 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 investigator (refer to Appendix 7 for country-specific requirements). 
Participants with a contraindication to SOC therapy should be excluded based on the 
following:
•
Has a history of a GI condition or procedure that in the opinion of the investigator 
may affect oral study drug absorption.
•
Has a history of a severe and unexpected reaction to a fluoropyrimidine-containing 
treatment. 
•
Has severe dyspnea at rest related to advanced disease stage or oxygen-dependent 
complications.
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•
Has hypokalemia, hypomagnesemia, or hypocalcemia.
•
Participant had active hemoptysis (bright red blood of at least 0.5 teaspoon) within 3 
weeks or tumor bleeding within 2 weeks prior to the first dose of study intervention.
25. Has peripheral neuropathy ≥Grade 2.
26. Has a known psychiatric or substance abuse disorder that would interfere with 
cooperation with the requirements of the study.
27. Has clinically significant cardiovascular disease within 12 months from first dose of 
study intervention, including New York Heart Association Class III or IV congestive 
heart failure, unstable angina, myocardial infarction, cerebral vascular accident, or 
cardiac arrhythmia associated with hemodynamic instability. Note: Medically controlled 
arrhythmia would be permitted.
28. Has a known history of HIV (HIV antibodies). No testing for HIV is required unless 
mandated by local health authority. Refer to Appendix 7 for country-specific 
requirements.
29. Has a known history of hepatitis B (defined as HBsAg reactive) or known active hepatitis 
C virus (defined as HCV RNA [qualitative] is detected) infection. No testing for hepatitis 
B/C is required unless mandated by local health authority. Refer to Appendix 7 for 
country-specific requirements.
Other Exclusions
30. Has weight loss of >20% within the last 3 months.
Country-specific requirements are listed in Appendix 7.
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
Photosensitivity
Investigators are advised to counsel participants assigned to receive capecitabine or 5-FU 
about the risk of photosensitivity and to take sun protection measures accordingly.
5.3.3
Caffeine, Alcohol, and Tobacco Restrictions
There are no restrictions in caffeine, alcohol and tobacco consumption/use.
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5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study, but 
are not subsequently entered in the study. A minimal set of screen-failure information is 
required to ensure transparent reporting of screen-failure participants to meet the CONSORT 
publishing requirements and to respond to queries from regulatory authorities. Minimal 
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
In Part 1, if one of the Safety Run-in participants does not receive at least 1 dose of 
lenvatinib plus pembrolizumab plus chemotherapy (either mFOLFOX6 or CAPOX), the 
participant will be replaced.
In Part 2, a participant who discontinues from study intervention OR withdraws from the 
study will not be replaced.
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6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
Clinical supplies (study intervention(s) provided by the Sponsor) will be packaged to support 
enrollment.  Clinical supplies will be affixed with a clinical label in accordance with 
regulatory requirements.
Global clinical supply complaints and/or temperature excursions are to be reported as soon as 
possible upon first becoming aware of the issue by completing the Online Form at 
www.csincident.msd.com or via email to clinical.complaints.intake@MSD.com in case of 
system downtime or technical issues with the online form.
6.1
Study Intervention(s) Administered
The study interventions to be used in this study are outlined in Table 4.
Country-specific requirements are noted in Appendix 7.
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Table 4
Study Interventions
Arm 
Name
Arm Type
Intervention 
Name
Intervention 
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen/
Treatment 
Period/
Vaccination 
Regimen
Use
IMP or 
NIMP/
AxMP
Sourcing
Arm 1
Experimental Pembrolizumab Drug
Solution
25 mg/mL
400 mg
IV Infusion
Q6W
Test Product IMP
Central
Arm 1
Experimental Lenvatinib
Drug
Capsule
10 mg/
4 mg / 1mg
8 mg induction/
20 mg 
consolidation
Oral
Once daily
Test Product IMP
Central
Arm 1
Experimental Capecitabine
(CAPOX)
Drug
Tablet
150 mg 
tablet
or
500 mg 
tablet
1000 mg/m2
Oral
BID for 14 
days Q3W 
for 4 cycles 
Test Product IMP
Local and 
Central
Arm 1
Experimental Oxaliplatin
(CAPOX)
Drug
Solution
100 mg/ 20 
mL vial or 
50 mg vial
130 mg/m2
IV Infusion
Once Q3W 
for 4 cycles
Test Product IMP
Local and 
Central
Arm 1
Experimental Oxaliplatin
(mFOLFOX)
Drug
Solution
100 mg/ 20 
mL vial or 
50 mg vial
85 mg/m2
IV Infusion
Once Q2W 
for 6 cycles
Test Product IMP
Local and 
Central
Arm 1
Experimental 5-FU 
(mFOLFOX)
Drug
Solution
500 mg/ 10 
mL vial or
250 mg/ 10 
mL vial
400 mg/m2
(bolus) plus 
2400 mg/m2
(continuous)
IV Infusion
Q2W for 6 
cycles
Test Product IMP
Local and 
Central
Arm 1
Experimental Leucovorin or 
Levoleucovorin 
(mFOLFOX)
Drug
Solution
100 mg vial 
or 300 mg 
vial
400 mg/m² (or 
200 mg/m² for 
levoleucovorin)
IV Infusion
Q2W for 6 
cycles
Test Product IMP
Local and 
Central
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Arm 
Name
Arm Type
Intervention 
Name
Intervention 
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen/
Treatment 
Period/
Vaccination 
Regimen
Use
IMP or 
NIMP/
AxMP
Sourcing
Arm 2
Active 
Comparator
Capecitabine
(CAPOX)
Drug
Tablet
150 mg 
tablet
or
500 mg 
tablet
1000 mg/m2
Oral
bid for 14 
days q3w
Comparator
IMP
Local and 
Central
Arm 2
Active 
Comparator
Oxaliplatin
(CAPOX)
Drug
Solution
100 mg/ 20 
mL vial or 
50 mg vial
130 mg/m2
IV Infusion
q3w
Comparator
IMP
Local and 
Central
Arm 2
Active 
Comparator
Oxaliplatin
(mFOLFOX)
Drug
Solution
100 mg/ 20 
mL vial or 
50 mg vial
85 mg/m2
IV Infusion
q2w
Comparator
IMP
Local and 
Central
Arm 2
Active 
Comparator
5-FU 
(mFOLFOX)
Drug
Solution
500 mg/ 10 
mL vial or
250 mg/ 10 
mL vial
400 mg/m2
(bolus) plus 
2400 mg/m2
(continuous)
IV Infusion
q2w
Comparator
IMP
Local and 
Central
Arm 2
Active 
Comparator
Leucovorin or 
Levoleucovorin 
(mFOLFOX)
Drug
Solution
100 mg vial 
or 300 mg 
vial
400 mg/m² (or
200 mg/m² for 
levoleucovorin)
IV Infusion
q2w
Comparator
IMP
Local and 
Central
AxMP=auxiliary medical product; bid=twice a day; IMP=investigational medicinal product; IV=intravenous.; NIMP=noninvestigational medical product,; q2w=every two weeks; q3w=every three 
weeks.; 5-FU= fluorouracil
The classification of IMP in this table is based on guidance issued by the European Commission and applies to countries in the European Economic Area (EEA). Country differences with respect to 
the definition/classification of IMP/NIMP may exist. In these circumstances, local legislation is followed. 
Investigator decision regarding the type of backbone chemotherapy (CAPOX or mFOLFOX6) should be determined prior to allocation/randomization. Participants should continue on the type of 
backbone chemotherapy chosen prior to randomization throughout the study.
Lenvatinib capsules may be added without breaking or crushing them to a tablespoon of water or apple juice in a small glass to produce a suspension (please refer to Pharmacy Manual).
Clinical supply concentration and formulation of chemotherapy may vary by local source.
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All study interventions will be administered on an outpatient basis.
All products indicated in Table 4 will be provided centrally by the Sponsor or locally by the 
study site, subsidiary, or designee, depending on local country operational or regulatory 
requirements as per the “Sourcing” column.
For any commercially available product that is provided by the study site, subsidiary, or 
designee, every attempt will be made to source these supplies from a single lot/batch number. 
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product as per local guidelines unless otherwise instructed by the 
Sponsor.
Refer to Section 8.1.8 for details regarding administration of the study intervention.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
Details on preparation and administration of lenvatinib and pembrolizumab are provided in 
the Pharmacy Manual. For participants who have difficulty swallowing capsules, lenvatinib 
can be dissolved into a suspension. Please refer to Pharmacy Manual for full details. 
Concomitant chemotherapeutic agents will be prepared and administered as per the approved 
product labels.
The body surface area in m2 should be calculated per local guidance. The dose of 
chemotherapy should be recalculated for fluctuation of body weight ≥10% at the beginning 
of a cycle only. For weight fluctuation <10%, recalculation may be performed at the 
discretion of the investigator. The rationale for selection of doses to be used in this study is 
provided in Section 4.3.
6.2.2
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
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and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
The Safety Run-in (Part 1), comprising approximately 12 participants, will be open-label and 
non-randomized. The Main Study (Part 2) will be open-label and randomized. Intervention 
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 plus 
pembrolizumab plus chemotherapy study intervention and chemotherapy study intervention, 
respectively.
6.3.2
Stratification
Part 1 (Safety Run-in): 
There are no stratification factors for Part 1.
6.3.3
Blinding
This is an open-label study (Part 1 and Part 2); therefore, the Sponsor, investigator, and 
participant will know the intervention administered.
6.4
Study Intervention Compliance
Interruptions from the protocol-specified pembrolizumab treatment for ≥12 weeks, or 
lenvatinib treatment for ≥4 weeks, or chemotherapy treatment for ≥3 weeks require 
CCI
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consultation between the investigator and the Sponsor and written documentation of the 
collaborative decision on participant management.
6.5
Concomitant Therapy
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing study. If there is a clinical indication for any medication or vaccination 
specifically prohibited, discontinuation from study therapy or vaccination may be required. 
The investigator should discuss any questions regarding this with the Sponsor's Clinical 
Director. The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the participant's primary physician. However, the decision to continue the 
participant on study intervention requires the mutual agreement of the investigator, the 
Sponsor, and the participant.
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements or other specific categories of interest) that the participant is 
receiving at the time of enrollment or receives during the study must be recorded along with:
•
Reason for use
•
Dates of administration including start and end dates
•
Dosage information including dose and frequency
•
Listed below are concomitant therapies prohibited during the course of the study:
•
Antineoplastic systemic chemotherapy or biological therapy
•
Immunotherapy not specified in this protocol
•
Chemotherapy not specified in this protocol
•
Investigational agents other than lenvatinib or pembrolizumab
•
Radiation therapy
Note: Radiation therapy to a symptomatic solitary lesion may be allowed at the 
investigator’s discretion. 
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•
Live or live-attenuated vaccines within 30 days prior to the first dose of study 
intervention and while participating in the study. Administration of killed vaccines is 
allowed.
Note: Any licensed COVID 19 vaccine (including for Emergency use) in a particular 
country is allowed in the study as long as they are mRNA vaccines, adenoviral vaccines, 
or inactivated vaccines. These vaccines will be treated just as any other concomitant 
therapy.
-
Investigational vaccines (ie, those not licensed or approved for Emergency Use) are 
not allowed
•
Systemic glucocorticoids are permitted only for the following purposes:
-
To modulate symptoms from an AE that is suspected to have an immunologic 
etiology. 
Note: Inhaled or topical steroids are allowed, and systemic steroids at doses ≤10 
mg/day prednisone or equivalent are allowed. 
-
The use of doses higher than 10 mg/day prednisone or equivalent may be approved 
after consultation with the Sponsor. 
-
To treat asthma or COPD exacerbations (only short-term oral or IV use in doses >10 
mg/day prednisone equivalent).
-
A short course of steroids may be used as concomitant medication for either treatment 
of an AE or medical condition with Sponsor approval.
-
Use of prophylactic corticosteroids to avoid allergic reactions (eg, IV contrast dye or 
transfusions) is permitted.
-
The use of intermittent inhaled steroids or intranasal or local injection of 
corticosteroids is permitted.
-
Use of steroids for antiemetic purposes is permitted.
-
Use of steroids for premedication for chemotherapy, per local guidance may be 
permitted with Sponsor approval.
•
For participants receiving 5-FU, or capecitabine:
-
Brivudine, Sorivudine analogs, and other inhibitors of the enzyme dihydropyrimidine 
dehydrogenase
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Concomitant Medications to be Used with Caution
•
Caution is advised when oxaliplatin and lenvatinib treatment is coadministered with other 
medicinal products known to cause QT interval prolongation. In case of combination 
with such medicinal products, the QT interval should be closely monitored. Cimetidine, 
metronidazole and interferons may increase levels of 5-FU. Reliable sources such as 
crediblemeds.org can be used to assist in identification of medicinal products known to 
cause QT interval prolongation.
•
Participants who are taking phenytoin in conjunction with 5-FU should be examined 
regularly due to a potential elevation in phenytoin plasma levels. Hepatotoxic effects 
(increase in alkaline phosphatase, transaminase, or bilirubin levels) are frequently 
observed under the treatment with 5-FU and levamisole.
•
For participants receiving oxaliplatin:
-
Caution is advised if medicinal products associated with rhabdomyolysis are 
administered concomitantly with oxaliplatin. 
All treatments that the investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care. All concomitant medication will be recorded on the eCRF including all 
prescription, OTC products, herbal supplements, and IV medications and fluids. If changes 
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. If 
participants experience an SAE or ECI, All concomitant medications administered during 
SAEs or ECIs (30 days or more after the last dose of study intervention) are to be recorded. 
SAEs and ECIs are defined in Section 8.4.
6.5.1
Rescue Medications and Supportive Care
Participants should receive appropriate supportive care measures as deemed necessary by the 
treating investigator. For participants receiving lenvatinib plus pembrolizumab, suggested 
supportive care measures for the management of AEs with potential immunologic etiology 
along with the dose modification guidelines are outlined in Section 6.6. Where appropriate, 
these guidelines include the use of oral or IV treatment with corticosteroids, as well as 
additional anti-inflammatory agents if symptoms do not improve with administration of 
corticosteroids. Note that several courses of steroid tapering may be necessary as symptoms 
may worsen when the steroid dose is decreased. For each disorder, attempts should be made 
to rule out other causes such as metastatic disease or bacterial or viral infection, which might 
require additional supportive care. The treatment guidelines are intended to be applied when 
the investigator determines the events to be related to pembrolizumab or lenvatinib. Refer to 
Section 6.6.2 for guidelines regarding dose modification and supportive care.
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
other procedures as part of evaluation of the event.
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6.5.1.1
Supportive Care Guidelines for Capecitabine
Please refer to the product label or local standards of care for capecitabine supportive 
measures.
6.5.1.2
Supportive Care Guidelines for Oxaliplatin
Please refer to the product label or local standards of care for oxaliplatin supportive 
measures.
6.5.1.3
Supportive Care Guidelines for 5-FU
Please refer to the product label or local standards of care for 5-FU supportive measures.
6.5.2
Drug Interactions
There are no DDI-related concomitant medication prohibitions or restrictions. 
Lenvatinib is not expected to clinically meaningfully alter exposure to CYP3A4/ Pgp 
substrates based on results from a lenvatinib DDI study with midazolam (a sensitive CYP3A 
and Pgp substrate). 
Clinical studies also showed that coadministration of lenvatinib with either inducers or 
inhibitors of CYP3A4/Pgp are not of clinical concern.
No drug interaction is expected between lenvatinib and pembrolizumab because of their 
divergent metabolic pathways. Pembrolizumab is a mAb and is primarily catabolized like 
other proteins, while lenvatinib is metabolized by enzymatic (CYP3A and aldehyde oxidase) 
and nonenzymatic processes (lenvatinib IB). 
6.5.3
Concomitant Surgery
In general, surgical resection in participants who have metastatic disease is not encouraged 
except in exceptional cases as the benefit of surgery is unknown in this setting. However, if it 
is determined that participants are eligible for potential curative surgical resection, in the 
event of strong tumor response, please contact the Sponsor for guidance. Participants who 
have curative surgery while on study will be defined as are participants who have had tumor 
resection and a postresection imaging restaging to include at minimum contrasted CT chest, 
abdomen, pelvis, plus imaging of any part of the body previously known to have tumor and 
must show no residual disease. MRI with IV contrast or PET CT may be allowed if 
appropriate for restaging imaging. Participants who have surgery should continue imaging as 
detailed in the SoA (Section 1.3) until PD, or they otherwise meet the discontinuation criteria 
(Section 7.1).
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6.6
Dose Modification (Escalation/Titration/Other)
Adverse events will be graded using NCI CTCAE v5.0. Investigators will decide the 
probability of the event being related to one or more drugs as to whether dose modification of 
one or more drugs is required.
This is an open-label protocol with a novel combination of pembrolizumab, lenvatinib, and 
chemotherapy (CAPOX or mFOLFOX6). Because of the multiple agents included in this 
protocol, overlapping toxicities may occur and the determination of the contribution of 
agents to specific toxicities may be challenging. Dose modifications can be handled 
individually or in concert depending on determined relatedness. Refer to Section 6.6.2, 
Section 6.6.3 and Section 6.6.4 for guidance with regards to dose interruption, dose 
modification, and overlapping toxicities. Please contact the Sponsor for additional guidance 
if needed.
Participants who interrupt or discontinue one of the study medications (pembrolizumab, 
lenvatinib, or chemotherapy) due to toxicity may continue with the other drug(s) in the 
combination until the criteria for treatment discontinuation are met (eg, unacceptable 
toxicity, disease progression).
6.6.1
Initial Treatment or First Course
The number of treatments is calculated starting with the first dose. Participants who stop the 
combination or pembrolizumab after receiving 18 doses may be eligible for retreatment if 
they progress after stopping study intervention provided, they meet the requirements detailed 
in Section 6.6.6. Participants may be retreated in Second Course (Retreatment) for up to an 
additional 9 cycles (approximately 1 year).
6.6.2
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue)
Dose Modification and Toxicity Management for Immune-related AEs Associated with 
Pembrolizumab
AEs associated with pembrolizumab exposure may represent an immune-related response. 
These irAEs may occur shortly after the first dose or several months after the last dose of 
pembrolizumab treatment and may affect more than one body system simultaneously. 
Therefore, early recognition and initiation of treatment is critical to reduce complications. 
Based on existing clinical study data, most irAEs were reversible and could be managed with 
interruptions of pembrolizumab, administration of corticosteroids and/or other supportive 
care. For suspected irAEs, ensure adequate evaluation to confirm etiology or exclude other 
causes. Additional procedures or tests such as bronchoscopy, endoscopy, skin biopsy may be 
included as part of the evaluation. 
Dose Modification and Toxicity Management Guidelines for irAEs associated with 
pembrolizumab monotherapy, coformulations, or IO combinations are provided in Table 5.
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Table 5
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 
(CTCAE v5.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or IO 
Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Pneumonitis 
Grade 2
Withhold 
Administer corticosteroids 
(initial dose of 1 to 2 mg/kg 
prednisone or equivalent) 
followed by taper
Add prophylactic antibiotics 
for opportunistic infections
Monitor participants for signs and symptoms of 
pneumonitis
Evaluate participants with suspected pneumonitis 
with radiographic imaging and initiate 
corticosteroid treatment
Recurrent Grade 2, 
Grade 3 or 4 
Permanently 
discontinue
Diarrhea/Colitis 
Grade 2 or 3
Withhold
Administer corticosteroids 
(initial dose of 1 to 2 mg/kg 
prednisone or equivalent) 
followed by taper
Monitor participants for signs and symptoms of 
enterocolitis (ie, diarrhea, abdominal pain, blood 
or mucus in stool with or without fever) and of 
bowel perforation (ie, peritoneal signs and ileus)
Participants with ≥Grade 2 diarrhea suspecting 
colitis should consider GI consultation and
performing endoscopy to rule out colitis
Participants with diarrhea/colitis should be 
advised to drink liberal quantities of clear fluids. 
If sufficient oral fluid intake is not feasible, fluid 
and electrolytes should be substituted via IV 
infusion
Recurrent Grade 3 
or Grade 4
Permanently 
discontinue
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irAEs
Toxicity Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or IO 
Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
AST or ALT 
Elevation or 
Increased Bilirubin
Grade 2 a
Withhold
Administer corticosteroids 
(initial dose of 0.5 to 
1 mg/kg prednisone or 
equivalent) followed by 
taper
Monitor with liver function tests (consider weekly 
or more frequently until liver enzyme value 
returned to baseline or is stable)
Grade 3 b or 4 c
Permanently 
discontinue
Administer corticosteroids 
(initial dose of 1 to 2 mg/kg 
prednisone or equivalent) 
followed by taper
T1DM or 
Hyperglycemia
New onset T1DM or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -cell 
failure
Withhold d
Initiate insulin replacement 
therapy for participants with 
T1DM
Administer 
antihyperglycemic in 
participants with 
hyperglycemia
Monitor participants for hyperglycemia or other 
signs and symptoms of diabetes
Hypophysitis
Grade 2
Withhold
Administer corticosteroids 
and initiate hormonal 
replacements as clinically 
indicated
Monitor for signs and symptoms of hypophysitis 
(including hypopituitarism and adrenal 
insufficiency)
Grade 3 or 4
Withhold or 
permanently 
discontinue d
Hyperthyroidism
Grade 2
Continue
Treat with nonselective 
beta-blockers (eg, 
propranolol) or thionamides 
as appropriate
Monitor for signs and symptoms of thyroid 
disorders
Grade 3 or 4
Withhold or 
permanently 
discontinue d
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irAEs
Toxicity Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or IO 
Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Hypothyroidism
Grade 2, 3 or 4
Continue
Initiate thyroid replacement 
hormones (eg, levothyroxine 
or liothyronine) per standard 
of care
Monitor for signs and symptoms of thyroid 
disorders
Nephritis:
grading according 
to increased 
creatinine or acute 
kidney injury
Grade 2
Withhold
Administer corticosteroids 
(prednisone 1 to 2 mg/kg or 
equivalent) followed by 
taper
Monitor changes of renal function
Grade 3 or 4
Permanently 
discontinue
Neurological 
Toxicities
Grade 2
Withhold
Based on severity of AE 
administer corticosteroids
Ensure adequate evaluation to confirm etiology 
and/or exclude other causes
Grade 3 or 4
Permanently 
discontinue
Myocarditis
Asymptomatic 
cardiac enzyme 
elevation with 
clinical suspicion of 
myocarditis (which 
was previously 
myocarditis Grade 1
using CTCAE v4.0)
Withhold
Based on severity of AE 
administer corticosteroids
Ensure adequate evaluation to confirm etiology 
and/or exclude other causes
Grade 2, 3 or 4
Permanently 
discontinue
Exfoliative 
Dermatologic 
Conditions
Suspected SJS, 
TEN, or DRESS
Withhold
Based on severity of AE 
administer corticosteroids
Ensure adequate evaluation to confirm etiology or 
exclude other causes
Confirmed SJS, 
TEN, or DRESS
Permanently 
discontinue
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irAEs
Toxicity Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or IO 
Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
All Other irAEs
Persistent Grade 2
Withhold
Based on severity of AE 
administer corticosteroids
Ensure adequate evaluation to confirm etiology or 
exclude other causes
Grade 3
Withhold or 
discontinue based on 
the event e
Recurrent Grade 3 
or Grade 4 
Permanently 
discontinue
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for Adverse Events; DRESS=Drug Rash 
with Eosinophilia and Systemic Symptom; GI=gastrointestinal; IO=immuno-oncology; ir=immune related; IV=intravenous; SJS=Stevens-Johnson Syndrome; 
T1DM=type 1 diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal.
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations.
a
AST/ALT: >3.0 to5.0 x ULN if baseline normal; >3.0 to 5.0 x baseline, if baseline abnormal; 
bilirubin:>1.5 to 3.0 x ULN if baseline normal; >1.5 to 3.0 x baseline if baseline abnormal
b
AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 to 20.0 x baseline, if baseline abnormal; bilirubin:>3.0 to 10.0 x ULN if baseline normal; >3.0 to 10.0 x baseline if 
baseline abnormal
c
AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal; 
bilirubin: >10.0 x ULN if baseline normal; >10.0 x baseline if baseline abnormal
d The decision to withhold or permanently discontinue pembrolizumab monotherapy, coformulations or IO combinations is at the discretion of the investigator or treating  
physician. If control achieved or ≤Grade 2, pembrolizumab monotherapy, coformulations or IO combinations may be resumed.
e
Events that require discontinuation include, but are not limited to: encephalitis and other clinically important irAEs (eg, vasculitis and sclerosing cholangitis).
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Dose Modification and Toxicity Management of Infusion Reactions Related to 
Pembrolizumab
Pembrolizumab may cause severe or life-threatening infusion reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion. 
Dose modification and toxicity management guidelines on pembrolizumab associated 
infusion reaction are provided in Table 6.
Table 6
Pembrolizumab Infusion Reaction Dose Modification and Treatment 
Guidelines
NCI CTCAE Grade
Treatment
Premedication at Subsequent Dosing
Grade 1
Mild reaction; infusion 
interruption not 
indicated; intervention 
not indicated
Increase monitoring of vital signs 
as medically indicated until the 
participant is deemed medically 
stable in the opinion of the 
investigator
None
Grade 2
Requires therapy or 
infusion interruption 
but responds promptly 
to symptomatic 
treatment (eg, 
antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated 
for ≤24 hrs
Stop Infusion
Additional appropriate medical 
therapy may include but is not 
limited to:
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Increase monitoring of vital signs 
as medically indicated until the 
participant is deemed medically 
stable in the opinion of the 
investigator.
If symptoms resolve within 1 hour 
of stopping drug infusion, the 
infusion may be restarted at 50% of 
the original infusion rate (eg, from 
100 mL/hr to 50 mL/hr). Otherwise 
dosing will be held until symptoms 
resolve and the participant should 
be premedicated for the next 
scheduled dose.
Participants who develop Grade 2 
toxicity despite adequate 
premedication should be 
permanently discontinued from 
further study drug intervention.
Participant may be premedicated 1.5 h (±30 
minutes) prior to infusion of study 
intervention with:
Diphenhydramine 50 mg PO (or equivalent 
dose of antihistamine).
Acetaminophen 500-1000 mg PO (or 
equivalent dose of analgesic).
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NCI CTCAE Grade
Treatment
Premedication at Subsequent Dosing
Grades 3 or 4
Grade 3:
Prolonged (ie, not 
rapidly responsive to 
symptomatic 
medication and/or brief 
interruption of 
infusion); recurrence of 
symptoms following 
initial improvement; 
hospitalization 
indicated for other 
clinical sequelae (eg, 
renal impairment, 
pulmonary infiltrates)
Grade 4:
Life-threatening; 
pressor or ventilatory 
support indicated
Stop Infusion.
Additional appropriate medical 
therapy may include but is not 
limited to:
Epinephrine**
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Increase monitoring of vital signs 
as medically indicated until the 
participant is deemed medically 
stable in the opinion of the 
investigator.
Hospitalization may be indicated.
**In cases of anaphylaxis, 
epinephrine should be used 
immediately.
Participant is permanently 
discontinued from further study 
drug intervention.
No subsequent dosing
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 Common Terminology Criteria for Adverse Events v5.0 
(CTCAE) at http://ctep.cancer.gov
Other Allowed Dose Interruptions for Pembrolizumab
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as 
medical/surgical events or logistical reasons not related to study therapy. Participants should 
be placed back on study therapy within 6 weeks of the scheduled interruption, unless 
otherwise discussed with the Sponsor. The reason for interruption should be documented in 
the participant’s study record.
6.6.3
Lenvatinib Dose Modification and Toxicity Management
Lenvatinib dose modification during Safety Run-in (Part 1), induction, dose guidance to start 
consolidation, and dose modification during consolidation are specified below. Variation in 
dose modification guidance is because of differences in treatment regimen and recommended 
starting dose. Please refer to the section that applies to the correct phase of therapy (ie, 
induction or consolidation).  
CCI
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CCI
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6.6.3.3
Management of QT Prolongation
Lenvatinib should be withheld in the event of development of QT interval prolongation 
greater than 500 msec. Lenvatinib should be resumed at a reduced dose when QTc 
prolongation is resolved to <480 msec or baseline. Monitor potassium, calcium and 
magnesium and replenish as appropriate.
6.6.3.4
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). Hypertension will 
be graded using NCI CTCAE v5.0, based on BP measurements only (and not on the number 
of antihypertensive medications). Refer to Appendix 8 (Figure 8, Figure 9) for additional 
information on the management of hypertension during Induction and Consolidation.
If the participant’s first BP measurement of the current assessment is elevated (ie, systolic BP 
≥140 mm Hg or diastolic BP ≥90 mm Hg), the BP measurement should be repeated at least 
5 minutes later. One BP assessment is defined as the mean value of 2 measurements at least 
5 minutes apart. If the BP assessment (ie, the mean of the 2 BP measurements obtained at 
least 5 minutes apart) is elevated (systolic BP ≥140 mm Hg or diastolic BP ≥90 mm Hg), a 
confirmatory assessment should be obtained at least 30 minutes later by performing 2 
measurements (at least 5 minutes apart) to yield a mean value. 
Antihypertensive agents should be started as soon as elevated BP (systolic BP ≥140 mm Hg 
or diastolic BP ≥90 mm Hg) is confirmed on 2 assessments at least 30 minutes apart. The 
choice of antihypertensive treatment should be individualized to the participant’s clinical 
circumstances and follow standard medical practice. For previously normotensive 
participants, appropriate antihypertensive therapy should be started when systolic BP ≥140 
mm Hg or diastolic BP ≥90 mm Hg is first observed on 2 assessments at least 30 minutes 
apart. For those participants already on antihypertensive medication, treatment modification 
may be necessary if hypertension persists.  
Lenvatinib should be withheld in any instance where a participant is at imminent risk to 
develop a hypertensive crisis or has uncontrolled hypertension with significant risk factors 
for severe complications (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 
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cycles. If a repeat event of systolic BP ≥160 mm Hg or diastolic BP ≥100 mm Hg occurs, the 
participant must resume 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 drug and institute antihypertensive therapy for participants not already 
receiving this.
2. For those participants already on antihypertensive medication, the dose of the current 
agent may be increased, if appropriate, or 1 or more agents of a different class of 
antihypertensive should be added. Study treatment can be continued without dose 
modification.
3. If systolic BP ≥160 mm Hg or diastolic BP ≥100 mm Hg persists despite maximal 
antihypertensive therapy, then lenvatinib administration should be interrupted and 
restarted at 1 dose level reduction only when systolic BP ≤150 mm Hg and diastolic BP 
≤95 mm Hg and the participant has been on a stable dose of antihypertensive medication 
for at least 48 hours. 
•
If systolic BP ≥160 mm Hg or diastolic BP ≥100 mm Hg recurs on the first dose 
reduction despite optimal management of hypertension with antihypertensive 
medications (either by dose increase or the addition of a different class of 
antihypertensive), then lenvatinib administration should be interrupted and restarted 
at an additional dose reduction only when systolic BP ≤150 mm Hg and diastolic BP 
≤95 mm Hg and the participant has been on a stable dose of antihypertensive 
medication for at least 48 hours. 
•
If systolic BP ≥160 mm Hg or diastolic BP ≥100 mm Hg recurs on the second dose 
reduction despite optimal management of hypertension with antihypertensive 
medications (either by dose increase or the addition of a different class of 
antihypertensive), then lenvatinib administration should be interrupted and restarted 
at a third dose reduction only when systolic BP ≤150 mm Hg and diastolic BP ≤95 
mm Hg and the participant has been on a stable dose of antihypertensive medication 
for at least 48 hours.
•
Additional dose reduction should be discussed with the Sponsor.
The following guidelines should be followed for the management of Grade 4 hypertension 
(life-threatening consequences):
1. Institute appropriate medical management
2. Discontinue study intervention
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6.6.3.5
Management of Proteinuria
Regular assessment of proteinuria should be conducted as detailed in the SoA (Section 1.3). 
Guidelines for assessment and management of proteinuria are as follows:
Detection and Confirmation
1. Perform urine dipstick testing or urinalysis per the SoA (Section 1.3). Urine dipstick 
testing is the preferred method for testing for urinary protein, however, urinalysis may be 
used if the use of urine dipstick is not feasible.
2. A 24-hour urine collection initiated as soon as possible and at least within 72 hours (or an 
immediate spot UPCR test) is required in the following situations: 

The first (initial) occurrence of ≥2+ (≥100 mg/dL) proteinuria on urine dipstick (or 
urinalysis) while the participant is receiving lenvatinib.

A subsequent increase in severity of urine dipstick or urinalysis proteinuria occurring 
on the same lenvatinib dose level.
-
When there has been a lenvatinib dose reduction and at the new dose level the 
urine protein dipstick result is ≥2+ (≥100 mg/dL). A 24-hour urine collection 
(initiated as soon as possible and at least within 24 hours) to verify the grade of 
proteinuria is required when UPCR is ≥2.4.
Grading of Proteinuria
Grading according to NCI CTCAE v5.0 will be based on the 24-hour urinary protein result if 
one has been obtained. If the participant has a 4+ proteinuria by dipstick (≥1000 mg/dL by 
urinalysis), a 24-hour urinary protein result is required to confirm Grade 3 proteinuria. 
Management of lenvatinib administration will be based on the grade of proteinuria according 
to Table 8.
Monitoring 
•
Urine dipstick testing or urinalysis for participants with proteinuria ≥2+ (≥100 
mg/dL) should be performed Q2W (or more frequently as clinically indicated) until 
the results have been 1+ (30 mg/dL) or negative for 6 weeks.
•
Proteinuria monitoring can be performed at the local laboratory or investigator site 
but must be managed by the site physician.
•
In the event of nephrotic syndrome, lenvatinib must be discontinued.
•
If proteinuria does not resolve, a nephrology consultation is recommended.
6.6.3.6
Management of Diarrhea
An antidiarrheal agent should be recommended to the participant at the start of study 
treatment and participants should be instructed and educated to initiate antidiarrheal 
treatment at the first onset of soft bowel movements. The choice of antidiarrheal agent should 
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be individualized to the participant’s clinical circumstances and follow standard medical 
practice. If signs/symptoms of diarrhea persist despite optimal medical management, 
instructions contained in Table 8 should be followed. 
6.6.3.7
Management of Hepatotoxicity
Liver function tests (ALT, AST, bilirubin levels) should be conducted as detailed in the SoA 
(Section 1.3) and as clinically indicated. If signs/symptoms indicating liver injury occur, 
instructions contained in Table 8 and Table 9 should be followed. Appropriate supportive 
care should be provided together with close monitoring. If hepatic failure (any grade per NCI 
CTCAE v5.0) occurs, lenvatinib must be discontinued. Hepatic failure is defined as per the 
CTCAE definition.
6.6.3.8
Management of Thromboembolic Events
Participants should be advised to pay attention to symptoms suggestive of venous 
thromboembolic events, which include acute onset of shortness of breath, dyspnea, chest 
pain, cough, hemoptysis, tachypnea, tachycardia, cyanosis, deep vein thrombosis signs 
including lower extremity swelling, and warmth to touch or tenderness. 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 8
should be followed. Appropriate supportive care should be provided together with close 
monitoring. If a participant experiences a Grade 3 or a life-threatening (Grade 4) 
thromboembolic reactions, including pulmonary embolism, lenvatinib must be discontinued. 
Arterial thromboembolic events (eg, new onset, worsening, or unstable angina, myocardial 
infarction, transient ischemic attack, and cerebrovascular accident) of any grade require 
lenvatinib discontinuation.
6.6.3.9
Management of 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 8 should be followed. 
6.6.3.10
Management of Hypocalcemia
Serum calcium should be monitored per the SoA (Section 1.3). Corrected serum calcium 
should be used to assess the grade of hypocalcemia per NCI CTCAE v5.0, using the 
following formula: 
Corrected calcium = ([4 – serum albumin in g/dL] × 0.8 + serum calcium)
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The formula is not applicable when serum albumin concentration is normal (˃4 g/dL); in 
such situations, the total (uncorrected) serum calcium should be used instead. 
Hypocalcemia should be treated per institutional guidelines (eg, using appropriate calcium, 
magnesium, and vitamin D supplementation) until resolution.
6.6.3.11
Management of Hemorrhage
Guidelines in Table 8 should be followed for the management of hemorrhage. Either resume 
at a reduced dose or discontinue lenvatinib depending on the severity and persistence of 
hemorrhage.
6.6.3.12
Management of Gastrointestinal Perforation or Fistula Formation
Participants with gastric cancer are at increased risk for GI perforation and fistula formation. 
Lenvatinib should be discontinued in any participants who develop GI perforation of any 
grade or Grade 4 fistula.
6.6.3.13
Management of Palmar-plantar Erythrodysesthesia Syndrome
PPES is common across TKI therapies, and the strategies used for managing PPES in 
participants receiving TKIs (lenvatinib) range from preventative measures to topical 
medication once it has developed [Lacouture, M. E., et al 2014] [Lacouture, M. E., et al
2008]. 
Participants should be educated about the visible signs of PPES to help with the early 
detection of symptoms [Lacouture, M. E., et al 2014]. During treatment, participants should 
be encouraged to reduce exposure of the hands and feet to hot water, avoid tight footwear, 
and limit damage caused by vigorous exercise. Prophylaxis may include pretreatment 
examination of the soles of the feet and palms and removal of any existing hyperkeratotic 
areas and calluses present, which can then be protected by cushioning and treated with 
moisturizing creams and keratolytic agents [Lacouture, M. E., et al 2008]. A suggested 
treatment algorithm for PPES is outlined in Figure 5.
As most participants develop PPES within the first 2 to 4 weeks of initiating TKI therapy, 
avoiding traumatic activity and having sufficient rest during this time may be important
[Lacouture, M. E., et al 2008]. PPES management can require dose reduction or interruption 
of lenvatinib treatment until the AE has resolved back to ≤Grade 1 severity [Lacouture, M. 
E., et al 2008]. It may also be appropriate to consult with a dermatologist and/or podiatrist for 
participants experiencing persistent Grade 2 or Grade 3 PPES.
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Figure 5
Treatment Algorithm for Palmar-Plantar Erythrodysesthesia
ADL=activities of daily living; CTCAE=Common Terminology Criteria for Adverse Events; GABA=gamma-aminobutyric 
acid; NSAIDs=nonsteroidal anti-inflammatory drugs.
Source: [Lacouture, M. E., et al 2014] [Lacouture, M. E., et al 2008]
6.6.3.14
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 
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lenvatinib if ONJ develops and restart based on clinical judgment of adequate resolution (see 
Section 6.6.3.15).
6.6.3.15
Other Allowed Dose Interruptions for Lenvatinib
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.
•
For participants who experience hand-foot syndrome that is related to both capecitabine 
and lenvatinib dosing, it is recommended that the capecitabine dose be reduced first, as 
described in Table 10.
6.6.4
Dose Modifications for Overlapping Toxicities
In this study, participants will be administered multiagent/multitargeted anticancer therapy. 
Although ample safety data are available for each of the components of recommended 
treatment regimens, the combination of all treatment medications is expected to have 
potential overlapping toxicities. As this study is open-label, participant safety will be actively 
monitored, as well as reviewed by an eDMC. A 21-day Safety Run-in including 
approximately 12 participants will evaluate safety as detailed in Section 4.1. Potential 
expected overlapping toxicities for participants on this study may include, but not limited to, 
hematologic, GI toxicity, cardiac toxicity, skin toxicity, and renal toxicity.
6.6.4.1
Lenvatinib and Pembrolizumab
Based on the known toxicity profiles of lenvatinib and pembrolizumab, 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 irAEs are risks for pembrolizumab treatment. However, 
certain AEs, such as diarrhea, hypothyroidism, and liver enzyme elevation, may be initially 
considered attributable to either study drug. Therefore, evaluation of attribution is important 
for determining the study drug most likely related to the AE, or an alternative etiology, and 
subsequently proper clinical management. The following aspects should be considered:
1. Timing of AE onset
•
Because lenvatinib dosed daily and continuously due to a relatively short half-life (28 
hours), and pembrolizumab is dosed Q6W due to a long half-life, lenvatinib can be 
interrupted to assess whether an AE improves/resolves with dechallenge (ie, 
interruption of treatment) based on the following 2 scenarios:
-
If an AE is identified during a treatment cycle (ie, between 2 pembrolizumab 
doses), only lenvatinib dose interruption is needed.
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-
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, Type 1 diabetes 
mellitus) and other supportive care should be taken promptly.
3. Participants receiving combination therapy (lenvatinib + pembrolizumab) must 
discontinue study intervention if any of the following occur:
a.
ALT or AST >5 X ULN for more than 2 weeks. Pembrolizumab will have already 
been permanently discontinued per Table 5, but lenvatinib may be administered at a 
reduced dose by the time this criterion is met and must be permanently discontinued 
immediately.
b.
ALT or AST >3 × ULN and (TBL >2 × ULN or INR >1.5). Although Table 5 advises 
pembrolizumab to be withheld (interrupted), Table 8 and Table 9 advises lenvatinib 
to have no dose modification or a reduction, if this criterion is met, both drugs must 
be permanently discontinued immediately.
6.6.4.2
Chemotherapy 
The investigator may also attribute each toxicity event to the chemotherapy administered 
(capecitabine, oxaliplatin, and/or 5 FU). Dose modification should be performed taking the 
following criteria into consideration.
•
Treatment for each new cycle may be delayed if the scheduled off-drug periods are not 
adequate to allow for recovery to the guideline for restarting each study treatment.  
•
If a dose reduction for toxicity occurs with any agent, the dose may not be re-escalated.  
•
Dose reduction of only one chemotherapy agent is appropriate if, in the opinion of the 
investigator, the toxicity is clearly related to one of the treatments. If, in the opinion of 
the investigator, the toxicity is related to a combination of 2 chemotherapy agents, the 
dose of both drugs may be reduced according to the recommended dose modifications. If 
the toxicity is considered related to the combination of 3 agents, chemotherapy may be 
considered to be reduced, interrupted or discontinued. Lenvatinib and/or pembrolizumab 
should be interrupted or discontinued according to the recommended dose modifications
(Section 6.6.2 and Section 6.6.3, respectively).
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•
If any adjustments to the chemotherapy dose modification guidelines are required per 
local guidelines, a Sponsor consultation is strongly recommended. 
If toxicity is not otherwise specified, investigators should refer to the label or local guidelines 
for oxaliplatin, 5-FU, and capecitabine for dose adjustments.
CCI
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6.6.5
Chemotherapy Dose Modification
Dose delays and treatment restarts will be made at the discretion of the site investigator 
according to institutional guidelines or local standard practice. If any adjustments to the 
chemotherapy dose modification guidelines are required per local guidelines, a Sponsor 
consultation is strongly recommended. If a dose reduction for toxicity occurs with any agent, 
the dose may not be re-escalated.
In participants with unrecognized DPD deficiency, acute, life-threatening toxicity may occur 
when participants are treated with fluoropyrimidine. We recommend DPD testing as 
appropriate per local guidelines. Participants who require dose modification on Cycle 1 are 
not eligible for the study.
6.6.5.1
CAPOX (Capecitabine/Oxaliplatin)
CAPOX treatment will comprise the following:
•
Capecitabine (1000 mg/m2, bid for 14 days, Q3W) 
•
Oxaliplatin (130 mg/m2, IV infusion, Q3W) 
For capecitabine, older participants are more susceptible to the effects of fluoropyrimidine-
based therapies with increased Grade 3/4 adverse effects, especially when used in 
combination. For oxaliplatin, participants ≥65 years have a higher incidence of GI toxicity, 
myelosuppression, syncope and fatigue. No dose adjustments are needed but caution should 
be exercised.
Dose modifications for CAPOX are outlined in Table 10 and Table 11.
Table 10
Recommended Dose Modification (Reduction) Guidelines for CAPOX 
Drug-Related Adverse Events
Dose Level 0
Dose Level 1
Dose Level 2
Dose Level 3
Dose Level 4
Oxaliplatin (mg/m2)
130
100
75
50
Discontinue
Capecitabine (mg/m2 BID)
1000
750
500
Discontinue
Discontinue
BID=twice daily
CCI
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Table 11
Recommended Dose Modification Guidelines for CAPOX Drug-Related 
Adverse Events
Category
Toxicity
Oxaliplatin
Capecitabine
Hematologic
Neutropeniaa
3
b
Hold until neutrophil count
resolves to ≥1500/mm
3
No reduction (*consider G-
CSF)
Hold until neutrophil count
resolves to >1500/mm3
No dose reduction (consider
G-CSF)
4
b
Hold until neutrophil count
resolves to ≥1500/mm
3
Reduce by 1 DL (*recommend
G-CSF)
Hold until neutrophil count
resolves to >1500/mm3
Reduce by 1 DL (consider
G-CSF)
Febrile
neutropeniaa
3
b
Hold until neutrophil count 
resolves to ≥1,500/mm3

First occurrence: Consider 
G-CSF

Second occurrence: Dose 
reduce by 1 DL 
*recommend G-CSF

Further occurrences: Dose 
reduce by 2 DL 
*recommend G-CSF
Hold until toxicity resolves to
Grade 0-1
Reduce by 1 DL
4
b
Discontinue
Discontinue
Thrombocytopenia 
1-2
Hold until platelet count 
resolves to >75,000/mm3. For 
first occurrence, no change in 
dose. For further occurrence 
dose reduce by 1 DL each 
occurrence.
Hold until platelet count resolves 
to >75,000/mm3. First occurrence 
no change in capecitabine dose. 
For further occurrences dose 
reduce by 1 DL for each 
occurrence.
3-4
b
Hold until platelet count 
resolves to >75,000/mm3
Reduce by 1 DL
Hold until platelet count resolves 
to >75,000/mm3.
Reduce by 1 DL
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Category
Toxicity
Oxaliplatin
Capecitabine
Neurotoxicity
Persistent paresthesia 
Reduce 1DL
No holding dose. No change in 
dose
Persistent Paresthesia with 
pain
Reduce 2DL or discontinue
No holding dose. No change in 
dose
Paresthesia with 
functional impairment 
Reduce 2DL if lasting 7-14 
days or discontinue if 
persistent
No holding dose. No change in 
dose
Hepatic 
impairment
Bilirubin 1 to 2 x ULN
No change
Caution
Bilirubin >2 to 4 x ULN 
AND/OR AST/ALT 2 to 
4 x ULN
No change
Caution
Bilirubin >4 x ULN 
AND/OR AST/ALT 4 x 
ULN
No data available
OMIT if bilirubin >4 x ULN
Bilirubin ANY OR
AST/ALT >4 x ULN
No data available
OMIT if bilirubin >4 x ULN)
Renal 
impairment
Creatinine clearance: 50 to 
80 mL/min
No change
No dose reduction with close 
monitoring
Creatinine clearance: 30 to 
<50 mL/min
Caution, consider dose 
reduction
Reduce by 1 DL (use with 
caution)
Creatinine clearance: <30 
mL/min
Discontinue
Discontinue
Other
Diarrhea, 
mucositis, or 
hand-foot 
syndrome 
2-3
Strongly consider discontinuing 
for diarrhea associated with 
severe infectious 
colitis/typhlitis. Reduce by 1DL 
(or consider discontinue) for 
diarrhea associated with febrile 
neutropenia or sepsis.
Hold until toxicity resolves to
Grade 0-1
Reduce by 1 DL
4
Hold until resolves to Grade 1 
or 2
Reduce by I DL
Discontinue
Other toxicitiesc
3-4b
First occurrence: Reduce by 1 
DL
Second occurrence: Reduce by 
2 DL
Hold until toxicity resolves to
Grade 0-1
Reduce by 1 DL
Laboratory
adverse events
3-4b
Hold until toxicity resolves to 
Grade 0-1
Reduce by 1 DL
Hold until toxicity resolves to
Grade 0-1
Reduce by 1 DL
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Category
Toxicity
Oxaliplatin
Capecitabine
DL=dose level; 5-FU=5-fluorouracil; G-CSF=granulocyte colony-stimulating factor; N/A=not applicable.
a
May consider restarting when neutrophil count resolves to ≥1000/mm3 per local guidance. 
b
Permanent discontinuation should be considered for any severe or life-threatening event and/or if toxicity does not 
resolve within 4-5 weeks of last administration. 
c
Participants with intolerable or persistent Grade 2 drug-related adverse event may hold at physician discretion. 
Permanently discontinue from agent for persistent Grade 2 adverse reactions for which treatment has been held and 
did not recover to Grades 0-1 within 12 weeks of the last dose.
*To avoid treatment delays, secondary prophylaxis with G-CSF will be required for all subsequent cycles if one of the 
following criteria is applicable: 
occurrence of febrile neutropenia or infection in neutropenia at any time or; 
occurrence of NCI-CTC Grade 4 neutropenia or; delay of one therapy cycle because of leukopenia or neutropenia by 
more than 3 days.
6.6.5.2
mFOLFOX6
mFOLFOX6 treatment will comprise the following:
•
Oxaliplatin
(85 mg/m2, IV infusion, Q2W)
•
5-FU (400 mg/m2, bolus IV infusion followed by 2400 mg/m2 continuous IV 
infusion, Q2W)
•
Leucovorin (400 mg/m2, IV infusion, Q2W) or levoleucovorin (200 mg/m2, IV 
infusion, Q2W)
Refer to Table 12 for dose modification criteria for mFOLFOX6.
Table 12
Recommended Dose Modification Guidelines for mFOLFOX6 Drug-related 
Adverse Events
Category
Toxicity Grade
Oxaliplatina
5-FU
Hematological
Neutropeniaa 
3-4
Hold until neutrophil count 
resolves to ≥1,500/mm3
Reduction from 85 mg/m2 to 
75 mg/m2
Hold until neutrophil 
count resolves to 
>1500/mm3
Reduce by 20% (consider 
G-CSF)
Febrile 
neutropeniaa
3-4
Hold until neutrophil count 
resolves to ≥1,500/mm3
Reduction from 85 mg/m2 to 
75 mg/m2
Hold until neutrophil 
count resolves to 
>1500mm3
Reduce by 20% (consider 
G-CSF)
Thrombocytopeniab
3-4
Hold until platelet count 
resolves to > 75 000/mm3. 
Reduction from 85 mg/m2 to 
75 mg/m2
Hold until platelet count 
resolves to >75 000/mm3.
Reduce by 20%
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Category
Toxicity Grade
Oxaliplatina
5-FU
Neurotoxicity
Persistentc Grade 1 or 2 
neurotoxicity
Reduction from 85 mg/m2 to 
75 mg/m2
No change
Transientc Grade 3 
neurotoxicity
Reduction from 85 mg/m2 to 
75 mg/m2
No change
Persistentc ≥ Grade 3 
neurotoxicity OR
any Grade 4 neurotoxicity
Discontinue
No change
PRES/RPLS
Discontinue permanently
Hepatic 
Impairment
Bilirubin 1 to 2 x ULN
No change
Caution
Bilirubin >2 to 4 x ULN 
AND/OR 
AST/ALT 2.5 to 5 x ULN
No change
Caution
Bilirubin >4 x ULN 
AND/OR
AST/ALT 5 x ULN
No data available
OMIT if bilirubin >4 x 
ULN
(Leucovorin to be omitted 
if 5-FU omitted)
Bilirubin ANY OR
AST/ALT >5 x ULN
No data available
OMIT if bilirubin >4 x 
ULN
(Leucovorin to be omitted 
if 5-FU omitted)
Renal Impairment
Creatinine clearance: 50 to 
80 mL/min
No change
No change
Creatinine clearance: 30 to 
<50 mL/min
Caution, consider dose 
reduction
No change; monitor
Creatinine clearance: 
<30 mL/min
Discontinue
Consider dose reduction
Other
≥ Grade 3 GI toxicity (after 
prophylaxis) 
Hold until resolves to Grade 
0-1
Reduction from 85 mg/m2 to 
75 mg/m2 c
Hold until resolves to 
Grade 0-1
Reduce by 20%c
Sepsis/septic shock
Discontinue
Discontinue
Hemolytic uremic syndrome 
OR
any signs of 
microangiopathic hemolytic 
anemia
Discontinue permanently
Other ≥ Grade 3 related 
organ toxicityd
Reduction from 85 mg/m2 to 
75 mg/m2
Reduce by 20%
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Category
Toxicity Grade
Oxaliplatina
5-FU
5-FU=fluorouracil; ALT=alanine aminotransferase; AST=aspartate aminotransferase; RPLS=reversible posterior 
leukoencephalopathy syndrome; ULN=upper limit of normal
Further dose reduction may be considered on Sponsor’s approval.
Do not retreat until the ANC ≥1.5 x 109/L and the platelets ≥75-100 x 109/L, GI and neurotoxicities have resolved and 
other nonhematologic toxicities ≤ Grade 1.
a May consider restarting when neutrophil count resolves to ≥1000/mm3 per local guidance.
b Discontinue if sepsis/septic shock.
c Transient ≥7days-<1 cycle; persistent ≥1 cycle.
d For skin toxicity, reduce 5-FU dose only.
For participants in the lenvatinib plus pembrolizumab plus chemotherapy arm: if 
chemotherapy (CAPOX/mFOLFOX6) is interrupted due to adverse events, the participants 
may extend the Induction Phase for a maximum of 6 weeks on approval by the Sponsor. The 
participant should not exceed 4 cycles of CAPOX treatment, or 6 cycles of mFOLFOX6 
treatment. 
6.6.6
Second Course 
Note: As of Amendment 8, Second Course will no longer be offered. Any participant 
currently receiving Second Course retreatment will be able to continue treatment as planned.
Imaging will be performed per local standard of care. Participants who either complete 18 
cycles of pembrolizumab or discontinue pembrolizumab will be discontinued from the study 
following the Safety Follow-up visit. AE, SAE, and other reportable safety events will be 
reported and followed as described under Section 8.4. All participants in Efficacy Follow-up 
prior to initiation of Amendment 8 will stop efficacy assessments and be discontinued from 
the study. All participants in Survival Follow-up are considered to have completed the study 
and should have a final survival contact; these participants will no longer be contacted for 
survival information. 
Participants who stop study intervention with SD or better and have radiographic disease 
progression verified by a BICR, may be eligible for up to an additional 9 cycles 
(approximately 1 year) of pembrolizumab treatment if they progress after stopping study 
intervention from the initial treatment phase. 
This retreatment is termed the Second Course. Participants must provide new documented 
informed consent using the most recent IRB-approved version of the main consent form prior 
to starting the Second Course. All participants who receive the Second Course must be given 
pembrolizumab. In addition, participants who did not discontinue lenvatinib in the First 
Course (due to lenvatinib-related AEs) may begin the Second Course with lenvatinib at the 
highest tolerable dose received during the Consolidation Phase, per investigator’s decision.
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The Second Course phase of this study is only available if the study remains open and the 
participant meets the following conditions:
Either
•
Stopped initial study intervention after attaining an investigator-determined 
confirmed CR based on RECIST 1.1, and
•
Was treated with at least 4 cycles of pembrolizumab before discontinuing treatment, 
and
•
Received at least 1 treatment with pembrolizumab beyond the date when the initial 
CR was declared
OR
•
Had SD, PR, or CR and stopped study intervention after completion of 18 
administrations (approximately 2 years) of study intervention for reasons other than 
disease progression or intolerability
AND
•
Experienced an investigator-determined radiographic disease progression by RECIST 
1.1 after stopping initial treatment, and
•
On unblinding at the time of centrally verified disease progression were found to have 
received 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.
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.
6.7
Intervention After the End of the Study
There is no study-specified intervention after the end of the study.
6.8
Clinical Supplies Disclosure
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.
6.9
Standard Policies
Not applicable.
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7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
Discontinuation of study intervention does not represent withdrawal from the study.
As certain data on clinical events beyond study intervention discontinuation may be 
important to the study, they must be collected through the participant’s last scheduled follow-
up, even if the participant has discontinued study intervention. Therefore, all participants 
who discontinue study intervention prior to completion of the protocol-specified treatment 
period/vaccination regimen will still continue to participate in the study as specified in 
Section 1.3 and Section 8.11.3 unless the participant has withdrawn from the study (Section 
7.2).
Participants may discontinue study intervention at any time for any reason or be discontinued 
from the study intervention at the discretion of the investigator should any untoward effect 
occur. In addition, a participant may be discontinued from study intervention by the 
investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or 
for administrative and/or other safety reasons. 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.
•
The participant has a medical condition or personal circumstance, which, in the opinion 
of the investigator and/or Sponsor, placed the participant at unnecessary risk from 
continued administration of study intervention.
•
The participant has a confirmed positive serum pregnancy test.
•
The participant has a positive urine drug screen at any time during the course of the 
study.
•
Confirmed radiographic disease progression outlined in Section 8.2.1.5. In some rare 
circumstances, the investigator may believe the participant could benefit from continuing 
on study treatment. In these cases, the participant must continue to show clinical stability 
as defined in Section 8.2.1.5, and the Sponsor should be consulted for approval. 
Considerations for evaluation of whether a participant may continue treatment after 
confirmed disease progression include:
•
Presence or absence of clinical symptoms or signs indicating clinically significant disease 
progression
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•
Decline in performance status
•
Lack of rapid disease progression or threat to vital organs or critical anatomic sites (eg, 
CNS metastasis, respiratory failure due to tumor compression, spinal cord compression) 
requiring urgent alternative medical intervention
•
Presence or absence of significant, unacceptable or irreversible toxicities related to study 
treatment
•
Any progression or recurrence of any malignancy, or any occurrence of another 
malignancy that requires active treatment
For participants who are discontinued from study intervention but continue to be monitored 
in the study, all visits and procedures, as outlined in the SoA, should be completed.
Discontinuation from study intervention is “permanent.” Once a participant is discontinued 
from study intervention, they shall not be allowed to restart study intervention.
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, are outlined in Section 8.1.9. The procedures to be performed should a participant 
repeatedly fail to return for scheduled visits and/or if the study site is unable to contact the 
participant are outlined in Section 7.3.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
•
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
•
The investigator or designee must make every effort to regain contact with the participant 
at each missed visit (eg, telephone calls and/or a certified letter to the participant’s last 
known mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
Note: A participant is not considered lost to follow-up until the last scheduled visit for the 
individual participant. The missing data for the participant will be managed via the 
prespecified statistical data handling and analysis guidelines.
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8
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and their timing are summarized in the SoA.
•
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
•
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified (by education, training, and experience) staff. Delegation of 
study-site personnel responsibilities will be documented in the Investigator Trial File 
Binder (or equivalent).
•
All study-related medical and 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 used for screening or baseline purposes 
provided the procedures meet the protocol-specified criteria and were performed within 
the time frame defined in the SoA.
•
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, hepatitis C), and thus local regulations 
may require that additional informed consent be obtained from the participant. In these 
cases, such evaluations/testing will be performed in accordance with those regulations.
Information regarding the amount of blood collected from each participant over the duration 
of the study can be found in the Laboratory Manual.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
8.1
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented informed consent from each potential participant (or their legally 
acceptable representative) prior to participating in this clinical study or FBR. If there are 
changes to the participant’s status during the study (eg, health or age of majority 
requirements), the investigator or medically qualified designee must ensure the appropriate 
documented informed consent is in place.
8.1.1.1
General Informed Consent
Informed consent given by the participant or their legally acceptable representative must be 
documented on a consent form. The form must include the study protocol number, study 
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protocol title, dated signature, and agreement of the participant (or their legally acceptable 
representative) and of the person conducting the consent discussion.
A copy of the signed and dated informed consent form should be given to the participant (or 
their legally acceptable representative) before participation in the study.
The initial ICF, any subsequent revised ICF, and any written information provided to the 
participant must receive the IRB/IEC’s approval/favorable opinion in advance of use. The 
participant or their legally acceptable representative should be informed in a timely manner if 
new information becomes available that may be relevant to the participant’s willingness to 
continue participation in the study. The communication of this information will be provided 
and documented via a revised consent form or addendum to the original consent form that 
captures the participant’s or the participant’s legally acceptable representative’s dated 
signature.
If the investigator recommends continuation of study intervention beyond disease 
progression, the participant or their legally acceptable representative will be asked to provide 
documented informed consent.
Specifics about the study and the study population are to be included in the study informed 
consent form.
Informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, and 
Sponsor requirements.
Prior to entering Second Course, participant must provide documented informed consent 
using the most recent IRB-approved version of the main consent form.
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator, who is a qualified 
physician, to ensure that the participant qualifies for the study.
8.1.3
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study-site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant provides documented informed consent. At the time of intervention 
randomization, site personnel will add the treatment/randomization number to the participant 
identification card.
The participant ID card also contains contact information for the emergency unblinding call 
center so that a health care provider can obtain information about study intervention in 
emergency situations where the investigator is not available.
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8.1.4
Medical History
8.1.4.1
General Medical History
A medical history will be obtained by the investigator or qualified designee.
Medical history will include all active conditions, drug allergies, significant medical 
procedures, smoking status, and any condition diagnosed within the previous 10 years that is 
considered to be clinically important by the investigator. Any cancer, other than the cancer 
under study, will be recorded as medical history, even if diagnosed greater than 10 years 
before enrollment. Details regarding the cancer under study will be recorded separately and 
not listed as medical history.
8.1.4.2
Oncologic Disease Details
The investigator or qualified designee will obtain historic and current details of the 
participant’s cancer under study. This information will include, but is not limited to, date of 
diagnosis, stage, histology, location(s) of primary lesions, and location(s) of metastases, if 
applicable.
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review before medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant 
within 30 days before the first dose of study intervention.
8.1.5.2
Prior Oncologic Treatment
The investigator or qualified designee will review and record all treatments for the cancer 
under study, including systemic and local treatment, vaccinations, radiation, and surgeries. 
Additional information collected on these treatments will include, but is not limited to, 
reason for discontinuation, best response, and date of progression after each treatment as 
applicable.
8.1.5.3
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study through the Safety Follow-up Visit. Concomitant medications will be 
recorded for 30 days after the last dose of study intervention (or 90 days if used to treat an 
SAE). In addition, medications taken 30 days before the first dose of the Second Course 
Treatment, during the Second Course Treatment Phase, and for 30 days after the last dose of 
the Second Course Treatment (or 90 days if used to treat an SAE) will be recorded.
Any new anticancer therapy started after the participant’s discontinuation from the treatment 
period will be recorded separately. Additional information collected on this treatment will 
include, but is not limited to, best response and date of progression.
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8.1.6
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur before allocation/randomization. Each 
participant will be assigned only 1 screening number. Screening numbers must not be reused 
for different participants.
Any participant who is screened multiple times will retain the original screening number 
assigned at the initial screening visit. Specific details on the screening/rescreening visit 
requirements are provided in Section 8.11.1.
8.1.7
Assignment of Treatment/Randomization Number
In Part 2, 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 reassigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
8.1.8
Study Intervention Administration
Study intervention(s) will be administered by the investigator and/or study staff according to 
the specifications within the Pharmacy Manual. Administration of pembrolizumab, lenvatinib 
and CAPOX/mFOLFOX6 are detailed in Sections 8.1.8.1 and 8.1.8.2.
Study intervention should begin within 3 days of allocation.
8.1.8.1
Timing of Dose Administration
Study treatment in all arms will begin on Day 1 of each 6-week dosing cycle after all 
procedures/assessments have been completed as detailed in the SoA (Section 1.3). Study 
treatments may be administered up to 3 days before or after the scheduled Day 1 of each 
cycle due to administrative reasons.
All study treatments may be administered on an outpatient basis.
Treatments will be administered in the order presented below:
•
Pembrolizumab infusion will be administered first, followed by lenvatinib, then 
oxaliplatin infusion, and then other treatment regimens will be administered.
Treatment may continue until confirmed disease progression, clinical progression, 
unacceptable AE(s), intercurrent illness that prevents further administration of treatment, 
investigator’s decision to withdraw the participant, participant withdraws consent, pregnancy 
of the participant, noncompliance with study treatment or procedure requirements, participant 
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receives 18 administrations (approximately 2 years) of study medication, achievement of a 
CR, or administrative reasons requiring cessation of treatment.
Note: Dosing interruptions are permitted in the case of medical/surgical events or logistical 
reasons (ie, elective surgery, unrelated medical events, participant vacation, and holidays) not 
related to study therapy. Participants should be placed back on study therapy as soon as 
clinically appropriate per the investigator, and not exceeding 6 weeks from the interrupted 
dosing. Day 1 of subsequent cycles should be adjusted accordingly to adhere to Q6W dosing 
schedule. Discuss with the Sponsor if participants cannot restart study medication within 6 
weeks. The reason for interruption should be documented in the participant’s study record.
8.1.8.1.1
Pembrolizumab
Pembrolizumab will be administered by IV infusion over 30 minutes as the first study 
intervention on Day 1 of each 42-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 0 minutes: -5/+10 minutes). After Cycle 1 Day 1, pembrolizumab may be 
administered up to 3 days before or after the scheduled Day 1 of each cycle for 
administrative reasons.
Details on preparation and administration of pembrolizumab are provided in the Pharmacy 
Manual. Concomitant chemotherapeutic/immunotherapeutic agents will be prepared and 
administered as per the approved product label(s). 
8.1.8.1.2
Lenvatinib
Lenvatinib 8 mg (2 4 mg capsules) once daily will be taken orally with water (with or 
without food) at approximately the same time each day in each 42-day cycle. However, on 
Day 1 of each pembrolizumab cycle, lenvatinib will be administered in the clinic 0 to 4 hours 
after completion of pembrolizumab administration. 
After the last cycle of the Induction Phase, lenvatinib will be maintained at the current dose 
(usually 8 mg daily if there are no dose reductions) until the start of the Consolidation Phase. 
The Consolidation Phase, and the corresponding lenvatinib dose escalation to 20 mg, will 
begin 3 weeks after the start of the last cycle of induction for CAPOX and 3 weeks after 
C2D29 of mFOLFOX6, when the dose will be escalated to 20 mg in participants who 
tolerated 8 mg. Refer to Section 6.6.3 for detailed guidance on dose modification and 
escalation. 
8.1.8.1.3
CAPOX 
Oxaliplatin 130 mg/m2 IV infusion will be administered on Day 1 of Weeks 1 and 4 of each 
Q6W cycle.
Capecitabine 1000 mg/m2 will be administered orally BID on Days 1-14, 22-35 of each Q6W 
cycle.
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Note: Dosing interruptions are permitted in the case of medical/surgical events or logistical 
reasons (ie, elective surgery, unrelated medical events, participant vacation, and holidays) not 
related to study therapy. Participants should be placed back on study therapy as soon as 
clinically appropriate per the investigator, and not exceeding 3 weeks from the interrupted 
dosing. Day 1 of subsequent cycles should be adjusted accordingly to adhere to Q6W dosing 
schedule. Discuss with the Sponsor if participants cannot restart study medication within 3 
weeks. The reason for interruption should be documented in the participant’s study record.
In Arm 1, CAPOX will be administered for 4 x Q3W cycles during induction and will not be 
administered during consolidation. 
In Arm 2, duration of oxaliplatin may be capped at 6 to 8 x Q3W cycles as per local country 
guidelines; however, treatment with capecitabine may continue per protocol.
8.1.8.1.4
mFOLFOX6 
Oxaliplatin 85 mg/m2 will be administered by IV infusion on Day 1 and Week 1, 3 and 5 of 
each Q6W cycle.
Leucovorin 400 mg/m2 or levoleucovorin 200 mg/m2 will be administered by IV infusion on 
Day 1, and Week 1, 3 and 5 of each Q6W cycle.
5-FU 400 mg/m2 bolus IV infusion followed by 2400 mg/m2 continuous IV infusion, will be 
administered on Day 1, and Week 1, 3, 5, of each Q2W cycle.
In Arm 1, mFOLFOX6 will be administered for 6 x Q2W cycles during induction and will 
not be administered during consolidation. 
In Arm 2, the duration of mFOLFOX6 may be capped at 9 to12 x Q2W cycles per local 
country guidance. 
8.1.8.2
Treatment Compliance
8.1.8.2.1
Lenvatinib
During onsite visits, lenvatinib will be administered by the investigator and/or study staff 
according to the specifications within the Pharmacy Manual. The administration, the dose, 
the time of administration, as well as any immediate reactions at the time of intake will be 
documented in the eCRF.
On all other days, lenvatinib will be taken at home. When a participant attends a study visit, 
he or she will bring any unused tablets.
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.
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8.1.8.2.2
Pembrolizumab/CAPOX/mFOLFOX6
Pembrolizumab will be administered by the investigator and/or study staff according to the 
specifications within the Pharmacy Manual. CAPOX and mFOLFOX6 will be administered 
as per local guidelines. The total volume of study intervention infused will be compared with 
the total volume prepared to determine compliance with each dose administered.
8.1.9
Discontinuation and Withdrawal
Participants who discontinue study intervention before completion of the treatment period
should be encouraged to continue to be followed for all remaining study visits as outlined in 
the SoA and Section 8.11.3.
Participants who withdraw from the study should be encouraged to complete all applicable 
activities scheduled for the end of treatment visit at the time of withdrawal. Any AEs that are 
present at the time of withdrawal should be followed in accordance with the safety 
requirements outlined in Section 8.4.
8.1.10
Participant Blinding/Unblinding
This is an open-label study; there is no blinding for this study.
8.1.11
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained are reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
8.2
Efficacy/Immunogenicity Assessments
8.2.1
Tumor Imaging and Assessment of Disease
Throughout this section, the term ‘scan’ refers to any medical imaging data used to assess 
tumor burden and may include cross-sectional imaging (such as CT or MRI), medical 
photography, or other methods as specified in this protocol.
The process for scan collection and transmission to the iCRO can be found in the Site 
Imaging Manual. Tumor scans are strongly preferred to be acquired by CT. For the chest, 
abdomen and pelvis, contrast enhanced MRI may be used when CT with iodinated contrast is 
contraindicated, or when mandated by local practice. MRI is the strongly preferred modality 
for imaging the brain. The same scan 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 scans. Note: For the purposes 
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of assessing tumor scans, the term “investigator” refers to the local investigator at the site 
and/or the radiological reviewer located at the site or at an offsite facility.
Participant eligibility will be determined using investigator assessment. All scheduled scans 
for all participants from the sites will be submitted to the iCRO. In addition, scans (including 
via other modalities) that are obtained at an unscheduled time point to determine disease 
progression (regardless of whether disease progression was verified or not), as well as scans 
obtained for other reasons, but which demonstrates radiologic progression, should also be 
submitted to the iCRO.
When the investigator identifies disease progression, the iCRO will verify this progression 
and email the results to the study site and Sponsor (see Section 8.2.1.5 and Figure 6). In 
clinically stable participants, scans are to continue until disease progression has been verified 
by BICR. If initial investigator-assessed progression was not verified by BICR, each 
subsequent scan must be submitted to the iCRO. Once progression is verified by BICR, 
subsequent scans (if acquired) should not be submitted to the iCRO. 
8.2.1.1
Initial Tumor Scans
Initial tumor scans at Screening must be performed within 28 days prior to the date of 
randomization. Any scan obtained after Cycle 1 Day 1 of treatment cannot be included in the 
screening assessment. The site study team must review screening scans to confirm the 
participant has measurable disease per RECIST 1.1. The screening scans must be submitted 
to the iCRO for retrospective review.
Tumor scans performed as part of routine clinical management is acceptable for use as 
screening tumor scans if they are of diagnostic quality and performed within 28 days prior to 
the date of randomization and can be assessed by the iCRO.
8.2.1.2
Tumor Scans During the Study
The first on-study imaging assessment should be performed at 42 days (+7 days) from the 
day of randomization. Subsequent tumor scans should be performed every 42 days (±7 days) 
or more frequently if clinically indicated. Scan timing follows calendar days from 
randomization and should not be adjusted for delays in cycle starts. Scans are to be 
performed until disease progression is identified by the investigator and verified by the 
BICR, the start of new anticancer treatment, withdrawal of consent, or death.
Note: Imaging following approval of Amendment 8 is not required. For participants active on 
treatment, imaging should be performed per local standard of care. Scans performed per local 
standard of care are not required to be provided to the iCRO.
Objective response should be confirmed by a repeat scan performed at least 4 weeks after the 
first indication of a response is observed. Participants will then return to regular scan 
schedule, starting with the next scheduled imaging time point. Participants who receive 
additional scans for confirmation do not need to undergo the next scheduled scan if it is 
fewer than 4 weeks later; scans may resume at the subsequent scheduled imaging time point. 
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On-study bone scans should be performed if clinically indicated or to confirm CR (if other 
lesions indicate CR and bone lesions existed at baseline).
8.2.1.3
End-of-treatment and Follow-up Tumor Scans
If participants discontinue study treatment, tumor scans should be performed at the time of 
treatment discontinuation (±4-week window) unless previous scans were obtained within 
4 weeks of discontinuation. If participants discontinue study intervention due to documented 
disease progression, this is the final required tumor scan. Note: Following approval of 
Amendment 8, follow-up tumor scans are not required. Scans performed per local standard of 
care are not required to be provided to the iCRO.
For participants who discontinue study treatment without documented disease progression, 
every effort should be made to continue monitoring disease status by tumor scan using the 
same scan schedule used while on treatment (see Section 8.2.1.2) until the start of a new 
anticancer treatment, disease progression, pregnancy, death, withdrawal of consent, or the 
end of the study, whichever occurs first.
8.2.1.4
Second Course (Retreatment) Tumor Scans
Note: Imaging following approval of Amendment 8 is not required. For participants active on 
treatment, imaging should be performed per local standard of care. Scans performed per local 
standard of care are not required to be provided to the iCRO.
If disease progression has been verified by BICR for the First Course, the Second Course 
may be initiated. The disease progression scan may also be used as the Second Course 
baseline scan if performed within 4 weeks prior to dosing and meets the scan standards. 
The first scan should be performed within 28 days prior to restarting study intervention. 
Subsequent tumor scans are to be performed every 12 weeks (84 days ± 7 days) after the 
restart of study intervention or more frequently if clinically indicated. 
Scans are to be performed until disease progression, the start of a new anticancer treatment, 
withdrawal of consent, death, completion of Second Course, or notification by the Sponsor, 
whichever occurs first.
If participants discontinue study intervention, tumor scans are to be performed at 
discontinuation (± 4-week window) unless previous scans were obtained within 4 weeks of 
discontinuation. If participants discontinue study intervention due to documented disease 
progression, this is the final required tumor scan.
If participants discontinue study intervention without documented disease progression, every 
effort is to be made to monitor disease status by acquiring tumor scans every 12 weeks 
(±7 days) until the start of a new anticancer treatment, disease progression, death, or the end 
of the study, whichever occurs first.
Response assessments and progressive disease are determined by investigator assessment.
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The only Second Course scan to be provided to the iCRO is the baseline scan if it is the final 
scan for the Initial Treatment or First Course.
Refer to Section 6.6.6 for further details on Second Course (Retreatment).
8.2.1.5
RECIST 1.1 Assessment of Disease
Note: Imaging following approval of Amendment 8 is not required. For participants active on 
treatment, imaging should be performed per local standard of care. Scans performed per local 
standard of care are not required to be provided to the iCRO.
RECIST 1.1 will be used by BICR as the primary measure for assessment of tumor response, 
date of disease progression, and as a basis for all protocol guidelines related to disease status 
(eg, discontinuation of study treatment). Although RECIST 1.1 references a maximum of 
5 target lesions in total and 2 per organ, this protocol allows a maximum of 10 target lesions 
in total and 5 per organ, if clinically relevant to enable a broader sampling of tumor burden.  
On investigator-assessed disease progression, the indicative scans are to be submitted 
immediately to 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 
-
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
Before stopping study intervention or imaging or starting new anticancer therapy in a 
participant who is clinically stable, communication with the Sponsor is required. 
If disease progression is verified, the process continues as follows:
1. Investigator judgment will determine action
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2. If the participant is clinically stable and study intervention is to continue, 
communication with the Sponsor is required and a documented reconsent addendum 
must be provided 
•
Note: the documented reconsent addendum may be provided any time after 
investigator-assessed progression is identified but must be provided prior to 
starting study intervention after verification of disease progression is provided by 
the iCRO.
•
Obtain scans locally per original protocol schedule
•
Do not send scans to iCRO
Figure 6 illustrates the decision process involving verification of disease progression for 
participants. 
For the purpose of this decision process, lack of clinical stability is defined as:
1. Unacceptable toxicity
2. Clinical signs or symptoms indicating clinically significant disease progression
3. Decline in performance status
4. 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 6
Decision-making Process When Progression Observed by Investigator
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided. Information on the amount of blood/tissue to be drawn/collected over the course of 
the study (from prestudy to poststudy visits), can be found in the Laboratory Manual.
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Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
A complete physical examination including oral examination will be conducted by an 
investigator or medically qualified designee (consistent with local requirements) as per 
institutional standard during the Screening period and as indicated in the SoA (Section 1.3). 
Height and weight will also be measured and recorded. Clinically significant abnormal 
findings at Screening should be recorded as medical history. After the first dose of study 
intervention, new clinically significant abnormal findings should be recorded as AEs. 
For cycles that do not require a full physical examination per the SoA (Section 1.3), the 
investigator or qualified designee will perform a directed physical examination including oral 
examination as clinically indicated.
During the treatment period, physical examinations should be performed prior to dosing. 
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
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]), weight (kg), and 
height (cm) will be obtained at the visits designated in the SoA (Section 1.3) by a validated 
method.
•
BP and heart rate will be measured after the participant has been resting for 5 minutes. 
All BP measurements should be performed on the same arm, preferably by the same 
person.
•
Only 1 BP measurement is needed for participants with systolic BP <140 mm Hg and 
diastolic BP <90 mm Hg. If the participant’s first BP measurement of the current 
assessment is elevated (ie, systolic BP ≥140 mm Hg or diastolic BP ≥90 mm Hg), the 
BP measurement should be repeated at least 5 minutes later. One BP assessment is 
defined as the mean value of 2 measurements at least 5 minutes apart. If the BP 
assessment (ie, the mean of the 2 BP measurements obtained at least 5 minutes apart) 
shows an elevated BP (systolic BP ≥140 mm Hg or diastolic BP ≥90 mm Hg), a 
confirmatory assessment should be obtained at least 30 minutes later by performing 2 
measurements (at least 5 minutes apart) to yield a mean value.
•
Between clinic visits, and in particular for phone or virtual visits at C1D8 and C3D8, 
BP may be measured. If the participant does not return to the study site for this BP 
measurement, BP may be measured, for example, at home or at a local pharmacy, and 
the results will be reviewed with the investigator or designee. The investigator/site 
may provide a diary as a tool to aid the participant in collecting BP evaluations 
between clinic visits. The Sponsor will not provide diaries to the site. If BP result 
raises concerns, the investigator may require additional follow-up, including an onsite 
BP retest, or other clinically appropriate intervention(s).
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8.3.3
Electrocardiograms
ECGs will be obtained as designated in the SoA (Section 1.3). Complete, standardized, 12-
lead ECG recordings that permit all 12 leads to be displayed on a single page with an 
accompanying lead II rhythm strip below the customary 3 × 4 lead format are to be used. In 
addition to a rhythm strip, a minimum of 3 full complexes should be recorded from each lead 
simultaneously. Participants must be in the recumbent position for a period of 5 minutes prior 
to the ECG. The Fridericia correction method for calculating QTc will be used.
Note: A 6-lead ECG is allowed per institutional standard.
An ECG abnormality may meet the criteria of an AE as described in this protocol (see 
Appendix 3) and the CRF Completion Guidelines. In these instances, the AE corresponding 
to the ECG abnormality will be recorded on the appropriate CRF.
QTc prolongation has been seen in some lenvatinib studies. Monitor ECGs every cycle (as 
specified in the SoA) in participants with congenital long QT syndrome, CHF, 
bradyarrhythmias, or those who are taking drugs known to prolong the QT interval, including 
Class Ia and III antiarrhythmics. Refer to the lenvatinib IB.
8.3.4
Echocardiogram or Multiple Gated Acquisition Scan
A MUGA scan (using technetium-based tracer) or an ECHO will be performed to assess 
LVEF as designated in the SoA (Section 1.3). MUGA or ECHO scans should be performed 
locally in accordance with the institution’s standard practice. MUGA scans are the preferred 
modality; however, whichever modality is used for an individual participant at baseline 
should be repeated for all subsequent LVEF assessments for that participant. LVEFs as 
assessed by the institution will be entered onto the CRF. Investigator assessment will be 
based on institutional reports.
Country-specific requirements are noted in Appendix 7.
8.3.5
Clinical Safety Laboratory Assessments (Hematology, Chemistry, and 
Urinalysis)
Details regarding specific laboratory procedures/assessments to be performed in this study 
are provided below. The total amount of blood/tissue to be drawn/collected over the course 
of the study (from prestudy to poststudy visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per participant can be found in the Laboratory 
Manual. 
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency.
•
The investigator or medically qualified designee (consistent with local requirements) 
must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the CRF. The laboratory 
reports must be filed with the source documents. Clinically significant abnormal 
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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 timing in 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 (or 90 days if considered an SAE) 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.
•
CBC with differential and clinical chemistry results must be reviewed before 
administration of study intervention. Electrolytes such as potassium, calcium, and 
magnesium should be monitored and abnormalities, when considered clinically 
significant, should be corrected in all participants before starting study intervention.
8.3.6
Pregnancy Testing
Pregnancy testing ([urine or serum] as required by local regulations) should be conducted 
according to Section 1.3 (SoA) and at the end of relevant systemic exposure for all arms (120 
days after last dose of pembrolizumab, 30 days after last dose of lenvatinib, or 180 days after 
last dose of chemotherapy, whichever occurs last).

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 must be performed by WOCBP at the study Discontinuation Visit and 
consistent with the contraception requirements 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.
Country-specific requirements are noted in Appendix 7.
8.3.7
Eastern Cooperative Oncology Group Performance Scale
The investigator or qualified designee will assess ECOG status at Screening, prior to the 
administration of each dose of study intervention and during the follow-up period as 
specified in the SoA (Section 1.3).
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8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3.
Progression of the cancer under study is not considered an AE as described in Section 8.4.6 
and Appendix 3.
Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant’s legally authorized 
representative).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators need to document if an SAE was associated with a medication error, misuse, or 
abuse.
Investigators remain responsible for following up AEs, SAEs, and other reportable safety 
events for outcome according to Section 8.4.3. The investigator, who is a qualified physician, 
will assess events that meet the definition of an AE or SAE as well as other reportable safety 
events with respect to seriousness, intensity/toxicity, and causality.
Adverse events will not be collected for participants during the prescreening period (for 
determination of archival tissue status) as long as that participant has not undergone any 
protocol-specified procedure or intervention. If the participant requires a blood draw, fresh 
tumor biopsy, etc., the participant is first required to provide consent to the main study, and 
AEs will be captured according to guidelines for standard AE reporting.
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
All AEs, SAEs, and other reportable safety events that occur after the participant provides 
documented informed consent, but before intervention allocation/randomization, must be 
reported by the investigator if the participant is receiving placebo run-in or other run-in 
treatment, if the event causes the participant to be excluded from the study, or is the result of 
a protocol-specified intervention, including, but not limited to washout or discontinuation of 
usual therapy, diet, or a procedure.
•
All AEs from the time of intervention allocation/randomization through 30 days after 
cessation of study intervention must be reported by the investigator.
•
All AEs meeting serious criteria, from the time of intervention allocation/randomization 
through 90 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.
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•
All pregnancies and exposure during breastfeeding, from the time of 
allocation/intervention randomization through 120 days after cessation of pembrolizumab 
or 30 days after cessation of lenvatinib, or 180 days after chemotherapy, whichever 
occurs last, must be reported by the investigator. If the participant initiates new 
anticancer therapy after discontinuation of study intervention, the time for reporting 
pregnancies and exposure during breastfeeding is reduced to 30 days after cessation of 
study intervention.
•
Additionally, any SAE brought to the attention of an investigator at any time outside the 
time specified above must be reported immediately to the Sponsor if the event is 
considered related to study intervention.
•
Country-specific requirements are listed in Appendix 7.
Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and the investigator 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor. 
Once a participant has been consented for the extension study, safety events, including those 
considered related to study intervention, will be collected as instructed in the extension study.
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 13.
Exception: A positive pregnancy test at the time of initial screening is not a reportable event 
unless the participant has received study intervention.
Table 13
Reporting Periods and Time Frames for Adverse Events and Other Reportable 
Safety Events
Type of Event
Reporting Period:
Consent to 
Randomization/ 
Allocation
Reporting 
Period:
Randomization/ 
Allocation 
Through 
Protocol-
specified AE 
Collection 
Period
Reporting Period:
After the Protocol-
specified AE 
Collection 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
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Type of Event
Reporting Period:
Consent to 
Randomization/ 
Allocation
Reporting 
Period:
Randomization/ 
Allocation 
Through 
Protocol-
specified AE 
Collection 
Period
Reporting Period:
After the Protocol-
specified AE 
Collection Period
Time Frame 
to Report 
Event and 
Follow-up 
Information 
to Sponsor
SAE
Report if:
– due to protocol-
specified 
intervention
– causes exclusion
– participant is 
receiving placebo 
run-in or other run-
in treatment
Report all
Report if:
– drug/vaccine related.
(Follow ongoing to 
outcome)
Within 
24 hours of 
learning of 
event
Pregnancy/Lactation 
Exposure
Report if:
– participant has 
been exposed to 
any protocol-
specified 
intervention (eg, 
procedure, 
washout, or run-in 
treatment 
including placebo 
run-in)
Exception: A 
positive pregnancy 
test at the time of 
initial screening is 
not a reportable 
event.
Report all
Previously reported –
Follow to completion/ 
termination; report 
outcome
Within 
24 hours of 
learning of 
event
Potential DILI 
events meeting 
biochemical criteria 
of Hy’s Law 
(require regulatory 
reporting)
Report if:
– due to intervention
– causes exclusion
Report
- regardless of 
suspected 
etiology
- to be reported as 
an ECI and SAE 
with OME criteria 
in the absence of 
other serious 
criteria
Previously reported –
Follow to 
completion/termination; 
report outcome
Within 
24 hours of 
learning of 
event
ECI (requires 
regulatory 
reporting)
Report if:
– due to intervention
– causes exclusion
Report
– requires 
regulatory 
reporting
Previously reported –
Follow to 
completion/termination; 
report outcome
Within 
24 hours of 
learning of 
event
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Type of Event
Reporting Period:
Consent to 
Randomization/ 
Allocation
Reporting 
Period:
Randomization/ 
Allocation 
Through 
Protocol-
specified AE 
Collection 
Period
Reporting Period:
After the Protocol-
specified AE 
Collection Period
Time Frame 
to Report 
Event and 
Follow-up 
Information 
to Sponsor
ECI (does not 
require regulatory 
reporting)
Report if:
– due to intervention
– causes exclusion
Report
– those not 
requiring 
regulatory 
reporting
Not required
Within 
5 calendar 
days of 
learning of 
event (unless 
an SAE)
New Cancer (that is 
not the cancer under 
study)
Report if:
– due to intervention
– causes exclusion
Report all
Not required
Within 
5 calendar 
days of 
learning of 
event (unless 
an SAE)
Overdose
Report if:
– receiving placebo 
run-in or other run-
in medication
Report all
Not required
Within 
5 calendar 
days of 
learning of 
event (unless 
an SAE)
AE=adverse event; DILI=drug-induced liver injury; ECI=event of clinical interest; NSAE=nonserious adverse event; 
OME=other important medical 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.
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. SAEs and other reportable safety events, including 
potential DILI events meeting biochemical criteria of Hy’s Law, pregnancy and exposure 
during breastfeeding, ECIs, cancer, and overdose will be followed until resolution, 
stabilization, until the event is otherwise explained, or the participant is lost to follow-up (as 
defined in Section 7.3). The investigator will also make every attempt to follow nonserious 
AEs that occur in randomized participants for outcome. Further information on follow-up 
procedures is given in Appendix 3.
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8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities toward the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and Sponsor policy and forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
Note: To meet EU CTR requirements, the Sponsor will report SUSARs to the Eudravigilance 
database via E2B(R3) electronic ICSR form in compliance with CTR 536/2014.
8.4.5
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to 
the investigator or their designee), including the pregnancy of a male participant’s female 
partner, 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 an 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 spontaneous abortion, missed abortion, benign hydatidiform mole, 
blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth must be reported as 
serious events (Important Medical Events). If the pregnancy continues to term, the outcome 
(health of infant) must also be reported.
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
Efficacy endpoints as outlined in Section 3 will not be reported to the Sponsor as AEs/SAEs. 
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Specifically, the suspected/actual events covered in this exception include any event that is 
progression of the cancer under study.
The Sponsor will ensure that aggregated efficacy endpoint events and safety data are 
monitored to safeguard the participants in the study.
8.4.7
Events of Clinical Interest
Selected serious and nonserious AEs are also known as ECIs and must be reported to the 
Sponsor.
ECIs for this study include:
•
An overdose of Sponsor's product, as defined in Section 8.5; lenvatinib overdose 
without an associated AE is not considered an ECI.
•
All potential DILI events meeting biochemical criteria of Hy’s Law will be reported 
to the Sponsor, regardless of suspected etiology, as both an ECI and SAE, with OME criteria 
in the absence of other SAE criteria, within 24 hours of learning of the event. Potential DILI 
events are defined as:
•
An elevated AST or ALT laboratory value that is greater than or equal to 3× the ULN 
and,
•
An elevated total bilirubin laboratory value that is greater than or equal to 2× the ULN 
and, 
•
At the same time, an alkaline phosphatase laboratory value that is less than 2× the ULN, 
determined by way of protocol-specified laboratory testing or unscheduled laboratory 
testing.*
*Note: These criteria are based on 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: any dose of 1000 mg or greater
•
Lenvatinib: any dose above the protocol-prescribed dose if associated with an AE
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 
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at the recommended dose for differentiated thyroid cancer, RCC, and HCC. No specific 
information is available on the treatment of overdose of pembrolizumab or lenvatinib.
All reports of pembrolizumab overdose with and without an AE and all reports of lenvatinib 
overdose with an AE must be reported by the investigator within 24 hours to the Sponsor 
either by electronic media or paper.
Reports of pembrolizumab overdose without any associated clinical symptoms or abnormal 
laboratory results, should be reported using the terminology “accidental or intentional 
overdose without adverse effect.”
CAPOX/mFOLFOX6: ≥10% over the prescribed dose should be reported as detailed in 
Section 10.3.1 (Note: an overdose is not considered an ECI).
8.6
Pharmacokinetics
8.6.1
Plasma Collection for Lenvatinib
Plasma samples will be collected as specified in the SoA (Section 1.3). Study sites must have 
appropriately trained staff and adequate equipment for procuring and processing specimens. 
Instructions for the collection, handling, and shipping procedures of PK samples will be 
provided in the Laboratory Manual.
Plasma samples will be collected from all participants in the Induction Phase and may only 
be stored at this time. Plasma concentrations of lenvatinib when co-administered with 
pembrolizumab and chemotherapy will be measured. Lenvatinib may be analyzed using a 
population PK approach.
If at some point during the study, prospective PK blood sample collection is deemed to be 
unnecessary by the Sponsor, it may be reduced or discontinued, and sites will be notified 
accordingly.
8.6.2
Serum Collection for Pembrolizumab
To evaluate pembrolizumab immunogenicity and exposure when administered in 
combination with lenvatinib and chemotherapy, sample collections for analysis of ADAs and 
PK are currently planned as specified in the SoA (Section 1.3). Study sites must have 
appropriately trained staff and adequate equipment for procuring and processing specimens. 
Instructions for the collection, handling, and shipping procedures of pembrolizumab ADA 
and PK samples will be provided in the Laboratory Manual.
Serum samples for pembrolizumab PK and ADA collected may only be stored at this time. 
Further analysis may be performed if required and reported separately if conducted. If 
ongoing PK and/or ADA sampling is deemed to be unnecessary by the Sponsor, it may be 
reduced or discontinued.
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8.7
Pharmacodynamics
Not applicable.
CCI
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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
Up to 28 days prior to randomization, potential participants will be evaluated to determine 
that they fulfill the entry requirements as set forth in Section 5. Screening procedures may be 
repeated after consultation with the Sponsor.
Documented informed consent must be provided prior to performing any protocol-specific 
procedure. Results of a test performed prior to the participant providing documented 
informed consent as part of routine clinical management are acceptable in lieu of a screening 
test if performed within the specified time frame.
Participants may be rescreened after initially failing to meet the inclusion/exclusion criteria. 
Results from assessments during the initial screening period are acceptable in lieu of a repeat 
screening test if performed within the specified time frame and the corresponding 
inclusion/exclusion criteria is met. Participants who are rescreened will retain their original 
screening number.
8.11.2
Safety Run-in
A 21-day Safety Run-in period will enroll approximately12 participants as described in 
Section 4.1.
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8.11.3
Treatment Period Visit
Visit requirements are outlined in the SoA (Section 1.3). Specific procedure-related details 
are provided in Section 8.1, Section 8.2, and Section 8.3. 
In the Safety Run-in Phase (Part 1), approximately 12 participants who are eligible for study 
participation will receive unblinded, open-label treatment with either lenvatinib plus 
pembrolizumab plus CAPOX or lenvatinib plus pembrolizumab plus mFOLFOX6 
chemotherapy.
In the Induction Phase, participants who are eligible for study participation will be assigned 
to receive unblinded, open-label treatment with lenvatinib plus pembrolizumab plus CAPOX 
or mFOLFOX6 chemotherapy (Arm 1), or CAPOX or mFOLFOX6 only (Arm 2) 
chemotherapy.
In the Consolidation Phase, participants will receive lenvatinib plus pembrolizumab only 
(Arm 1) or CAPOX or mFOLFOX6 (Arm 2).
Lenvatinib will be taken orally once daily, and pembrolizumab will be given by IV infusion 
on Day 1 of each 42-day cycle, as outlined in Section 8.1.8. CAPOX or mFOLFOX6 
chemotherapy will be administered on a 3-weekly or 2-weekly schedule, respectively.
Participants will be scheduled to visit the clinic as follows:
•
For lenvatinib plus pembrolizumab plus CAPOX, study visits will occur on Days 1, 
15, 22 and 36 of Cycle 1, Days 1 and 22 of Cycle 2; Days 1, 15 and 22 of Cycle 3, 
and Day 1 and Day 22 of Cycles 4-18. Participants will be contacted by 
telephone/virtually on Cycle 1, Day 8, Cycle 1 Day 29, and Cycle 3 Day 8. 
•
For lenvatinib plus pembrolizumab plus mFOLFOX6, study visits will occur on 
Days 1, 15, and 29 of Cycle 1 and Cycle 2; Days 1, 15 and 22 of Cycle 3, and Day 1 
and Day 22 of Cycles 4-18. Participants will be contacted by telephone/virtually on 
Cycle 1, Day 8 and Cycle 3 Day 8.
•
For CAPOX only, study visits will occur on Day 1 and Day 22 of every cycle. 
•
For mFOLFOX6 only, study visits will occur on Day 1, Day 15 and Day 29 of every 
cycle.
Due to the differences in visit schedule, once randomized, the participants cannot switch 
between chemotherapy backbones.
Participants may be seen more frequently, if clinically indicated. Tumor imaging and 
response assessment will occur every 6 weeks from the day of randomization.
Study interventions will continue until reaching a discontinuation criterion (Section 7.1), 
examples of which include disease progression which is radiographically documented and 
verified by BICR per RECIST 1.1, unacceptable toxicity; intercurrent illness that prevents 
further administration of treatment; investigator’s decision to withdraw treatment; participant 
withdrawal of consent; pregnancy; noncompliance with study intervention or procedure 
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requirements; administrative reasons requiring cessation of treatment; or, for CAPOX, 
mFOLFOX6, and pembrolizumab ONLY, treatment completion (18 cycles of 
pembrolizumab; maximum cycles of CAPOX/mFOLFOX6 as per local standard). There is 
no treatment duration limit for lenvatinib.
Completion of pembrolizumab Q6W consists of 18 treatments (approximately 2 years). 
Discontinuation of treatment may be considered for participants who have attained a 
confirmed CR and have been treated for at least 4 cycles (at least 24 weeks) of 
pembrolizumab, receiving 2 cycles of the combination including 2 doses of pembrolizumab 
and at least 80% of the planned doses of pembrolizumab beyond the date when the initial CR 
was declared. These participants may be eligible for Second Course Treatment described in 
Section 6.6.6.
8.11.4
Discontinued Participants Continuing to be Monitored in the Study
The Discontinuation Visit should occur at the time study intervention is discontinued for any 
reason. If the Discontinuation Visit occurs 30 days from the last dose of study intervention, at 
the time of the mandatory Safety Follow-up Visit, the Discontinuation Visit procedures, and 
any additional Safety Follow-up procedures should be performed.
Visit requirements are outlined in the SoA. Additional details regarding participant 
withdrawal and discontinuation are presented in Section 8.1.9.
8.11.5
Posttreatment
8.11.5.1
Safety Follow-up Visit
The mandatory Safety Follow-up Visit should be conducted approximately 30 days after the 
last dose of study intervention or before initiation of a new anticancer therapy, whichever is 
earlier.
Participants who are eligible for retreatment with pembrolizumab may have up to 2 Safety 
Follow-up Visits, 1 after the Initial Treatment or First Course and 1 after Second Course.
8.11.5.2
Efficacy Follow-up Visit(s)
Note: As of Amendment 8, this section is no longer applicable. Participants in Efficacy 
Follow-up prior to the initiation of Amendment 8 will stop efficacy assessments and be 
discontinued from the study and should continue with tumor imaging per local standard of 
care. AEs and other reportable safety events will be reported and followed as described under 
Section 8.4.
Participants who discontinue study intervention for a reason other than progressive disease 
will begin Efficacy Follow-up and should be assessed as outlined in the SoA (Section 1.3) to 
monitor disease status. Every effort should be made to collect information regarding disease 
status until the start of new anticancer therapy, disease progression, death, or end of study, or 
if the participant begins retreatment with pembrolizumab, as detailed in Section 6.6.6. 
Information regarding poststudy anticancer treatment will be collected if new treatment is 
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initiated. Participants who completed all efficacy assessments and/or will not have further 
efficacy assessments must enter Survival Follow-up.
Participants who are eligible to receive retreatment with pembrolizumab according to the 
criteria in Section 6.6.6 will move from Efficacy Follow-up to Second Course when they 
experience disease progression. Details are provided in the SoA (Section 1.3) for retreatment 
with pembrolizumab.
8.11.5.3
Survival Follow-up Contacts
Note: As of Amendment 8, this section is no longer applicable. Participants in Survival 
Follow-up prior to initiation of Amendment 8 are considered to have completed the study and 
should have a final survival contact; these participants will no longer be contacted for 
survival information. AE, SAE, and other reportable safety events will be reported and 
followed as described under Section 8.4.
Participant survival follow-up status will be assessed approximately every 12 weeks to assess 
for survival status until death, withdrawal of consent, or the end of the study, whichever 
occurs first.
The first survival follow-up assessment should be scheduled as described below:
For participants who discontinue treatment intervention and who will not enter Efficacy 
Follow-up, the first survival follow-up contact will be scheduled 12 weeks after the 
Discontinuation Visit and/or Safety Follow-up Visit (whichever is last).
For participants who completed assessments in Efficacy Follow-up, the first survival follow-
up contact will be scheduled 12 weeks after the last efficacy assessment follow-up visit has 
been performed.
8.11.6
Vital Status
To ensure current and complete survival information (vital status) is available at the time of 
database locks, updated vital status may be requested during the study by the Sponsor. For 
example, updated vital status may be requested before but not limited to, an eDMC review, 
interim and/or final analysis. Upon Sponsor notification, all participants who do not/will not 
have a scheduled study visit or study contact during the Sponsor-defined period will be 
contacted for their vital status.
If a participant withdraws consent, vital status (survival information) may be obtained by 
review of public records, in accordance with local regulations. If a participant is lost to 
follow-up, vital status (survival information) can be conducted by review of medical records 
or public records when vital status is in question in accordance with local regulations.
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9
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study. If, after the 
study has begun but prior to the conduct of any planned analysis, 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 E9). Changes 
to exploratory or other non-confirmatory analyses made after the protocol has been finalized, 
but prior to the conduct of any planned analysis, will be documented in an sSAP and 
referenced in the CSR for the study. Other planned analyses (ie, those specific to the analysis 
of PK data and biomarker data) will be documented in separate analysis/operational plans. 
Post hoc exploratory analyses will be clearly identified in the CSR.
9.1
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Section 9.2 through Section 9.12.
Study Design 
Overview
A Phase 3, randomized, open-label study of lenvatinib plus pembrolizumab plus 
chemotherapy compared with chemotherapy only in participants with locally 
advanced unresectable/metastatic gastroesophageal adenocarcinoma 
Treatment 
Assignment
Part 1: Approximately 12 participants will be assigned to one of 2 treatment 
groups at the discretion of the investigator with ~6 participants treated per 
treatment group:
Lenvatinib + pembrolizumab + CAPOX
Lenvatinib + pembrolizumab + mFOLFOX6
Part 2: Approximately 878 participants will be randomized in a 1:1 ratio to the 
experimental group and the control group:
Lenvatinib + pembrolizumab + CAPOX/ mFOLFOX6
CAPOX/ mFOLFOX6
Stratification factors for Part 2 are: 1) region (East Asia, North America + 
Western Europe versus Rest of World), 2) ECOG (0 or 1) and 3) Intended 
chemotherapy (CAPOX or mFOLFOX6). 
Analysis 
Populations
Part 1 and Part 2 participants will be analyzed separately.
Efficacy: ITT
Safety: APaT
Primary 
Endpoints
Part 1: Safety and tolerability
Part 2: 
OS
PFS per RECIST 1.1 assessed by BICR
Key Secondary 
Endpoint
Part 2:
OR per RECIST 1.1 assessed by BICR
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Statistical 
Methods for Key 
Efficacy 
Analyses
Part 2: 
The primary hypotheses on PFS and OS will be evaluated by comparing the 
experimental group to the control group using a stratified log-rank test. The HR 
will be estimated using a stratified Cox regression model. Event rates over time 
will be estimated within each treatment group using the Kaplan-Meier method. 
The stratified M&N method with strata weighted by sample size willbe used for 
analysis of ORR.
The study will be considered to have met its primary objective if at least 1 
primary hypothesis testing is statistically significant.
Statistical 
Methods for Key 
Safety Analyses
Part 1: Descriptive summary statistics will be provided for safety endpoints by 
treatment as appropriate. 
Part 2: For analyses in which 95% CIs will be provided for between-treatment 
differences in the percentage of participants with events, these analyses will be 
performed using the M&N method [Miettinen, O. and Nurminen, M. 1985].
Interim Analyses
Part 1: No IA is planned. Participants will be closely followed for DLTs for 21 
days after the first dose of study intervention. 
Part 2: One IA will be performed in this study. Results will be reviewed by an 
eDMC. Details are provided in Section 9.7.
IA:
Timing: to be performed after both ~494 PFS events have occurred in CPS ≥1 
participants and ~8 months after the last participant randomized. 
Primary purpose: efficacy analysis for ORR, PFS and OS. 
Final analysis (FA):
Timing: to be performed after both ~537 deaths have occurred in CPS ≥1 
participants and ~18 months after the last participant randomized. 
Primary purpose: efficacy analysis for OS.
Note for IA and FA, if the events accrue slower than expected, the Sponsor may 
conduct the analysis with up to 3 additional months of follow-up than the 
follow-up as described above, or when the specified number of events is 
observed, whichever occurs first.
Multiplicity
Part 1: No multiplicity adjustment is planned.
Part 2: The overall type I error over the primary endpoints (PFS and OS) and the 
key secondary endpoint (ORR) is strongly controlled at 2.5% (one-sided), with 
initially 0% allocated to ORR, 0.7% to PFS and 1.8% to OS in CPS ≥1 
participants.
By using the graphical approach of Maurer and Bretz, if one hypothesis is 
rejected, the alpha will be shifted to other hypotheses [Maurer, W. and Bretz, F. 
2013].
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Sample Size and 
Power
Part 1: Approximately 12 participants will be enrolled.
Part 2: Approximately 878 participants are planned to be enrolled. The actual 
overall sample size of the study for all participants is 880. The sample size for 
CPS ≥1 participants is approximately 680.  
For OS, there will be ~537 deaths in CPS ≥1 participants at the OS final 
analysis. With 537 deaths, the study has ~85% power for detecting a hazard 
ratio (HR) of 0.76 at an initially assigned 1.8% (one-sided) significance level.
For PFS, there will be ~494 events in CPS ≥1 participants at IA. With 494 PFS 
events, the study has ~94% power for detecting a HR of 0.7 at an initially 
assigned 0.7% (one-sided) significance level. 
For ORR, with sample size of 680 in CPS ≥1 participants at IA, the study has 
~98.5% power for detecting a 20-percentage point difference in ORR (57% 
versus 37%) at a significance level of 0.1001% (if H2 rejected only).
The median PFS of 6 months and the median OS of 11.5 months, and the ORR 
of 37% in the control group for the sample size estimations are based on CPS 
≥1 participants treated with the standard care of chemotherapy from KN062 
(the first line of HER-2 negative, previously untreated, unresectable or 
metastatic gastric/GEJ adenocarcinoma).
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.
Part 1 of the study is being conducted as an open-label study, ie, participants, investigators, 
and Sponsor personnel will be aware of treatment assignments after each participant is 
enrolled and treatment is assigned. Safety data will be closely monitored for 21 days after the 
first dose of study intervention.
Although Part 2 of the study is open-label, analyses or summaries generated by randomized 
intervention assignment, or actual treatment received will be limited and documented. 
Further documentation will be provided in the sSAP. In addition, independent radiologists 
will perform the central imaging review without knowledge of treatment assignments.
Blinding procedures related to the planned interim analyses are described in Section 9.7. 
The Clinical Biostatistics department will generate the randomized allocation schedule(s) for 
study intervention assignment.
9.3
Hypotheses/Estimation 
Objectives and hypotheses of the study are stated in Section 3.
9.4
Analysis Endpoints 
Efficacy and safety endpoints that will be evaluated for within- and/or between-treatment 
differences are listed below.
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9.4.1
Efficacy/Immunogenicity/Pharmacokinetics Endpoints 
9.4.1.1
Primary
Overall Survival (OS)
OS is defined as the time from randomization to death due to any cause.
Progression-free Survival (PFS) per RECIST 1.1 Assessed by BICR
PFS is defined as the time from randomization to the first documented disease progression 
per RECIST 1.1 by BICR or death due to any cause, whichever occurs first. See Section 
9.6.1 for the censoring rules.
9.4.1.2
Secondary
Objective Response per RECIST 1.1 by BICR
The OR is defined as a confirmed CR or a PR per RECIST 1.1 as assessed by BICR (note: 
only CR or PR prior to a curative surgical resection will be used among participants with 
curative surgical resection).
Duration of Response (DOR) per RECIST 1.1 by BICR
For participants who showed confirmed CR or PR, DOR is defined as the time from first 
response (CR or PR) to subsequent disease progression or death from any cause, whichever 
occurs first.
9.4.1.3
Exploratory
PFS and OR per RECIST 1.1 as assessed by the investigator. 
9.4.2
Safety Endpoint
DLTs for Part 1 are defined in Table 2. Other safety and tolerability will be assessed by 
clinical review of all relevant parameters including AEs, laboratory values, and vital signs.
9.4.3
Patient-reported Outcome (PRO) Endpoint
Exploratory PRO endpoints (eg, score change from baseline over time), which include 
EORTC QLQ-C30, EORTC QLQ-STO22, and EQ-5D-5L scores, are described in Section 3 
and Section 4.2.1.3. Details will be provided in the sSAP.
9.5
Analysis Populations 
9.5.1
Efficacy Analysis Populations
The ITT population will serve as the population for efficacy analysis other than DOR. All 
randomized participants, whether treatment was administered, will be included in this 
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population. Participants will be included in the treatment group to which they are 
randomized. The DOR analysis will be based on the population of responders (participants 
that achieved complete or PR). 
Part 1 participants will be excluded from all Part 2 efficacy analyses and therefore will not 
contribute to the analyses to assess the primary/secondary objectives of Part 2. 
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 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. 
For most participants, this will be the study intervention group to which they are randomized. 
Participants who receive incorrect study intervention for the entire treatment period will be 
included in the treatment group corresponding to the study intervention actually received.
Any participant who receives the incorrect study intervention for 1 or more cycles but 
receives the correct study intervention for the remaining cycles will be analyzed according to 
the participant’s randomized treatment group, and a narrative will be provided for any events 
that occur during the cycle for which the participant was incorrectly dosed.
At least 1 laboratory or vital sign measurement obtained after at least 1 dose of study 
intervention is required for inclusion in the analysis of each specific parameter. To assess 
change from baseline, a baseline measurement is also required.
Participants in Part 1 and Part 2 will be analyzed separately.
9.5.3
PRO Analysis Populations
The PRO analyses are based on the PRO FAS population, defined as all randomized 
participants who have at least one PRO assessment available for the specific endpoint and 
have received at least one dose of the study intervention. Participants will be analyzed in the 
treatment group to which they are randomized.
PRO analyses will be performed in Part 2 participants only. 
9.6
Statistical Methods 
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, Multiplicity. Nominal p-values will be
computed for other efficacy analyses but should be interpreted with caution due to potential 
issues of multiplicity.
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9.6.1
Statistical Methods for Efficacy Analyses
Efficacy analyses will be performed in Part 2 participants only. This section describes the 
statistical methods that address the primary and secondary objectives. Methods related to 
exploratory objectives will be described in the sSAP. 
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 M&N method. If there 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 any efficacy IA or final 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.
Response or progression in the Second Course phase will not count toward the PFS, OR, and 
DOR analyses in this study.
9.6.1.1
Overall Survival
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. 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, HR). The HR and its 95% CI from the Cox model 
with a single treatment covariate will be reported. The stratification factors used for 
randomization (see 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 last known alive date.
9.6.1.2
Progression-free Survival
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, HR) between the treatment 
groups. 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 (see Section 6.3.2) will be applied to both the stratified log-rank test and 
the stratified Cox model. 
Because disease progression is assessed periodically, PD can occur any time in the time 
interval between the last assessment where PD was not documented and the assessment when 
PD is documented. The true date of disease progression will be approximated by the earlier 
of the date of the first assessment at which PD is objectively documented per RECIST 1.1 by 
BICR and the date of death. Death is always considered as a confirmed PD event. To 
evaluate the robustness of the PFS endpoint per RECIST 1.1 by BICR, 1 primary and 2 
sensitivity analyses with a different set of censoring rules will be performed. 
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For the primary analysis, any participant who experiences an event (PD or death) 
immediately after 2 or more missed disease assessments will be censored at the last disease 
assessment prior to the missed visits. In addition, any participant who initiates new 
anticancer therapy prior to documented progression will be censored at the last disease 
assessment prior to the initiation of new anticancer therapy. Participants who do not start new 
anticancer therapy and who do not experience an event will be censored at the last disease 
assessment. If a participant meets multiple criteria for censoring, the censoring criterion that 
occurs earliest will be applied. 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 by BICR, 2 sensitivity 
analyses with different sets of censoring rules will be performed. The first sensitivity analysis 
follows the intention-to-treat principle. That is, PDs/deaths are counted as events regardless 
of missed study visits or initiation of new anticancer therapy. The second sensitivity analysis 
considers discontinuation of treatment due to reasons other than CR or initiation of new 
anticancer treatment, 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 14.
Table 14
Censoring Rules for Primary and Sensitivity Analyses of PFS
Situation
Primary Analysis
Sensitivity 
Analysis 1
Sensitivity 
Analysis 2
PD or death documented 
after ≤1 missed disease 
assessment, and before 
new anticancer therapy, if 
any
Progressed at date of 
documented PD or 
death
Progressed at date of 
documented PD or 
death
Progressed at date of 
documented PD or death
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 intervention or
completed study 
intervention
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Situation
Primary Analysis
Sensitivity 
Analysis 1
Sensitivity 
Analysis 2
No PD and no death; new 
anticancer treatment is 
initiated
Censored at last 
disease assessment 
before new 
anticancer treatment
Censored at last 
disease assessment
Progressed at date of new 
anticancer treatment
PD=progressive disease; PFS=progression-free survival; the curative surgical resection (details in Section 
6.5.3) will be excluded for the new anticancer therapy.
As imaging will continue per protocol Section 6.5.3, participants who have curative surgical
resection during the study will be followed for PFS events after surgery until local
recurrence, distant metastasis, or death for the primary analysis of PFS. An additional
sensitivity analysis will be conducted for PFS in which these participants will be censored at 
last disease assessment prior to the time of curative surgical resection.
9.6.1.3
Objective Response Rate
The stratified M&N method [Miettinen, O. and Nurminen, M. 1985] will be used for the 
comparison of the ORR between the 2 treatment groups. The difference in ORR and its 95% 
CI from the stratified M&N method with strata weighting by sample size will be reported 
[Miettinen, O. and Nurminen, M. 1985]. The stratification factors used for randomization 
(Section 6.3.2) will be applied to the analysis.
The point estimate of ORR will be provided by treatment group, together with 95% CI using 
exact binomial method proposed by Clopper and Pearson [Clopper, C. J. and Pearson, E. S. 
1934].
9.6.1.4
Duration of Response 
If sample size permits, DOR will be summarized descriptively using Kaplan-Meier medians 
and quartiles. Only the subset of participants who show a CR or PR will be included in this 
analysis. For each DOR analysis, a corresponding summary of the reasons responding 
participants are censored will also be provided. Responding subjects who are alive, have not 
progressed, have not initiated new anticancer treatment, have not been determined to be lost 
to follow-up, and have had a disease assessment within ~5 months of the data cutoff date are 
considered ongoing responders at the time of analysis. If a participant meets multiple criteria 
for censoring, the censoring criterion that occurs earliest will be applied. The censoring rules 
are summarized in Table 15. 
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Table 15
Censoring Rules for Duration of Response
Situation
Date of Progression or Censoring
Outcome
No progression nor death, no 
new anticancer therapy initiated
Last adequate disease assessment
Censor
(nonevent)
No progression nor death, new 
anticancer therapya initiated
Last adequate disease assessment 
before new anticancer therapy 
initiated
Censor
(nonevent)
Death or progression 
immediately after ≥2 
consecutive missed disease 
assessments or after new 
anticancer therapy if any
Earlier date of last adequate disease 
assessment prior to ≥2 missed 
adequate disease assessments and new 
anticancer therapy, if any
Censor
(nonevent)
Death or progression after ≤1 
missed disease assessments and 
before new anticancer therapy, 
if any
PD or death
End of response
(Event)
A missed disease assessment includes any assessment that is not obtained or is considered inadequate for evaluation of 
response.
a
new anticancer therapy: excluding curative surgical resection.
9.6.1.5
Analysis Strategy for Key Efficacy Endpoints 
Table 16 summarizes the primary analysis approach for key efficacy endpoints.
Table 16
Analysis Strategy for Key Efficacy Endpoints
Endpoint
Statistical Method a
Analysis 
Population
Missing Data Approach
Primary Endpoints
OS
Test: Stratified log-rank 
test
Estimation: Stratified 
Cox model with Efron’s 
tie handling method
ITT
(CPS ≥1 and all 
participants)
Censored at the last known alive 
date
PFS per RECIST 
1.1 by BICR
Test: Stratified log-rank 
test
Estimation: Stratified 
Cox model with Efron’s 
tie handling method
ITT
(CPS ≥1 and all 
participants)
Primary censoring rule
Sensitivity analysis 1
Sensitivity analysis 2 (More 
details are provided in 
Table 14, Censoring Rules for 
Primary and Sensitivity 
Analyses of PFS)
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Endpoint
Statistical Method a
Analysis 
Population
Missing Data Approach
Key Secondary Endpoint
Objective response 
per RECIST 1.1 by 
BICR
Test and Estimation: 
Stratified M&N method 
with sample size weight
ITT
(CPS ≥1 and all 
participants)
Participants without assessments 
are considered nonresponders and 
conservatively included in
the denominator
BICR=blinded independent central review; CPS=combined positive score; ITT=Intention-to-Treat; M&N=Miettinen and 
Nurminen; ORR=objective response rate; OS=overall survival; PFS=progression-free survival; RECIST=Response 
Evaluation Criteria in Solid Tumors.
a
Statistical models are described in further detail in the text. For stratified analyses, the stratification factors used for 
randomization (Section 6.3.2) will be applied to the analysis. Small strata will be combined in a way specified by a 
blinded statistician prior to database lock for any efficacy interim or final analysis.
The strategy to address multiplicity issues with regard to multiple endpoints and interim 
analyses is described in Section 9.7 (Interim Analyses) and Section 9.8 (Multiplicity).
9.6.2
Statistical Methods for Safety Analyses
9.6.2.1
Overall Safety Assessment 
Part 1: Participants will be closely followed for DLTs for 21 days after the first dose of study 
intervention. Descriptive summary statistics (eg, counts, percentages) will be provided for 
DLTs by treatment as appropriate. Other safety and tolerability will also be assessed by 
clinical review of all relevant parameters.
Part 2: The primary safety analyses will include only events that occur prior to Second 
Course Treatment. 
The overall safety evaluation will include a summary by treatment group of the number and 
percentage of participants with at least one AE, a drug-related AE, an SAE, a serious drug-
related AE, a Grade 3 to 5 AE, a drug-related Grade 3 to 5 AE, a discontinuation from study 
intervention due to an AE, and an AE resulting in death. Point estimates and 95% CIs for the 
differences between treatment groups in the percentages of participants with the event will be 
provided based on the criteria described below.  
Point estimate and 95% CIs for the difference between treatment groups in the percentage of 
participants with specific AEs will be provided for AEs that occur in at least 10% of 
participants in any treatment group. The threshold of at least 10% of participants was chosen 
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, difference in 
the percentage of participants with specific Grade 3 to 5 AEs (≥5% of participants in 1 of the 
treatment groups) will also be summarized by point estimate and 95% CIs.
CIs for between treatment group differences will be provided using the M&N method 
[Miettinen, O. and Nurminen, M. 1985]. Because many 95% CIs may be provided without 
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adjustment for multiplicity, the CIs should be regarded as a helpful descriptive measure to be 
used in safety review, not as a formal method for assessing the statistical significance of the 
between-group differences.
9.6.2.2
Assessment of Safety Topics of Special Interest 
AEs that are immune-mediated or potentially immune-mediated will be evaluated separately. 
These events have been characterized consistently throughout the pembrolizumab clinical 
development program. Point estimates and 95% CIs for between-group difference is not 
expected to add value to the safety evaluation, and hence only number and percentage of 
participants with such pembrolizumab AEOSI will be provided, as well as the number and 
percentage of participants with corticosteroids administration to treat an AEOSI. Summary 
statistics will be provided for the analysis of time from first dose to the onset of an AEOSI. 
Similar approach will be applied to CSAE for lenvatinib.
Table 17 summarizes the analysis strategy for safety endpoints in this study.
Table 17
Analysis Strategy for Safety Parameters
Analysis Part
Safety Endpoint
Descriptive 
Statistics
95% between-group 
CI (Graphical 
display)
Overall Safety 
Assessment
Specific AEs (incidence ≥10% of participants 
in one of the treatment groups)
X
X
Specific Grade 3-5 AE (incidence ≥5% of 
participants in one of the treatment groups)
X
X
Specific serious AE (incidence ≥5% of 
participants in one of the treatment groups)
X
X
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 study treatment due to AE
X
AE that resulted in death
X
Change from Baseline Results (lab toxicity 
shift, vital signs)
X
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Analysis Part
Safety Endpoint
Descriptive 
Statistics
95% between-group 
CI (Graphical 
display)
Assessment of 
safety topics of 
special interest
Pembrolizumab AEOSI
X
Lenvatinib CSAE
X
AE=adverse event; CI=confidence interval; SAE=serious adverse event; AEOSI=adverse event of special interest; 
CSAE=clinically significant adverse event; X = results will be provided.
9.6.3
Statistical Methods for Patient-Reported Outcome Analyses
PRO analyses will be performed in Part 2 participants only. Details of PRO analyses will be 
described in the sSAP.
9.6.4
Summaries of Demographic and Baseline Characteristics
Part 1: The relevant demographics and baseline characteristics will be summarized. The 
number and percentage of participants screened, randomized, and the primary reasons for 
screening failure and discontinuation will be displayed.
Part 2: The comparability of the treatment groups for each relevant demographic and baseline 
characteristic will be assessed by the use of tables and/or graphs. No statistical hypothesis 
tests will be performed on these characteristics. The number and percentage of participants 
screened, randomized, and the primary reasons for screening failure and discontinuation will 
be displayed.
Demographic variables (eg, age), baseline characteristics, primary and secondary diagnoses, 
and prior and concomitant therapies will be summarized by treatment either by descriptive 
statistics or categorical tables.
9.7
Interim Analyses 
Part 1
In this open-label Safety Run-in Phase, participants will be closely followed for DLTs for 21 
days after the first dose of study intervention. If 3 or more DLTs occur in either 
chemotherapy backbone treatment group during this Safety Run-in, enrollment to Part 2 may 
be delayed to further examine safety data and consider study design changes.
Part 2
An eDMC will review the unblinded efficacy results and accumulating safety data at planned 
interim analysis. Treatment-level results of the interim analysis will be provided by the 
unblinded statistician to the eDMC. The eDMC responsibilities and review schedules will be 
outlined in the DMC Charter. The recommendations of the eDMC will be communicated to 
the EOC. If the eDMC recommends modifications to the design of the protocol or 
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discontinuation of the study, the EOC, and possibly other limited numbers of additional 
Sponsor personnel, may be unblinded to results at the treatment level to act on these 
recommendations. Participant-level unblinding to support regulatory filing, should this occur 
before the end of the study, will be restricted to a designated Sponsor team, who will have no 
other responsibilities associated with the study. The extent to which individuals are 
unblinded with respect to the results will be documented. 
Additional logistical details, revisions to the above plan, and data monitoring guidance will 
be provided in the eDMC Charter.
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 analysis.
9.7.1
Efficacy Interim Analysis
One interim analysis is planned in addition to the final analysis for this study. For the interim 
and final analyses, all randomized participants will be included. Results of the interim 
analysis will be reviewed by the eDMC. The timing and the purpose of the interim and final 
analyses are summarized in Table 18. Type I error control for the efficacy analyses as well as 
efficacy bounds are described in Section 9.8.
Table 18
Summary of Interim and Final Analyses Strategy for Efficacy
Analyses
Timing
Estimated Time 
after First 
Participant 
Randomized
Primary Purpose of Analysis
IA
Both ~494 PFS events have 
occurred in CPS ≥1 participants 
and ~8 months after the last 
participant randomized.
Approximately, 450 OS events 
in CPS ≥1 participants are 
expected with this trigger. 
~31 months
Efficacy analysis for ORR, PFS and 
OS in CPS ≥1 and all participants. 
This is the final analysis of ORR 
and PFS, and the IA of OS.
Final 
Analysis
Both ~537 deaths have occurred 
in CPS ≥1 participants and ~18 
months after the last participant 
randomized. 
~41 months
Efficacy analysis for OS in CPS ≥1 
and all participants.
This is the final analysis of OS.
IA=interim analysis; CPS=combined positive score; ORR=objective response rate; OS=overall survival; 
PFS=progression-free survival
Note for IA and FA: if the events accrue slower than expected, the Sponsor may conduct the analysis with up to 3 
additional months of follow-up than the follow-up as described above, or when the specified number of events is 
observed, whichever occurs first.
9.7.2
Safety Interim Analysis
In Part 2, the eDMC will be responsible for periodic interim safety reviews, as specified in 
the DMC Charter. Interim safety analysis will also be performed at the time of interim 
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efficacy analysis. In this open-label study, participants will be actively monitored at ongoing 
basis. Because there is limited experience in the full combination of pembrolizumab with 
lenvatinib and CAPOX or mFOLFOX6, there will be an independent first safety review by 
an eDMC after at least 20 participants in the experimental arm have completed 2 cycles of 
induction therapy.
9.8
Multiplicity 
Part 1
No multiplicity adjustment is needed because there is no hypothesis testing.
Part 2
The study uses an extension of the graphical method of Maurer and Bretz [Maurer, W. and 
Bretz, F. 2013] to provide strong multiplicity control for multiple hypotheses while making 
the interim and final analysis timing more flexible. According to the Maurer and Bretz 
approach, study hypotheses may be tested in a group sequential fashion, and when a 
particular null hypothesis is rejected, the alpha allocated to that hypothesis can be reallocated 
to other hypothesis tests. Figure 7 shows the initial 1-sided alpha allocation for each 
hypothesis in the ellipse representing the hypothesis. The weights for reallocation from each 
hypothesis to the others are represented in the boxes on the lines connecting hypotheses.
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Figure 7
Multiplicity Graph for Type I Error Control of Study Hypotheses
CPS=combined positive score; ORR=objective response rate; OS=overall survival; PFS=progression-free survival
The extended graphical method spends alpha as a function of the minimum of the actual 
event information fraction and the expected event information fraction. This ensures that the 
actual spending will be no more aggressive than the planned spending while at the same time 
ensuring that not all alpha is spent prior to final planned event counts.
9.8.1
OS Hypotheses
Figure 7 shows that initial alpha=0.018 will be allocated to the OS hypothesis in CPS ≥1 
participants (H1) and no initial alpha will be allocated the OS hypothesis in all participants 
(H3). According to Figure 7, H1 may also be tested at alpha=0.023999 (H2 and H4 rejected), 
0.019001 (H2, H5, and H6 rejected), and 0.025 (H2, H5, H4, and H6 rejected). As an 
example, Table 19 shows the bounds and boundary properties for H1, when tested at initial 
alpha=0.018 and full alpha=0.025, derived using a Lan-DeMets O’Brien-Fleming spending 
function based on the predicted number of events, at the planned time of analysis.
The bounds provided in Table 19 are based on the assumption that the expected events at IA 
and FA are 450 and 537 in CPS ≥1 participants, respectively. At the time of an analysis, the 
observed number of events may differ substantially from the expected. To avoid 
overspending at the IA and leave reasonable alpha for the final analysis, the minimum alpha 
spending strategy will be adopted. At the IA, the information fraction used in Lan-DeMets 
spending function to determine the alpha spending at the IA will be based on the minimum of 
the expected information fraction and the actual information fraction at each analysis. 
Specifically,
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In the scenario that the events accrue slower than expected and the observed number of 
events is less than the expected events at a given analysis, the information fraction will be 
calculated as the observed number of events at the IA over the target number of events at FA.
In the scenario that the events accrue faster than expected and the observed number of events 
exceed the expected number of events at a given analysis, then the information fraction will 
be calculated as the expected number of events at the IA over the target number of events at 
FA. For example, at IA, if 470 OS events have occurred (ie, more than the expected 450 OS 
events), the alpha spending at IA will be according to the expected information fraction 
(450/537= 84%) instead of the actual information fraction (470/537 = 88%). 
The final analysis timing is driven by OS events from the CPS ≥1 participants. The final 
analysis will use the remaining Type I error that has not been spent at the IA. The event 
counts for all analyses will be used to compute correlations. 
Of note, while the information fraction used for alpha spending calculation will be the 
minimum of the actual information fraction and the expected information fraction, the 
correlations required for deriving the bounds will still be computed using the actual 
information fraction based on the observed number of events at each analysis over the target 
number of events at FA.
The minimum spending approach assumes timing is not based on any observed Z-value and 
thus the Z test statistics used for testing conditioned on timing are multivariate normal. Given 
the probabilities derived with the proposed spending method, the correlations based on actual 
event counts are used to compute bounds that control the Type I error at the specified alpha 
level for a given hypothesis conditioned on the IA timing. Because this is true regardless of 
what is conditioned on, the overall Type I error for a given hypothesis unconditionally is 
controlled at the specified level. By using more conservative spending early in the study, 
power can be retained to detect situations where the treatment effect may be delayed. 
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Table 19
Efficacy Boundaries and Properties for OS Analysis in CPS ≥1 Participants
Analysis
Value
α=0.018
α=0.025
IA : 84%a
Z
2.3350
2.1880
N: 680
p (1-sided)
b
0.0098
0.0143
Events: 450
HR at bound
c
0.8022
0.8135
Month: 31
P(Cross) if HR=1
d
0.0098
0.0143
P(Cross) if HR=0.76
e
0.7182
0.7657
Final
Z
2.1660
2.0360
N: 680
p (1-sided)
b
0.0152
0.0209
Events: 537
HR at bound
c
0.8294
0.8388
Month: 41
P(Cross) if HR=1
d
0.0180
0.0250
P(Cross) if HR=0.76
e
0.8541
0.8825
CPS=combined positive score; HR=hazard ratio; IA=interim analysis
a Percentage of expected number of events at the IA over the expected number at final analysis.
b Nominal alpha for group sequential testing.
c HR at bound is the approximate HR required to reach an efficacy bound.
d Probability of crossing a bound under the null hypothesis.
e Probability of crossing a bound under the alternative hypothesis.
OS hypothesis in all participants (H3) does not have initial alpha assignment but may receive 
alpha stepped down from OS hypothesis in CPS ≥1 participants (H1). H3 may be tested at 
alpha= 0.018 (H1 rejected), 0.023999 (H1, H2, and H4 rejected), 0.019001 (H1, H2, H5, and 
H6 rejected), and 0.025 (H1, H2, H5, H4, and H6 rejected). As an example, Table 20 shows 
the bounds and boundary properties for H3, when tested at alpha=0.018 and full alpha=0.025, 
derived using a Lan-DeMets O’Brien-Fleming spending function based on the predicted 
number of events at the planned time of analysis.
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Table 20
Efficacy Boundaries and Properties for OS Analysis in All Participants 
Analysis
Value
α=0.018
α=0.025
IA: 84%a
Z
2.3350
2.1870
N: 880
p (1-sided)
b
0.0098
0.0144
Events: 588
HR at bound
c
0.8247
0.8349
Month: 31
P(Cross) if HR=1
d
0.0098
0.0144
P(Cross) if HR=0.80
e
0.6452
0.6984
Final
Z
2.1660
2.0360
N: 880
p (1-sided)
b
0.0152
0.0209
Events: 701
HR at bound
c
0.8491
0.8575
Month: 41
P(Cross) if HR=1
d
0.0180
0.0250
P(Cross) if HR=0.80
e
0.7969
0.8326
HR=hazard ratio; IA=interim analysis; OS=overall survival.
a Percentage of expected number of events at the IA over the expected number at final analysis.
b Nominal alpha for group sequential testing.
c HR at bound is the approximate HR required to reach an efficacy bound.
d Probability of crossing a bound under the null hypothesis.
e Probability of crossing a bound under the alternative hypothesis.
9.8.2
PFS Hypotheses
Figure 7 shows that initial alpha=0.007 will be allocated to the PFS hypothesis in CPS ≥1 
participants (H2) and no initial alpha will be allocated the PFS hypothesis in all participants 
(H4). According to Figure 7, H2 may also be tested at alpha= 0.025 (H1and H3 rejected). As 
an example, Table 21 shows the bounds and boundary properties for H2, when tested at 
initial alpha=0.007 and full alpha=0.025, derived using a Lan-DeMets O’Brien-Fleming 
spending function based on the predicted number of events, at the planned time of analysis.
The bounds provided in Table 21 are based on the assumption that the expected number of 
events at IA is 494 in CPS1 participants.
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Table 21
Efficacy Boundaries and Properties for PFS Analysis in CPS ≥1 Participants
Analysis
Value
α=0.007
α=0.025
IA 
Z
2.4573
1.96
N: 680
p (1-sided)
a
0.007
0.025
Events: 494
HR at bound
b
0.8016
0.8383
Month: 31
P(Cross) if HR=1
c
0.007
0.025
P(Cross) if HR=0.7
d
0.9352
0.9778
CPS=combined positive score; HR=hazard ratio; IA=interim analysis.
a Nominal alpha for group sequential testing.
b HR at bound is the approximate HR required to reach an efficacy bound.
c Probability of crossing a bound under the null hypothesis.
d Probability of crossing a bound under the alternative hypothesis.
PFS hypothesis in all participants (H4) did not have initial alpha assignment but will receive 
alpha stepped down from PFS hypothesis in CPS ≥1 participants (H2). H4 may be tested at 
alpha= 0.005999 (H2 rejected), 0.021425 (H1, H2, and H3 rejected), and 0.025 (H1, H2, H3, 
H5, and H6 rejected). As an example, Table 22 shows the bounds and boundary properties 
for H4, when tested at alpha=0.005999 and full alpha=0.025, derived using a Lan-DeMets 
O’Brien-Fleming spending function based on the predicted number of events at the planned 
time of analysis.
Table 22
Efficacy Boundaries and Properties for PFS Analysis in All Participants 
Analysis
Value
α=0.005999
α=0.025
IA
Z
2.5122
1.96
N: 880
p (1-sided) a
0.005999
0.025
Events: 644
HR at bound b
0.8204
0.8569
Month: 31
P(Cross) if HR=1c
0.005999
0.025
P(Cross) if HR=0.73d
0.9316
0.9792
HR=hazard ratio; IA=interim analysis; PFS=progression-free survival.
a Nominal alpha for group sequential testing.
b HR at bound is the approximate HR required to reach an efficacy bound.
c Probability of crossing a bound under the null hypothesis.
d Probability of crossing a bound under the alternative hypothesis.
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If H1 and H3 with regard to OS hypotheses is either rejected at the IA or rejected at final 
analysis, the reallocation strategy allows retesting of PFS based on the data for the PFS final 
analysis at IA.
9.8.3
ORR Hypotheses
No initial alpha will be allocated for the ORR hypothesis in CPS ≥1 participants (H5) or in 
all participants (H6). H5 will receive alpha stepped down from PFS hypothesis in CPS ≥1 
participants (H2). H5 may be tested at alpha= 0.001001 (H2 rejected), 0.003575 (H1, H2 and 
H3 rejected) and 0.025 (H1, H2, H3 and H4 rejected).
H6 will receive alpha stepped down from ORR hypothesis in CPS ≥1 participants (H5). H6 
may be tested at alpha= 0.001001 (H2 and H5 rejected), 0.003575 (H1, H2, H3 and H5 
rejected) and 0.025 (H1, H2, H3, H4 and H5 rejected). If H1 and H3 with regard to OS 
hypotheses is either rejected at the IA or rejected at final analysis, the reallocation strategy 
allows retesting of PFS based on the data for the PFS final analysis at IA, and then retesting 
of ORR based on the data from the ORR final analysis at IA if H2 rejected.
The statistical power at an alpha-levels of 0.001001 and 0.025 (one-sided) as well as the 
approximate treatment difference required to reach the bound in terms of ORR difference are 
shown in Table 23.
Table 23
Statistical Power and Approximate ORR Difference Required to Show 
Efficacy for ORR at IA
Sample Size
Expected treatment 
difference 
Alpha
Observed Difference 
Required to Show 
Efficacy
Power
CPS ≥1 (N=680)
20%
0.001001
~11.8%
98.5%
0.025
~7.5%
99.9%
All (N=880)
15%
0.001001
~10.4%
92.0%
0.025
~6.6%
99.5%
CPS=combined positive score; IA=interim analysis; ORR=overall response rate.
9.8.4
Safety Analyses
The eDMC has responsibility for assessment of overall risk:benefit. When prompted by 
safety concerns, the eDMC can request corresponding efficacy data. External DMC review of 
efficacy data to assess the overall risk:benefit to study participants will not require a 
multiplicity adjustment typically associated with a planned efficacy IA. However, to account 
for any multiplicity concerns raised by the eDMC review of unplanned efficacy data 
prompted by safety concerns, a sensitivity analysis for efficacy endpoints adopting a 
conservative multiplicity adjustment will be prespecified in the sSAP. This analysis will be 
performed if requested by the eDMC.
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9.9
Sample Size and Power Calculations 
The enrollment is complete.
Part 1
Approximately 12 subjects will be enrolled in Part 1. The sample size is determined based on 
clinical considerations to rule out dose-limiting toxicities. 
Part 2
The study will randomize participants in a 1:1 ratio into the experimental group and the 
control group. PFS and OS are primary endpoints for the study, with ORR as the key 
secondary endpoint. Approximately 878 participants are planned to be enrolled. The actual 
overall sample size of the study for all participants is 880. The sample size for CPS ≥1 
participants is approximately 680. Power and IA calculations were performed using the 
gsDesign R package.
9.9.1
Overall Survival 
There will be ~537 deaths at the OS final analysis in CPS ≥1 participants. With 537 deaths, 
the study has ~85% power for detecting an HR of 0.76 at an initially assigned 0.018 
(one-sided) significance level.
If H1 (ie, OS endpoint in CPS ≥1 participants) is rejected, alpha=0.018 can be passed from 
H1 to H3 (OS endpoint in all participants). There will be ~701 deaths in all participants at the 
final OS analysis. With 701 deaths, the study has ~80% power for detecting an HR of 0.80 at 
a significance level of 0.018 (1-sided).
The sample size (number of participants) calculations are based on the following 
assumptions: (1) the actual enrollment period is 22 months, and the ramp-up period of 
enrollment is 6 months; (2) the duration of OS follow exponential distribution; (3) median 
OS is 11.5 months in the control group and the true HR are 0.76 in CPS ≥1 participants and 
0.80 in all participants; (4) the annual dropout rate is 1% for OS endpoint. The median OS in 
the control group is based on CPS ≥1 participants treated with the standard care of 
chemotherapy from KN062 (the first line of HER-2 negative, previously untreated, 
unresectable or metastatic gastric/GEJ adenocarcinoma).  
9.9.2
Progression-free Survival
There will be ~494 events at the PFS final analysis in CPS ≥1 participants. With 494 events, 
the study has ~94% power for detecting an HR of 0.7 at an initially assigned 0.007 
(one-sided) significance level.
If H2 (ie, PFS endpoint in CPS ≥1 participants) is rejected, alpha=0.005999 (ie, 85.7% of the 
initially assigned 0.007) can be passed from H2 to H4 (PFS endpoint in all participants). 
There will be ~644 PFS events in all participants at the final PFS analysis. With 644 PFS 
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events, the study has ~93% power for detecting an HR of 0.73 at a significance level of 
0.005999 (1-sided).
The sample size (number of participants) calculations are based on the following 
assumptions: (1) the actual enrollment period is 22 months, and the ramp-up period of 
enrollment is 6 months; (2) the duration of PFS follow exponential distribution; (3) median 
PFS is 6 months in the control group and the true HR are 0.7 in CPS ≥1 participants and 0.73 
in all participants; (4) the annual dropout rate is 25% for PFS endpoint. The median PFS in 
the control group is based on CPS ≥1 participants treated with the standard care of 
chemotherapy from KN062.  
9.9.3
Objective Response Rate
If H2 (ie, PFS endpoint in CPS ≥1 participants) is rejected, alpha=0.001001 can be passed 
from H2 to H5 (ORR endpoint in CPS ≥1 participants). There will be approximately 680 in 
CPS ≥1 participants at IA. With sample size of 680 in CPS ≥1 participants at IA, the study 
has ~98.5% power for detecting a 20-percentage point difference in ORR (57% in the 
experimental group versus 37% in the control group) at a significance level of 0.001001 
(one-sided). 
If H2 and H5 (ie, PFS and ORR endpoint in CPS ≥1 participants) are rejected, 
alpha=0.001001 can be passed from H5 to H6 (ORR endpoint in all participants). There will 
be 880 in all participants at IA. With sample size of 880 in all participants at IA, the study 
has ~92% power for detecting a 15-percentage point difference in ORR (52% in the 
experimental group versus 37% in the control group) at a significance level of 0.001001 
(one-sided). The ORR in the control group is based on CPS ≥1 participants treated with the 
standard care of chemotherapy from KN062. 
9.10
Subgroup Analyses 
To determine whether the treatment effect is consistent across various subgroups, the 
estimate of the between-group treatment effect (with a nominal 95% CI) for the efficacy 
endpoints (ORR, PFS and OS) will be estimated and plotted within each category of each 
subgroup. The subgroup analyses will be conducted for CPS ≥1 participants and ITT 
population, respectively. The following are examples of classification variables:
•
Age category: (<65 versus ≥65 years)
•
Sex: (female versus male)
•
Race: (Asian versus non-Asian)
•
Region: (East Asia, North America + Western Europe versus Rest of World) 
•
PD-L1: (Positive versus Negative)
•
MSI status: (MSI-H versus non-MSI-H)
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•
ECOG status: (0 versus 1)
•
Disease status (locally advanced versus metastatic)
•
Primary location (Gastric Cardia versus GEJ versus Esophageal Adenocarcinoma)
•
Histologic subtype (diffuse versus indeterminate versus intestinal)
•
Tumor Burden: (≥median versus <median)
•
Prior gastrectomy/esophagectomy: (yes versus no) 
•
Chemotherapy (CAPOX versus mFOLFOX6)
The consistency of the treatment effect will be assessed using descriptive statistics for each 
category of the subgroup variables listed above. If the number of participants in a category of 
a subgroup variable is less than 10% of the analysis population, the subgroup analysis will 
not be performed for this category of the subgroup variable, and this subgroup variable may 
not be displayed in the forest plot. The subgroup analyses for PFS and OS will be conducted 
using an unstratified Cox model and the subgroup analyses for ORR will be conducted using 
the unstratified M&N method.
9.11
Compliance (Medication Adherence) 
Drug accountability data for study intervention will be collected during the study. Any 
deviation from protocol-directed administration will be reported.
9.12
Extent of Exposure 
The extent of exposure will be summarized as duration of treatment in months and number of 
cycles or administrations, as appropriate. Summary statistics will be provided on the 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)
I.
Introduction
A. Purpose
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD), through its subsidiaries, 
conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, planning, conducting, analyzing, 
and reporting these trials in compliance with the highest ethical and scientific 
standards. Protection of participants in clinical trials is the overriding concern in the 
design and conduct of clinical trials. In all cases, MSD clinical trials will be 
conducted in compliance with MSD’s global standards, local and/or national 
regulations (including all applicable data protection laws and regulations), Regulation 
(EU) 536/2014, the International Council for Harmonisation Good Clinical Practice 
(ICH GCP) E6 and ICH General Considerations for Clinical Studies E8, and in 
accordance with the ethical principles that have their origin in the Declaration of 
Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical 
interventional investigations sponsored by MSD irrespective of the party (parties) 
employed for their execution (e.g., contract research organizations, collaborative 
research efforts). This Code is not intended to apply to trials that are observational in 
nature, or which are retrospective. Further, this Code does not apply to investigator-
initiated trials, which are not under the full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-
driven to assess safety, efficacy and/or pharmacokinetic or pharmacodynamic 
indices of MSD or comparator products. Alternatively, MSD may conduct 
outcomes research trials, trials to assess or validate various endpoint measures, or 
trials to determine patient preferences, etc.
The design (i.e., participant population, duration, statistical power) must be 
adequate to address the specific purpose of the trial and shall respect the data 
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protection rights of all participants, trial site staff and, where applicable, third 
parties. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
MSD selects investigative sites based on medical expertise, access to appropriate 
participants, adequacy of facilities and staff, previous performance in clinical 
trials, as well as budgetary considerations. Prior to trial initiation, sites are 
evaluated by MSD personnel (or individuals acting on behalf of MSD) to assess 
the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol 
and Good Clinical Practice (GCP). MSD reviews clinical data for accuracy, 
completeness, and consistency. Data are verified versus source documentation 
according to standard operating procedures. Per MSD policies and procedures, if 
potential fraud, scientific/research misconduct, privacy incidents/breaches or 
Clinical Trial-related Significant Quality Issues are reported, such matters are 
investigated. When necessary, appropriate corrective and/or preventative actions 
are defined and regulatory authorities and/or ethics review committees are 
notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary 
results of its registered trials of marketed products in which treatment is assigned, 
according to the pre-specified plans for data analysis. To the extent scientifically 
appropriate, MSD seeks to publish the results of other analyses it conducts that are 
important to patients, physicians, and payers. Some early phase or pilot trials are 
intended to be hypothesis-generating rather than hypothesis testing; in such cases, 
publication of results may not be appropriate since the trial may be underpowered and 
the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the 
International Committee of Medical Journal Editors (ICMJE). In summary, 
authorship should reflect significant contribution to the design and conduct of the 
trial, performance or interpretation of the analysis, and/or writing of the manuscript. 
All named authors must be able to defend the trial results and conclusions. MSD 
funding of a trial will be acknowledged in publications.
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III. Participant Protection
A. Regulatory Authority and Ethics Committee Review (Institutional Review Board 
[IRB]/Independent Ethics Committee [IEC])
All protocols and protocol amendments will be submitted by MSD for regulatory 
authority acceptance/authorization prior to implementation of the trial or amendment, 
in compliance with local and/or national regulations.
The protocol, protocol amendment(s), informed consent form, investigator’s 
brochure, and other relevant trial documents must be reviewed and approved by an 
IRB/IEC before being implemented at each site, in compliance with local and/or 
national regulations. Changes to the protocol that are required urgently to eliminate 
an immediate hazard and to protect participant safety may be enacted in anticipation 
of ethics committee approval. MSD will inform regulatory authorities of such new 
measures to protect participant safety, in compliance with local and/or national 
regulations.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is 
of primary importance. Potential participants will be informed of the risks and 
benefits of, as well as alternatives to, trial participation. At a minimum, trial designs 
will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only 
after informed consent is obtained. Participants may withdraw from an MSD trial at 
any time, without any influence on their access to, or receipt of, medical care that 
may otherwise be available to them.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent 
possible, as well as all applicable data protection rights. Unless required by law, only 
the investigator, Sponsor (or individuals acting on behalf of MSD), ethics committee, 
and/or regulatory authorities will have access to confidential medical records that 
might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed 
consent authorized by an ethics committee.
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IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate 
investigators (or the sponsoring institution) in a fair manner for the work performed 
in support of MSD trials. MSD does not pay incentives to enroll participants in its 
trials. However, when enrollment is particularly challenging, additional payments 
may be made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate 
referring physicians for time spent on chart review and medical evaluation to identify 
potentially eligible participants.
B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD, and that the 
investigator or sponsoring institution is being paid or provided a grant for performing 
the trial. However, the local ethics committee may wish to alter the wording of the 
disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source 
of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, 
investigator meetings, etc.) will be consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial 
protocol, and in signing the protocol, agree to support these ethical and scientific standards.
10.1.2
Financial Disclosure
Financial disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor’s responsibility to determine, based on these regulations, whether a request for 
financial disclosure information is required. It is the investigator’s/subinvestigator’s 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide their financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, frequently known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
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information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
10.1.3
Data Protection
The Sponsor will conduct this study in compliance with all applicable data protection 
regulations.
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information that would make the participant identifiable will not be transferred.
The participant must be informed that their 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 their medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
The Sponsor has EU-approved Binding Corporate Rules since 2017, covering all aspects of 
its Global Privacy Program (Corporate Policy 20), and is self-certified pursuant to the EU-US 
Data Privacy Framework.
10.1.3.1
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the IRB, IEC, or similar or expert committee, affiliated institution, and 
employees, only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution, and employees. Data generated by this study will be 
considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol.
10.1.3.2
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF data. By signing the consent form, the participant agrees to this 
process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked before 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.
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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.
10.1.5
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 
CCI
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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 FDAAA of 2007 and the EMA clinical trials Regulation 536/2014, the 
Sponsor of the study is solely responsible for determining whether the study and its results 
are subject to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu, https://euclinicaltrials.eu, or other local registries. MSD, as 
Sponsor of this study, will review this protocol and submit the information necessary to 
fulfill these requirements. MSD entries are not limited to FDAAA or the EMA clinical trials 
Regulation 536/2014 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 Regulation 536/2014, or other locally mandated registries 
are that of the Sponsor and agrees not to submit any information about this study or its results 
to those registries.
10.1.7
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of GCP 
(eg, International Council on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use GCP: Consolidated Guideline and other generally accepted 
standards of GCP); and all applicable federal, state and local laws, rules and regulations 
relating to the conduct of the clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Trials.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
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The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority. 
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
For investigators located in countries with serious breach reporting requirements, investigator 
will promptly report to the Sponsor any serious breach or suspected serious breach that 
occurs in compliance with those requirements. Unless more specifically defined in the 
applicable requirements, a serious breach is any breach of the applicable clinical trial 
regulation or of the clinical trial protocol which is likely to affect to a significant degree: (i) 
the safety or rights of a trial participant, or (ii) the reliability and robustness of the data 
generated in the clinical trial.
10.1.8
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
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 
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study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including participants’ documented informed consent, pertaining to 
the conduct of this study must be retained by the investigator for 15 years after study 
completion unless local regulations or institutional policies require a longer retention period 
(eg, EU CTR: 25 years after the end of the study). No records may be destroyed during the 
retention period without the written approval of the Sponsor. No records may be transferred 
to another location or party without written notification to the Sponsor.
10.1.9
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.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor or 
designee will promptly notify that study site’s IRB/IEC as specified by applicable regulatory 
requirement(s).
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10.2
Appendix 2: Clinical Laboratory Tests
•
The tests detailed in Table 24 will be performed by the local laboratory.
•
Central laboratory testing is only required if the local laboratory testing is not available.
•
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 (Appendix 7).
•
The investigator (or medically qualified designee) must document their review of each 
laboratory safety report.
Table 24
Protocol-Required Safety Laboratory Assessments
Hematology
Comprehensive 
Chemistry Panel
Urinalysis/Urine 
Dipsticka
Other
Hematocrit
Hemoglobin
Platelet count
RBC indices:
     MCVc
     MCHc
     % reticulocytesg
WBC count with 
differential 
(absolute or 
percentage):
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
Albumin
Alkaline phosphatase
ALT
Amylase AST
BUN or Uread 
Carbon dioxide (CO2 or 
Bicarbonate)g
Calcium
Chloride
CRP (as detailed in 
Section 1.3)
Creatinine
Glucose
Lipase
Magnesium
Phosphorus
Potassium
Sodium
Total bilirubin (and direct 
bilirubin, if total bilirubin 
is elevated above the 
upper limit of normal)
Total protein
Hemoglobin or blood
Glucose
pH Protein
Specific gravity Ketone
Microscopic 
examination 
(urinalysis), if abnormal 
results are noted 
Follicle-stimulating 
hormone (FSH)b
Pregnancy test (urine or 
serum)c
Hepatitis B and C testinge,f
HIV testingf
PT/INR and aPTT/PTT
Total T3, FT4, and TSHh,i
ALT=alanine aminotransferase; aPTT=activated partial thromboplastin time; AST=aspartate aminotransferase; BUN=blood urea 
nitrogen; DNA=deoxyribonucleic acid; FT3=free triiodothyronine; FT4=free thyroxine; HbsAg=hepatitis B surface antigen; 
HBV=hepatitis B virus; HCV=hepatitis C virus; HIV=human immunodeficiency virus; INR=international normalized ratio; 
PK=pharmacokinetics; PT=prothrombin time; PTT=partial thromboplastin time; RNA=ribonucleic acid; T3=triiodothyronine; 
T4=thyroxine; TSH=thyroid-stimulating hormone; WBC=white blood cell; WOCBP=women of childbearing potential
a
If urine dipstick is abnormal, urinalysis must be performed.
b
If necessary, to check menopausal status. 
c
Perform on WOCBP only 24 hours for urine or 72 hours for serum before first dose. Pregnancy tests must be repeated before 
every cycle.
d
BUN or urea (one or the other should be collected per institutional standard). 
e
HbsAg or HBV DNA. HCV RNA (qualitative) or HCV antibody.
f
Not required unless mandated by local health authorities (Appendix 7).
g
Only if available as standard of care in the region.
h
After Cycle 1, participants may be dosed while thyroid function test results are pending.
i
Free T3/T4 is acceptable when total T3/T4 cannot be determined.
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definitions of Medication Error, Misuse, and Abuse
Medication Error
This is an unintended failure in the drug treatment process that leads to or has the potential to 
lead to harm to the patient.
Misuse
This refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the terms of the product information.
Abuse
This corresponds to the persistent or sporadic intentional, excessive use of a medicinal 
product for a perceived psychological or physiological reward or desired nontherapeutic 
effect.
10.3.2
Definition of AE
AE definition
•
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.
•
Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.
•
Note: For purposes of AE definition, study intervention includes any pharmaceutical 
product, biological product, vaccine, diagnostic agent, medical device, combination 
product, or protocol-specified procedure whether investigational or marketed (including 
placebo, active comparator product, or run-in intervention), manufactured by, licensed 
by, provided by, or distributed by the Sponsor for human use in this study.
Events meeting the AE definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.
•
Exacerbation of a chronic or intermittent preexisting condition including either an 
increase in frequency and/or intensity of the condition.
•
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.
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•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.
•
For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”
•
Lenvatinib overdose without an associated adverse event is not reportable as an AE. 
•
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 preexisting disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
•
Surgical procedure(s) planned prior to informed consent to treat a preexisting condition 
that has not worsened.
•
Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.3
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b. Is life-threatening
-
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 preexisting condition that has not 
worsened is not an SAE.) A preexisting condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
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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.
-
All potential DILI events meeting biochemical criteria of Hy’s Law will be reported 
to the Sponsor, regardless of suspected etiology, as an ECI and SAE with OME 
criteria in the absence of other SAE criteria within 24 hours of learning of the event.
10.3.4
Additional Events Reported
Additional events that require reporting
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor 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 the cancer under study) as noted in Section 8.4.1.
•
Is associated with an overdose.
10.3.5
Recording AE and SAE
AE and SAE recording
•
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.
•
The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.
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•
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 CTCAE, version 5. 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 ADL.
-
Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care ADL.
-
Grade 4: Life-threatening consequences; urgent intervention indicated.
-
Grade 5: Death related to AE.
Assessment of causality
•
Did the Sponsor’s product cause the AE?
•
The determination of the likelihood that the Sponsor’s product caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed 
document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test product and the AE based upon the available information.
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•
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 
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RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR AS PER DOSE 
MODIFICATION GUIDELINES IN THE PROTOCOL, AND IF REQUIRED, THE 
INIRB/IEC.
•
Consistency with study intervention profile: Is the clinical/pathological presentation of 
the AE consistent with previous knowledge regarding the Sponsor’s product or drug class 
pharmacology or toxicology?
•
The assessment of relationship will be reported on the case report forms/worksheets by 
an investigator who is a qualified physician according to their best clinical judgment, 
including consideration of the above elements.
•
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a 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 they have 
reviewed the AE/SAE and have 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 their opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment.
•
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.
•
For studies in which multiple agents are administered as part of a combination regimen, 
the investigator may attribute each AE causality to the combination regimen or to a single 
agent of the combination. In general, causality attribution should be assigned to the 
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combination regimen (ie, to all agents in the regimen). However, causality attribution 
may be assigned to a single agent if in the investigator’s opinion, there is sufficient data 
to support full attribution of the AE to the single agent.
Follow-up of AE and SAE
•
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
•
New or updated information will be recorded in the CRF.
•
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool
•
The primary mechanism for reporting to the Sponsor will be the EDC tool.
-
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
-
If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper AE Reporting form.
-
Reference Section 8.4.1 for reporting time requirements.
•
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
•
After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.
•
If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).
•
Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF
•
If the EDC tool is not operational, facsimile transmission or secure email of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.
•
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
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•
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
•
Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
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10.4
Appendix 4: Medical Device and Drug–Device Combination Products: Product 
Quality Complaints/Malfunctions: Definitions, Recording, and Follow-up
Not applicable.
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10.5
Appendix 5: Contraceptive Guidance
10.5.1
Definitions
Women of Childbearing Potential (WOCBP)
A woman is considered fertile 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 one of the following:
-
Documented hysterectomy
-
Documented bilateral salpingectomy
Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.
•
Postmenopausal female
-
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.

A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. 
However, in the absence of 12 months of amenorrhea, confirmation with 2 FSH 
measurements in the postmenopausal range is required.
Females on HRT and whose menopausal status is in doubt will be required to use 1 of the 
nonhormonal highly effective contraception methods if they wish to continue their HRT 
during the study. Otherwise, they must discontinue HRT to allow confirmation of 
postmenopausal status before study enrolment.
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10.5.2
Contraceptive Requirements
Female Participants
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

Intrauterine hormone-releasing system (IUS)c

Nonhormonal intrauterine device (IUD)

Bilateral tubal occlusion

Azoospermic partner (vasectomized or secondary to medical cause)
This is a highly effective contraception method provided that the partner is the sole male sexual partner of 
the WOCBP, and the absence of sperm has been confirmed. If not, an additional highly effective method 
of contraception should be used. A spermatogenesis cycle is approximately 90 days.
Note: Documentation of azoospermia can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
Sexual Abstinence

Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual 
lifestyle of the participant.
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 Clinical Trial Facilitation Group (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:
o
Periodic abstinence (calendar, symptothermal, postovulation methods), withdrawal (coitus 
interruptus), spermicides only, and lactational amenorrhea method (LAM).
o
Male condom with cap, diaphragm, or sponge with spermicide.
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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
Laboratory Testing
HIV Status
While the protocol does not require specific testing for HIV at Screening, it does require 
testing if required by the local health authority. Sites should check with their local health 
authority to inquire if country-specific guidance regarding mandatory HIV testing at 
Screening is required. This can also be performed per the discretion of the investigator, if 
desired.
Hepatitis B/C Status
While the protocol does not require specific testing for hepatitis B/C at Screening, it does 
require testing if required by the local health authority. Sites should check with their local 
health authority to inquire if country-specific guidance regarding mandatory hepatitis B/C 
testing at Screening is required. This can also be performed per the discretion of the 
investigator, if desired.
10.7.2
Country-Specific Requirements
10.7.2.1
France
Electrocardiogram Assessment
An ECG must be arranged before and at the end of each oxaliplatin IV infusion to monitor 
participants treated with oxaliplatin.
Oxaliplatin administration must be discontinued in the case of QT/QTc interval prolongation 
>500 msec. Continuous ECG (telemetry) monitoring in a hospital setting under the care of a 
cardiologist will be required in the case of QT/QTc prolongation >500 msec.
Inclusion Criteria
The HER2 status of the tumor must be known before the inclusion of participants in the study 
and only participants with a HER2 negative status can be included in this study.
Exclusion Criteria
Sites in France will perform a systematic search for dihydropyrimidine dehydrogenase 
deficiency for participants who are naïve to 5-FU and capecitabine. This research should be 
performed before any administration of 5-FU and capecitabine.
Based on study design, participants on brivudine treatment or with less than 4 weeks since 
last dose of brivudine should be excluded from enrollment.
Live-attenuated vaccines must not be administered for 6 months after the last chemotherapy 
dose.
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Males should use effective contraception during treatment and at least 6 months after the last 
dose of 5-FU or of oxaliplatin treatment.
In the case of proteinuria ≥2 g/24 hours, lenvatinib must be interrupted until proteinuria 
resolves to <2 g/24 hours.
Participants with mild or moderate hepatic impairment liver function tests should be 
monitored every 2 weeks for the first 2 months and then follow protocol visit plan.
10.7.2.2
Argentina
Laboratory Testing
HIV testing and hepatitis B/C screening 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.
WOCBP at study sites in Argentina must have a pregnancy test performed before the start of 
the study, throughout the study and for the duration of the poststudy contraception 
requirements as per SoA in Section 1.3 and Appendix 10.5. Should the study treatment be 
delayed for any reason, then pregnancy testing should occur at least monthly during the 
treatment period. 
10.7.2.3
Germany
Throughout the protocol:
Legally Acceptable Representative
Persons of legal age, who are incapable of comprehending the nature, significance and 
implications of the clinical trial and of determining their will, are excluded from the trial at 
German sites; therefore, all references to a participant’s “legally acceptable representative” in 
the protocol are not applicable for participants in Germany.
Laboratory Testing
HIV testing, and hepatitis B/C screening 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.
Exclusion Criteria
Sites in Germany will perform a systematic search for dihydropyrimidine dehydrogenase 
deficiency for participants who are naïve to 5-FU and capecitabine. This research should be 
performed before any administration of 5-FU and capecitabine.
Based on study design, participants on brivudine treatment or with less than 4 weeks since 
last dose of brivudine should be excluded from enrollment in CAPOX-containing regimens.
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MUGA Scans (for LVEF assessment)
MUGA scans are not standard practice and are not notified to the Federal Office for 
Radiation Protection (BfS). Therefore, only ECHO scans will be performed at the German 
sites for LVEF assessment in accordance with the institution’s standard practice. No MUGA 
scans will be performed in Germany.
10.7.2.4
United Kingdom
Laboratory Testing
Tuberculosis testing, HIV testing, and hepatitis B/C screening 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.
Exclusion Criteria
Sites in United Kingdom will perform a systematic search for dihydropyrimidine 
dehydrogenase deficiency for participants who are naïve to 5-FU and capecitabine. This 
research should be performed before any administration of 5-FU and capecitabine.
Live vaccines must not be administered for 90 days after the last dose of study intervention.
Pregnancy testing must be performed by WOCBP at the study Discontinuation Visit and at 
the end of relevant systemic exposure; ie, 30 days after the last dose of lenvatinib, 120 days 
after last dose of pembrolizumab or 180 days after the last dose of chemotherapy, whichever 
is greater.
Contraception for male participants (as described in Inclusion Criteria 6) must be used during 
the intervention period and for at least 6 months after the last dose of 5-fluorouracil or of 
oxaliplatin.
10.7.2.5
Italy
Exclusion Criteria
Sites in Italy will perform a systematic search for dihydropyrimidine dehydrogenase 
deficiency for participants who are naïve to 5-FU and capecitabine. This research should be 
performed before any administration of 5-FU and capecitabine.
Participants on brivudine treatment or with less than 4 weeks since last dose of brivudine 
should be excluded from enrollment.
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10.7.2.6
Peru
Laboratory Testing
HIV testing and hepatitis B/C screening 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.
Justification of Inclusion of Esophageal Adenocarcinoma
Esophageal adenocarcinoma (EA) is a rare entity that is difficult to study in dedicated large 
randomized clinical trials due to the low prevalence. Often, participants with EA are included 
in esophageal cancer trials where the dominant histopathology is squamous cell carcinoma 
(ESCC). Clinically, participants with EA may be treated with ESCC treatment paradigms, 
which often include radiotherapy. Alternatively, EA may be treated per gastric 
adenocarcinoma (GA) treatment paradigms, which are chemotherapy-based, since the 
histology of EA is more closely related to GA than to ESCC.
The Sponsor acknowledges that the Phase 2 EPOC trial of lenvatinib + pembrolizumab in 
GA did not include participants with EA for practical reasons (low prevalence in a small 
study) [Kawazoe, A., et al 2020a]. However, in KN-590, a study of pembrolizumab/placebo 
+ chemotherapy in esophageal cancer, a prespecified analysis of participants with 
adenocarcinoma showed a benefit of the addition of pembrolizumab to chemotherapy with an 
HR = 0.74 (95% CI: 0.54, 1.02) that was similar to that seen in the ITT population [HR=0.73 
(95% CI: 0.62, 0.0.86; p< 0.0001)] [Sun, J. M., et al 2021]. Based on the results of KN-590, 
pembrolizumab is now approved in the United States and several other countries in 
combination with chemotherapy for the first-line treatment of locally advanced or metastatic 
esophageal or gastroesophageal junction (GEJ) (tumors with epicenter 1 to 5 centimeters 
above the GEJ) carcinoma.
In this LEAP-015 study, the Sponsor seeks to establish the approach for EA participants to be 
treated in line with GA participant treatment paradigms based on their similar 
histopathology. The Sponsor believes that the supportive data from the Phase 1b/2 study in 
upper GI adenocarcinoma participants warrant inclusion of these participants on our study.
10.7.2.7
Ireland
As per clinical practice in Ireland, HIV and Hep B/C testing is required for all participants. 
10.7.2.8
Russia
Inclusion Criteria
The HER2 status of the tumor must be known before the inclusion of participants in the study 
and only participants with a HER2 negative status can be included in this study.
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10.7.2.9
China
Inclusion Criteria
The HER2 status of the tumor must be known before the inclusion of participants in the study 
and only participants with a HER2 negative status can be included in this study.
10.7.2.10
Japan
Background chemotherapy
For 5-FU (mFOLFOX6), in addition to the 500 mg/10 mL or 250 mg/10 mL vials, 1,000 
mg/20 mL vials may also be used.
Study Intervention(s)
Capecitabine, oxaliplatin, 5-FU and levoleucovorin used in this study is categorized as 
“product(s) used in the clinical trial other than test product(s)” in Japan local regulation.
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10.8
Appendix 8: Management of Hypertension
Figure 8
Management of Hypertension – INDUCTION
Figure 9
Management of Hypertension – CONSOLIDATION
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10.9
Appendix 9: Abbreviations
Abbreviation
Expanded Term
5-FU
fluorouracil
ADA
antidrug antibodies
ADL
activities of daily living  
AE
adverse event 
AEOSI
adverse event of special interest
ALT
alanine aminotransferase
ApaT
All-Participants-as-Treated
ASCO
American Society of Clinical Oncology
ASCP
American Society of Clinical Pathology
AST
aspartate aminotransferase
AUC
area under the curve
BICR
blinded independent central review
bid
twice daily
BMI
body mass index
BP
blood pressure
CAP
College of American Pathologists
CAPOX
capecitabine and oxaliplatin
Cavg
average concentration over the dosing interval
CBC
complete blood count
CD28
cluster of differentiation 28
CD3ζ
cluster of differentiation zeta
CHF
congestive heart failure
CI
confidence interval
Cmin
minimum concentration
Cmax
maximum concentration
CNS
central nervous system 
CONSORT
Consolidated Standards of Reporting Trials
COPD
chronic obstructive pulmonary disease
CPS
combined positive score
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Abbreviation
Expanded Term
CrCl
creatinine clearance
CR
complete response
CRF
Case Report Form 
CSAE
clinically significant adverse event
CSR
Clinical Study Report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTCAE v5.0
Common Terminology Criteria for Adverse Events, v5.0
CTFG
Clinical Trial Facilitation Group 
CTLA-4
cytotoxic T-lymphocyte-associated protein 4
DCR
disease control rate
DDI
drug-drug interaction
DILI
drug-induced liver injury
DLT
dose-limiting toxicity
DMC
Data Monitoring Committee 
DNA
deoxyribonucleic acid 
DOR
duration of response
DPD
dihydropyrimidine dehydrogenase
DTC
differentiated thyroid cancer
ECG
electrocardiogram 
ECHO
echocardiogram
ECI
event of clinical interest
eCRF
electronic case report form
ECOG
Eastern Cooperative Oncology Group
EDC
electronic data collection 
EEA
European Economic Area
ELISA
enzyme-linked immunosorbent assay
EMA
European Medicines Agency
EOC
executive oversight committee 
EORTC QLQ-
C30
European Organization For Research & Treatment of Cancer Quality-
of-Life Questionnaire Global Health Status
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Abbreviation
Expanded Term
EORTC QLQ-
STO22
European Organization For Research & Treatment of Cancer Quality-
of-Life Questionnaire (Symptom Score For St022)
ePROs
electronic patient-reported outcomes
EQ-5D-5L
EuroQoL 5 Dimension Questionnaire
ER
exposure response
ESMO
European Society for Medical Oncology
EU CTR
European Union Clinical Trial Regulation
FA
final analysis
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FAS
Full Analysis Set
FGF
fibroblast growth factor
FGFR
fibroblast growth factor receptor
FSH
follicle-stimulating hormone 
FU
fluorouracil
GCP
good clinical practice 
G-CSF
granulocyte colony-stimulating factor
GEJ
gastroesophageal junction
GI
gastrointestinal
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCC
hepatocellular carcinoma
HCV
hepatitis C virus
HER-2
human epidermal growth factor receptor 2
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 
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Abbreviation
Expanded Term
IC50
inhibitor concentration required for 50 percent inhibition 
ICF
Informed Consent Form
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
iCRO
imaging Contract Research Organization
IEC
independent ethics committee
Ig
immunoglobulin
IgG4
immunoglobulin G4
IgV
immunoglobulin-variable
IHC
immunohistochemistry
IND
Investigational New Drug 
INR
international normalized ratio
irAEs
immune-related AEs
IRB
Institutional Review Board
IRT
interactive response technology
ITT
intent-to-treat
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IV
intravenous
IVD
in vitro diagnostic
JRCT
Japan Registry of Clinical Trials
LAM
lactational amenorrhoea method
LVEF
left ventricular ejection fraction
mAb
monoclonal antibody
M&N
Miettinen and Nurminen
M&S
modeling and simulation
MAPK
mitogen activated protein kinase
mFOLFOX6
5-FU + oxaliplatin + leucovorin
MHC1
major histocompatibility complex 1
MRI
magnetic resonance imaging
mRNA
messenger RNA
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Abbreviation
Expanded Term
MSI
microsatellite instability
MSI-H
microsatellite instability-high
MTD
maximum tolerated dose 
MUGA
multigated acquisition
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NSCLC
non–small cell lung cancer
OME
other medical event
ONJ
osteonecrosis of the jaw
ORR
objective response rate
OS
overall survival
OTC
over-the-counter
PD
disease progression
PD-1
programmed cell death 1
PDGR
platelet derived growth factor
PD-L1
programmed cell death ligand 1
PD-L2
programmed cell death ligand 2
PET
positron emission tomography 
PFS
progression-free survival
Pgp
p-glycoprotein
PI
principal investigator
PK
pharmacokinetic
PKCθ
protein kinase C-theta
po
orally
PPES
palmar-plantar erythrodysesthesia syndrome
PR
partial response
PRES
posterior reversible encephalopathy syndrome
PRO
patient-reported outcome
q2w
every 2 weeks
q3w
every 3 weeks
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Abbreviation
Expanded Term
q6w
every 6 weeks
q12w
every 12 weeks
qd
once daily
QoL
quality-of-life
QTcF
QT interval calculated according to the Fridericia
RAG
receptor for advanced glycation
RCC
renal cell carcinoma
RET
rearranged during transfection
RNA
ribonucleic acid
RPLS
reversible posterior leukoencephalopathy syndrome
SAE
serious adverse event 
SAP
Statistical Analysis Plan
SD
stable disease
SLAB
supplemental lab tests (CRF)
SoA
schedule of assessments
SOC
standard of care
sSAP
supplemental statistical analysis plan
SUSAR
suspected unexpected serious adverse reaction
TAM
tumor-associated macrophage
TB
tuberculosis
TBL
total bilirubin level
TCR
T-cell receptor
TKI
tyrosine kinase inhibitor
TRAE
treatment-related adverse events
ULN
upper limit of normal
UPC
urine protein creatinine
UPCR
urine protein creatinine ratio
US
United States
VEGFR
vascular endothelial growth factor receptor
WBC
white blood cell
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Abbreviation
Expanded Term
WOCBP
woman/women of childbearing potential 
XP
cisplatin and capecitabine
ZAP70
zeta-chain-associated protein kinase
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11
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