Clinical trial NCT04776148
Conditions: Colorectal Neoplasms
Keywords: Programmed Cell Death Receptor 1 (PD-1) Programmed Cell Death Receptor Ligand 1 (PD-L1) Programmed Cell Death Receptor Ligand 2 (PD-L2) PD-1 PDL1 PD-L1 PD-L2
Sponsor: Merck Sharp & Dohme LLC
Start date: 2021-03-29; Completion date: 2024-09-27
Enrollment: 480 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to assess the safety and efficacy of lenvatinib (MK-7902/E7080) in combination with pembrolizumab (MK-3475) in participants with metastatic colorectal cancer. The study will also compare lenvatinib plus pembrolizumab with the standard of care treatment of regorafenib and TAS-102 (trifluridine and tipiracil hydrochloride).

The primary study hypothesis is that lenvatinib plus pembrolizumab is superior to standard of care with respect to overall survival.

Detailed description:

Arms: arm 1: Participants receive pembrolizumab 400 mg via intravenous (IV) infusion on Day 1 of each 6-week (Q6W) Cycle for up to 18 cycles (up to approximately 2 years) PLUS lenvatinib 20 mg via oral capsule once daily until progressive disease. arm 2: Participants receive regorafenib 160 mg via oral tablet once daily on Days 1 through 21 of each 4-week cycle OR TAS-102 (trifluridine and tipiracil hydrochloride) 35 mg/m\^2 via oral tablet twice a day on Days 1 through 5 and Days 8-12 of each 4-week cycle until progressive disease.
Interventions: intervention 1: pembrolizumab intervention 2: lenvatinib intervention 3: regorafenib intervention 4: TAS-102 (trifluridine and tipiracil)
Intervention descriptions: intervention 1: IV infusion intervention 2: oral capsule intervention 3: oral tablet intervention 4: oral tablet

Protocol documents:
Prot_SAP_000.pdf: 
Official Protocol Title:
NCT number:
Document Date:
A Phase 3 Randomized Study of Lenvatinib in 
Combination with Pembrolizumab Versus Standard 
of Care in Participants with Metastatic Colorectal 
Cancer Who Have Received and Progressed On or 
After or Became Intolerant to Prior Treatment
NCT04776148
14 July 2022


PRODUCT: MK-7902  
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PROTOCOL/AMENDMENT NO.: 017-03 (E7080-G000-325)
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Title Page
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME LLC, RAHWAY, NJ, USA (MSD).
Protocol Title: A Phase 3 Randomized Study of Lenvatinib in Combination with 
Pembrolizumab Versus Standard of Care in Participants with Metastatic Colorectal Cancer 
Who Have Received and Progressed On or After or Became Intolerant to Prior Treatment
Protocol Number: MK-7902-017-03 (E7080-G000-325)
Compound Number: MK-7902 (E7080/lenvatinib) and MK-3475 (pembrolizumab)
Sponsor Name:
Merck Sharp & Dohme LLC
(hereafter referred to as the Sponsor or MSD)
The study is 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):
IND
140284
EudraCT
2020-004289-20
Approval Date: 14 July 2022
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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 03
14-JUL-2022
To clarify metastatic liver subgroup language.
Amendment 02
13-APR-2021
Response to Health Authority requests, updating lenvatinib toxicity information.
Amendment 01
12-FEB-2021
Update per country Health Authorities and clarify information.
Original Protocol
16-NOV-2020
Not applicable.
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PROTOCOL AMENDMENT SUMMARY OF CHANGES 
Amendment: 03
Overall Rationale for the Amendments:
To clarify metastatic liver subgroup language.
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
9.10 Subgroup Analyses
Clarified liver metastasis subgroup 
language.
Removed reference to HRD.
Clarification of parameters.
HRD status is not routinely tested in participants with 
CRC.
Title Page
10.1.1 Code of Conduct for 
Clinical Trials
Sponsor entity name and address change.
Merck Sharp & Dohme underwent an entity name and 
address change to Merck Sharp & Dohme LLC, 
Rahway, NJ, USA. This conversion resulted only in an 
entity name change and update to the address.
1.3.1 Arm A: Lenvatinib 
Plus Pembrolizumab 
Treatment
1.3.2 Arm B: Regorafenib 
Treatment
1.3.3 Arm B: TAS-102 
Treatment
Removed reference to AE/SAE safety 
assessment on clinic day every 2 weeks.
Text added in error.
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Section # and Name
Description of Change 
Brief Rationale 
4.1 Overall Design
4.2.1.3.2 EuroQoL EQ-5D-
5L
8.1.1.1 General Informed 
Consent
8.4.1 Time Period and 
Frequency for Collecting 
AE, SAE, and Other 
Reportable Safety Event 
Information
10.1.2 Financial Disclosure
10.1.3 Data Protection
10.3.5 Recording of AE and 
SAE
10.7.1 Germany-specific 
Requirements
Change “he/she” to “the investigator,” or 
“they” and “his/her” to “their”.
Adopt gender neutral language.
4.4 Beginning and End of 
Study Definition
Added language for European Economic 
Area countries
Per Regulation (EU) No 536/2014 of the European 
Parliament and of the Council
5.1 Inclusion Criteria
#12 Updated language related to 
breastfeeding and contraception use.
#13 Changed to documented informed 
consent
Clarification of breastfeeding and contraception 
requirements.
Per COVID-19 requirements
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Section # and Name
Description of Change 
Brief Rationale 
5.2 Exclusion Criteria
#9 Removed pacemaker language.
#20 Added COVID-19 reference.
To ensure that participants with QTcF interval to >480 
ms are not entered into the trial.
Adherence to COVID-19 requirements.
6.1 Study Intervention(s) 
Administered
Updated Table 6 to reflect proper 
nomenclature for study interventions.
To align with EU CTR.
6.5.1.1 Arm A Prohibited 
Concomitant Medication(s)
Added COVID-19 information.
Adherence to COVID-19 requirements.
8.3.6 Pregnancy Test
Removed reference to local regulations.
Clarification of information.
8.4 Adverse Events, Serious 
Adverse Events, and Other 
Reportable Safety Events
10.3.1 Definitions of 
Medication Error, Misuse, 
and Abuse
Added language related to investigator 
documenting SAE related to medication 
error, misuse, abuse, and their definition.
Added new Section 10.3.1.
Per Regulation (EU) No 536/2014 of the European 
Parliament and of the Council.
8.4.7 Events of Clinical 
Interest
10.3.2 Definition of AE
Added information regarding lenvatinib 
overdose.
To clarify that lenvatinib overdose without an associated 
AE is not to be reported as an ECI.
3 Hypotheses, Objectives, 
and Endpoints
4.2.1.1 Efficacy Endpoints
9.4.3 PRO Endpoints
Changed reference from health utility 
score / status to VAS.
Clarification of endpoint measure.
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Section # and Name
Description of Change 
Brief Rationale 
10.2 Appendix 2: Clinical 
Laboratory Tests
Removed bicarbonate from footnote a in 
Table 18.
Clarification of testing.
10.7.3 China-specific 
Requirements
Updated laboratory specimen collection 
information.
To accommodate central testing timelines for lipase, 
amylase, and 24-hour urine collection in China. Only 
applicable for sites that cannot perform these tests 
locally.
10.7.4 Korea-specific 
Requirements
Updated hepatic function test collection 
information.
To align with local regorafenib label.
Throughout Document
Minor administrative, formatting, 
grammatical, and/or typographical 
changes were made throughout the 
document.
To ensure clarity and accurate interpretation of the 
intent of the protocol.
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................18
1.1
Synopsis.................................................................................................................18
1.2
Schema ..................................................................................................................23
1.3
Schedule of Activities...........................................................................................24
Arm A: Lenvatinib Plus Pembrolizumab Treatment ...................................24
Arm B: Regorafenib Treatment ...................................................................46
Arm B: TAS-102 Treatment........................................................................65
2
INTRODUCTION..........................................................................................................83
2.1
Study Rationale....................................................................................................83
2.2
Background ..........................................................................................................85
Pharmaceutical and Therapeutic Background .............................................85
2.2.1.1
Lenvatinib ..........................................................................................85
2.2.1.2
Pembrolizumab ..................................................................................86
2.2.1.3
Pembrolizumab Plus Lenvatinib........................................................87
2.2.1.4
Standard of Care ................................................................................87
Preclinical and Clinical Studies ...................................................................88
2.2.2.1
Lenvatinib as Monotherapy in CRC ..................................................88
2.2.2.2
Pembrolizumab as Monotherapy in mCRC that is Not MSI-
H/dMMR............................................................................................88
2.2.2.3
Pembrolizumab Monotherapy in MSI-H/dMMR CRC .....................88
2.2.2.4
Lenvatinib in Combination with Pembrolizumab in CRC.................89
Ongoing Clinical Studies.............................................................................92
Information on Other Study-related Therapy ..............................................92
2.3
Benefit/Risk Assessment......................................................................................92
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................93
4
STUDY DESIGN............................................................................................................95
4.1
Overall Design......................................................................................................95
4.2
Scientific Rationale for Study Design.................................................................98
Rationale for Endpoints ...............................................................................99
4.2.1.1
Efficacy Endpoints.............................................................................99
4.2.1.1.1
RECIST 1.1..............................................................................99
4.2.1.2
Safety Endpoints..............................................................................100
4.2.1.3
Patient-reported Outcomes...............................................................100
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4.2.1.3.1
EORTC QLQ-C30 and EORTC QLQ-CR29 ........................100
4.2.1.3.2
EuroQoL EQ-5D-5L ..............................................................100
4.2.1.4
Pharmacokinetic Endpoints .............................................................101
4.2.1.5
Pharmacodynamic Endpoints...........................................................101
4.2.1.6
Planned Exploratory Biomarker Research.......................................101
Rationale for the Use of Comparator.........................................................103
4.3
Justification for Dose.........................................................................................103
Lenvatinib ..................................................................................................103
Pembrolizumab ..........................................................................................104
Maximum Dose/Exposure for This Study .................................................104
4.3.3.1
Arm A ..............................................................................................104
4.3.3.2
Arm B...............................................................................................104
4.4
Beginning and End of Study Definition ...........................................................105
Clinical Criteria for Early Study Termination ...........................................105
5
STUDY POPULATION ..............................................................................................105
5.1
Inclusion Criteria...............................................................................................105
5.2
Exclusion Criteria..............................................................................................110
5.3
Lifestyle Considerations....................................................................................113
Meals and Dietary Restrictions..................................................................113
Contraception.............................................................................................113
Caffeine, Alcohol, and Tobacco Restrictions ............................................113
Activity Restrictions ..................................................................................114
5.4
Screen Failures...................................................................................................114
5.5
Participant Replacement Strategy....................................................................114
6
STUDY INTERVENTION..........................................................................................114
6.1
Study Intervention(s) Administered.................................................................114
6.2
Preparation/Handling/Storage/Accountability ...............................................116
Dose Preparation........................................................................................116
6.2.1.1
Lenvatinib ........................................................................................116
6.2.1.2
Pembrolizumab ................................................................................116
6.2.1.3
Regorafenib......................................................................................116
6.2.1.4
TAS-102...........................................................................................117
Handling, Storage, and Accountability......................................................117
6.3
Measures to Minimize Bias: Randomization and Blinding............................118
Intervention Assignment............................................................................118
Stratification...............................................................................................118
Blinding......................................................................................................118
6.4
Study Intervention Compliance........................................................................118
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Arm A ........................................................................................................119
Arm B.........................................................................................................119
6.5
Concomitant Therapy........................................................................................119
Prohibited Concomitant Medication(s)......................................................120
6.5.1.1
Arm A Prohibited Concomitant Medication(s)................................120
6.5.1.2
Arm B Prohibited Concomitant Medication(s)................................121
Drug Interactions .......................................................................................121
6.5.2.1
Arm A Drug Interactions .................................................................121
6.5.2.2
Arm B Drug Interactions .................................................................121
Rescue Medications and Supportive Care .................................................121
6.6
Dose Modification (Escalation/Titration/Other).............................................122
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue)...............................................................................................123
6.6.1.1
Dose Modification and Toxicity Management of Infusion 
Reactions Related to Pembrolizumab..............................................128
Dose Modification and Toxicity Management Related to Lenvatinib.......129
6.6.2.1
Management of Hypertension..........................................................131
6.6.2.2
Management of Proteinuria..............................................................133
6.6.2.3
Management of Diarrhea .................................................................134
6.6.2.4
Management of Hepatotoxicity........................................................134
6.6.2.5
Management of Thromboembolic Events........................................134
6.6.2.6
Management of Posterior Reversible Encephalopathy 
Syndrome/Reversible Encephalopathy Syndrome/ Reversible 
Posterior Leukoencephalopathy Syndrome .....................................134
6.6.2.7
Management of Hypocalcemia ........................................................135
6.6.2.8
Management of Hemorrhage ...........................................................135
6.6.2.9
Management of Gastrointestinal Perforation or Fistula Formation .135
6.6.2.10
Management of QT Prolongation ....................................................135
6.6.2.11
Management of Osteonecrosis of the Jaw .......................................135
Dose Modifications for Overlapping Toxicities ........................................135
Other Allowed Dose Interruptions.............................................................137
6.7
Intervention After the End of the Study..........................................................137
6.8
Clinical Supplies Disclosure..............................................................................137
6.9
Standard Policies................................................................................................137
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL..........................................................................................................137
7.1
Discontinuation of Study Intervention.............................................................137
7.2
Participant Withdrawal From the Study.........................................................139
7.3
Lost to Follow-up ...............................................................................................139
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8
STUDY ASSESSMENTS AND PROCEDURES......................................................140
8.1
Administrative and General Procedures .........................................................140
Informed Consent.......................................................................................140
8.1.1.1
General Informed Consent...............................................................141
Inclusion/Exclusion Criteria ......................................................................141
MSI-H/dMMR Local Testing and Biopsy Sample....................................141
Participant Identification Card...................................................................142
Medical History .........................................................................................142
Oncologic Disease Medical History ..........................................................142
Prior and Concomitant Medications Review.............................................142
8.1.7.1
Prior Medications.............................................................................142
8.1.7.2
Concomitant Medications................................................................143
8.1.7.3
Prior Oncologic Treatment ..............................................................143
Assignment of Screening Number.............................................................143
8.1.8.1
Treatment Eligibility Assessment Form ..........................................143
Assignment of Treatment/Randomization Number...................................143
Study Intervention Administration ............................................................143
8.1.10.1
Timing of Dose Administration.......................................................144
8.1.10.1.1
Arm A ....................................................................................145
8.1.10.1.1.1
Lenvatinib Administration...........................................145
8.1.10.1.1.2
Pembrolizumab Administration...................................145
8.1.10.1.2
Arm B.....................................................................................145
8.1.10.1.2.1
Regorafenib Administration.........................................145
8.1.10.1.2.2
TAS-102 Administration .............................................145
8.1.10.2
Compliance ......................................................................................146
8.1.10.2.1
Lenvatinib ..............................................................................146
8.1.10.2.2
Pembrolizumab ......................................................................146
8.1.10.2.3
Regorafenib............................................................................146
8.1.10.2.4
TAS-102.................................................................................146
Discontinuation and Withdrawal ...............................................................147
Participant Blinding/Unblinding................................................................147
Calibration of Equipment...........................................................................147
Tumor Tissue for Biomarker Status...........................................................147
8.2
Efficacy Assessments .........................................................................................148
Tumor Imaging and Assessment of Disease..............................................148
8.2.1.1
Initial Tumor Scans..........................................................................149
8.2.1.2
Tumor Scans During the Study........................................................149
8.2.1.3
End-of-Treatment and Follow-up Tumor Scans..............................150
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8.2.1.4
RECIST 1.1 Assessment of Disease................................................150
Patient-reported Outcomes.........................................................................152
8.3
Safety Assessments.............................................................................................153
Physical Examinations...............................................................................153
8.3.1.1
Full Physical Examination...............................................................153
8.3.1.2
Directed Physical Examination........................................................153
Vital Signs..................................................................................................153
Electrocardiograms ....................................................................................154
Echocardiogram or Multiple Gated Acquisition Scan...............................154
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) 154
8.3.5.1
CBC With Differential and Clinical Chemistry...............................155
Pregnancy Test...........................................................................................155
Eastern Cooperative Oncology Group Performance Scale........................156
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events..................................................................................................................156
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ........................................................157
Method of Detecting AEs, SAEs, and Other Reportable Safety Events....158
Follow-up of AE, SAE, and Other Reportable Safety Event Information.159
Regulatory Reporting Requirements for SAE ...........................................159
Pregnancy and Exposure During Breastfeeding ........................................159
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs..........................................................................................160
Events of Clinical Interest..........................................................................160
8.5
Treatment of Overdose......................................................................................160
8.6
Pharmacokinetics...............................................................................................161
8.7
Pharmacodynamics............................................................................................161
8.8
Biomarkers .........................................................................................................161
Planned Genetic Analysis Sample Collection............................................162
8.9
Future Biomedical Research Sample Collection.............................................162
8.10
Medical Resource Utilization and Health Economics.....................................162
8.11
Visit Requirements.............................................................................................162
Screening....................................................................................................162
Treatment Period........................................................................................163
8.11.2.1
Telephone Contact Visit ..................................................................163
Discontinued Participants Continuing to be Monitored in the Study ........163
Posttreatment Visits ...................................................................................163
8.11.4.1
Safety Follow-up Visit.....................................................................163
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8.11.4.2
Efficacy Follow-up Visits................................................................163
8.11.4.3
Subsequent Anti-neoplastic Therapy ...............................................164
8.11.4.4
Survival Follow-up Contacts ...........................................................164
Survival Status ...........................................................................................164
9
STATISTICAL ANALYSIS PLAN ...........................................................................164
9.1
Statistical Analysis Plan Summary...................................................................165
9.2
Responsibility for Analyses/In-house Blinding ...............................................166
9.3
Hypotheses/Estimation ......................................................................................167
9.4
Analysis Endpoints.............................................................................................167
Efficacy Endpoints.....................................................................................167
Safety Endpoints........................................................................................167
PRO Endpoints...........................................................................................168
9.5
Analysis Populations..........................................................................................168
Efficacy Analysis Populations...................................................................168
Safety Analysis Populations ......................................................................168
PRO Analysis Populations.........................................................................168
9.6
Statistical Methods.............................................................................................169
Statistical Methods for Efficacy Analyses.................................................169
9.6.1.1
Overall Survival...............................................................................169
9.6.1.2
Progression-Free Survival................................................................169
9.6.1.3
Objective Response Rate .................................................................171
9.6.1.4
Analysis Strategy for Key Efficacy Variables.................................171
Statistical Methods for Safety Analyses ....................................................171
Statistical Methods for Patient-Reported Outcome Analyses....................173
Demographic and Baseline Characteristics ...............................................174
9.7
Interim Analyses ................................................................................................174
Efficacy Interim Analysis ..........................................................................175
Safety Interim Analysis..............................................................................175
9.8
Multiplicity .........................................................................................................175
Overall Survival.........................................................................................176
Progression-free Survival...........................................................................178
Objective Response Rate ...........................................................................178
Safety Analysis ..........................................................................................179
9.9
Sample Size and Power Calculations ...............................................................179
9.10
Subgroup Analyses.............................................................................................180
9.11
Compliance (Medication Adherence)...............................................................180
9.12
Extent of Exposure.............................................................................................181
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...................................................................................................182
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations......182
Code of Conduct for Clinical Trials...........................................................182
Financial Disclosure...................................................................................184
Data Protection...........................................................................................184
10.1.3.1
Confidentiality of Data ....................................................................185
10.1.3.2
Confidentiality of Participant Records.............................................185
10.1.3.3
Confidentiality of IRB/IEC Information..........................................185
Committees Structure.................................................................................186
10.1.4.1
External Data Monitoring Committee .............................................186
10.1.4.2
Executive Oversight Committee......................................................186
Publication Policy......................................................................................186
Compliance with Study Registration and Results Posting Requirements .186
Compliance with Law, Audit, and Debarment ..........................................187
Data Quality Assurance .............................................................................187
Source Documents .....................................................................................188
Study and Site Closure...............................................................................189
10.2
Appendix 2: Clinical Laboratory Tests............................................................190
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................192
Definitions of Medication Error, Misuse, and Abuse................................192
Definition of AE ........................................................................................192
Definition of SAE ......................................................................................194
Additional Events Reported in the Same Manner as SAE.........................195
Recording AE and SAE .............................................................................195
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................199
10.4
Appendix 4: Medical Device and Drug-device Combination Products: 
Product Quality Complaints/Malfunctions: Definitions, Recording, and 
Follow-up ............................................................................................................200
10.5
Appendix 5: Contraceptive Guidance..............................................................201
Definitions..................................................................................................201
Contraception Requirements......................................................................202
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................203
10.7
Appendix 7: Country-specific Requirements..................................................204
Germany-specific Requirements................................................................204
Argentina-specific Requirements...............................................................204
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China-specific Requirements.....................................................................204
Korea-specific Requirements.....................................................................206
Spain-specific Requirements .....................................................................208
UK-specific Requirements.........................................................................208
Canada-specific Requirements...................................................................208
10.8
Appendix 8: Description of the iRECIST Process for Assessment of 
Disease Progression............................................................................................209
10.9
Appendix 9: Abbreviations ...............................................................................210
11
REFERENCES.............................................................................................................216
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LIST OF TABLES
Table 1
Arm A: Lenvatinib Plus Pembrolizumab Treatment .......................................24
Table 2
Arm B: Regorafenib Treatment .......................................................................46
Table 3
Arm B: TAS-102 Treatment............................................................................65
Table 4
Summary of Efficacy Data in Studies With Monotherapy or Combination 
of RTKi and Anti-PD1/PD-L1 in Patients With mCRC Who Have 
Received and Progressed Through or Became Intolerant to Prior 
Treatment .........................................................................................................91
Table 5
Adequate Organ Function Laboratory Values ...............................................107
Table 6
Study Interventions........................................................................................115
Table 7
Dose Modification and Toxicity Management Guidelines for Immune-
related Adverse Events Associated with Pembrolizumab Monotherapy, 
Coformulations or IO Combinations .............................................................124
Table 8
Pembrolizumab Infusion Reaction Dose Modification and Treatment 
Guidelines ......................................................................................................128
Table 9
Dose Modification Guidelines for Lenvatinib-Related Adverse Events .......130
Table 10
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events...............................................................................158
Table 11
Censoring Rules for Primary and Sensitivity Analyses of PFS.....................170
Table 12
Analysis Strategy for Key Efficacy Variables...............................................171
Table 13
Analysis Strategy for Safety Parameters........................................................173
Table 14
Summary of Interim and Final Analyses Strategy.........................................175
Table 15
Efficacy Boundaries and Properties for Overall Survival Analyses..............177
Table 16
Efficacy Boundaries and Properties for Progression-Free Survival 
Analyses.........................................................................................................178
Table 17
Possible α Levels and Approximate ORR Difference Required to 
Demonstrate Efficacy for Objective Response at IA.....................................179
Table 18
Protocol-required Safety Laboratory Assessments........................................190
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LIST OF FIGURES
Figure 1
Study Schema...................................................................................................23
Figure 2
Decision Making Process When Progression Observed by Investigator.......152
Figure 3
Multiplicity Diagram for Type I Error Control..............................................176
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 3 Randomized Study of Lenvatinib in Combination with 
Pembrolizumab Versus Standard of Care in Participants with Metastatic Colorectal Cancer 
Who Have Received and Progressed On or After or Became Intolerant to Prior Treatment
Short Title: A Phase 3 Study of Lenvatinib Plus Pembrolizumab in Previously Treated
Participants with Metastatic Colorectal Cancer
Acronym: LEAP-017
Hypotheses, Objectives, and Endpoints:
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
Throughout this protocol, the term RECIST 1.1 refers to the adjustment of RECIST 1.1 to 
include a maximum of 10 target lesions and a maximum of 5 target lesions per organ. Refer 
to Section 4.2.1.1.1 for further details. 
In male and female participants with unresectable mCRC that is not MSI-H/dMMR who 
have received and progressed through or have become intolerant to prior treatment (refer to 
Section 5.1):
Primary Objectives
Primary Endpoints
Objective: To compare lenvatinib plus 
pembrolizumab combination therapy to 
SOC with respect to OS.
- Hypothesis (H1): lenvatinib plus 
pembrolizumab is superior to SOC with 
respect to OS.
OS: the time from randomization to death 
due to any cause.
Secondary Objectives
Secondary Endpoints
Objective: To compare lenvatinib plus 
pembrolizumab combination therapy to 
SOC with respect to PFS per RECIST 1.1 as 
assessed by BICR.
- Hypothesis (H2): lenvatinib plus 
pembrolizumab combination therapy is 
superior to SOC with respect to PFS per 
RECIST 1.1 by BICR.
PFS: the time from randomization to the 
first documented disease progression or 
death due to any cause, whichever occurs 
first.
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Objective: To compare lenvatinib plus 
pembrolizumab combination therapy to 
SOC with respect to ORR per RECIST 1.1 
as assessed by BICR.
- Hypothesis (H3): lenvatinib plus 
pembrolizumab is superior to SOC with 
respect to ORR per RECIST 1.1 by BICR.
Objective Response: CR or PR.
Objective: To assess the efficacy of 
lenvatinib plus pembrolizumab combination 
therapy and SOC with respect to DOR per 
RECIST 1.1 by BICR.
DOR, defined as the time from the first 
documented evidence of CR or PR until PD 
or death due to any cause, whichever occurs 
first, in participants demonstrating CR or 
PR.
Objective: To evaluate the safety and 
tolerability of pembrolizumab plus 
lenvatinib versus SOC.
- AEs.
- Study intervention discontinuation due to 
AEs.
Objective: To compare the change from 
baseline in global health status/QoL, 
physical functioning, appetite loss and 
bloating for the combination of 
pembrolizumab plus lenvatinib to SOC.
Score for the following PROs scales/items: 
global health status/QoL (EORTC QLQ-
C30 items 29 and 30), physical functioning 
(EORTC QLQ-C30 items 1-5), appetite loss 
(EORTC QLQ-C30 item 13) and bloating 
(EORTC QLQ-CR29 item 37).
Objective: To compare the TTD in global 
health status/QoL, physical functioning, 
appetite loss and bloating for the 
combination of pembrolizumab plus 
lenvatinib to SOC.
TTD, defined as the time from baseline to 
the first onset of a ≥10-point deterioration 
from baseline in global health status/QoL 
(EORTC QLQ-C30 items 29 and 30), 
physical functioning (EORTC QLQ-C30 
items 1-5), appetite loss (EORTC QLQ-C30 
item 13) and bloating (EORTC QLQ-CR29 
item 37).
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Overall Design:
Study Phase
Phase 3
Primary Purpose
Treatment
Indication
Colorectal Carcinoma
Population
Male and female participants with unresectable mCRC that 
is not MSI-H/dMMR who have received and progressed 
through or have become intolerant to prior treatment (refer 
to Section 5.1)
Study Type
Interventional
Intervention Model
Parallel
This is a multi-site study.
Type of Control
Active control
Study Blinding
Unblinded Open-label
Blinding Roles
No Blinding
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 40 months from the time the first 
participant (or their legally acceptable representative) 
provides documented informed consent until the last 
participant’s last study-related contact.
Number of Participants:
Approximately 434 participants will be randomized in this study. After enrollment of the 
global portion of the study is complete, the study may remain open to enrollment in China 
alone until the target number of participants from China have been enrolled to meet local 
regulatory requirements.
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Intervention Groups and Duration:
Intervention 
Groups
Inter-
vention 
Group 
Name
Drug
Dose 
Strength
Dose 
Frequency
Route of 
Adminis-
tration
Regimen/ 
Treatment 
Period/ 
Vaccination 
Regimen
Use
Arm A
Pembrolizumab
400 mg
Q6W
IV 
Infusion
Up to 18 
administrations
(approximately 
2 years)
Test Product
Lenvatinib
20 mg
QD
po
Until 
progressive 
disease 
Test Product
Arm B
Regorafenib
160 mga
Q4W
(QD on Days 
1-21, no dose 
Days 22-28)
po
Until 
progressive 
disease
Comparator
TAS-102b
35 mg/m2
Q4W (BID on 
Days 1-5 and 
Days 8-12, no 
dose on 
Days 6-7 and 
on 
Days 13-28)
po
Abbreviations: BID=twice daily; IV = intravenously; po = orally; Q6W = every 6 weeks; Q4W = every 
4 weeks; QD = daily; Exp=Experimental
a.
According to local/institutional guidelines, regorafenib may be administered as follows in Cycle 1:
80 mg regorafenib QD on Cycle 1 Days 1 to 7, then 120 mg QD on Days 8 to 14, followed by 160 mg 
QD on Days 15 to 21, and 160 mg QD on subsequent cycles (Days 1 to 21).
b.
TAS-102 is a combination of trifluridine and tipiracil hydrochloride.
Total 
Number of 
Intervention 
Groups/ 
Arms
2 intervention groups
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Duration of 
Participation
Each participant will take part in the study from the time the participant 
provides documented informed consent through the final protocol-specified
contact. 
After a screening phase of up to 28 days, each participant will be assigned 
to receive study intervention until one of the conditions for discontinuation 
of study intervention is met.
Participants may continue treatment with lenvatinib beyond 2 years until 
progression if they experience clinical benefit as assessed by the 
investigator, with Sponsor consultation and approval. Participants in Arm 
A will be permitted to continue study intervention beyond RECIST 1.1 
defined disease progression as long as the investigator considers that the 
participant may experience clinical benefit with continued treatment, and 
the participant is tolerating study intervention. 
Imaging should continue to be performed and submitted to the iCRO when 
progression is identified by the investigator until disease progression is 
verified by BICR, the start of new anticancer treatment, withdrawal of 
consent, or death, whichever occurs first. All decisions to continue 
treatment beyond 2 consecutive scans (at least 4 weeks apart) showing 
progression must be approved by the Sponsor.
At the end of treatment, each participant will be followed for the 
occurrence of adverse events and spontaneously reported pregnancy.
Participants who complete or discontinue study intervention in the absence 
of radiographic disease progression will have posttreatment follow up 
imaging for disease status until any of the conditions for discontinuation of 
imaging are met.
All participants will be followed for overall survival until death, withdrawal 
of consent, or the end of the study.
Study Governance Committees:
Steering Committee
No
Executive Oversight Committee
Yes
Data Monitoring Committee
Yes
Clinical Adjudication Committee
No
Study governance considerations are outlined in Appendix 1.
Study Accepts Healthy Volunteers: No
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A list of abbreviations used in this document can be found in Appendix 9.
1.2
Schema
The study design is depicted in Figure 1.
Figure 1
Study Schema
a.
Refer to Section 5.1, Inclusion Criterion #2 for a list of standard treatments a participant must have 
received.
b.
Refer to Section 1.1 table for Intervention Groups for schedule of administration of regorafenib and 
TAS-102.
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1.3
Schedule of Activities
Arm A: Lenvatinib Plus Pembrolizumab Treatment 
Refer to Appendix 7 for country-specific requirements.
Table 1
Arm A: Lenvatinib Plus Pembrolizumab Treatment 
Study Period
Screen
-ing
Intervention (28-Day Cycles)
Posttreatment Visits
Notes
Visit Number/
Title
Screen
-ing
C1
C2
C3
C4
C5
C6* to 
C26
≥C27
E
O
T
Safety 
FU
Efficacy 
FU
Sur-
vival 
FU
Cycle Day
1
8
15
1
15
1
15
1
15
1
15
1
15
1
15
Scheduling 
Window (days)
-28 to -
1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±
3
±3
±3
±3
±3
At 
D
C
Approx
30 days 
after 
last dose 
Q8W 
(± 7d)
Q12W
(± 14d)
Administrative Procedures
Informed 
Consent
X
If the investigator 
plans to treat 
beyond disease 
progression, 
additional consent 
is required.
Inclusion/ 
Exclusion 
Criteria
X
Participant 
Identification 
Card
X
X
Identification 
card will be 
updated with 
randomization 
number at C1D1.
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Study Period
Screen
-ing
Intervention (28-Day Cycles)
Posttreatment Visits
Notes
Visit Number/
Title
Screen
-ing
C1
C2
C3
C4
C5
C6* to 
C26
≥C27
E
O
T
Safety 
FU
Efficacy 
FU
Sur-
vival 
FU
Cycle Day
1
8
15
1
15
1
15
1
15
1
15
1
15
1
15
Scheduling 
Window (days)
-28 to -
1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±
3
±3
±3
±3
±3
At 
D
C
Approx
30 days 
after 
last dose 
Q8W 
(± 7d)
Q12W
(± 14d)
Demographic 
and Medical 
History and 
family history 
of premature 
CV disease
X
History of Lynch 
Syndrome needs 
to be recorded if 
known
CRC History 
X
Including (but not 
limited to) staging 
at the initial 
diagnosis and at 
study entry 
Prior CRC 
Therapy 
Review
X
Including neo-
adjuvant therapy, 
adjuvant therapy, 
any 
chemotherapy, 
surgery and 
radiation therapy.
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Study Period
Screen
-ing
Intervention (28-Day Cycles)
Posttreatment Visits
Notes
Visit Number/
Title
Screen
-ing
C1
C2
C3
C4
C5
C6* to 
C26
≥C27
E
O
T
Safety 
FU
Efficacy 
FU
Sur-
vival 
FU
Cycle Day
1
8
15
1
15
1
15
1
15
1
15
1
15
1
15
Scheduling 
Window (days)
-28 to -
1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±
3
±3
±3
±3
±3
At 
D
C
Approx
30 days 
after 
last dose 
Q8W 
(± 7d)
Q12W
(± 14d)
Prior/
Concomitant 
Medication 
Review
Concomitant 
medications 
received within 
28days before the 
first dose of study 
intervention 
through 30 days 
after the last dose 
(or 90 days if 
used to treat an 
SAE) will be 
recorded.
Subsequent 
Anti-Neoplastic 
Treatment
X
X
X
X
All anticancer 
therapy will be 
recorded until 
time of death or 
termination of 
survival follow-
up. If a clinical 
visit is not 
feasible, follow 
up information 
may be obtained 
by other means 
such as telephone 
or email
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Study Period
Screen
-ing
Intervention (28-Day Cycles)
Posttreatment Visits
Notes
Visit Number/
Title
Screen
-ing
C1
C2
C3
C4
C5
C6* to 
C26
≥C27
E
O
T
Safety 
FU
Efficacy 
FU
Sur-
vival 
FU
Cycle Day
1
8
15
1
15
1
15
1
15
1
15
1
15
1
15
Scheduling 
Window (days)
-28 to -
1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±
3
±3
±3
±3
±3
At 
D
C
Approx
30 days 
after 
last dose 
Q8W 
(± 7d)
Q12W
(± 14d)
Treatment 
Eligibility 
Assessment
X
Prior to 
randomization, 
the investigator 
must provide 
rationale for 
participants to 
receive 
regorafenib or 
TAS-102.
Randomization 
via IRT
X
It is strongly 
preferred that 
participants 
receive first dose 
of study 
intervention on 
day of 
randomization. 
Disease-specific 
Biomarker
Data Collection
X
Including 
MSI/MMR status, 
BRAF mutation 
status, RAS 
mutation status, 
PD-L1 expression 
(if available), 
TMB (if 
available) and 
HRD if available
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Study Period
Screen
-ing
Intervention (28-Day Cycles)
Posttreatment Visits
Notes
Visit Number/
Title
Screen
-ing
C1
C2
C3
C4
C5
C6* to 
C26
≥C27
E
O
T
Safety 
FU
Efficacy 
FU
Sur-
vival 
FU
Cycle Day
1
8
15
1
15
1
15
1
15
1
15
1
15
1
15
Scheduling 
Window (days)
-28 to -
1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±
3
±3
±3
±3
±3
At 
D
C
Approx
30 days 
after 
last dose 
Q8W 
(± 7d)
Q12W
(± 14d)
Survival Status
After investigator 
determined 
disease 
progression or 
start of new 
anticancer 
treatment. In 
addition, on 
Sponsor request, 
participants may 
be contacted for 
survival status at 
any time during 
the study.
Study Administration
Pembrolizumab 
administration
X
X
X
X
X
X
Participant dosed 
every 6 weeks. 
Starting from 
Cycle 7: 
treatment on D1 
of C7, C10, C13, 
C16, C19, C22, 
C25 and on D15 
of C8, C11, C14, 
C17, C20, C23, 
C26
Lenvatinib 
Dispensing
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispensed every 
2 weeks
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Study Period
Screen
-ing
Intervention (28-Day Cycles)
Posttreatment Visits
Notes
Visit Number/
Title
Screen
-ing
C1
C2
C3
C4
C5
C6* to 
C26
≥C27
E
O
T
Safety 
FU
Efficacy 
FU
Sur-
vival 
FU
Cycle Day
1
8
15
1
15
1
15
1
15
1
15
1
15
1
15
Scheduling 
Window (days)
-28 to -
1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±
3
±3
±3
±3
±3
At 
D
C
Approx
30 days 
after 
last dose 
Q8W 
(± 7d)
Q12W
(± 14d)
Lenvatinib 
Container 
Returned
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Container should 
be returned every 
2 weeks
Lenvatinib 
Administration
po QD
Taken at home 
every day (once 
daily) 
continuously 
On pembro-
lizumab clinic 
day will be taken 
0-4 hours after 
pembrolizumab.
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Study Period
Screen
-ing
Intervention (28-Day Cycles)
Posttreatment Visits
Notes
Visit Number/
Title
Screen
-ing
C1
C2
C3
C4
C5
C6* to 
C26
≥C27
E
O
T
Safety 
FU
Efficacy 
FU
Sur-
vival 
FU
Cycle Day
1
8
15
1
15
1
15
1
15
1
15
1
15
1
15
Scheduling 
Window (days)
-28 to -
1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±
3
±3
±3
±3
±3
At 
D
C
Approx
30 days 
after 
last dose 
Q8W 
(± 7d)
Q12W
(± 14d)
Efficacy 
Tumor Imaging
(Chest, 
abdomen and 
Pelvis)
X
Acquired at 
Screening; then first 
on-study imaging 
assessment after 
initial tumor 
imaging at 
Screening should be 
performed at 8 
weeks (56 days ±7 
days) from the date 
of randomization. 
Subsequent tumor 
imaging should be 
performed every 8 
weeks (56 days ±7 
days) or more 
frequently if 
clinically indicated. 
Imaging timing 
should follow 
calendar days and 
should not be 
adjusted for delays 
in cycle. 
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Study Period
Screen
-ing
Intervention (28-Day Cycles)
Posttreatment Visits
Notes
Visit Number/
Title
Screen
-ing
C1
C2
C3
C4
C5
C6* to 
C26
≥C27
E
O
T
Safety 
FU
Efficacy 
FU
Sur-
vival 
FU
Cycle Day
1
8
15
1
15
1
15
1
15
1
15
1
15
1
15
Scheduling 
Window (days)
-28 to -
1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±
3
±3
±3
±3
±3
At 
D
C
Approx
30 days 
after 
last dose 
Q8W 
(± 7d)
Q12W
(± 14d)
Patient Reported Outcomes 
EQ-5D-5L
EORTC QLQ-
C30
EORTC QLQ-
CR-29
X
X
X
X
X
X
X
X
X
X
X
ePROs should be 
performed in the 
order in the table. It 
is strongly 
recommended that 
ePROs are 
completed prior to 
drug administration, 
adverse event 
evaluation and 
disease status 
notification. ePRO 
collection is 
required at D1 and 
D15 of C1 through 
C3 and then D1 of 
C4 through C12 and 
then D1 of every 
other cycle 
thereafter (ie, C14, 
C16, etc. up to C26) 
until end of 
treatment visit or 
treatment 
discontinuation, or 2 
years, whichever 
occurs first, and at 
the D30 
posttreatment safety 
follow-up visit.
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Study Period
Screen
-ing
Intervention (28-Day Cycles)
Posttreatment Visits
Notes
Visit Number/
Title
Screen
-ing
C1
C2
C3
C4
C5
C6* to 
C26
≥C27
E
O
T
Safety 
FU
Efficacy 
FU
Sur-
vival 
FU
Cycle Day
1
8
15
1
15
1
15
1
15
1
15
1
15
1
15
Scheduling 
Window (days)
-28 to -
1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±
3
±3
±3
±3
±3
At 
D
C
Approx
30 days 
after 
last dose 
Q8W 
(± 7d)
Q12W
(± 14d)
Safety Assessments 
Full Physical 
Examination 
including height
X
X
To be performed 
within 7 days 
prior to start of 
study treatment. 
Directed 
Physical 
Examination
X
X
X
X
X
X#
X
X
X
#
X
X#
X
X#
X
On C1D1, 
C1D15, C2D1, 
C2D15 and on D1 
of each cycle and 
Safety visit. In 
addition to the 
directed PEs in 
the flowchart, a 
symptom-directed 
PE may be 
performed at any 
time during the 
study, as 
clinically 
indicated.
#Additional 
testing on D15 
every 8 weeks 
starting from C3 
(C3D15, C5D15, 
C7D15, C9D15, 
etc)
08G00Y


PRODUCT: MK-7902  
33
PROTOCOL/AMENDMENT NO.: 017-03 (E7080-G000-325)
MK-7902-017-03 FINAL PROTOCOL
14-JUL-2022
Study Period
Screen
-ing
Intervention (28-Day Cycles)
Posttreatment Visits
Notes
Visit Number/
Title
Screen
-ing
C1
C2
C3
C4
C5
C6* to 
C26
≥C27
E
O
T
Safety 
FU
Efficacy 
FU
Sur-
vival 
FU
Cycle Day
1
8
15
1
15
1
15
1
15
1
15
1
15
1
15
Scheduling 
Window (days)
-28 to -
1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±
3
±3
±3
±3
±3
At 
D
C
Approx
30 days 
after 
last dose 
Q8W 
(± 7d)
Q12W
(± 14d)
Weight
X
X
X
X
X
X
X
X
X
X
Taken every 4 
weeks, EOT and 
Safety Visit.
Vital Signs (BP, 
pulse, RR, 
temp) and 
height
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
To be performed 
within 7 days 
prior to start of 
study treatment 
and every 2 
weeks, EOT and 
Safety Visit; BP 
and pulse will be 
measured after 
the participant has 
been resting for 5 
minutes. Height 
measured at 
screening only.
08G00Y


PRODUCT: MK-7902  
34
PROTOCOL/AMENDMENT NO.: 017-03 (E7080-G000-325)
MK-7902-017-03 FINAL PROTOCOL
14-JUL-2022
Study Period
Screen
-ing
Intervention (28-Day Cycles)
Posttreatment Visits
Notes
Visit Number/
Title
Screen
-ing
C1
C2
C3
C4
C5
C6* to 
C26
≥C27
E
O
T
Safety 
FU
Efficacy 
FU
Sur-
vival 
FU
Cycle Day
1
8
15
1
15
1
15
1
15
1
15
1
15
1
15
Scheduling 
Window (days)
-28 to -
1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±
3
±3
±3
±3
±3
At 
D
C
Approx
30 days 
after 
last dose 
Q8W 
(± 7d)
Q12W
(± 14d)
12-lead ECG
X
X
X
X
X
X
X
X
ECG at screening, 
C1D1, C2D1, D1 
of every third 
cycle (12 weeks) 
thereafter (eg, C5, 
C8, C11, etc.), 
EOT, and safety 
follow-up. ECG 
at C1D1 and 
C2D1 should be 
performed 
approximately 2 
hours post-
lenvatinib dose.
For high-risk 
participants 
(Section 8.3.3), 
conduct ECG 
monitoring every 
cycle. If 
lenvatinib is 
discontinued, 
ECGs are only 
required at the 
EOT and Safety 
Follow-up visits.
08G00Y


PRODUCT: MK-7902  
35
PROTOCOL/AMENDMENT NO.: 017-03 (E7080-G000-325)
MK-7902-017-03 FINAL PROTOCOL
14-JUL-2022
Study Period
Screen
-ing
Intervention (28-Day Cycles)
Posttreatment Visits
Notes
Visit Number/
Title
Screen
-ing
C1
C2
C3
C4
C5
C6* to 
C26
≥C27
E
O
T
Safety 
FU
Efficacy 
FU
Sur-
vival 
FU
Cycle Day
1
8
15
1
15
1
15
1
15
1
15
1
15
1
15
Scheduling 
Window (days)
-28 to -
1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±
3
±3
±3
±3
±3
At 
D
C
Approx
30 days 
after 
last dose 
Q8W 
(± 7d)
Q12W
(± 14d)
MUGA Scan or 
ECHO 
X
X
Additional 
assessments as 
clinically 
indicated. 
Assessments 
should use the 
same method 
(MUGA or 
ECHO) 
throughout the 
study. Additional 
LVEF 
assessments may 
be performed as 
clinically
Indicated.
ECOG 
Performance 
Status
X*
X
X
X
X
X
X
X
X
X
*At screening and 
within 3 days 
before initiation 
of study 
intervention
To be obtained 
every 4 weeks on 
D1 of every 
cycle, EOT and 
Safety visit. 
08G00Y


PRODUCT: MK-7902  
36
PROTOCOL/AMENDMENT NO.: 017-03 (E7080-G000-325)
MK-7902-017-03 FINAL PROTOCOL
14-JUL-2022
Study Period
Screen
-ing
Intervention (28-Day Cycles)
Posttreatment Visits
Notes
Visit Number/
Title
Screen
-ing
C1
C2
C3
C4
C5
C6* to 
C26
≥C27
E
O
T
Safety 
FU
Efficacy 
FU
Sur-
vival 
FU
Cycle Day
1
8
15
1
15
1
15
1
15
1
15
1
15
1
15
Scheduling 
Window (days)
-28 to -
1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±
3
±3
±3
±3
±3
At 
D
C
Approx
30 days 
after 
last dose 
Q8W 
(± 7d)
Q12W
(± 14d)
AE/SAE 
Monitoring
AEs monitored up 
to 30 days after 
last dose. SAEs 
monitored up to 
90 days. 
Pregnancy 
monitored up to 
120 days after last 
dose, or 30 days 
after last dose if 
participant starts a 
new anticancer 
therapy, 
whichever is 
sooner.
08G00Y


PRODUCT: MK-7902  
37
PROTOCOL/AMENDMENT NO.: 017-03 (E7080-G000-325)
MK-7902-017-03 FINAL PROTOCOL
14-JUL-2022
Study Period
Screen
-ing
Intervention (28-Day Cycles)
Posttreatment Visits
Notes
Visit Number/
Title
Screen
-ing
C1
C2
C3
C4
C5
C6* to 
C26
≥C27
E
O
T
Safety 
FU
Efficacy 
FU
Sur-
vival 
FU
Cycle Day
1
8
15
1
15
1
15
1
15
1
15
1
15
1
15
Scheduling 
Window (days)
-28 to -
1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±
3
±3
±3
±3
±3
At 
D
C
Approx
30 days 
after 
last dose 
Q8W 
(± 7d)
Q12W
(± 14d)
Telephone 
Contact Visit
X
Telephone 
contact or visit on 
C1D8 will assess 
participants for 
development of 
early toxicity and 
to assess blood 
pressure. Refer to 
Section 8.11.2.1 
for further details. 
An unscheduled 
visit can occur 
prior C1D15 to 
next clinic visit if 
necessary, for 
safety.
08G00Y


PRODUCT: MK-7902  
38
PROTOCOL/AMENDMENT NO.: 017-03 (E7080-G000-325)
MK-7902-017-03 FINAL PROTOCOL
14-JUL-2022
Study Period
Screen
-ing
Intervention (28-Day Cycles)
Posttreatment Visits
Notes
Visit Number/
Title
Screen
-ing
C1
C2
C3
C4
C5
C6* to 
C26
≥C27
E
O
T
Safety 
FU
Efficacy 
FU
Sur-
vival 
FU
Cycle Day
1
8
15
1
15
1
15
1
15
1
15
1
15
1
15
Scheduling 
Window (days)
-28 to -
1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±
3
±3
±3
±3
±3
At 
D
C
Approx
30 days 
after 
last dose 
Q8W 
(± 7d)
Q12W
(± 14d)
Laboratory Procedures
Hematology and 
Chemistry
X*
X
X
X
X
X#
X
X
X#
X
X#
X
X#
X
X
*Screening 
laboratory 
assessments MUST 
be done within 3
days of first dose or 
on C1D1 if results 
are available before 
randomization and 
dosing. After C1, 
predose laboratory 
procedures can be 
conducted up to 72 
hours before dosing. 
Predose on C1D15 
and on D1 of every 
cycle (C2D1, C3D1, 
C4D1 etc.), EOT 
and Safety visit.
#Additional testing 
predose on D15 
every 8 weeks 
starting from C3 
(C3D15, C5D15, 
C7D15, C9D15, 
etc)
08G00Y


PRODUCT: MK-7902  
39
PROTOCOL/AMENDMENT NO.: 017-03 (E7080-G000-325)
MK-7902-017-03 FINAL PROTOCOL
14-JUL-2022
Study Period
Screen
-ing
Intervention (28-Day Cycles)
Posttreatment Visits
Notes
Visit Number/
Title
Screen
-ing
C1
C2
C3
C4
C5
C6* to 
C26
≥C27
E
O
T
Safety 
FU
Efficacy 
FU
Sur-
vival 
FU
Cycle Day
1
8
15
1
15
1
15
1
15
1
15
1
15
1
15
Scheduling 
Window (days)
-28 to -
1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±
3
±3
±3
±3
±3
At 
D
C
Approx
30 days 
after 
last dose 
Q8W 
(± 7d)
Q12W
(± 14d)
Urine Dipsticka
X*
X
X
X
X#
X
X
X
#
X
X#
X
X#
X
X
*Screening 
laboratory 
assessments 
MUST be done 
within 3 days of 
first dose or on 
C1D1 if results 
are available 
before 
randomization 
and dosing. After 
C1, predose 
laboratory 
procedures can be 
conducted up to 
72 hours before 
dosing. If urine 
dipstick is not 
able to be 
performed, 
urinalysis is 
acceptable.
08G00Y


PRODUCT: MK-7902  
40
PROTOCOL/AMENDMENT NO.: 017-03 (E7080-G000-325)
MK-7902-017-03 FINAL PROTOCOL
14-JUL-2022
Study Period
Screen
-ing
Intervention (28-Day Cycles)
Posttreatment Visits
Notes
Visit Number/
Title
Screen
-ing
C1
C2
C3
C4
C5
C6* to 
C26
≥C27
E
O
T
Safety 
FU
Efficacy 
FU
Sur-
vival 
FU
Cycle Day
1
8
15
1
15
1
15
1
15
1
15
1
15
1
15
Scheduling 
Window (days)
-28 to -
1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±
3
±3
±3
±3
±3
At 
D
C
Approx
30 days 
after 
last dose 
Q8W 
(± 7d)
Q12W
(± 14d)
Thyroid 
function (T3, 
T4, and TSH)
X*
X
X
X
X
X
X
X
X
X
*Screening 
laboratory 
assessments 
MUST be done 
within 3 days of 
first dose or on 
C1D1 if results 
are available 
before 
randomization 
and dosing. After 
C1, predose 
laboratory 
procedures can be 
conducted up to 
72 hours before 
dosing. Free T3 
and T4 are 
acceptable.
Collect on D1 of 
each cycle (every 
4 weeks), EOT 
and Safety visit.
08G00Y


PRODUCT: MK-7902  
41
PROTOCOL/AMENDMENT NO.: 017-03 (E7080-G000-325)
MK-7902-017-03 FINAL PROTOCOL
14-JUL-2022
Study Period
Screen
-ing
Intervention (28-Day Cycles)
Posttreatment Visits
Notes
Visit Number/
Title
Screen
-ing
C1
C2
C3
C4
C5
C6* to 
C26
≥C27
E
O
T
Safety 
FU
Efficacy 
FU
Sur-
vival 
FU
Cycle Day
1
8
15
1
15
1
15
1
15
1
15
1
15
1
15
Scheduling 
Window (days)
-28 to -
1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±
3
±3
±3
±3
±3
At 
D
C
Approx
30 days 
after 
last dose 
Q8W 
(± 7d)
Q12W
(± 14d)
INR or PT and 
aPTT (baseline 
only)
X*
*Screening 
laboratory 
assessments 
MUST be done 
within 3 days of 
first dose or on 
C1D1 if results 
are available 
before 
randomization 
and dosing. After 
C1, predose 
laboratory 
procedures can be 
conducted up to 
72 hours before 
dosing. 
Additional testing 
is to be performed 
as clinically 
indicated for 
participants 
taking 
anticoagulants
08G00Y


PRODUCT: MK-7902  
42
PROTOCOL/AMENDMENT NO.: 017-03 (E7080-G000-325)
MK-7902-017-03 FINAL PROTOCOL
14-JUL-2022
Study Period
Screen
-ing
Intervention (28-Day Cycles)
Posttreatment Visits
Notes
Visit Number/
Title
Screen
-ing
C1
C2
C3
C4
C5
C6* to 
C26
≥C27
E
O
T
Safety 
FU
Efficacy 
FU
Sur-
vival 
FU
Cycle Day
1
8
15
1
15
1
15
1
15
1
15
1
15
1
15
Scheduling 
Window (days)
-28 to -
1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±
3
±3
±3
±3
±3
At 
D
C
Approx
30 days 
after 
last dose 
Q8W 
(± 7d)
Q12W
(± 14d)
Serum Tumor 
Marker (CEA 
and CA-19-9)
X
X
X
X
X
X
X
Can be obtained 
within 72 hours 
prior to dosing at 
cycle start.
Screening, D1 of 
every other cycle 
(C1, C3, C5, C7 
etc.), EOT.
Serum hCG or 
Urine 
Pregnancy Test 
(WOCBP only)
X
X
X
X
X
X
X
X
X
WOCBP require a 
negative test prior 
to randomization. 
If more than 
24 hours have 
elapsed prior to 
the first dose of 
study 
intervention, 
another 
pregnancy test is 
required. Testing 
must be 
conducted as 
clinically 
indicated. Serum 
test is only 
required if urine 
test is positive or 
not evaluable.
08G00Y


PRODUCT: MK-7902  
43
PROTOCOL/AMENDMENT NO.: 017-03 (E7080-G000-325)
MK-7902-017-03 FINAL PROTOCOL
14-JUL-2022
Study Period
Screen
-ing
Intervention (28-Day Cycles)
Posttreatment Visits
Notes
Visit Number/
Title
Screen
-ing
C1
C2
C3
C4
C5
C6* to 
C26
≥C27
E
O
T
Safety 
FU
Efficacy 
FU
Sur-
vival 
FU
Cycle Day
1
8
15
1
15
1
15
1
15
1
15
1
15
1
15
Scheduling 
Window (days)
-28 to -
1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±
3
±3
±3
±3
±3
At 
D
C
Approx
30 days 
after 
last dose 
Q8W 
(± 7d)
Q12W
(± 14d)
Serum FSH
(WONCBP 
only)
X
In the absence of 
12 months of 
amenorrhea, 
confirmation with 
2 FSH 
measurements in 
postmenopausal 
range is required.
HIV, HBsAg, 
HCV
X
Only if required 
by local health 
authority.
Biomarker Assessments 
Blood for 
Serum 
Biomarker
Analysis
X
X
X
X
Collect predose 
on C1D1, C2D15, 
C4D1 and at 
EOT. 
Blood for RNA 
Analysis
X
X
X
X
Collect predose 
on C1D1, C2D15, 
C4D1 and at 
EOT. 
08G00Y


PRODUCT: MK-7902  
44
PROTOCOL/AMENDMENT NO.: 017-03 (E7080-G000-325)
MK-7902-017-03 FINAL PROTOCOL
14-JUL-2022
Study Period
Screen
-ing
Intervention (28-Day Cycles)
Posttreatment Visits
Notes
Visit Number/
Title
Screen
-ing
C1
C2
C3
C4
C5
C6* to 
C26
≥C27
E
O
T
Safety 
FU
Efficacy 
FU
Sur-
vival 
FU
Cycle Day
1
8
15
1
15
1
15
1
15
1
15
1
15
1
15
Scheduling 
Window (days)
-28 to -
1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±
3
±3
±3
±3
±3
At 
D
C
Approx
30 days 
after 
last dose 
Q8W 
(± 7d)
Q12W
(± 14d)
Blood for 
ctDNA
Analysis
X
X
X
X
X
X
X
Collect predose 
on C1D1, C2D15, 
C4D1 and then 
collected on Day 
1 of every other 
cycle (C5D1, 
C7D1, C9D1, 
etc.) and at EOT. 
Blood for 
Genetic 
Analysis
X
Collect predose. 
Archival or 
Newly Obtained 
Tissue 
Collection
X
Archival tissue 
should be ≤5 
years. If obtained 
at Screening, the 
procedure should 
be performed 
before screening 
/baseline scans 
are performed. 
Detailed 
instructions for 
the tissue 
specimen 
collection process 
and shipment are 
provided in the 
Laboratory 
Manual.
08G00Y


PRODUCT: MK-7902  
45
PROTOCOL/AMENDMENT NO.: 017-03 (E7080-G000-325)
MK-7902-017-03 FINAL PROTOCOL
14-JUL-2022
Study Period
Screen
-ing
Intervention (28-Day Cycles)
Posttreatment Visits
Notes
Visit Number/
Title
Screen
-ing
C1
C2
C3
C4
C5
C6* to 
C26
≥C27
E
O
T
Safety 
FU
Efficacy 
FU
Sur-
vival 
FU
Cycle Day
1
8
15
1
15
1
15
1
15
1
15
1
15
1
15
Scheduling 
Window (days)
-28 to -
1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±
3
±3
±3
±3
±3
At 
D
C
Approx
30 days 
after 
last dose 
Q8W 
(± 7d)
Q12W
(± 14d)
a.
For urine dipstick, perform 3 days prior to the first dose. Collect at screening, after C1, collect samples predose at C1D15, C2D15, and up to 3 days before D1 of each cycle, 
EOT and Safety Follow-up. Additional testing should be performed predose on D15 every 8 weeks starting from C3 (C3D15, C5D15, C7D15, C9D15, etc). Participants with 
≥2+ proteinuria on urine dipstick during screening will undergo 24-hour urine collection for quantitative assessment of proteinuria. Participants with urine protein ≥1 g/24-
hour will not be eligible. See Section 6.6.2.2 for management of proteinuria. After lenvatinib is discontinued, urine dipstick testing no longer required.
Abbreviations: AE = adverse event; aPTT = activated partial thromboplastin time; BICR = blinded independent central review; BP = blood pressure; hCG; = human chorionic 
gonadotropin; C = cycle; CEA = carcinoembryonic antigen; ctDNA = circulating tumor DNA; D = day; ePRO = electronic patient-reported outcome; ECG = electrocardiogram; 
ECOG = Eastern Cooperative Oncology Group; ECHO = echocardiogram; EORTC = European Organization for Research and Treatment of Cancer; EOT = end of treatment; EQ-
5D-5L = European Quality of Life Five-Dimensional Five-Level Scale Questionnaire; FSH = follicle-stimulating hormone; FU = follow-up; HBsAg = hepatitis B virus surface 
virus antigen; HIV = human immunodeficiency virus; INR = international normalized ratio; LVEF = left ventricular ejection fraction; MMRd = mismatch repair deficiency; MMRp 
= mismatch repair protein; MMS = microsatellite Stable; MSI-H = microsatellite instability-high; MUGA = multigated acquisition; PRO = patient-reported outcome; PT = 
prothrombin time; Q6W = every 6 weeks; Q9W = every 9 weeks; Q12W = every 12 weeks; QLQ-C30 = Quality of Life Questionnaire Core 30 items; QTcF = QT interval 
corrected with Fridericia’s formula; RNA= ribonucleic acid; RR = respiratory rate; SAE = serious adverse event; SoA = schedule of activities; T3 = triiodothyronine; T4 = 
thyroxine; TEA = Treatment Eligibility Assessment; TMB = Tumor mutational burden; TSH = thyroid-stimulating hormone; WOCBP = women of childbearing potential; 
WONCBP = women of nonchildbearing potential.   
08G00Y


PRODUCT: MK-7902  
46
PROTOCOL/AMENDMENT NO.: 017-03 (E7080-G000-325)
MK-7902-017-03 FINAL PROTOCOL
14-JUL-2022
Arm B: Regorafenib Treatment
Refer to Appendix 7 for country-specific requirements.
Table 2
Arm B: Regorafenib Treatment 
Study 
Period
Screening
Intervention (28-Day Cycles)
Posttreatment Visits
Notes
Visit 
Number/
Title
Screening
C1
C2
C3
C4
C5
C6 to 
C26
EOT
Safety 
FU
Efficacy
FU
Survival 
FU
Cycle Day
1
8
15
1
15
1
15
1
15
1
15
1
15
Scheduling 
Window 
(days)
-28 to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
At 
DC
Approx
30 days 
after 
last dose 
Q8W 
(± 7d)
Q12W
(± 14d)
Administrative Procedures
Informed 
Consent
X
Inclusion/
Exclusion 
Criteria
X
Participant 
Identificati
on Card
X
X
Identification card 
will be updated with 
randomization 
number at C1D1.
Demo-
graphics 
and 
Medical 
History and 
family 
history of 
premature 
CV disease
X
History of Lynch 
Syndrome needs to 
be recorded if 
known
08G00Y


PRODUCT: MK-7902  
47
PROTOCOL/AMENDMENT NO.: 017-03 (E7080-G000-325)
MK-7902-017-03 FINAL PROTOCOL
14-JUL-2022
Study 
Period
Screening
Intervention (28-Day Cycles)
Posttreatment Visits
Notes
Visit 
Number/
Title
Screening
C1
C2
C3
C4
C5
C6 to 
C26
EOT
Safety 
FU
Efficacy
FU
Survival 
FU
Cycle Day
1
8
15
1
15
1
15
1
15
1
15
1
15
Scheduling 
Window 
(days)
-28 to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
At 
DC
Approx
30 days 
after 
last dose 
Q8W 
(± 7d)
Q12W
(± 14d)
Colorectal 
Cancer 
History 
X
Including (but not 
limited to) staging 
at the initial 
diagnosis and at 
study entry 
Prior CRC 
Therapy 
Review
X
Including neo-
adjuvant therapy, 
adjuvant therapy, 
any chemotherapy, 
surgery and 
radiation therapy.
Prior/
Conco-
mitant 
Medication 
Review
Concomitant 
medications 
received within 30 
days before the first 
dose of study 
intervention through 
30 days after the last 
dose (or 90 days if 
used to treat an 
SAE) will be 
recorded.
08G00Y


PRODUCT: MK-7902  
48
PROTOCOL/AMENDMENT NO.: 017-03 (E7080-G000-325)
MK-7902-017-03 FINAL PROTOCOL
14-JUL-2022
Study 
Period
Screening
Intervention (28-Day Cycles)
Posttreatment Visits
Notes
Visit 
Number/
Title
Screening
C1
C2
C3
C4
C5
C6 to 
C26
EOT
Safety 
FU
Efficacy
FU
Survival 
FU
Cycle Day
1
8
15
1
15
1
15
1
15
1
15
1
15
Scheduling 
Window 
(days)
-28 to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
At 
DC
Approx
30 days 
after 
last dose 
Q8W 
(± 7d)
Q12W
(± 14d)
Subsequent 
Anti-
neoplastic
Treatment
X
X
X
X
All anticancer 
therapy will be 
recorded until time 
of death or 
termination of 
survival follow-up. 
If a clinical visit is 
not feasible, follow 
up information may 
be obtained by other 
means such as 
telephone or email
Treatment 
Eligibility 
Assessment
X
Prior to 
randomization, the 
investigator must 
provide rationale for 
participants to 
receive regorafenib 
or TAS-102.
Allocation 
(Rando-
mization) 
via IRT
X
It is strongly 
preferred that 
participants receive 
first dose of study 
intervention on day 
of randomization. 
08G00Y


PRODUCT: MK-7902  
49
PROTOCOL/AMENDMENT NO.: 017-03 (E7080-G000-325)
MK-7902-017-03 FINAL PROTOCOL
14-JUL-2022
Study 
Period
Screening
Intervention (28-Day Cycles)
Posttreatment Visits
Notes
Visit 
Number/
Title
Screening
C1
C2
C3
C4
C5
C6 to 
C26
EOT
Safety 
FU
Efficacy
FU
Survival 
FU
Cycle Day
1
8
15
1
15
1
15
1
15
1
15
1
15
Scheduling 
Window 
(days)
-28 to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
At 
DC
Approx
30 days 
after 
last dose 
Q8W 
(± 7d)
Q12W
(± 14d)
Disease-
specific 
Biomarker
Data 
Collection
X
Including 
MSI/MMR status, 
BRAF mutation 
status, RAS 
mutation status, PD-
L1 expression (if 
available), TMB (if 
available) and HRD 
if available
Survival 
Status
After investigator 
determined disease 
progression or start 
of new anticancer 
treatment. In 
addition, upon 
Sponsor request, 
participants may be 
contacted for 
survival status at 
any time during the 
study.
08G00Y


PRODUCT: MK-7902  
50
PROTOCOL/AMENDMENT NO.: 017-03 (E7080-G000-325)
MK-7902-017-03 FINAL PROTOCOL
14-JUL-2022
Study 
Period
Screening
Intervention (28-Day Cycles)
Posttreatment Visits
Notes
Visit 
Number/
Title
Screening
C1
C2
C3
C4
C5
C6 to 
C26
EOT
Safety 
FU
Efficacy
FU
Survival 
FU
Cycle Day
1
8
15
1
15
1
15
1
15
1
15
1
15
Scheduling 
Window 
(days)
-28 to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
At 
DC
Approx
30 days 
after 
last dose 
Q8W 
(± 7d)
Q12W
(± 14d)
Study Administration
Regora-
fenib 
Adminis-
tration
Q4W
Regorafenib: QD
Days 1-21, no dose 
Days 22-28. The 
C1D1 dose must be 
given to the 
participant at the 
site.
08G00Y


PRODUCT: MK-7902  
51
PROTOCOL/AMENDMENT NO.: 017-03 (E7080-G000-325)
MK-7902-017-03 FINAL PROTOCOL
14-JUL-2022
Study 
Period
Screening
Intervention (28-Day Cycles)
Posttreatment Visits
Notes
Visit 
Number/
Title
Screening
C1
C2
C3
C4
C5
C6 to 
C26
EOT
Safety 
FU
Efficacy
FU
Survival 
FU
Cycle Day
1
8
15
1
15
1
15
1
15
1
15
1
15
Scheduling 
Window 
(days)
-28 to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
At 
DC
Approx
30 days 
after 
last dose 
Q8W 
(± 7d)
Q12W
(± 14d)
Efficacy 
Tumor 
Imaging
(Chest, 
Abdomen, 
and Pelvis)
X
Acquired at 
Screening; then first 
on-study imaging 
assessment after 
initial tumor 
imaging at 
Screening should be 
performed at 8 
weeks (56 days ±7 
days) from the date 
of randomization. 
Subsequent tumor 
imaging should be 
performed every 8 
weeks (56 days ±7 
days) or more 
frequently if 
clinically indicated. 
Imaging timing 
should follow 
calendar days and 
should not be 
adjusted for delays 
in cycle. 
08G00Y


PRODUCT: MK-7902  
52
PROTOCOL/AMENDMENT NO.: 017-03 (E7080-G000-325)
MK-7902-017-03 FINAL PROTOCOL
14-JUL-2022
Study 
Period
Screening
Intervention (28-Day Cycles)
Posttreatment Visits
Notes
Visit 
Number/
Title
Screening
C1
C2
C3
C4
C5
C6 to 
C26
EOT
Safety 
FU
Efficacy
FU
Survival 
FU
Cycle Day
1
8
15
1
15
1
15
1
15
1
15
1
15
Scheduling 
Window 
(days)
-28 to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
At 
DC
Approx
30 days 
after 
last dose 
Q8W 
(± 7d)
Q12W
(± 14d)
Patient Reported Outcomes 
EQ-5D-5L
EORTC 
QLQ-C30
EORTC 
QLQ-CR-29
X
X
X
X
X
X
X
X
X
X
X
ePROs should be done 
in the order in the 
table. It is strongly 
recommended that 
ePROs are completed 
prior to drug 
administration, 
adverse event 
evaluation and disease 
status notification. 
ePRO collection is 
required at D1 and 
D15 of C1 through C3 
and then D1 of C4 
through C12 and then 
D1 of every other 
cycle thereafter (ie,
C14, C16, etc. up to 
C26) and at end of 
treatment visit or 
treatment 
discontinuation, or 2 
years, whichever 
occurs first, and at the 
D30 posttreatment 
safety follow-up visit.
08G00Y


PRODUCT: MK-7902  
53
PROTOCOL/AMENDMENT NO.: 017-03 (E7080-G000-325)
MK-7902-017-03 FINAL PROTOCOL
14-JUL-2022
Study 
Period
Screening
Intervention (28-Day Cycles)
Posttreatment Visits
Notes
Visit 
Number/
Title
Screening
C1
C2
C3
C4
C5
C6 to 
C26
EOT
Safety 
FU
Efficacy
FU
Survival 
FU
Cycle Day
1
8
15
1
15
1
15
1
15
1
15
1
15
Scheduling 
Window 
(days)
-28 to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
At 
DC
Approx
30 days 
after 
last dose 
Q8W 
(± 7d)
Q12W
(± 14d)
Safety Assessments
Full 
Physical 
Examin-
ation 
including 
height
X
X
To be performed 
within 7 days prior 
to start of study 
treatment
Directed 
Physical 
Examin-
ation
X
X
X
X
X
X#
X
X
X#
X
X#
X
On C1D1, C1D15, 
C2D1, C2D15 and 
on D1 of each cycle 
and Safety visit. In 
addition to the 
directed PEs in the 
flowchart, a 
symptom-directed 
PE may be 
performed at any 
time during the 
study, as clinically 
indicated.
#Additional testing 
on D15 every 8 
weeks starting from 
C3 (C3D15, C5D15, 
C7D15, C9D15, etc)
Weight
X
X
X
X
X
X
X
X
X
Taken every 4 
weeks, EOT and 
Safety Visit
08G00Y


PRODUCT: MK-7902  
54
PROTOCOL/AMENDMENT NO.: 017-03 (E7080-G000-325)
MK-7902-017-03 FINAL PROTOCOL
14-JUL-2022
Study 
Period
Screening
Intervention (28-Day Cycles)
Posttreatment Visits
Notes
Visit 
Number/
Title
Screening
C1
C2
C3
C4
C5
C6 to 
C26
EOT
Safety 
FU
Efficacy
FU
Survival 
FU
Cycle Day
1
8
15
1
15
1
15
1
15
1
15
1
15
Scheduling 
Window 
(days)
-28 to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
At 
DC
Approx
30 days 
after 
last dose 
Q8W 
(± 7d)
Q12W
(± 14d)
Vital Signs 
(resting
BP, pulse, 
RR, temp) 
and height
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
To be performed 
within 7 days prior 
to start of study 
treatment and then 
weekly for the first 
6 weeks of 
treatment and then 
every 2 weeks, EOT 
and Safety Visit.
BP and pulse will be 
measured after the 
participant has been 
resting for 5 
minutes. 
Height measured at 
screening only.
12-lead 
ECG with 
QTcF 
Determine-
eation
X
X
X
X
X
X
X
ECG at screening, 
C1D1, C2D1, D1 of 
every third cycle 
(12 weeks) 
thereafter (eg, C5, 
C8, C11, etc.), EOT, 
and Safety follow-
up visits.
08G00Y


PRODUCT: MK-7902  
55
PROTOCOL/AMENDMENT NO.: 017-03 (E7080-G000-325)
MK-7902-017-03 FINAL PROTOCOL
14-JUL-2022
Study 
Period
Screening
Intervention (28-Day Cycles)
Posttreatment Visits
Notes
Visit 
Number/
Title
Screening
C1
C2
C3
C4
C5
C6 to 
C26
EOT
Safety 
FU
Efficacy
FU
Survival 
FU
Cycle Day
1
8
15
1
15
1
15
1
15
1
15
1
15
Scheduling 
Window 
(days)
-28 to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
At 
DC
Approx
30 days 
after 
last dose 
Q8W 
(± 7d)
Q12W
(± 14d)
MUGA 
Scan or 
ECHO 
X
X
Additional 
assessments as 
clinically indicated. 
Assessments should 
use the same 
method (MUGA or 
ECHO) throughout 
the study. 
Additional LVEF 
assessments may be 
performed as 
clinically indicated.
ECOG 
Performance 
Status
X*
X
X
X
X
X
X
X
X
*At screening and 
within 3 days before 
initiation of study 
intervention. To be 
obtained every 4 
weeks on D1 of 
every cycle, EOT 
and Safety visit.
08G00Y


PRODUCT: MK-7902  
56
PROTOCOL/AMENDMENT NO.: 017-03 (E7080-G000-325)
MK-7902-017-03 FINAL PROTOCOL
14-JUL-2022
Study 
Period
Screening
Intervention (28-Day Cycles)
Posttreatment Visits
Notes
Visit 
Number/
Title
Screening
C1
C2
C3
C4
C5
C6 to 
C26
EOT
Safety 
FU
Efficacy
FU
Survival 
FU
Cycle Day
1
8
15
1
15
1
15
1
15
1
15
1
15
Scheduling 
Window 
(days)
-28 to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
At 
DC
Approx
30 days 
after 
last dose 
Q8W 
(± 7d)
Q12W
(± 14d)
Telephone 
Contact 
Visit
X
Telephone contact 
or visit on C1D8 
will assess 
participants for 
development of 
early toxicity. The 
investigator or 
medically qualified 
designee (consistent 
with local 
requirements) will 
assess participants 
for development of 
early toxicity. An 
unscheduled visit 
can occur prior 
C1D15 to next 
clinic visit if 
necessary, for 
safety.
08G00Y


PRODUCT: MK-7902  
57
PROTOCOL/AMENDMENT NO.: 017-03 (E7080-G000-325)
MK-7902-017-03 FINAL PROTOCOL
14-JUL-2022
Study 
Period
Screening
Intervention (28-Day Cycles)
Posttreatment Visits
Notes
Visit 
Number/
Title
Screening
C1
C2
C3
C4
C5
C6 to 
C26
EOT
Safety 
FU
Efficacy
FU
Survival 
FU
Cycle Day
1
8
15
1
15
1
15
1
15
1
15
1
15
Scheduling 
Window 
(days)
-28 to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
At 
DC
Approx
30 days 
after 
last dose 
Q8W 
(± 7d)
Q12W
(± 14d)
AE/SAE 
monitoring
AEs monitored up 
to 30 days after last 
dose. SAEs 
monitored up to 90 
days. Pregnancy 
monitored up to 180 
days after last dose, 
or 30 days after last 
dose if participant 
starts a new 
anticancer therapy, 
whichever is sooner.
08G00Y


PRODUCT: MK-7902  
58
PROTOCOL/AMENDMENT NO.: 017-03 (E7080-G000-325)
MK-7902-017-03 FINAL PROTOCOL
14-JUL-2022
Study 
Period
Screening
Intervention (28-Day Cycles)
Posttreatment Visits
Notes
Visit 
Number/
Title
Screening
C1
C2
C3
C4
C5
C6 to 
C26
EOT
Safety 
FU
Efficacy
FU
Survival 
FU
Cycle Day
1
8
15
1
15
1
15
1
15
1
15
1
15
Scheduling 
Window 
(days)
-28 to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
At 
DC
Approx
30 days 
after 
last dose 
Q8W 
(± 7d)
Q12W
(± 14d)
Local Laboratory Procedures 
Hema-
tology and 
Chemistry
X*
X
X
X
X
X
X#
X
X
X#
X
X#
X
X
*Screening 
laboratory 
assessments MUST 
be done within 3
days of first dose or 
on C1D1 if results 
are available before 
randomization and 
dosing. After C1, 
predose laboratory 
procedures can be 
conducted up to 72 
hours before dosing. 
Predose on C1D15 
and on D1 of every 
cycle (C2D1, C3D1, 
C4D1 etc.), EOT 
and Safety visit.
#Additional testing 
predose on C2D15 
and on D15 every 8 
weeks starting from 
C3 (C3D15, C5D15, 
C7D15, C9D15, etc)
08G00Y


PRODUCT: MK-7902  
59
PROTOCOL/AMENDMENT NO.: 017-03 (E7080-G000-325)
MK-7902-017-03 FINAL PROTOCOL
14-JUL-2022
Study 
Period
Screening
Intervention (28-Day Cycles)
Posttreatment Visits
Notes
Visit 
Number/
Title
Screening
C1
C2
C3
C4
C5
C6 to 
C26
EOT
Safety 
FU
Efficacy
FU
Survival 
FU
Cycle Day
1
8
15
1
15
1
15
1
15
1
15
1
15
Scheduling 
Window 
(days)
-28 to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
At 
DC
Approx
30 days 
after 
last dose 
Q8W 
(± 7d)
Q12W
(± 14d)
Urine 
Dipsticka
X*
X
X
X
X
X
X
X#
X
X
X
X
*Screening 
laboratory 
assessments MUST 
be done within 3 
days of first dose or 
on C1D1 if results 
are available before 
randomization and 
dosing. After C1, 
predose laboratory 
procedures can be 
conducted up to 72 
hours before dosing. 
If urine dipstick is 
unable to be 
performed, 
urinalysis is 
acceptable.
08G00Y


PRODUCT: MK-7902  
60
PROTOCOL/AMENDMENT NO.: 017-03 (E7080-G000-325)
MK-7902-017-03 FINAL PROTOCOL
14-JUL-2022
Study 
Period
Screening
Intervention (28-Day Cycles)
Posttreatment Visits
Notes
Visit 
Number/
Title
Screening
C1
C2
C3
C4
C5
C6 to 
C26
EOT
Safety 
FU
Efficacy
FU
Survival 
FU
Cycle Day
1
8
15
1
15
1
15
1
15
1
15
1
15
Scheduling 
Window 
(days)
-28 to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
At 
DC
Approx
30 days 
after 
last dose 
Q8W 
(± 7d)
Q12W
(± 14d)
Thyroid 
function 
(T3, T4, 
and TSH)
X*
X
X
X
X
X
X
X
X
*Screening 
laboratory 
assessments MUST 
be done within 3 
days of first dose or 
on C1D1 if results 
are available before 
randomization and 
dosing. After C1, 
predose laboratory 
procedures can be 
conducted up to 72 
hours before dosing.
Free T3 and T4 are 
acceptable.
Collect on D1 of 
each cycle (every 4 
weeks), EOT and 
Safety visit
08G00Y


PRODUCT: MK-7902  
61
PROTOCOL/AMENDMENT NO.: 017-03 (E7080-G000-325)
MK-7902-017-03 FINAL PROTOCOL
14-JUL-2022
Study 
Period
Screening
Intervention (28-Day Cycles)
Posttreatment Visits
Notes
Visit 
Number/
Title
Screening
C1
C2
C3
C4
C5
C6 to 
C26
EOT
Safety 
FU
Efficacy
FU
Survival 
FU
Cycle Day
1
8
15
1
15
1
15
1
15
1
15
1
15
Scheduling 
Window 
(days)
-28 to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
At 
DC
Approx
30 days 
after 
last dose 
Q8W 
(± 7d)
Q12W
(± 14d)
INR or PT 
and aPTT 
(baseline 
only)
X*
*Screening 
laboratory 
assessments MUST 
be done within 3 
days of first dose or 
on C1D1 if results 
are available before 
randomization and 
dosing. After C1, 
predose laboratory 
procedures can be 
conducted up to 72 
hours before dosing. 
Additional testing is 
to be performed as 
clinically indicated 
for participants 
taking 
anticoagulants.
Serum 
Tumor 
Marker 
(CEA and 
CA-19-9)
X
X
X
X
X
X
Can be obtained 
within 72 hours 
prior to dosing at 
cycle start.
Screening, D1 of 
every other cycle 
(C1, C3, C5, C7 
etc.), EOT.
08G00Y


PRODUCT: MK-7902  
62
PROTOCOL/AMENDMENT NO.: 017-03 (E7080-G000-325)
MK-7902-017-03 FINAL PROTOCOL
14-JUL-2022
Study 
Period
Screening
Intervention (28-Day Cycles)
Posttreatment Visits
Notes
Visit 
Number/
Title
Screening
C1
C2
C3
C4
C5
C6 to 
C26
EOT
Safety 
FU
Efficacy
FU
Survival 
FU
Cycle Day
1
8
15
1
15
1
15
1
15
1
15
1
15
Scheduling 
Window 
(days)
-28 to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
At 
DC
Approx
30 days 
after 
last dose 
Q8W 
(± 7d)
Q12W
(± 14d)
Serum hCG 
or Urine 
Pregnancy 
Test 
(WOCBP 
only)
X
X
X
X
X
X
X
X
WOCBP require a 
negative test prior to 
randomization. If 
more than 24 hours 
have elapsed prior 
to the first dose of 
study intervention, 
another pregnancy 
test is required. 
Testing must be 
conducted as 
clinically indicated. 
Serum test is only 
required if urine test 
is positive or not 
evaluable.
Serum FSH
(WONCBP 
only)
X
In the absence of 
12 months of 
amenorrhea, 
confirmation with 
2 FSH 
measurements in 
postmenopausal 
range is required.
HIV, 
HBsAg, 
HCV
X
Testing is not 
required unless 
mandated by local 
health authority.
08G00Y


PRODUCT: MK-7902  
63
PROTOCOL/AMENDMENT NO.: 017-03 (E7080-G000-325)
MK-7902-017-03 FINAL PROTOCOL
14-JUL-2022
Study 
Period
Screening
Intervention (28-Day Cycles)
Posttreatment Visits
Notes
Visit 
Number/
Title
Screening
C1
C2
C3
C4
C5
C6 to 
C26
EOT
Safety 
FU
Efficacy
FU
Survival 
FU
Cycle Day
1
8
15
1
15
1
15
1
15
1
15
1
15
Scheduling 
Window 
(days)
-28 to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
At 
DC
Approx
30 days 
after 
last dose 
Q8W 
(± 7d)
Q12W
(± 14d)
Biomarker Assessments
Blood for 
Serum 
Biomarker
Analysis
X
X
X
X
Collect predose on 
C1D1, C2D15, 
C4D1 and at EOT. 
Blood for 
RNA 
Analysis
X
X
X
X
Collect predose on 
C1D1, C2D15, 
C4D1 and at EOT. 
Blood for 
ctDNA
Analysis
X
X
X
X
X
X
Collect at predose 
on C1D1, C2D15, 
C4D1, and then 
collected on Day 1 
of every other cycle 
(C5D1, C7D1, 
C9D1, etc.) and at 
EOT. 
Blood for 
Genetic 
Analysis
X
Collect predose. 
08G00Y


PRODUCT: MK-7902  
64
PROTOCOL/AMENDMENT NO.: 017-03 (E7080-G000-325)
MK-7902-017-03 FINAL PROTOCOL
14-JUL-2022
Study 
Period
Screening
Intervention (28-Day Cycles)
Posttreatment Visits
Notes
Visit 
Number/
Title
Screening
C1
C2
C3
C4
C5
C6 to 
C26
EOT
Safety 
FU
Efficacy
FU
Survival 
FU
Cycle Day
1
8
15
1
15
1
15
1
15
1
15
1
15
Scheduling 
Window 
(days)
-28 to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
At 
DC
Approx
30 days 
after 
last dose 
Q8W 
(± 7d)
Q12W
(± 14d)
Archival or 
Newly 
Obtained 
Tissue 
Collection
X
Archival tissue 
should be ≤5 years.
If obtained at 
Screening, the 
procedure should be 
performed before 
screening /baseline 
scans are 
performed. Detailed 
instructions for the 
tissue specimen 
collection process 
and shipment are 
provided in the 
Laboratory Manual.
a.  For urine dipstick, perform 3 days prior to the first dose. Collect at screening, after C1, collect samples predose at C1D15, C2D15, and up to 3 days before D1 of each cycle, 
EOT and Safety follow-up. #Additional testing should be performed predose on D15 every 8 weeks starting from C3 (C3D15, C5D15, C7D15, C9D15, etc) Participants with 
≥1+ proteinuria on urine dipstick during screening will undergo 24-hour urine collection for quantitative assessment of proteinuria. 
Abbreviations: AE = adverse event; aPTT = activated partial thromboplastin time; BICR = blinded independent central review; BP = blood pressure; hCG; = human chorionic 
gonadotropin; C = cycle; CEA = carcinoembryonic antigen; ctDNA = circulating tumor DNA; D = day; ePRO = electronic patient-reported outcome; ECG = electrocardiogram; 
ECOG = Eastern Cooperative Oncology Group; ECHO = echocardiogram; EORTC = European Organization for Research and Treatment of Cancer; EOT = end of treatment; 
EQ-5D-5L = European Quality of Life Five-Dimensional Five-Level Scale Questionnaire; FSH = follicle-stimulating hormone; FU = follow-up; HBsAg = hepatitis B virus 
surface virus antigen; HIV = human immunodeficiency virus; INR = international normalized ratio; LVEF = left ventricular ejection fraction; MMRd = mismatch repair 
deficiency; MMRp = mismatch repair protein; MMS = microsatellite Stable; MSI-H = microsatellite instability-high; MUGA = multigated acquisition; PRO = patient-reported 
outcome; PT = prothrombin time; Q6W = every 6 weeks; Q9W = every 9 weeks; Q12W = every 12 weeks; QLQ-C30 = Quality of Life Questionnaire Core 30 items; QTcF = 
QT interval corrected with Fridericia’s formula; RNA= ribonucleic acid; RR = respiratory rate; SAE = serious adverse event; SoA = schedule of activities; T3 = 
triiodothyronine; T4 = thyroxine; TEA = Treatment Eligibility Assessment; TMB = Tumor mutational burden; TSH = thyroid-stimulating hormone; WOCBP = women of 
childbearing potential; WONCBP = women of nonchildbearing potential.   
08G00Y


PRODUCT: MK-7902  
65
PROTOCOL/AMENDMENT NO.: 017-03 (E7080-G000-325)
MK-7902-017-03 FINAL PROTOCOL
14-JUL-2022
Arm B: TAS-102 Treatment
Refer to Appendix 7 for country-specific requirements.
Table 3
Arm B: TAS-102 Treatment
Study 
Period:
Screening
Intervention (28-Day Cycles)
Posttreatment Visits
Notes
Visit 
Number/
Title:
Screening
C1
C2
C3
C4
C5
C6 to 
C26
EOT
Safety FU
Efficacy 
FU
Survival 
FU
Cycle Day
1
15
1
15
1
15
1
15
1
15
1
15
Scheduling 
Window 
(days)
-28 to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
At DC
Approx 30 
days after 
last dose 
Q8W 
(± 7d)
Q12W
(± 14d)
Administrative Procedures
Informed 
Consent
X
Inclusion/
Exclusion 
Criteria
X
Participant 
Identification 
Card
X
X
Identification card 
will be updated with 
randomization 
number at C1D1.
Demo-
graphics and 
Medical 
History [and 
family history 
of premature 
CV disease]
X
History of Lynch 
Syndrome needs to 
be recorded if known
08G00Y


PRODUCT: MK-7902  
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PROTOCOL/AMENDMENT NO.: 017-03 (E7080-G000-325)
MK-7902-017-03 FINAL PROTOCOL
14-JUL-2022
Study 
Period:
Screening
Intervention (28-Day Cycles)
Posttreatment Visits
Notes
Visit 
Number/
Title:
Screening
C1
C2
C3
C4
C5
C6 to 
C26
EOT
Safety FU
Efficacy 
FU
Survival 
FU
Cycle Day
1
15
1
15
1
15
1
15
1
15
1
15
Scheduling 
Window 
(days)
-28 to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
At DC
Approx 30 
days after 
last dose 
Q8W 
(± 7d)
Q12W
(± 14d)
CRC History 
X
Including (but not 
limited to) staging at 
the initial diagnosis 
and at study entry 
Prior CRC 
Therapy 
Review
X
Neo-adjuvant 
therapy, adjuvant 
therapy, any 
chemotherapy, 
surgery and radiation 
therapy during the 
treatment of the 
metastatic disease
Prior/
Concomitant 
Medication 
Review
Concomitant 
medications received 
within 30 days before 
the first dose of study 
intervention through 
30 days after the last 
dose (or 90 days if 
used to treat an SAE) 
will be recorded.
08G00Y


PRODUCT: MK-7902  
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PROTOCOL/AMENDMENT NO.: 017-03 (E7080-G000-325)
MK-7902-017-03 FINAL PROTOCOL
14-JUL-2022
Study 
Period:
Screening
Intervention (28-Day Cycles)
Posttreatment Visits
Notes
Visit 
Number/
Title:
Screening
C1
C2
C3
C4
C5
C6 to 
C26
EOT
Safety FU
Efficacy 
FU
Survival 
FU
Cycle Day
1
15
1
15
1
15
1
15
1
15
1
15
Scheduling 
Window 
(days)
-28 to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
At DC
Approx 30 
days after 
last dose 
Q8W 
(± 7d)
Q12W
(± 14d)
Subsequent 
antineoplastic
treatment
X
X
X
X
All anticancer 
therapy will be 
recorded until time of 
death or termination 
of survival follow-up. 
If a clinical visit is 
not feasible, follow 
up information may 
be obtained by other 
means such as 
telephone or email
Treatment 
Eligibility 
Assessment 
(TEA)
X
Prior to 
randomization, the 
investigator must 
provide rationale for 
participants to 
receive regorafenib 
or TAS-102.
Allocation/ 
Randomizatio
n via IRT
X
It is strongly 
preferred that 
participants receive 
first dose of study 
intervention on day 
of randomization. 
08G00Y


PRODUCT: MK-7902  
68
PROTOCOL/AMENDMENT NO.: 017-03 (E7080-G000-325)
MK-7902-017-03 FINAL PROTOCOL
14-JUL-2022
Study 
Period:
Screening
Intervention (28-Day Cycles)
Posttreatment Visits
Notes
Visit 
Number/
Title:
Screening
C1
C2
C3
C4
C5
C6 to 
C26
EOT
Safety FU
Efficacy 
FU
Survival 
FU
Cycle Day
1
15
1
15
1
15
1
15
1
15
1
15
Scheduling 
Window 
(days)
-28 to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
At DC
Approx 30 
days after 
last dose 
Q8W 
(± 7d)
Q12W
(± 14d)
Disease-
specific 
Biomarker
Data 
Collection
X
Including 
MSI/MMR, BRAF 
mutation status, RAS 
mutation status, PD-
L1 expression (if 
available), TMB (if 
available) and HRD 
if available
Survival 
Status
After investigator 
determined disease 
progression or start 
of new anticancer 
treatment. In 
addition, upon 
Sponsor request, 
participants may be 
contacted for survival 
status at any time 
during the study.
08G00Y


PRODUCT: MK-7902  
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PROTOCOL/AMENDMENT NO.: 017-03 (E7080-G000-325)
MK-7902-017-03 FINAL PROTOCOL
14-JUL-2022
Study 
Period:
Screening
Intervention (28-Day Cycles)
Posttreatment Visits
Notes
Visit 
Number/
Title:
Screening
C1
C2
C3
C4
C5
C6 to 
C26
EOT
Safety FU
Efficacy 
FU
Survival 
FU
Cycle Day
1
15
1
15
1
15
1
15
1
15
1
15
Scheduling 
Window 
(days)
-28 to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
At DC
Approx 30 
days after 
last dose 
Q8W 
(± 7d)
Q12W
(± 14d)
Study Administration
TAS-102
Q4W TAS-102: BID 
on Days 1-5 and on 
Days 8-12, no dose 
Days 6-7 or Days 13-
28. The C1D1 dose 
must be given to the 
participant at the site. 
Participants must 
return to the site 
every 2 weeks.
08G00Y


PRODUCT: MK-7902  
70
PROTOCOL/AMENDMENT NO.: 017-03 (E7080-G000-325)
MK-7902-017-03 FINAL PROTOCOL
14-JUL-2022
Study 
Period:
Screening
Intervention (28-Day Cycles)
Posttreatment Visits
Notes
Visit 
Number/
Title:
Screening
C1
C2
C3
C4
C5
C6 to 
C26
EOT
Safety FU
Efficacy 
FU
Survival 
FU
Cycle Day
1
15
1
15
1
15
1
15
1
15
1
15
Scheduling 
Window 
(days)
-28 to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
At DC
Approx 30 
days after 
last dose 
Q8W 
(± 7d)
Q12W
(± 14d)
Efficacy 
Tumor 
Imaging 
(Chest, 
Abdomen and 
Pelvis)
X
Acquired at 
Screening; then first 
on-study imaging 
assessment after 
initial tumor imaging 
at Screening should 
be performed at 8 
weeks (56 days ±7 
days) from the date 
of randomization. 
Subsequent tumor 
imaging should be 
performed every 8
weeks (56 days ±7 
days) or more 
frequently if 
clinically indicated. 
Imaging timing 
should follow 
calendar days and 
should not be 
adjusted for delays in 
cycle. 
08G00Y


PRODUCT: MK-7902  
71
PROTOCOL/AMENDMENT NO.: 017-03 (E7080-G000-325)
MK-7902-017-03 FINAL PROTOCOL
14-JUL-2022
Study 
Period:
Screening
Intervention (28-Day Cycles)
Posttreatment Visits
Notes
Visit 
Number/
Title:
Screening
C1
C2
C3
C4
C5
C6 to 
C26
EOT
Safety FU
Efficacy 
FU
Survival 
FU
Cycle Day
1
15
1
15
1
15
1
15
1
15
1
15
Scheduling 
Window 
(days)
-28 to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
At DC
Approx 30 
days after 
last dose 
Q8W 
(± 7d)
Q12W
(± 14d)
Patient Reported Outcomes (PRO) 
EQ-5D-5L
EORTC QLQ-
C30
EORTC QLQ-
CR-29
X
X
X
X
X
X
X
X
X
X
X
ePROs should be done 
in the order in the table. 
It is strongly 
recommended that 
ePROs are completed 
prior to drug 
administration, adverse 
event evaluation and 
disease status 
notification. ePRO 
collection is required at 
D1 and D15 of C1 
through C3 and then D1 
of C4 through C12 and 
then D1 of every other 
cycle thereafter (i.e. 
C14, C16, etc. up to 
C26) and at end of 
treatment visit or 
treatment 
discontinuation, or 2 
years, whichever occurs 
first, and at the D30 
posttreatment safety 
follow-up visit.
Safety Assessment 
Full Physical 
Examination 
including 
height
X
X
To be performed 
within 7 days prior to 
start of study 
treatment.
08G00Y


PRODUCT: MK-7902  
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PROTOCOL/AMENDMENT NO.: 017-03 (E7080-G000-325)
MK-7902-017-03 FINAL PROTOCOL
14-JUL-2022
Study 
Period:
Screening
Intervention (28-Day Cycles)
Posttreatment Visits
Notes
Visit 
Number/
Title:
Screening
C1
C2
C3
C4
C5
C6 to 
C26
EOT
Safety FU
Efficacy 
FU
Survival 
FU
Cycle Day
1
15
1
15
1
15
1
15
1
15
1
15
Scheduling 
Window 
(days)
-28 to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
At DC
Approx 30 
days after 
last dose 
Q8W 
(± 7d)
Q12W
(± 14d)
Directed 
Physical 
Examination
X
X
X
X
X
X#
X
X
X#
X
X#
X
On C1D1, C1D15, 
C2D1, C2D15 and on 
D1 of each cycle and 
Safety visit. In 
addition to the 
directed PEs in the 
flowchart, a 
symptom-directed PE 
may be performed at 
any time during the 
study, as clinically 
indicated.
#Additional testing on 
D15 every 8 weeks 
starting from C3 
(C3D15, C5D15, 
C7D15, C9D15 etc)
Weight
X
X
X
X
X
X
X
X
X
Taken every 4 weeks, 
EOT and Safety 
Visit. TAS-102 dose 
must be adjusted if 
weight fluctuates by 
≥10%.
08G00Y


PRODUCT: MK-7902  
73
PROTOCOL/AMENDMENT NO.: 017-03 (E7080-G000-325)
MK-7902-017-03 FINAL PROTOCOL
14-JUL-2022
Study 
Period:
Screening
Intervention (28-Day Cycles)
Posttreatment Visits
Notes
Visit 
Number/
Title:
Screening
C1
C2
C3
C4
C5
C6 to 
C26
EOT
Safety FU
Efficacy 
FU
Survival 
FU
Cycle Day
1
15
1
15
1
15
1
15
1
15
1
15
Scheduling 
Window 
(days)
-28 to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
At DC
Approx 30 
days after 
last dose 
Q8W 
(± 7d)
Q12W
(± 14d)
Vital Signs 
(resting BP, 
pulse, RR, 
temp) and 
height
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
To be performed 
within 7 days prior to 
start of study 
treatment and every 2 
weeks, EOT and 
Safety Visit; BP and 
pulse will be 
measured after the 
participant has been 
resting for 5 minutes. 
Height measured at 
screening only.
12-lead ECG 
with QTcF 
Determination
X
X
X
X
X
X
X
ECG at screening, 
C1D1, C2D1, D1 of 
every third cycle (12 
weeks) thereafter (eg, 
C5, C8, C11, etc.), 
EOT, and Safety 
follow-up visits
08G00Y


PRODUCT: MK-7902  
74
PROTOCOL/AMENDMENT NO.: 017-03 (E7080-G000-325)
MK-7902-017-03 FINAL PROTOCOL
14-JUL-2022
Study 
Period:
Screening
Intervention (28-Day Cycles)
Posttreatment Visits
Notes
Visit 
Number/
Title:
Screening
C1
C2
C3
C4
C5
C6 to 
C26
EOT
Safety FU
Efficacy 
FU
Survival 
FU
Cycle Day
1
15
1
15
1
15
1
15
1
15
1
15
Scheduling 
Window 
(days)
-28 to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
At DC
Approx 30 
days after 
last dose 
Q8W 
(± 7d)
Q12W
(± 14d)
MUGA Scan 
or ECHO 
X
X
Additional 
assessments as 
clinically indicated. 
Assessments should 
use the same method 
(MUGA or ECHO) 
throughout the study. 
Additional LVEF 
assessments may be 
performed as 
clinically indicated.
ECOG 
Performance 
Status
X*
X
X
X
X
X
X
X
X
*At screening and 
within 3 days before 
initiation of study 
intervention.
To be obtained every 
4 weeks on D1 of 
every cycle, EOT and 
Safety visit.
08G00Y


PRODUCT: MK-7902  
75
PROTOCOL/AMENDMENT NO.: 017-03 (E7080-G000-325)
MK-7902-017-03 FINAL PROTOCOL
14-JUL-2022
Study 
Period:
Screening
Intervention (28-Day Cycles)
Posttreatment Visits
Notes
Visit 
Number/
Title:
Screening
C1
C2
C3
C4
C5
C6 to 
C26
EOT
Safety FU
Efficacy 
FU
Survival 
FU
Cycle Day
1
15
1
15
1
15
1
15
1
15
1
15
Scheduling 
Window 
(days)
-28 to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
At DC
Approx 30 
days after 
last dose 
Q8W 
(± 7d)
Q12W
(± 14d)
AE/SAE 
monitoring
AEs monitored up to 
30 days after last 
dose. SAEs 
monitored up to 90 
days. Pregnancy 
monitored up to 180 
days after last dose, 
or 30 days after last 
dose if participant 
starts a new 
anticancer therapy, 
whichever is sooner.
08G00Y


PRODUCT: MK-7902  
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PROTOCOL/AMENDMENT NO.: 017-03 (E7080-G000-325)
MK-7902-017-03 FINAL PROTOCOL
14-JUL-2022
Study 
Period:
Screening
Intervention (28-Day Cycles)
Posttreatment Visits
Notes
Visit 
Number/
Title:
Screening
C1
C2
C3
C4
C5
C6 to 
C26
EOT
Safety FU
Efficacy 
FU
Survival 
FU
Cycle Day
1
15
1
15
1
15
1
15
1
15
1
15
Scheduling 
Window 
(days)
-28 to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
At DC
Approx 30 
days after 
last dose 
Q8W 
(± 7d)
Q12W
(± 14d)
Laboratory Procedures 
Hematology 
and 
Chemistry
X*
X
X
X
X
X#
X
X
X#
X
X#
X
X
*Screening 
laboratory 
assessments MUST 
be done within 3 days 
of first dose or on 
C1D1 if results are 
available before 
randomization and 
dosing. After C1, 
predose laboratory 
procedures can be 
conducted up to 72 
hours before dosing. 
Predose on C1D15 
and on D1 of every 
cycle (C2D1, C3D1, 
C4D1 etc.), EOT and 
Safety visit.
#Additional testing 
predose on D15 
every 8 weeks 
starting from C3 
(C3D15, C5D15, 
C7D15, C9D15, etc)
08G00Y


PRODUCT: MK-7902  
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PROTOCOL/AMENDMENT NO.: 017-03 (E7080-G000-325)
MK-7902-017-03 FINAL PROTOCOL
14-JUL-2022
Study 
Period:
Screening
Intervention (28-Day Cycles)
Posttreatment Visits
Notes
Visit 
Number/
Title:
Screening
C1
C2
C3
C4
C5
C6 to 
C26
EOT
Safety FU
Efficacy 
FU
Survival 
FU
Cycle Day
1
15
1
15
1
15
1
15
1
15
1
15
Scheduling 
Window 
(days)
-28 to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
At DC
Approx 30 
days after 
last dose 
Q8W 
(± 7d)
Q12W
(± 14d)
Urine 
Dipsticka
X*
X
X
X
X
X
X
X#
X
X
X
X
*Screening 
laboratory 
assessments MUST 
be done within 3 days 
of first dose or on 
C1D1 if results are 
available before 
randomization and 
dosing. After C1, 
predose laboratory 
procedures can be 
conducted up to 72 
hours before dosing. 
If urine dipstick is 
unable to be 
performed, urinalysis 
is acceptable.
08G00Y


PRODUCT: MK-7902  
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PROTOCOL/AMENDMENT NO.: 017-03 (E7080-G000-325)
MK-7902-017-03 FINAL PROTOCOL
14-JUL-2022
Study 
Period:
Screening
Intervention (28-Day Cycles)
Posttreatment Visits
Notes
Visit 
Number/
Title:
Screening
C1
C2
C3
C4
C5
C6 to 
C26
EOT
Safety FU
Efficacy 
FU
Survival 
FU
Cycle Day
1
15
1
15
1
15
1
15
1
15
1
15
Scheduling 
Window 
(days)
-28 to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
At DC
Approx 30 
days after 
last dose 
Q8W 
(± 7d)
Q12W
(± 14d)
Thyroid 
function (T3, 
T4, and TSH)
X*
X
X
X
X
X
X
X
X
*Screening 
laboratory 
assessments MUST 
be done within 3 days 
of first dose or on 
C1D1 if results are 
available before 
randomization and 
dosing. After C1, 
predose laboratory 
procedures can be 
conducted up to 72 
hours before dosing. 
Free T3 and T4 are 
acceptable.
Collect on D1 of each 
cycle (every 4 
weeks), EOT and 
Safety visit
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Study 
Period:
Screening
Intervention (28-Day Cycles)
Posttreatment Visits
Notes
Visit 
Number/
Title:
Screening
C1
C2
C3
C4
C5
C6 to 
C26
EOT
Safety FU
Efficacy 
FU
Survival 
FU
Cycle Day
1
15
1
15
1
15
1
15
1
15
1
15
Scheduling 
Window 
(days)
-28 to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
At DC
Approx 30 
days after 
last dose 
Q8W 
(± 7d)
Q12W
(± 14d)
INR or PT 
and aPTT 
(baseline 
only)
X*
*Screening 
laboratory 
assessments MUST 
be done within 3 days 
of first dose or on 
C1D1 if results are 
available before 
randomization and 
dosing. After C1, 
predose laboratory 
procedures can be 
conducted up to 72 
hours before dosing.
Additional testing is 
to be performed as 
clinically indicated 
for participants 
taking 
anticoagulants.
Serum Tumor 
Marker (CEA 
and CA-19-9)
X
X
X
X
X
X
Can be obtained 
within 72 hours prior 
to dosing at cycle
start; 
Screening, D1 of 
every other cycle 
(C1, C3, C5, C7 etc.), 
EOT.
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Study 
Period:
Screening
Intervention (28-Day Cycles)
Posttreatment Visits
Notes
Visit 
Number/
Title:
Screening
C1
C2
C3
C4
C5
C6 to 
C26
EOT
Safety FU
Efficacy 
FU
Survival 
FU
Cycle Day
1
15
1
15
1
15
1
15
1
15
1
15
Scheduling 
Window 
(days)
-28 to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
At DC
Approx 30 
days after 
last dose 
Q8W 
(± 7d)
Q12W
(± 14d)
Serum hCG 
or Urine 
Pregnancy 
Test 
(WOCBP 
only)
X
X
X
X
X
X
X
X
WOCBP require a 
negative test prior to 
randomization. If 
more than 24 hours 
have elapsed prior to 
the first dose of study 
intervention, another 
pregnancy test is 
required. Testing 
must be conducted as 
clinically indicated. 
Serum test is only 
required if urine test 
is positive or not 
evaluable.
Serum FSH
(WONCBP 
only)
X
In the absence of 
12 months of 
amenorrhea, 
confirmation with 
2 FSH measurements 
in postmenopausal 
range is required.
HIV, HBsAg, 
HCV
X
Testing is not 
required unless 
mandated by local 
health authority.
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Study 
Period:
Screening
Intervention (28-Day Cycles)
Posttreatment Visits
Notes
Visit 
Number/
Title:
Screening
C1
C2
C3
C4
C5
C6 to 
C26
EOT
Safety FU
Efficacy 
FU
Survival 
FU
Cycle Day
1
15
1
15
1
15
1
15
1
15
1
15
Scheduling 
Window 
(days)
-28 to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
At DC
Approx 30 
days after 
last dose 
Q8W 
(± 7d)
Q12W
(± 14d)
Central Laboratory Assessments 
Blood for 
Serum 
Biomarker
Analysis
X
X
X
X
Collect predose on 
C1D1, C2D15, C4D1 
and at EOT. 
Blood for 
RNA 
Analysis
X
X
X
X
Collect predose on 
C1D1, C2D15, 
C4D1, and at EOT. 
Blood for 
ctDNA
Analysis
X
X
X
X
X
X
Collect at predose on
C1D1, C2D15, 
C4D1, and then 
collected on Day 1 of 
every other cycle 
(C5D1, C7D1, C9D1, 
etc.) and at EOT. 
Blood for 
Genetic 
Analysis
X
Collect predose. 
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Study 
Period:
Screening
Intervention (28-Day Cycles)
Posttreatment Visits
Notes
Visit 
Number/
Title:
Screening
C1
C2
C3
C4
C5
C6 to 
C26
EOT
Safety FU
Efficacy 
FU
Survival 
FU
Cycle Day
1
15
1
15
1
15
1
15
1
15
1
15
Scheduling 
Window 
(days)
-28 to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
At DC
Approx 30 
days after 
last dose 
Q8W 
(± 7d)
Q12W
(± 14d)
Archival or 
Newly 
Obtained 
Tissue 
Collection
X
Archival tissue 
should be ≤5 years. If 
obtained at 
Screening, the 
procedure should be 
performed before 
screening /baseline 
scans are performed. 
Detailed instructions 
for the tissue 
specimen collection 
process and shipment 
are provided in the 
Laboratory Manual.
a.  For urine dipstick, perform 3 days prior to the first dose. Collect at screening, after C1, collect samples predose at C1D15, C2D15, and up to 3 days before D1 of each cycle, 
EOT and Safety follow-up. #Additional testing should be performed predose on D15 every 8 weeks starting from C3 (C3D15, C5D15, C7D15, C9D15, etc) Participants with 
≥1+ proteinuria on urine dipstick during screening will undergo 24-hour urine collection for quantitative assessment of proteinuria. 
Abbreviations: AE = adverse event; aPTT = activated partial thromboplastin time; BICR = BP = blood pressure; hCG; = human chorionic gonadotropin; C = cycle; CEA = 
carcinoembryonic antigen; ctDNA = circulating tumor DNA; D = day; ePRO = electronic patient-reported outcome; ECG = electrocardiogram; ECOG = Eastern Cooperative 
Oncology Group; ECHO = echocardiogram; EORTC = European Organization for Research and Treatment of Cancer; EOT = end of treatment; EQ-5D-5L = European Quality 
of Life Five-Dimensional Five-Level Scale Questionnaire; FSH = follicle-stimulating hormone; FU = follow-up; HBsAg = hepatitis B virus surface virus antigen; HIV = human 
immunodeficiency virus; INR = international normalized ratio; LVEF = left ventricular ejection fraction; MMRd = mismatch repair deficiency; MMRp = mismatch repair 
protein; MMS = microsatellite Stable; MSI-H = microsatellite instability-high; MUGA = multigated acquisition; PRO = patient-reported outcome; PT = prothrombin time; 
Q6W = every 6 weeks; Q9W = every 9 weeks; Q12W = every 12 weeks; QLQ-C30 = Quality of Life Questionnaire Core 30 items; QTcF = QT interval corrected with 
Fridericia’s formula; RNA= ribonucleic acid; RR = respiratory rate; SAE = serious adverse event; SoA = schedule of activities; T3 = triiodothyronine; T4 = thyroxine; TEA = 
Treatment Eligibility Assessment; TMB = Tumor mutational burden; TSH = thyroid-stimulating hormone; WOCBP = women of childbearing potential; WONCBP = women of 
nonchildbearing potential.
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2
INTRODUCTION
This study is a Phase 3 randomized, controlled, open-label, multi-center study evaluating the 
safety and efficacy of lenvatinib plus pembrolizumab in comparison to SOC in participants 
with mCRC who progressed on or could not tolerate prior treatment before participating in 
the study, as defined in Section 5.1.
2.1
Study Rationale
Colorectal cancer is a serious, life-threatening condition. Worldwide, CRC is the second 
leading cause of cancer-related death with ~881,000 cancer-related deaths and a global 
incidence of ~1.8M (~10% of all cancers) in 2018 [Bray, F., et al 2018]. In the US, CRC is 
the third most common diagnosed cancer [Siegel, R. L., et al 2020]. It is estimated that 
147,950 individuals will be newly diagnosed with CRC and 53,200 CRC deaths will occur in 
2020 [Siegel, R. L., et al 2020]. The annual age-adjusted incidence rate is 38.2 per 100,000
persons and the mortality rate is 13.9 per 100,000 persons [Siegel, R. L., et al 2020] 
[National Cancer Institute 2020]. The median age at diagnosis is 67 years [National Cancer 
Institute 2020]. Stage at diagnosis is the most important predictor of survival. The 5-year 
relative survival rate for CRC was approximately 64% with only 14% for distant disease 
(22% of CRC patients at diagnosis) [National Cancer Institute 2020]. 
Despite improvements in treatment and earlier detection through screening, prognosis 
remains poor for patients with recurrent or distant disease; therefore, mCRC continues to be a 
serious, life-threatening condition. 
Across all stages of disease, 95% of mCRC patients have tumors that are not MSI-H/dMMR. 
Despite recent advances, treatment for most mCRC patients is palliative with few patients 
achieving long-term survival. Primary treatment with two-drug combinations of fluorouracil 
(plus leucovorin) and either irinotecan (FOLFIRI) or oxaliplatin (FOLFOX) plus 
bevacizumab are widely adopted treatments for metastatic colorectal cancer (NCCN; ESMO; 
JSCCR guidelines). Initial treatment strategies led to similar results regardless of which drug 
— irinotecan or oxaliplatin — was used; therefore, the choice of the primary treatment 
regimen is commonly based on the physician’s or patient’s preferences, regional differences, 
and whether the patient has or has not already received an adjuvant oxaliplatin-containing 
treatment.
Treatment options for heavily pretreated patients beyond the second-line setting are limited 
and associated toxicities can be severe. Although regorafenib and TAS-102 are the 2 
commonly accepted SOC therapies for patients who have been treated with 
fluoropyrimidine-, irinotecan-, oxaliplatin-containing chemotherapies, anti-VEGF and an 
anti-EGFR agent (if RAS [KRAS/NRAS] WT), they offer minimal benefit with an ORR of 
≤2% for both agents. In the CORRECT study, a median PFS and OS reported among patients 
randomized to the regorafenib arm was 2 months (95% CI: 1.9-2.3) and 6.4 months (95% CI 
5.8-7.3), respectively [Grothey, A., et al 2013]. In the RECOURSE study, the median PFS 
and OS reported among patients randomized to the TAS-102 arm was 2 months (95% CI: 
1.9-2.1) and 7.1 months (95% CI 6.5-7.8), respectively [Mayer, R. J., et al 2015].
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Several distinct genetically defined subgroups of patients with mCRC will also be allowed to 
participate in LEAP-017. Although new therapies are becoming available for these patients
in addition to SOC, their prognosis remains dismal. Therefore, lenvatinib in combination 
with pembrolizumab will also be evaluated in these subgroups of patients.
Patients with RAS WT mCRC represent about 52% of the patient population with mCRC. 
The current SOC for patients with RAS WT mCRC is FOLFOX or FOLFIRI in combination 
with cetuximab or panitumumab in the ﬁrst-line setting [Stintzing, S., et al 2017] [Stintzing, 
S., et al 2016]; FOLFIRI plus panitumumab in the second-line setting; and panitumumab
monotherapy following disease progression after prior chemotherapy treatment 
(ﬂuoropyrimidine-, oxaliplatin- and irinotecan-containing regimens). The activity of 
panitumumab monotherapy in 3L has been compared to that of cetuximab, the ﬁrst approved 
anti-EGFR agent, in an open-label randomized Phase 3 trial in patients with chemotherapy-
refractory KRAS exon 2 WT mCRC[Price, T. J., et al 2014]. Panitumumab was noninferior 
to cetuximab in terms of OS, PFS, and ORR, with reported OS of 10.4 months and 10 
months, respectively (HR 0.97, 95% CI 0.84–1.11, p=0.0007). Thus, patients with RAS WT 
have a high unmet need in that setting.
The BRAF V600E mutation occurs in approximately 10% of patients with metastatic
colorectal cancer, with recent estimates ranging from as low as 5% to as high as 21%
[Clarke, C. N. 2015]. This mutation identifies a distinct subtype of colorectal cancer and 
patients with metastatic colorectal cancer with the BRAF V600E mutation have a poor 
prognosis, with a median overall survival of 4 to 6 months after failure of initial therapy 
[Tran, B., et al 2011] [Loupakis, F., et al 2014]. Recently, results from the BEACON 
randomized Phase 3 study showed that a combination of the BRAF inhibitor encorafenib, in 
combination with the anti-EGFR monoclonal antibody cetuximab, +/- the MEK inhibitor 
binimetinib resulted in significantly longer overall survival and a higher response rate than 
standard therapy in patients with metastatic colorectal cancer with the BRAF V600E 
mutation. Among the 665 patients enrolled and randomized 1:1:1 to either encorafenib, 
binimetinib, and cetuximab (triplet-therapy group); encorafenib and cetuximab (doublet-
therapy group); or the investigators’ choice of either cetuximab and irinotecan or cetuximab 
and FOLFIRI (control group), the median OS was 9.3 months in the triplet-therapy and 
doublet-therapy groups, and 5.9 months in the control group (HR=0.60 [95%CI: 0.47-0.75] 
and HR=0.61 [95%CI: 0.48-0.77], respectively). The confirmed response rate was 27% (95% 
CI, 21 to 33) in the triplet-therapy, 20% (95% CI, 15 to 25) in the doublet-therapy group and 
2% (95% CI, <1 to 5) in the control group. AEs of Grade 3 or higher occurred in 58% of 
patients in the triplet-therapy group, in 50% in the doublet-therapy group, and in 61% in the 
control group [Kopetz, S., et al 2019] [Kopetz, S., et al 2019].
The doublet combination was approved in the US and encorafenib is indicated in 
combination with cetuximab for patients with mCRC with a BRAF V600E mutation after 
prior therapy (refer to current package insert for encorafenib). It is anticipated that doublet 
combination will be approved and licensed in several countries. In LEAP-017, participants 
with a BRAF V600E mutation will be eligible if they have received all applicable SOC, 
including encorafenib in combination with cetuximab (doublet) when locally licensed and 
available.
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Microsatellite instability-high or dMMR CRC comprises approximately 15% of sporadic 
CRC and 5% of Stage IV CRC, whereas MSS CRC comprises the remainder [Smyrk, T. C., 
et al 2001] [Xiao, Y. 2015]. The estimates for MSI-H/dMMR CRC in Stage IV patients range 
from ~3.5% to 5%. Recently, KEYNOTE-177 and KEYNOTE-164 demonstrated that 
pembrolizumab showed significant efficacy in monotherapy whether in 1L or 2L+ 
(Section 2.2.2.3). These patients represent a separate subgroup of mCRC patients with a 
different prognosis due to the availability of anti-PD1 mAbs and will not be included in 
LEAP-017. 
Therefore, patients who received prior treatment for mCRC with tumors that are not MSI-
H/pMMR (including RAS or BRAF V600E mutated or RAS WT tumors) remain a population 
with a high unmet medical need. Developing novel combinations to improve the clinical 
outcome in this population is crucial. Emerging data suggest that combining lenvatinib with 
pembrolizumab may provide improved efficacy in mCRC as well as in other indications.
2.2
Background
Lenvatinib (also known as E7080 or MK-7902) inhibits the kinase activities of VEGF 
receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). Lenvatinib inhibits
other kinases that have been implicated in pathogenic angiogenesis, tumor growth, and 
cancer progression in addition to their normal cellular functions, including FGF receptors 
FGFR1, 2, 3, and 4; PDGFRα, KIT, and RET. Lenvatinib exhibits antiproliferative activity in 
cell lines dependent on activated FGFR signaling with a concurrent inhibition of FGFR
substrate 2α phosphorylation.
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. 
Refer to the respective IB/approved labeling for detailed background information on 
pembrolizumab and lenvatinib.
Information on the SOC (regorafenib or TAS-102) in Arm B is provided in Section 2.2.4 and 
respective approved labeling as per local regulations.
Pharmaceutical and Therapeutic Background
2.2.1.1
Lenvatinib
Angiogenesis is defined as the formation of new blood vessels from a preexisting vascular 
network and is essential for tumor growth and metastasis. The VEGF family of receptors 
(VEGFRs 1 to 3) play a major role in tumor angiogenesis [Ferrara, N., et al 2003] [Ellis, L. 
M. 2008] [Tammela, T. 2010] Accumulated evidence suggests that FGF and its receptor 
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tyrosine kinase, FGFR play important roles for tumor angiogenesis [Cross, M. J. 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), and VEGFR3 (FLT4), FGFR1-4, PDGFRα, KIT, and RET. 
Among known kinase inhibitors in clinical use, lenvatinib is one of the only inhibitors 
currently labeled with a mechanism of action as an inhibitor of not only VEGFRs, but also 
FGFRs, both of which are currently believed to be very important for tumor angiogenesis.
Lenvatinib inhibits 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 HUVECs with IC50 values of 2.1 and 7.3 
nmol/L, respectively. Analysis of the signal transduction molecules revealed that lenvatinib 
inhibited both the MAPK pathway and the mTOR-S6K-S6 pathway in HUVECs triggered by 
activated VEGFR and FGFR. Furthermore, lenvatinib (10, 30 mg/kg) significantly inhibited 
both VEGF- and FGF-driven angiogenesis in a murine in vivo model [Yamamoto, Y., et al 
2014]. In vivo, lenvatinib exhibited antitumor activity against various human tumor 
xenografts in athymic mice including 5 types of thyroid carcinomas (differentiated [papillary 
and follicular], anaplastic, squamous, and medullary thyroid carcinomas), RCC, HCC, 
melanoma, gastric cancer, NSCLC, ovarian cancer, Ewing’s sarcoma, and osteosarcoma. In 
addition, the antitumor activity of lenvatinib in combination with other anticancer agents in 
several xenograft models was greater than that of lenvatinib or the other agents alone.
In summary, lenvatinib inhibited VEGF-driven VEGFR2 phosphorylation and suppressed 
proliferation and tube formation in HUVEC models. Antitumor activity of lenvatinib in vivo 
has been shown in numerous xenograft animals. These results suggest that lenvatinib may be 
a novel anticancer therapy through inhibition of angiogenesis and may be useful as either 
monotherapy or in combination with other anticancer drugs.
2.2.1.2
Pembrolizumab
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control. The normal function of PD-1, expressed on the cell surface of activated T-
cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an Ig 
superfamily member related to CD28 and CTLA-4 that has been shown to negatively 
regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2) 
[Greenwald, R. J., et al 2005] [Okazaki, T., et al 2001].
The structure of murine PD-1 has been resolved [Zhang, X., et al 2004]. PD-1 and its family 
members are type I transmembrane glycoproteins containing an IgV–type domain 
responsible for ligand binding and a cytoplasmic tail responsible for the binding of signaling 
molecules. The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an 
immunoreceptor tyrosine-based inhibition motif, and an immunoreceptor tyrosine-based 
switch motif. Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases, SHP-1 
and SHP-2, to the immunoreceptor tyrosine-based switch motif within its cytoplasmic tail, 
leading to the dephosphorylation of effector molecules such as CD3ζ, PKCθ, and ZAP70, 
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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 mCRC.
2.2.1.3
Pembrolizumab Plus Lenvatinib
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades [Disis, M. L. 2010]. Accumulating evidence 
shows a correlation between TILs 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+ Tregs correlates with improved prognosis and long-term survival in solid 
malignancies, such as ovarian, colorectal, and pancreatic cancer; hepatocellular carcinoma; 
malignant melanoma; and renal cell carcinoma. Tumor-infiltrating lymphocytes can be 
expanded ex vivo and reinfused, inducing durable objective tumor responses in cancers such 
as melanoma [Dudley, M. E., et al 2005] [Hunder, N. N., et al 2008].
In nonclinical 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 anti-human PD-1 
humanized mAb was investigated in 4 murine tumor isograft models, which showed
significant tumor growth inhibition compared to control. In the RAG murine tumor isograft 
tumor model, survival in the group treated with the combination was significantly longer than 
that of the respective monotherapy groups. In the CT26 murine tumor isograft model, 
treatment with the combination significantly increased the population of activated cytotoxic 
T cells compared to that of the respective monotherapy groups [Kato, Y., et al 2019]. All 
treatments were well-tolerated and severe body weight loss was not observed.
2.2.1.4
Standard of Care
TAS-102 is a combination of trifluridine and tipiracil hydrochloride (Trifluridine/tipiracil; 
TAS-102; eg, LONSURF®) and will be hereafter referred to as TAS-102.
Regorafenib (BAY 73-4506; eg, STIVARGA® or REGONIX®) will be hereafter referred to 
as regorafenib.
Additional information on TAS-102 and regorafenib can be found in the respective 
prescribing information for each compound and in Section 2.2.4.
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Preclinical and Clinical Studies
Refer to the respective IBs for preclinical and clinical study data for and lenvatinib and 
pembrolizumab.
This section summarizes preliminary safety and efficacy data from clinical studies of 
lenvatinib and/or pembrolizumab in patients with mCRC. Efficacy from these previous
studies specifically in mCRC MSS is also summarized in Table 4.
2.2.2.1
Lenvatinib as Monotherapy in CRC
The LEMON (NCCH1503) clinical study, a Phase 2 study of lenvatinib in patients with 
mCRC refractory to standard chemotherapy including: fluoropyrimidine, oxaliplatin, 
irinotecan, bevacizumab, cetuximab or panitumumab (if RAS WT), and TAS-102 
(trifluridine/tipiracil). Prior treatment with regorafenib was not allowed. Patients received 
lenvatinib orally at a dose of 24 mg once daily in 28-day cycles until unacceptable toxicity or 
disease progression. The primary endpoint was DCR assessed by BICR. Secondary endpoints 
included safety, response rate, PFS, and OS. Of 30 patients enrolled, 2 patients achieved PR
and 19 patients had SD, resulting in a response rate of 6.7% and DCR of 70.0% (95% CI: 
50.6, 85.3%). Median PFS was 3.6 months (95% CI: 2.6, 3.7). The most common Grade ≥ 3 
AEs were hypertension (53%), elevated serum AST (13%), thrombocytopenia (10%), and 
anorexia (7%), without unexpected safety signals [Iwasa, S., et al 2020]. 
2.2.2.2
Pembrolizumab as Monotherapy in mCRC that is Not MSI-H/dMMR
KEYNOTE-016 (NCT01876511) is an investigator-initiated Phase 2 Study of MK-3475 in 
patients with treatment-refractory advanced metastatic cancer (NCT01876511). 
Pembrolizumab was administered intravenously at 10 mg/kg every 14 days in patients with 
dMMR colorectal cancers (Cohort A), pMMR colorectal cancers (Cohort B), and dMMR
cancers that were not colorectal (Cohort C). All CRC patients had received >2 prior
chemotherapy regimens (median=4) except for one MSS patient who had received 1 
chemotherapeutic and 1 immunotherapeutic (non-PD-1-based) regimen. The primary 
endpoints were immune-related ORR and 20-week immune-related PFS rate. Of the 21 
patients in Cohort B, the ORR was 0% (0 of 18 patients), and the 20-week PFS rate was 11% 
(2 of 18 patients). The median PFS and OS, determined by Kaplan-Meier method, were 2.2 
(95% CI [1.4, 2.8]) and 5.0 months (95% CI [3.0, NR]), respectively [Le, D. T., et al 2015].
2.2.2.3
Pembrolizumab Monotherapy in MSI-H/dMMR CRC
As summarized above, KEYNOTE-016 evaluated pembrolizumab monotherapy in patients
with CRC who had received at least 2 prior cancer therapies. In the 40 patients with MSI-
H/dMMR CRC (Cohort A), the ORR was 52% (95% CI [36, 68%]), with 5 CR. Median PFS 
was NR (95% CI [16.1, NR]) and median OS was NR (95% CI [NR, NR]). In patients with 
MSS CRC (Cohort B), no OR was observed (ORR 0%; 0/18). About 74% of patients 
experienced an adverse effect. Adverse events during treatment were manageable and most 
were low-grade. Endocrine disorders, mostly hypothyroidism, occurred in 21% of patients
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and were easily managed with thyroid hormone replacement [Le, D. T., et al 2015] [Le, D. 
T., et al 2017].
In KEYNOTE-164, a Phase 2 open-label study (NCT02460198), 61 patients with MSI-
H/dMMR mCRC, who had received at least 2 prior lines of treatment (Cohort A) were 
administered pembrolizumab 200 mg every 3 weeks for up to 2 years. ORR was 33% (95% 
CI [21%, 46%]), with 2 CR and median duration of response not reached. Median PFS was 
2.3 months (95% CI [2.1, 8.1]) and median OS was 31.4 months (95% CI [21.4, NR]). In 
Cohort B, 63 patients had received ≥1 prior lines of therapy. ORR was 33% (95% CI [22%,
46%]), with 5 CR and median duration of response not reached. Median PFS was 4.1 months 
(95% CI [2.1, 18.9]) in Cohort B, and median OS was not reached (95% CI [19.2, NR]). 
Treatment-related Grade 3-4 AEs occurred in 10 patients (16%) in Cohort A and 8 (13%) in 
Cohort B, with the most common occurring in ≥2 patients being pancreatitis, fatigue, 
increased ALT, and increased lipase (2 patients each; 3%) in Cohort A [Le, D. T., et al 
2019].
KEYNOTE-177 (NCT02563002) is a 2-arm, randomized, open-label, controlled Phase 3 
study of pembrolizumab (monotherapy) versus standard chemotherapy in previously 
untreated patients who have Stage IV MSI-H or dMMR CRC. Patients were randomized in a 
1:1 ratio to receive pembrolizumab (experimental arm) or the Investigator’s choice of SOC 
chemotherapy (control arm). Pembrolizumab was superior to chemotherapy for PFS (median 
16.5 vs 8.2 months; HR 0.60; 95% CI [0.45-0.80]; p=0.0002).. Grade 3-5 treatment-related 
AE rates were 22% versus 66% for pembrolizumab vs chemotherapy. One patient in the 
chemotherapy arm died due to a treatment-related AE [Andre, T., et al 2020].
Taken together, these data demonstrate a favorable safety profile of pembrolizumab in 
monotherapy in patients with mCRC, even in later lines of treatment. 
Pembrolizumab is now approved to treat unresectable or metastatic, MSI-H/dMMR 
colorectal cancer in the first line of treatment in addition to later lines of treatment (refer to
pembrolizumab package insert). Patients with metastatic MSI-H/dMMR CRC represent a 
separate subgroup of patients. Due to the efficacy benefit provided by anti-PD1 mAbs in 
monotherapy in this population, patients with MSI-H/dMMR mCRC will not be enrolled in 
LEAP-017, a Phase 3 study of pembrolizumab in combination with lenvatinib.
2.2.2.4
Lenvatinib in Combination with Pembrolizumab in CRC
LEAP-005 (E7080-G000-224) is a multicenter, open-label Phase 2 study of lenvatinib plus
pembrolizumab in previously treated participants with selected solid tumors, including 
Cohort D CRC (not MSI-H/pMMR) who have progressed following treatment with 
fluoropyrimidine, oxaliplatin, and irinotecan. Participants in LEAP-005 received 
pembrolizumab 200 mg Q3W and lenvatinib 20 mg QD. The primary efficacy endpoint is 
ORR per RECIST 1.1 by investigator assessment in the initial cohort(s), and by BICR in 
cohorts that expand combining initial cohort(s) and expansion cohorts(s). The key secondary 
endpoints are disease DCR, DOR, PFS, and OS.
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As of the 10-APR-2020 data cut off, 32 patients were treated in Cohort D. Primary (ORR)
and secondary efficacy outcomes (DCR and DOR) for Cohort D CRC are presented in 
Table 4.
 The median follow-up for Cohort 
D is 6.5 months with 15 participants still on study. 
All 32 patients in the CRC cohort of LEAP-005 had previously been treated for their cancer. 
The 21.9% ORR per BICR using RECIST 1.1 observed in the CRC cohort is numerically
higher than standard therapies historically reported in this setting (~ 2%), as well as that of 
either lenvatinib or pembrolizumab monotherapies. Of note, the majority of these responses 
are ongoing as the DOR for these participants was NR (2.1+, 10.4+).
Although the safety data in this indication are limited at this time, the safety profile appears 
generally consistent with what has been previously observed for the combination of 
lenvatinib + pembrolizumab in other indications [Taylor, M. H., et al 2020] [Kawazoe, A., et 
al 2020] [Makker, V., et al 2020].
Recently in a Phase 1b trial a similar combination (regorafenib 80 mg plus nivolumab)
showed a manageable safety profile and encouraging antitumor activity in patients with 
gastric and colorectal cancer. Enrolled patients received regorafenib plus nivolumab in a 
dose-finding part and additional patients were enrolled in a dose-expansion part. The primary 
end point was DLT during the first 4 weeks to estimate the RP2D. Fifty patients (25 each 
with gastric and colorectal cancer) were enrolled. All patients had received 2 or more 
previous lines of chemotherapy, including anti-angiogenetic inhibitors in 96% of patients. 
One patient had MSI-H/dMMR CRC, whereas the remaining patients had MSS or pMMR 
tumors. RP2D was determined to be 80 mg for regorafenib in combination with nivolumab. 
Objective tumor response was observed in 20 patients (40%), including 9 with CRC (36%). 
Median PFS was 7.9 months in patients CRC [Fukuoka, S., et al 2020].
In the Phase 2 REGOMUNE study of regorafenib + avelumab in mCRC that is not MSI-
H/pMMR/, the combination was shown to achieve PFS and OS that compared favorably to 
historical data with regorafenib used as a single agent alone in a similar clinical setting 
[Cousin, S., et al 2020]. Median PFS was 3.6 months (95% CI, 1.8-5.4), while median OS 
was 10.8 months (95% CI, 5.9-NA).
Based on the promising efficacy data from LEAP-005 and the manageable safety profile 
observed in these patients who have limited available effective treatments and a poor 
survival, a Phase 3 study of lenvatinib plus pembrolizumab in comparison to SOC is
warranted in patients with unresectable mCRC Stage IV, who have progressed on prior 
therapies.
CCI
CCI
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Table 4
Summary of Efficacy Data in Studies With Monotherapy or Combination of RTKi and Anti-PD1/PD-L1 in Patients With 
mCRC Who Have Received and Progressed Through or Became Intolerant to Prior Treatment
Lenvatinib
LEMON
Ph2
Lenvatinib + 
pembrolizumab
LEAP-005 Cohort D
Ph2
Regorafenib
CORRECT
Ph3
Regorafenib + 
nivolumab
REGONIVO
Ph1b
Avelumab + regorafenib
REGOMUNE
Ph1b
n
30
32
505
25
43
ORRa
6.7 (0.8-22.1)
21.9 (9.3-40.0)
1 (5/505)
33.3 (15.6-53.3)
0
DCRa
70 (90% CI 53.5-83.4)
46.9 (29.1-65.3)
41
80
53.5 (23/43)
PFSb
3.6 (2.6-3.7)
2.3 (2.0-5.2)
1.9 (IQR 1.6-3.9)
7.9 (2.9-NR)
3.6 (1.8-5.4)
OSb
7.4 (6.4-10.8)
7.5 (3.9-NR)
6.4 (IQR 3.6-11.8)
NR (9.8-NR)
10.8 (5.9-NR)
a Objective response rate (ORR) and disease control rate (DCR) in % with (95% confidence interval) unless otherwise noted.  
b Progression free survival (PFS) and overall survival (OS) in months with (95% confidence interval) unless otherwise noted. 
IQR: interquartile range; NR: not reached
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Ongoing Clinical Studies
Refer to the respective IBs for ongoing clinical study data for lenvatinib plus pembrolizumab. 
Information on Other Study-related Therapy
Regorafenib is a small molecule inhibitor with numerous targets, including VEGFR 1-3, 
PDGFR, tyrosine receptor kinase 2, FGFRs, BRAF, KIT, and RET [Loree, J. M. 2017]. The 
Phase 3 CORRECT trial has established regorafenib as a SOC therapy for mCRC patients
who are refractory to oxaliplatin and irinotecan-based therapy. In this study, median OS 
improved from 5.0 months with placebo to 6.4 months with regorafenib at a preplanned IA
(HR 0.77, 95% CI 0.64–0.94, one-sided p = 0.0052) [Grothey, A., et al 2013]. The 
CORRECT trial results were confirmed in a broader Asian population in another Phase 3 
trial, CONCUR. Regorafenib resulted in a significantly longer OS (primary endpoint) and 
PFS compared with placebo (HR 0.55; 95%, median 8.8 vs. 6.3 months; p = 0.00016 and 
HR 0.31; median 3.2 vs.1.7 months; p < 0.0001, respectively) [Li, J., et al 2015]. 
Regorafenib was approved in several countries for patients with mCRC who have been 
previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, 
with an anti-VEGF therapy, and, if RAS (KRAS/NRAS) wild type, with an anti-EGFR 
therapy.
TAS-102 is an orally administered combination of a thymidine-based nucleic acid analog, 
trifluridine and a thymidine phosphorylase inhibitor, tipiracil hydrochloride. Trifluridine is 
the active cytotoxic component of TAS-102; its triphosphate form is incorporated into DNA, 
with such incorporation appearing to result in antitumor effects [Tanaka, N., et al 2014]. 
Tipiracil hydrochloride is a potent inhibitor of thymidine phosphorylase and, when combined 
with trifluridine to form TAS-102, prevents the rapid degradation of the trifluridine, resulting 
in the maintenance of adequate plasma levels of the active drug. The Phase 3 RECOURSE 
trial of TAS-102 plus best supportive care versus Placebo plus best supportive care in 
patients with mCRC refractory to standard chemotherapies increased OS from 5.3 months to 
7.1 months compared with placebo (HR 0.68, 95% CI 0.58–0.81, p < 0.001) in treatment-
refractory mCRC [Mayer, R. J., et al 2015] and was approved in several countries. 
From these results, both regorafenib and TAS-102 have been recognized as standard treatments 
for refractory mCRC.
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.
Proposed study-specific benefits of the treatment combination of lenvatinib plus 
pembrolizumab include: 

the potential for improved OS, ORR, DOR and PFS 
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Proposed study-specific risks of the treatment combination of lenvatinib plus pembrolizumab 
include: 

mean decreased survival due to shorter duration of exposure to chemotherapy or VEGFR 
TKI

lenvatinib and/or pembrolizumab specific side effects

unanticipated side effects 
To reduce the effects of potential side effects of the treatment combination of lenvatinib plus 
pembrolizumab, participants will be followed as per the SoA (Section 1.3). Detailed 
guidelines for dose modification and interruption are also provided in Section 6.6.
Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the accompanying IB and ICFs.
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
Throughout this protocol, the term RECIST 1.1 refers to the adjustment of RECIST 1.1 to 
include a maximum of 10 target lesions and a maximum of 5 target lesions per organ. Refer 
to Section 4.2.1.1.1 for further details. 
In male and female participants with unresectable mCRC that is not MSI-H/dMMR who 
have received and progressed through or have become intolerant to prior treatment (refer to 
Section 5.1):
Objectives
Endpoints
Primary
Objective: To compare lenvatinib plus 
pembrolizumab combination therapy to
SOC with respect to OS.

Hypothesis (H1): lenvatinib plus 
pembrolizumab is superior to SOC with 
respect to OS.
OS: the time from randomization to death 
due to any cause.
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Objectives
Endpoints
Secondary
Objective: To compare lenvatinib plus 
pembrolizumab combination therapy to
SOC with respect to PFS per RECIST 1.1 as 
assessed by BICR.

Hypothesis (H2): lenvatinib plus 
pembrolizumab combination therapy is 
superior to SOC with respect to PFS per 
RECIST 1.1 by BICR.
PFS: the time from randomization to the 
first documented disease progression or 
death due to any cause, whichever occurs 
first.
Objective: To compare lenvatinib plus 
pembrolizumab combination therapy to
SOC with respect to ORR per RECIST 1.1 
as assessed by BICR.

Hypothesis (H3): lenvatinib plus 
pembrolizumab is superior to SOC with 
respect to ORR per RECIST 1.1 by 
BICR.
Objective Response: CR or PR.
Objective: To assess the efficacy of 
lenvatinib plus pembrolizumab combination 
therapy and SOC with respect to DOR per 
RECIST 1.1 by BICR.
DOR, defined as the time from the first 
documented evidence of CR or PR until PD 
or death due to any cause, whichever occurs 
first, in participants demonstrating CR or 
PR.
Objective: To evaluate the safety and 
tolerability of pembrolizumab plus 
lenvatinib versus SOC.

AEs.

Study intervention discontinuation due 
to AEs.
Objective: To compare the change from 
baseline in global health status/QoL, 
physical functioning, appetite loss and 
bloating for the combination of 
pembrolizumab plus lenvatinib to SOC.
Score for the following PROs scales/items: 
global health status/QoL (EORTC QLQ-
C30 items 29 and 30), physical functioning 
(EORTC QLQ-C30 items 1-5), appetite 
loss (EORTC QLQ-C30 item 13) and 
bloating (EORTC QLQ-CR29 item 37).
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Objectives
Endpoints
Objective: To compare the TTD in global 
health status/QoL, physical functioning, 
appetite loss and bloating for the 
combination of pembrolizumab plus 
lenvatinib to SOC.
TTD, defined as the time from baseline to 
the first onset of a ≥10-point deterioration
from baseline in global health status/QoL 
(EORTC QLQ-C30 items 29 and 30), 
physical functioning (EORTC QLQ-C30 
items 1-5), appetite loss (EORTC QLQ-
C30 item 13) and bloating (EORTC QLQ-
CR29 item 37).
Tertiary/Exploratory
Objective: To compare change from 
baseline in VAS using the EuroQoL EQ-5D-
5L instrument for the combination of 
lenvatinib plus pembrolizumab to SOC.
Change from baseline in EQ-5D VAS.
Objective: To identify molecular (genomic, 
metabolic, and/or proteomic) biomarkers 
that may be indicative of clinical 
response/resistance, safety, and/or the 
mechanism of action of pembrolizumab and 
lenvatinib.
Molecular (genomic, metabolic, and/or 
proteomic) determinants of response or 
resistance to treatments, using blood and/or 
tumor tissue.
4
STUDY DESIGN
4.1
Overall Design
This study is a Phase 3, randomized, controlled, 2-arm, open-label, multicenter, international, 
study of lenvatinib in combination with pembrolizumab versus standard chemotherapy in 
male and female participants with unresectable mCRC that is not MSI-H/dMMR mCRC who 
have received and progressed through or have become intolerant to prior treatment (refer to 
Section 5.1).
Participants with unresectable mCRC Stage IV as defined by AJCC eighth edition, with
tumors that are not MSI-H/dMMR, with or without RAS mutations, with or without BRAF 
mutation, will be enrolled if they have progressed on or could not tolerate prior treatment as 
defined in Sections 5.1 and 5.2. No specific number of lines of prior treatment is required, 
providing that participants have received prior SOC treatment, as indicated per local 
guidelines and recommendations. The study will be stratified by presence of liver metastasis 
(Yes/No). The presence of liver metastasis and other sites of tumor lesions will be collected 
based on site radiological assessment at the screening visit. Oncologic medical history 
including presence of liver metastasis and prior oncologic surgeries will be collected at 
screening.
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Approximately 434 participants will be randomized in a 1:1 ratio to receive lenvatinib in 
combination with pembrolizumab (Arm A) or Investigator’s choice of SOC therapy (Arm B). 
The SOC treatment to be used in Arm B must be chosen by the Investigator between 
regorafenib and TAS-102 before randomization and reasons for selection of one or the other 
treatment will be documented. Participants will be required to have at least 1 measurable 
lesion per investigator assessment by RECIST 1.1 for response assessment.
In Arm A, participants will receive up to 18 administrations of pembrolizumab 400 mg Q6W 
(approximately 2 years). Lenvatinib treatment may continue for participants past 25 cycles 
until reaching a discontinuation criterion (Section 7.1).
Participants may continue treatment with lenvatinib beyond 2 years if they experience 
clinical benefit according to the Investigator, with Sponsor consultation and approval.  
The primary endpoint for this study is OS. Secondary endpoints include safety and 
tolerability, PFS, ORR, DOR per RECIST 1.1 and PRO endpoints. On-study imaging 
assessments performed Q8W, will be calculated from the date of randomization and 
independent of treatment delays for both treatment arms.
For participants in the study, all disease assessments, including expedited verification of PD 
by BICR, will be made using RECIST 1.1. Tumor-imaging showing site-assessed PD will be 
submitted for verification by BICR. In Arm A, treatment beyond centrally verified PD per 
RECIST 1.1 may be permitted at the discretion of the investigator (if eg, no new symptoms, 
stable or decreasing tumor markers CEA or CA 19-9, etc.) after consultation with the 
Sponsor. Updated documented informed consent for continuing treatment on Arm A must be 
obtained prior to receiving the next study treatment. Participants in Arm B who have PD per 
RECIST 1.1 as verified by BICR must be discontinued from study intervention. Participants 
in Arm B may not crossover to Arm A intervention.
All participants will continue to be treated with study medication until PD, unacceptable 
AEs, intercurrent illness that prevents further administration of treatment, investigator’s 
decision to discontinue the participant, participant withdraws consent, pregnancy of the 
participant, noncompliance with study medication or procedure requirements, administrative 
reasons, or a participant in Arm A has received 18 treatments (approximately 2 years). 
Adverse events will be monitored throughout the study and graded in severity according to 
the guidelines outlined in the NCI CTCAE version 5.0 (Section 10.3). Each participant will 
be monitored for AEs for 30 days after discontinuation of study intervention, and for SAEs 
for 90 days after the end of study intervention or 30 days after the end of study intervention if 
the participant initiates new anticancer therapy, whichever is earlier.
Participants may undergo resection of the primary tumor and metastasectomy with curative 
intent after achieving a radiographic response to study intervention converting unresectable 
to resectable disease if deemed eligible per investigator’s discretion in a multidisciplinary 
approach according to their institutional standard and following consultation with the 
Sponsor. Information on the resectability, site of the nodule removed and curative intent 
assessment during surgery will be captured on a designated CRF. In addition, participants 
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will be reevaluated by imaging based on RECIST 1.1 to establish a new baseline prior to 
potentially resuming treatment.
Following surgical resection, and at the discretion of the site Principal Investigator, 
participants randomized to either arm of the study may resume the same protocol-specified 
treatment as received preoperatively. Study treatment may resume no earlier than 6 weeks 
and no later than 12 weeks following surgical resection. If receiving pembrolizumab, study 
participants may receive up to 18 total administrations of pembrolizumab inclusive of doses 
administered both preoperatively and postoperatively. If receiving either regorafenib or TAS-
102, postoperative study therapy may continue until radiographic disease progression has 
been verified by the central vendor or until intolerable adverse events preclude further 
administration.
Participants who discontinue study intervention for reasons other than disease progression,
will have postintervention imaging follow-up for disease status Q8W (± 7 days) from date of 
randomization until PD (verified in an expedited manner by BICR per RECIST 1.1), start of 
a nonstudy anticancer therapy, consent withdrawal, becoming lost to follow-up, death, or end 
of the study. 
All participants will be followed Q12W (± 14 days) for OS until consent withdrawal, 
becoming lost to follow-up, death, or end of the study.
Details regarding interim analyses are provided in Section 9.7. An eDMC will serve as the 
primary reviewer of the treatment-level results and will make recommendations for 
discontinuation or modification of the study. These recommendations will be made to an 
executive oversight committee of the SPONSOR. The eDMC responsibilities and review 
schedules will be outlined in the eDMC charter.
After enrollment of the global portion of the study is complete, the study may remain open to 
enrollment in China alone until the target number of participants in China has been enrolled 
to meet local regulatory requirements. An extension portion of the study will be identical to 
the global study, (eg, inclusion and exclusion criteria, study endpoints, primary and 
secondary objectives, and study procedures) and details pertaining to the statistical analyses 
for participants enrolled in China will be provided in a separate sSAP.
This study will be conducted in conformance with GCP.
Details regarding specific benefits and risks for participants participating in this clinical study
may be found in the accompanying IB and ICF documents. 
Specific procedures to be performed during the study, as well as their prescribed times and 
associated visit windows, are outlined in the SoA in Section 1.3. Details of each procedure 
are provided in Section 8.
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4.2
Scientific Rationale for Study Design
The combination of lenvatinib and pembrolizumab is being developed to treat solid tumors
and hematologic malignancies. 
The rationale for this randomized Phase 3 study is based on data from LEAP-005, a Phase 2 
basket study where lenvatinib plus pembrolizumab was administered in single arm cohorts. 
Cohort D enrolled participants with mCRC who had received 2 prior lines of treatment. 
The randomized, parallel design of the current study will permit to assess the safety and 
efficacy of the combination in comparison to SOC.
In LEAP-005 Cohort D, the combination of lenvatinib plus pembrolizumab was generally 
safe and well tolerated (Refer to Section 2.2.2.4). These data corroborated the acceptable 
safety profile of the combination reported for other indications [Taylor, M. H., et al 2020] 
[Kawazoe, A., et al 2020] [Makker, V., et al 2020].
Preliminary efficacy data of lenvatinib plus pembrolizumab in participants (N=32) enrolled 
in Cohort D of LEAP-005 showed an ORR of 21.9% (95% CI:9.3-40.0) in patients with 
mCRC that is not MSI-H/dMMR mCRC. The ORR is higher than that was observed with 
standard of care, regorafenib and TAS-102 - 1.0% and 1.6%, respectively [Grothey, A., et al
2013] [Mayer, R. J., et al 2015]. In addition, based on the mechanism of action of lenvatinib 
and pembrolizumab, as discussed in Section 2.2, and based on the increased ORR observed 
in LEAP-005, this combination appears promising in comparison to SOC in this setting.
The current study is designed as an unblinded, open-label study. Administration of placebo 
infusion to participants with advanced mCRC, together with additional unnecessary visits to 
the clinic would be an unethical burden for those participants in poor state of health.
However, central review for imaging will be performed by independent radiologist(s) without 
knowledge of participant treatment assignment.
Participants with mCRC that is MSI-H/dMMR will not be included in this study. Local 
testing for MSI-H/dMMR for each participant is mandatory at Screening to confirm status.
No cross over will be allowed in the study. The primary endpoint is OS and would be 
confounded by participants crossing over from Arm B to Arm A.
The study will be stratified by the presence of liver metastasis (Yes/No). The effects of 
different prognostic factors were assessed in exploratory subgroup analysis in the 
RECOURSE trial [Tabernero, J., et al 2019] [Van Cutsem, E., et al 2018]. The best 
prognostic factor was absence of liver metastasis. Therefore, study participants will be 
stratified by the presence of liver metastasis (Yes/No).
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Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
The primary efficacy endpoint in this trial is OS. Overall survival represents the most important 
and reliable endpoint to measure clinical efficacy in a population of patients with unresectable 
mCRC who have received and progressed on or after or became intolerant to fluoropyrimidine, 
irinotecan, oxaliplatin and other SOC treatment (refer to Sections 5.1 and 5.2).
Standard of care in later lines of treatment, such as regorafenib and TAS-102, are associated 
with median OS of only 6.4 and 7.1 months in these patients, respectively [Grothey, A., et al 
2013] [Mayer, R. J., et al 2015].
The sample size is estimated based on the primary endpoint of OS, and the required target 
number of events to detect the superiority of lenvatinib plus pembrolizumab treatment versus 
standard of care in the comparison of OS.
The secondary efficacy endpoints will include PFS, ORR and DOR per RECIST 1.1 as 
assessed by BICR and PROs as assessed by the EORTC QLQ-C30 and EORTC QLQ-CR29, 
which are standard questionnaires utilized in this population of patients with mCRC. These 
endpoints are commonly accepted endpoints by both regulatory authorities and the oncology 
community. Objective response rate was not chosen as the primary endpoint, as OS 
represents a more complete assessment of the clinical benefit experienced by these patients.
Overall survival has been recognized as the gold standard for the demonstration of 
superiority of a new antineoplastic therapy in randomized clinical studies.
The use of BICR and RECIST 1.1, to assess PFS, ORR and DOR is considered acceptable by 
regulatory authorities. Images will be submitted to an iCRO and read by BICR to minimize 
bias in the response assessments. In addition, the final determination of radiologic 
progression will be based on BICR, rather than a local site investigator/radiology assessment. 
Expedited verification of radiologic progression as determined by BICR will be 
communicated to the site and Sponsor.
Exploratory endpoints will include additional PRO measures as assessed by the EQ-5D-5L
questionnaire.
4.2.1.1.1
RECIST 1.1
RECIST 1.1 will be used by the BICR when assessing images for efficacy measures. 
Although original RECIST 1.1 publication recommends a maximum of 5 target lesions in 
total and 2 per organ, this protocol has implemented an adjustment to RECIST 1.1 to allow a 
maximum of 10 target lesions in total and 5 per organ, if a larger number of target lesions is 
needed to adequately represent the tumor burden. Refer to Section 8.2.1.4 for additional 
detail.
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4.2.1.2
Safety Endpoints
Safety parameters commonly used for evaluating investigational systemic anticancer 
treatments are included as safety endpoints including, but not limited to, the incidence of, 
causality, and outcome of AEs/SAEs; and changes in vital signs and laboratory values. AEs 
will be assessed as defined by CTCAE, Version [5.0].
4.2.1.3
Patient-reported Outcomes
Symptomatic improvement is considered a clinical benefit and accepted by health authorities 
as additional evidence of the risk-benefit profile of any new study intervention. As part of the 
analyses for this study, health-related quality of life (HRQoL) and disease-related symptoms 
will be investigated among all participants via the following assessment tools: EORTC QLQ-
C30 and the EuroQol EQ-5D-5L questionnaires. Health utilities will be evaluated using the 
EQ-5D-5L PRO instrument. PRO instruments will be administered by trained site personnel 
and completed electronically by participants in the following order: EORTC QLQ-C30 and 
EQ-5D-5L. These measures are not pure efficacy or safety endpoints because they are 
affected by both disease progression and treatment tolerability.
4.2.1.3.1
EORTC QLQ-C30 and EORTC QLQ-CR29
The EORTC QLQ-C30 is a psychometrically and clinically validated instrument appropriate 
for assessing HRQoL in oncology studies [Aaronson, N. K., et al 1993]. The EORTC QLQ-
C30 is the most widely used cancer-specific HRQoL instrument, which contains 30 items and 
measures 5 functional dimensions (physical, role, emotional, cognitive and social), 3 
symptom items (fatigue, nausea/vomiting, and pain), 6 single items (dyspnea, sleep 
disturbance, appetite loss, constipation, diarrhea, and financial impact), and a global health 
and QoL scale [Aaronson, N. K., et al 1993]. For the global health status or QoL and function 
scales, a higher value indicates a better level of function; for symptom scales and items, a 
higher value indicates increased severity of symptoms. Time to true deterioration, mean 
change from baseline in global health status or QoL, physical functioning and appetite loss 
scale of the EORTC QLQ-C30, will be evaluated as secondary objectives.
The EORTC QLQ-CR29, a supplemental colorectal cancer-specific module, comprises 
multi-item and single-item measures of colorectal cancer-associated symptoms and impact. It 
includes 4 scales assessing urinary frequency, fecal seepage, stool consistency, and body 
image, and single items assessing other common problems following CRC therapy. Specific 
questions are also to be answered if participants have / do not have a stoma bag to assess any 
impact on HRQoL or symptoms. Time to deterioration and mean change from baseline in 
bloating scale of the EORTC QLQ-C29, will be evaluated as secondary objectives.
4.2.1.3.2
EuroQoL EQ-5D-5L
The EQ-5D-5L is a standardized instrument for use as a measure of health outcome and will 
provide data to develop health utilities for use in health economic analyses [Rabin, R. and de 
Charro, F. 2001]. The 5 health state dimensions in the EQ-5D-5L include the following: 
mobility, selfcare, usual activities, pain/discomfort, and anxiety/depression. Each dimension 
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is rated on a 5 point scale from 1 (no problem) to 5 (unable to/extreme problems). The EQ-
5D-5L also includes a graded (0 to 100) vertical visual analog scale on which the participant 
rates their general state of health at the time of the assessment. This instrument has been used 
extensively in cancer studies and published results from these studies support its validity and 
reliability [Pickard, A. S., et al 2007].
The EQ5D-5L will always be completed by participants first before completing the EORTC 
QLQ-C30 and EORTC QLQ-CR29. All questionnaires are to be completed at various time 
points as specified in the SoA in Section 1.3.
4.2.1.4
Pharmacokinetic Endpoints
To reduce the burden to the participants, there will be no pharmacokinetic or ADA studies 
performed in this study, as the PK profile for the combination of pembrolizumab and 
lenvatinib and the ADA to pembrolizumab have been previously characterized. Please see 
the respective IBs for more details.
4.2.1.5
Pharmacodynamic Endpoints
There will be no pharmacodynamic studies performed in this study.
4.2.1.6
Planned Exploratory Biomarker Research
Cancer immunotherapies represent an important and novel class of antitumor agents. 
However, the mechanism of action of these exciting new therapies is not completely 
understood and much remains to be learned regarding how best to leverage these new drugs 
in treating patients. Thus, to aid future patients, it is important to investigate the determinants 
of response or resistance to cancer immunotherapy and other treatments administered, as well 
as determinants of AEs in the course of our clinical studies. These efforts may identify novel 
predictive/PD biomarkers and generate information that may better guide single-agent and 
combination therapy with immuno-oncology drugs.
This research may evaluate whether genetic variation within a clinical study population 
correlates with response to the treatment(s) under evaluation. If genetic variation is found to 
predict efficacy or AEs, the data might inform optimal use of therapies in the patient 
population.
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Proteomics and IHC using blood or tumor
Tumor and blood samples from this study may undergo proteomic analyses (eg, PD-L1 IHC). 
PD-L1 protein level in tumor sections, assessed by IHC, has been shown to correlate with 
response to pembrolizumab in patients with NSCLC, and an IVD device has been developed 
for use with pembrolizumab in NSCLC.
Other blood-derived biomarkers
In addition to expression on the tumor tissue, PD-L1 and other tumor derived proteins can be 
shed from tumor and released into the blood. Assays such as ELISA measure such proteins in 
serum. Correlation of expression with response to pembrolizumab therapy may identify new 
approaches for predictive biomarkers in blood, representing a major advance from today’s 
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reliance on assessing tumor biomarkers. This research would serve to develop such assays for 
future clinical use.
Other molecular changes of interest include the subtype of T-cells in the tumor 
microenvironment. The T-cell repertoire from tumor tissue and blood components may be 
evaluated.
Rationale for the Use of Comparator
Regorafenib and TAS-102 are considered SOC globally for patients with mCRC whose 
disease is refractory to fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, 
as recommended by formal guidelines [Chiorean, E. G., et al 2020] [Hashiguchi, Y., et al 
2020] [Van Cutsem, E., et al 2014] [National Comprehensive Cancer Network 2020] 
[Sepulveda, A. R., et al 2017]. Therefore, study treatment in the comparator arm (Arm B) in 
this study will be physician’s choice of regorafenib or TAS-102.
4.3
Justification for Dose
Lenvatinib
The dosing regimen of lenvatinib was selected based on the results of the Phase 1b portion of 
Phase 1b/2 Study 111/KEYNOTE-146, the primary endpoint of which was to determine the 
MTD and RP2D for lenvatinib in combination with pembrolizumab 200 mg Q3W. Thirteen 
participants (lenvatinib 24 mg/day + pembrolizumab 200 mg IV Q3W: n=3; lenvatinib 
20 mg/day + pembrolizumab 200 mg: n=10) were enrolled in the Phase 1b portion of the 
study. Eight of the participants had RCC, 2 had NSCLC, 2 had endometrial carcinoma, and 1 
had melanoma. There were 2 DLTs at the dose of lenvatinib 24 mg/day + pembrolizumab 
200 mg IV Q3W (1 participant had Grade 3 arthralgia, and another had Grade 3 fatigue); 
hence, this was defined as the toxic dose. No DLTs were reported in the next 10 participants 
(expansion part), all of whom received the lenvatinib 20 mg/day + pembrolizumab 200 mg 
Q3W dose.
Based on review of all of the clinical data from these 13 participants, the MTD and RP2D 
were determined to be 20 mg lenvatinib daily in combination with a fixed dose of 200 mg 
pembrolizumab given Q3W.
In mCRC, the safety data of lenvatinib in combination with pembrolizumab in this indication 
are limited. Based on IA1 in LEAP-005 Cohort D, the safety profile appears generally 
consistent with what has been previously observed for the combination of pembrolizumab + 
lenvatinib in other indications (Section 2.2.2.4). Based on the promising efficacy data and the 
manageable safety profile observed in this patient population with limited available effective 
treatments and a poor survival, the starting dose of lenvatinib at 20mg QD is justified.
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Pembrolizumab
The planned dose of pembrolizumab for this study is 400 mg Q6W. 
Based on the totality of data generated in the pembrolizumab development program, 200 mg 
Q3W is the appropriate dose of pembrolizumab for adults across all indications and 
regardless of tumor type.
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 2020]. Specifically, the dosing regimen of 400 mg Q6W 
for pembrolizumab is considered adequate based on Modeling & Simulation 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.

Trough concentrations (Cmin) at 400 mg Q6W are generally within the range of those 
achieved with 2 mg/kg or 200 mg Q3W in the majority (>99%) of patients.

Peak concentrations (Cmax) at 400 mg Q6W are well below the Cmax for the highest 
clinically tested dose of 10 mg/kg Q2W, supporting that the safety profile for 400 mg 
Q6W should be comparable to the established safety profile of pembrolizumab.

E-R 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.
Maximum Dose/Exposure for This Study
4.3.3.1
Arm A
The maximum dose/exposure of lenvatinib allowed in this study is 20 mg QD. The maximum 
dose/exposure of pembrolizumab allowed in this study is 400 mg Q6W up to 18 
administrations. Participants may continue treatment with lenvatinib if they experience 
clinical benefit according to the Investigator with Sponsor consultation until disease 
progression or unacceptable toxicity. 
4.3.3.2
Arm B
Doses for regorafenib or TAS-102 used in this study are defined based on prescribing 
information and local guidelines (Refer to Section 6.1 and Table 6). Please refer to package 
inserts and local guidelines for maximum used dose, overdosage and corresponding 
guidelines for regorafenib and TAS-102.
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4.4
Beginning and End of Study Definition
The overall study begins when the first participant (or their legally acceptable representative) 
provides documented informed consent. The overall study ends when the last participant 
completes the last study-related contact, withdraws consent, or is lost to follow-up (ie, the 
participant is unable to be contacted by the investigator).
Upon study completion, participants are discontinued and may be enrolled in a 
pembrolizumab extension study.
For purposes of analysis and reporting, the overall study ends when the Sponsor receives the 
last laboratory 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 EAA is defined as First Site Ready (FSR) in any Member State.
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.
Early trial termination criteria:

The clinical trial may be stopped for a safety reason at the recommendation of the eDMC.
5
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
A participant will be eligible for inclusion in the study if the participant:
Type of Participant and Disease Characteristics
1. Has histologically or cytologically confirmed diagnosis of unresectable and metastatic 
colorectal adenocarcinoma (Stage IV A, B and C as defined by AJCC 8th edition).
Note: Tumor must be determined to be NOT MSI-H/dMMR by local testing.
2. Has been previously treated for their disease and has shown disease progression as 
defined by RECIST 1.1 on or after, or could not tolerate standard treatment, which must 
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include ALL of the following agents if approved and locally available in the country 
where the participant is randomized:
Note: Adjuvant chemotherapy counts as prior systemic therapy if there is documented 
disease progression within 6 months of chemotherapy completion.
Note: A participant who has withdrawn from standard treatment due to unacceptable 
toxicity warranting discontinuation of treatment and precluding retreatment with the same 
agent prior to progression of disease will also be eligible to enter the study. If a 
participant is determined to be intolerant to a prior line of therapy, the participant must 
have had a minimum of 2 cycles of that therapy.
a.
Fluoropyrimidine, irinotecan and oxaliplatin.
Note: Capecitabine is acceptable as equivalent to fluoropyrimidine in prior therapy 
(XELOX/CAPOX and XELIRI are considered equivalent to FOLFOX and FOLFIRI, 
respectively).
Note: Participants who have previously received fluoropyrimidine, oxaliplatin, and 
irinotecan as part of the same and only chemotherapy regimen, e.g., FOLFOXIRI or 
FOLFIRINOX, may participate the study.
b. With or without an anti-VEGF monoclonal antibody (bevacizumab)
c.
With anti-EGFR mAbs (cetuximab or panitumumab) for RAS (KRAS/NRAS) WT
participants.
Note: RAS (KRAS/NRAS) WT participants with right or left CRC lesions who may
have not been treated based on local guidelines with anti-EGFR mAbs are eligible.
Note: For participants with ctDNA RAS mutant, but RAS mutation negative in tissue, 
enrollment into the study before anti-EGFR mAbs administration is allowed.
d. BRAF inhibitor (in combination with cetuximab +/- binimetinib) for BRAF V600E 
mutated mCRC.
3. Has measurable disease per RECIST 1.1 assessed by the investigator.
Note: Participants with brain metastases are not eligible to be enrolled.
4. Has provided to a designated central laboratory an archival tumor tissue sample or newly 
obtained core, incisional or excisional biopsy of a tumor lesion which has not been
previously irradiated. Formalin-fixed, paraffin embedded tissue blocks are preferable to 
slides. Newly obtained biopsies are preferable to archived tissue. Details pertaining to 
tumor tissue submission can be found in the Laboratory Manual.
5. Has an ECOG performance status of 0 to 1 within 3 days prior to randomization.
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6. Has a life expectancy of at least 3 months, based on the investigator assessment.
7. Has the ability to swallow capsules or ingest a suspension orally or by a feeding tube.
8. Has adequately controlled BP with or without antihypertensive medications, defined as 
BP ≤150/90 mm Hg with no change in antihypertensive medications within 1 week prior 
to randomization.
9. Has adequate organ function as defined in the following Table 5. Specimens must be 
collected within 3 days prior to the start of study intervention.
Table 5
Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
ANC
≥1500/µL
Platelets
≥100 000/µL
Hemoglobin
≥9.0 g/dL or ≥5.6 mmol/L1
Renal
Creatinine OR
Measured or calculated2 creatinine clearance
(GFR can also be used in place of creatinine or 
CrCl)
≤1.5 × ULN OR
≥30 mL/min for participant with creatinine 
levels >1.5 × institutional ULN
Hepatic
Total bilirubin
≤1.5 ×ULN OR direct bilirubin ≤ULN for 
participants with total bilirubin levels 
>1.5 × ULN
AST (SGOT) and ALT (SGPT)
≤2.5 × ULN (≤5 × ULN for participants with 
liver metastases)
Albumin
≥3 g/dL3
Coagulation
INR or PT
aPTT
≤1.5 × ULN unless participant is receiving 
anticoagulant therapy as long as PT or aPTT is 
within therapeutic range of intended use of 
anticoagulants
ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); ANC=Absolute neutrophil count; 
aPTT=Activated partial thromboplastin time; AST (SGOT)=aspartate aminotransferase (serum glutamic oxaloacetic 
transaminase); GFR=glomerular filtration rate; INR= International normalized ratio; PT= prothrombin time; ULN=upper 
limit of normal.
1 Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within 
last 2 weeks.
2 Creatinine clearance (CrCl) should be calculated per institutional standard.
3 Albumin infusion will not be allowed for 14 days before enrollment into the study
Note: This table includes eligibility-defining laboratory value requirements for intervention; laboratory value 
requirements should be adapted according to local regulations and guidelines for the administration of specific 
chemotherapies.
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Demographics
10. Is male or female ≥18 years of age at the time of providing documented informed 
consent.
Male Participants
11. Male participants are eligible to participate if they agree to the following during the 
intervention period and for at least 90 days after the last dose of regorafenib or TAS-102
and at least 7 days after the last dose of lenvatinib:

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 unless confirmed to be azoospermic (vasectomized 
or secondary to medical cause [Appendix 5]) as detailed below:
-
Agree to use a male condom plus partner use of an additional contraceptive 
method when having penile-vaginal intercourse with a WOCBP who is not 
currently pregnant. Note: Men with a pregnant or breastfeeding partner must 
agree to remain abstinent from penile-vaginal intercourse or use a male condom 
during each episode of penile-vaginal penetration.
-
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 interventions is 
more stringent than the requirements above, the local label requirements are to be 
followed.
-
The male contraception period should continue for at least 7 days after 
discontinuation of lenvatinib. Please note that 7 days after lenvatinib is stopped, if 
the participant is on pembrolizumab only, no male contraception measures are 
needed.
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.
Refer to Appendix 7 for country-specific requirements.
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Female Participants
12. A female participant is eligible to participate if she is not pregnant or breastfeeding, and 
at least one of the following conditions applies:

Is not a WOCBP 
OR

Is a WOCBP and using a contraceptive method that is highly effective (with a failure 
rate of <1% per year), with low user dependency or be abstinent from heterosexual 
intercourse as their preferred and usual lifestyle (abstinent on a long-term and 
persistent basis), as described in Appendix 5 during the intervention period and for at 
least 30 days after the last dose of lenvatinib, 120 days after the last dose of 
pembrolizumab (whichever is last), and 180 days after the last dose of regorafenib or 
TAS-102 and agrees 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 before the first dose of study 
intervention.
-
If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum 
pregnancy test is required. In such cases, the participant must be excluded from 
participation if the serum pregnancy result is positive.

Additional requirements for pregnancy testing during and after study intervention are 
in Section 8.3.5 and Appendix 5.

Abstains from breastfeeding during the study intervention period and for at least 120
days after study intervention.

The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy.

Contraceptive use by women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies. If the 
contraception requirements in the local label for any of the study interventions is 
more stringent than the requirements above, the local label requirements are to be 
followed.
Refer to Appendix 7 for country-specific requirements.
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Informed Consent
13. The participant (or legally acceptable representative if applicable) provides documented
informed consent/assent for the study.
5.2
Exclusion Criteria
The participant must be excluded from the study if the participant:
Medical Conditions
1. Has a tumor that is MSI-H/dMMR per local testing.
2. Has presence of gastrointestinal condition, eg, malabsorption, that might affect the 
absorption of study drug. 
3. Has present or progressive accumulation of pleural, ascitic, or pericardial fluid requiring 
drainage or diuretic drugs within 2 weeks prior to enrollment. The participant can receive
diuretic drugs as needed per the treating physician, outside of the above-mentioned
conditions. 
4. Has radiographic evidence of encasement or invasion of a major blood vessel invasion, or 
of intratumoral cavitation. In the chest, major blood vessels include the main pulmonary 
artery, the left and right pulmonary arteries, the 4 major pulmonary veins, the superior or 
inferior vena cava, and the aorta,
Note: The degree of proximity to major blood vessels should be considered because of 
the potential risk of severe hemorrhage associated with tumor shrinkage/necrosis 
following lenvatinib therapy.
5. Has clinically significant hemoptysis or tumor bleeding within 2 weeks prior to the first 
dose of study drug. 
6. 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: Participants with cardiac failure NYHA Class II, III and IV are not allowed to be 
assigned to the regorafenib in Arm B.
Note: Medically controlled arrhythmia would be permitted.
7. Has a history of arterial thromboembolism within 12 months of start of study drug.
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8. Has urine protein ≥1 g/24h. 
Note: Participants with proteinuria ≥2+ (≥100 mg/dL) on urine dipstick testing 
(urinalysis) will undergo 24-hour urine collection for quantitative assessment of 
proteinuria.
9. Has prolongation of QTcF interval to >480 ms.
10. Has LVEF below the institutional (or local laboratory) normal range as determined by 
MUGA or ECHO.
11. Has a known additional malignancy that is progressing or has required active treatment 
within the past 3 years. Exceptions include early-stage cancers (carcinoma in situ or stage 
1, non-ulcerated primary melanoma <1 mm in depth with no nodal involvement) treated 
with curative intent, basal cell carcinoma of the skin, squamous cell carcinoma of the 
skin, in situ cervical cancer, or in situ breast cancer that has undergone potentially 
curative therapy.
12. Has serious nonhealing wound, ulcer or bone fracture.
13. Has had major surgery within 3 weeks prior to first dose of study interventions. 
Note: If the participant had major surgery, the participant must have recovered 
adequately from the procedure and/or any complications from the surgery prior to starting 
study intervention. Adequate wound healing after major surgery must be assessed 
clinically, independent of time elapsed for eligibility.
14. Has received biologic response modifiers (eg, granulocyte colony-stimulating factor) 
within 4 weeks before study entry. Chronic erythropoietin therapy is permitted provided 
that no dose adjustments were made within 2 months before first dose of study treatment.
15. Has preexisting ≥Grade 3 gastrointestinal or nongastrointestinal fistula.
Prior/Concomitant Therapy
16. Has received prior treatment with a combination of an anti-PD-1, anti-PD-L1, or anti PD-
L2 agent with anti-VEGF mAbs or VEGFR inhibitors.
Note: Participants who have received an anti-PD-1, anti-PD-L1, or anti PD-L2 agent in 
combination with an anti-CTLA-4 agent as a prior line of treatment, are eligible.
Note: Participants who have received an anti-PD-1, anti-PD-L1, or anti PD-L2 agent in 
combination with anti-VEGF mAbs or VEGFR inhibitors in combination with 
chemotherapy are not eligible.
17. Has previously received regorafenib or TAS-102.
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18. Has received prior systemic anti-cancer therapy including investigational agents within 
28 days prior to randomization.
Note: Participants must have recovered from all AEs due to previous therapies to ≤Grade 
1 or baseline. Participants with ≤Grade 2 neuropathy may be eligible. Participants with 
endocrine-related AEs Grade ≤2 requiring treatment or hormone replacement may be 
eligible. 
19. Has received prior radiotherapy within 2 weeks of start of study intervention. Participants 
must have recovered from all radiation-related toxicities, not require corticosteroids, and 
not have had radiation pneumonitis. A 1-week washout is permitted for palliative 
radiation (≤2 weeks of radiotherapy) to non-CNS disease. Lesions situated in a 
previously irradiated area are considered measurable if progression has been 
demonstrated in such lesions.
20. Has received a live or live-attenuated vaccine within 30 days prior to the first dose of 
study intervention. Administration of killed vaccines are allowed.
Refer to Section 6.5.1 for information on COVID-19 vaccines.
21. Has known intolerance to lenvatinib, regorafenib or TAS-102 and/or any of their
excipients.
  
Note: Participants receiving inhibitors or inducers of CYP3A and BCRP substrates 
should not receive regorafenib in Arm B.
Prior/Concurrent Clinical Study Experience
22. Is currently participating in or has participated in a study of an investigational agent or 
has used an investigational device within 28 days 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 28 days after the last dose of the previous investigational 
agent.
Diagnostic Assessments
23. Has known CNS metastases and/or carcinomatous meningitis.
24. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
25. Has an active autoimmune disease that has required systemic treatment in past 2 years 
(ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs). 
Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency) is not considered a form of systemic 
treatment and is allowed.
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26. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in 
dosing exceeding 10 mg daily of prednisone equivalent) or any other form of 
immunosuppressive therapy within 7 days prior the first dose of study medication.
27. Has a history of (non-infectious) pneumonitis that required steroids or has current 
pneumonitis.
28. Has an active infection requiring systemic therapy.
29. Has a known history of HIV infection. No HIV testing is required unless mandated by 
local health authority.
30. Has a known history of Hepatitis B (defined as HBsAg reactive) or known active 
Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection. 
Note: No testing for Hepatitis B and Hepatitis C is required unless mandated by local 
health authority.
31. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the study, interfere with the participant's participation 
for the full duration of the study, or is not in the best interest of the participant to 
participate, in the opinion of the treating investigator.
32. Has a known psychiatric or substance abuse disorder that would interfere with the 
participant’s ability to cooperate with the requirements of the study.
Other Exclusions
33. Has had an allogenic tissue/solid organ transplant.
5.3
Lifestyle Considerations
Meals and Dietary Restrictions
Participants should generally maintain a normal diet unless modifications are required to 
manage an AE such as diarrhea, nausea, or vomiting.
Participants randomized to regorafenib should avoid food containing strong CYP3A4 
inducers, strong CYP3A4 inhibitors as per local guidelines and regulations.
Contraception 
Study interventions in Arm A and Arm B may have adverse effects on a fetus in utero. Refer 
to Appendix 5 for approved methods of contraception.
Caffeine, Alcohol, and Tobacco Restrictions
No restrictions are required.
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Activity Restrictions
No restrictions are required.
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
A participant who discontinues from study intervention OR withdraws from the study will 
not be replaced.
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 (lenvatinib and/or pembrolizumab and/or regorafenib and/or TAS-102) will 
be packaged to support enrollment. Clinical supplies will be affixed with a clinical label in 
accordance with regulatory requirements.
6.1
Study Intervention(s) Administered
The study interventions to be used in this study are outlined in Table 6.
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Table 6
Study Interventions
Arm 
Name
Arm Type
Intervention 
Name
Intervention 
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Adminis-
tration
Regimen/
Treatment 
Period
Use
IMP or 
NIMP/
AxMP
Sourcing
Arm 
A
Experimental
Lenvatinib
Drug
Capsule
10 mg
4 mg
20 mg
Oral
QD
Test 
Product
IMP
Centrally by 
Sponsor
Arm 
A
Experimental
Pembrolizumab
Biological/
Vaccine
Solution for 
Infusion
25 mg/mL
400 mg
IV 
Infusion
Q6W
Test 
Product
IMP
Centrally by 
Sponsor
Arm 
B
Active 
Comparator
Regorafenib
Drug
Tablet
40 mg/tablet
160 mg 
Oral
Q4W 
(QD Days 
1-21, no 
dose Days 
22-28)
Comparator
IMP
Centrally by 
the Sponsor or 
locally by the 
trial site, 
subsidiary, or 
designee
Arm 
B
Active 
Comparator
TAS-102
Drug
Tablet
15 mg 
trifluridine/
6.14 mg 
tipiracil
20 mg 
trifluridine/
8.19 mg 
tipiracil
35 
mg/m2
Oral
Q4W 
(BID Days 
1-5 and 
Days 8-12, 
no dose 
Days 6-7, 
or Days 
13-28)
Comparator
IMP
Centrally by 
the Sponsor or 
locally by the 
trial site, 
subsidiary, or 
designee
Abbreviations: AxMP = auxiliary medicinal product; BID=twice daily; IMP= investigational medicinal product; IV= intravenous; mg=milligram mL=milliliter; NIMP= non investigational medicinal 
product; Q4W= every 4 weeks; Q6W= every 6 weeks; QD=daily
The classification of Investigational Medicinal Product (IMP), Auxiliary Medicinal Product (AxMP) and Non-Investigational Medicinal Product (NIMP) 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 or NIMP/AxMP may exist. In 
these circumstances, local legislation is followed.
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All study interventions will be administered on an outpatient basis.
All products indicated in Table 6 will be provided centrally by the Sponsor or locally by the 
study site, subsidiary or designee, depending on local country operational or regulatory 
requirements.   
For any commercially available product that is provided by the study site, subsidiary, or 
designee, every attempt will be made to source these supplies from a single lot/batch number. 
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product as per local guidelines unless otherwise instructed by the 
Sponsor.
Refer to Section 8.1.8 for details regarding administration of the study intervention.
6.2
Preparation/Handling/Storage/Accountability
Dose Preparation
6.2.1.1
Lenvatinib
Lenvatinib is a capsule for oral administration and does not require preparation. Details on 
administration of lenvatinib 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.
If a dose of lenvatinib is missed and cannot be taken within 12 hours from the scheduled 
administration, the participant should skip this dose and take the next dose at the scheduled 
time the next day. See Pharmacy Manual for additional information.
6.2.1.2
Pembrolizumab
Details on preparation and administration of pembrolizumab are provided in the Pharmacy 
Manual.
6.2.1.3
Regorafenib
Regorafenib will be prepared and administered as per the approved product label and should 
follow local therapeutic guidelines. According to local/institutional guidelines, regorafenib 
may be administered as follows in Cycle 1: 80 mg regorafenib QD on Cycle 1 Days 1 to 7, 
then 120 mg QD on Days 8 to 14, followed by 160 mg QD on Days 15 to 21, and 160 mg 
QD on subsequent cycles (Days 1 to 21) [Bekaii-Saab, T. S., et al 2018].
Participants are advised to swallow the regorafenib tablet whole with water at the same time 
each day following a low-fat meal. Refer to local guidelines and regulations for more details. 
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Any missed dose or regorafenib should be taken on the same day, as soon as the participant 
remembers, although 2 doses should not be taken on the same day to make up for a dose 
missed on the previous day. Refer to local guidelines and regulations for more details. 
6.2.1.4
TAS-102
TAS-102 will be prepared and administered as per the approved product label and should 
follow local therapeutic guidelines. The BSA in m2 should be calculated per local guidance.
The dose of TAS-102 should be recalculated for fluctuation of body weight ≥10% at the 
beginning of a cycle only. For weight fluctuation <10%, recalculation may be done at the 
discretion of the investigator. When recalculating, BSA in m2 should be calculated per local 
guidance.
Participants in Arm B should be advised to take TAS-102 with food. Participants or anyone 
else who handles their medication should be advised to wear gloves as per local guidelines 
and regulations.
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
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.
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6.3
Measures to Minimize Bias: Randomization and Blinding
Intervention Assignment
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 study intervention (Arm A) or physician’s choice of SOC (Arm B).
The SOC treatment to be used must be chosen by the Investigator between regorafenib and 
TAS-102 before randomization and reasons for selection of one or the other treatment will be 
documented.
Stratification
Intervention randomization will be stratified according to the following factor, as described 
in Section 4.2:

Presence of liver metastasis (Yes/No)
Blinding
This is an open-label study; therefore, the Sponsor, Investigator and participant will know the 
treatment administered.
Imaging data will be centrally reviewed by independent radiologist(s) without knowledge of 
participant treatment assignment.
6.4
Study Intervention Compliance
If there are interruptions in the study intervention schedule, the details of and reason for any 
interruption of study intervention will be documented in the participant’s medical record.
Lenvatinib, regorafenib, and TAS-102 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.
Interruptions from the protocol specified intervention plan for nondrug-related or 
administrative reasons require consultation between the investigator and the Sponsor and 
written documentation of the collaborative decision on participant management.
When participants self-administer study intervention at home, compliance with study
intervention will be assessed at each visit. Compliance will be assessed by direct questioning, 
counting returned tablets/capsules, etc, during the site visits and documented in the source 
documents and CRF. Deviation(s) from the prescribed dosage regimen should be recorded in 
the CRF.
A record of the number of lenvatinib capsules or regorafenib tablets or TAS-102 tablets 
dispensed to and taken by each participant must be maintained and reconciled with study 
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intervention and compliance records. Intervention start and stop dates, including dates for 
intervention delays and/or dose reductions will also be recorded in the CRF.
Arm A
Lenvatinib: On the day of a clinic visit lenvatinib will be taken at the clinic after laboratory 
assessment. On the day of pembrolizumab administration, lenvatinib will be taken in the 
clinic, 0 to 4 hours after pembrolizumab infusion (Refer to Section 1.3). For all other days 
lenvatinib will be taken at home.
Pembrolizumab: Pembrolizumab will be administered by the investigator and/or study staff
according to the specifications within the Pharmacy Manual. The total volume of study
intervention infused will be compared with the total volume prepared to determine
compliance with each dose administered.
Refer to Section 6.6.1 for dose modification and toxicity management for irAEs associated 
with pembrolizumab and for other allowed dose interruption of pembrolizumab.
Arm B
For Arm B, the first dose of Cycle 1 SOC (regorafenib or TAS-102) must be given to the 
participant at the site and will be witnessed by the investigator and/or study staff, and/or 
qualified designee per institutional guidelines and procedures. For medication taken at home, 
the site will validate compliance with study medication at each site visit according to their 
standard operating procedure.
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 is to discuss prohibited medication/vaccination 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.
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. 
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All concomitant medications administered during SAEs or ECIs are to be recorded. SAEs 
and ECIs are defined in Section 8.4.
Prohibited Concomitant Medication(s)
6.5.1.1
Arm A Prohibited Concomitant Medication(s) 
Participants are prohibited from receiving the following therapies during the Screening and
Treatment Phase of this study:

Antineoplastic systemic chemotherapy or biological therapy

Immunotherapy not specified in this protocol

Chemotherapy not specified in this protocol

Investigational agents other than lenvatinib and pembrolizumab

Radiation therapy
Note: Radiation for pain or palliation treatment may be acceptable (in case of target 
lesion, please refer to the imaging manual and charter to the iCRO)

Live or live-attenuated vaccines within 30 days before 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, replication-
incompetent adenoviral vaccines, or inactivated vaccines. These vaccines will be 
treated just as any other concomitant therapy.
-
Investigational vaccines (ie, those not licensed or approved for Emergency Use) are 
not allowed.

Systemic glucocorticoids are permitted only for the following purposes:
-
To modulate symptoms of an AE that is suspected to have an immunologic etiology.
-
As needed for the prevention of emesis.
-
Premedication for IV contrast allergies.
-
Short-term oral or IV use in doses >10 mg/day prednisone equivalent to treat asthma 
or COPD exacerbations.
-
For chronic systemic replacement not to exceed 10 mg/day prednisone equivalent.
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
In addition, the following glucocorticoid use is allowed:
-
For topical use or ocular use.
-
Intraarticular joint use.
-
For inhalation in the management of asthma or chronic obstructive pulmonary 
disease.
6.5.1.2
Arm B Prohibited Concomitant Medication(s) 
Restriction on the use of concomitant drug during administration of regorafenib or TAS-102
should follow the local guidelines and regulations (see the respective regorafenib or TAS-102
package inserts for more information).
Drug Interactions
6.5.2.1
Arm A Drug Interactions
There are no DDI-related concomitant medication prohibitions or restrictions. Lenvatinib is
not expected to clinically meaningfully alter exposure to CYP3A4/P-gp substrates based on 
results from a lenvatinib DDI study with midazolam (a sensitive CYP3A and P-gp substrate). 
Clinical studies also showed that coadministration of lenvatinib with either inducers or 
inhibitors of CYP3A4/P-gp are not of clinical concern. 
No drug interaction is expected between pembrolizumab and lenvatinib because of their 
divergent metabolic pathways. Pembrolizumab is a monoclonal antibody and is primarily 
catabolized like other proteins, while lenvatinib is metabolized by enzymatic (CYP3A and 
aldehyde oxidase) and nonenzymatic processes (see the lenvatinib IB).
Use medicinal products with known potential to prolong the QT/QTc interval with caution 
when coadministered with lenvatinib.
6.5.2.2
Arm B Drug Interactions
During administration of regorafenib, avoid concomitant use of strong CYP3A4 inducers, 
strong CYP3A4 inhibitors, and BCRP substrate as recommended by local guidelines and 
regulations (see regorafenib package insert). Monitor participants closely for signs and 
symptoms of exposure-related toxicity when concomitant use with these compounds.
Local guidelines for TAS-102 should be followed, as well as information contained in the 
TAS-102 package insert.
Rescue Medications and Supportive Care
The investigator should follow institution guidelines for use of supportive care in participants 
treated with standard of care. For participants in Arm A receiving lenvatinib plus 
pembrolizumab, suggested supportive care measures for the management of AEs with 
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potential immunologic etiology are outlined along with the dose modification guidelines in 
Section 6.6, Table 7. 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 lenvatinib or pembrolizumab.
Note: If after the evaluation of the event, it is determined not to be related to pembrolizumab, 
the investigator does not need to follow the treatment guidance. Refer to Table 7 in Section 
6.6.1 for guidelines regarding dose modification and supportive care.
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event.
Participants in Arm B should receive appropriate supportive care measures as deemed 
necessary by the treating investigator. The investigator should follow institution guidelines
for use of supportive care in participants treated with regorafenib or TAS-102.
6.6
Dose Modification (Escalation/Titration/Other)
Adverse events will be graded using NCI CTCAE Version v5.0. Investigators will decide the 
probability of the event being related to one or both drugs as to whether dose modification of 
one or both drugs is required.
Participants in Arm A who interrupt or discontinue one drug in the lenvatinib-
pembrolizumab combination due to toxicity can continue with the other drug in the 
combination until criteria for treatment discontinuation are met (eg, unacceptable toxicity, 
disease progression).
Refer to Section 6.6.3 for dose modification guidance for overlapping toxicity for the 
pembrolizumab plus lenvatinib combination.
For participants in Arm B, refer to the labeling or local guidelines for dose modification for 
regorafenib or TAS-102.
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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 7.
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Table 7
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
Grade 1
Withhold
Based on severity of AE 
administer corticosteroids
Ensure adequate evaluation to confirm etiology 
and/or exclude other causes
Grade 2, 3 or 4
Permanently 
discontinue
Exfoliative 
Dermatologic 
Conditions
Suspected SJS, 
TEN, or DRESS
Withhold
Based on severity of AE 
administer corticosteroids
Ensure adequate evaluation to confirm etiology or 
exclude other causes
Confirmed SJS, 
TEN, or DRESS
Permanently 
discontinue
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irAEs
Toxicity Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or IO 
Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
All Other irAEs
Persistent Grade 
2
Withhold
Based on severity of AE 
administer corticosteroids
Ensure adequate evaluation to confirm etiology or 
exclude other causes
Grade 3
Withhold or 
discontinue based on 
the event e
Recurrent 
Grade 3 or 
Grade 4 
Permanently 
discontinue
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for Adverse Events; DRESS=Drug Rash 
with Eosinophilia and Systemic Symptom; GI=gastrointestinal; IO=immuno-oncology; ir=immune related; IV=intravenous; SJS=Stevens-Johnson Syndrome; 
T1DM=type 1 diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal.
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations.
a
AST/ALT: >3.0 to5.0 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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6.6.1.1
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 8. 
Table 8
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 Interruption for Pembrolizumab
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as 
medical or surgical events and/or unforeseen circumstances not related to study intervention. 
However, study intervention is to be restarted within 6 weeks of the originally scheduled 
dose and within 84 days of the previously administered dose, unless otherwise discussed with 
the Sponsor. The reason for study intervention interruption is to be documented in the 
participant's study record.
Dose Modification and Toxicity Management Related to Lenvatinib 
Lenvatinib dose reduction and interruption for participants who experience lenvatinib-
pembrolizumab combination therapy-related toxicity will be in accordance with the dose 
modification guidelines described in Table 9. An interruption of lenvatinib for more than 28 
days regardless of etiology will require Sponsor approval before treatment can be resumed.
Asymptomatic laboratory abnormalities, including Grade ≥3 abnormalities (eg, elevations of 
amylase and lipase) that are not considered clinically relevant by the investigator should be 
managed per institutional guidelines; continuation of treatment should be discussed with the 
Sponsor.
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The starting dose of lenvatinib is 20 mg/day. Dose reductions of lenvatinib occur in 
succession based on the previous dose level 14, 10, 8 mg/day. Any dose reduction below 
8 mg/day must be discussed with the Sponsor. Once the lenvatinib dose has been reduced, it 
may not be increased at a later date, unless the dose has been mistakenly decreased; in this 
situation, the Sponsor’s approval is required to increase the dose.
Refer to the subsections below for management of hypertension (Section 6.6.2.1), proteinuria 
(Section 6.6.2.2), diarrhea (Section 6.6.2.3), hepatotoxicity (Section 6.6.2.4), 
thromboembolic events (Section 6.6.2.5), posterior reversible encephalopathy syndrome/ 
reversible posterior leukoencephalopathy syndrome (PRES/RPLS; Section 6.6.2.6), 
hypocalcemia (Section 6.6.2.7), hemorrhage (Section 6.6.2.8), gastrointestinal perforation or 
fistula formation (Section 6.6.2.9), QT prolongation (Section 6.6.2.10) and osteonecrosis of 
the jaw (Section 6.6.2.11) as appropriate, before consulting the dose modification Table 9. 
For overlapping toxicities of pembrolizumab and lenvatinib, please refer to Section 6.6.3.
Table 9
Dose Modification Guidelines for Lenvatinib-Related Adverse Events 
Treatment-Related Toxicitya,b
Management
Dose Adjustment
Grade 1 or Tolerable Grade 2
Continue treatment
No change
Intolerable Grade 2c, d or Grade 3e, f
First occurrence
Interrupt lenvatinib until resolved 
to Grade 0-1, or tolerable Grade 2
Reduce lenvatinib dose to 14 mg 
once a day (1-level reduction) / 
Second occurrence (same 
toxicity or new toxicity)
Interrupt lenvatinib until resolved 
to Grade 0-1, or tolerable Grade 2
Reduce lenvatinib dose to 10 mg 
once a day (1-level reduction) / 
Third occurrence (same toxicity 
or new toxicity)
Interrupt lenvatinib until resolved 
to Grade 0-1, or tolerable Grade 2
Reduce lenvatinib dose to 8 mg 
orally once a day (1-level 
reduction) / 
Fourth occurrence (same 
toxicity or new toxicity)
Interrupt lenvatinib 
Discuss with Sponsor
Grade 4g: Discontinue Study Treatment
Abbreviations: AE = adverse event; BMI = body mass index; CTCAE = Common Terminology Criteria for Adverse 
Events.
Note: For grading see CTCAE version 5.0. Collect all AE grades (i.e., decreasing and increasing CTCAE grade). 
a.
An interruption of study treatment for more than 28 days will require Sponsor approval before treatment can be 
resumed.
b.
Initiate optimal medical management for nausea, vomiting, hypertension, hypothyroidism and/or diarrhoea prior to 
any lenvatinib interruption or dose reduction. 
c.
Applicable only to Grade 2 toxicities judged by the participant and/or physician to be intolerable.
d.
Obese participants (BMI ≥30) with weight loss do not need to return to their baseline weight or within 10% of their 
baseline weight (ie, Grade 1 weight loss). These participants may restart study intervention at a lower dose once their 
weight remains stable for at least 1 week and they have a minimum BMI of 25. The new stable weight should be 
used as the new baseline for further dose reductions.
e.
For asymptomatic laboratory abnormalities, such as Grade ≥3 elevations of amylase and lipase that are not 
considered clinically relevant by the investigator, continuation of treatment should be discussed with Sponsor. 
f.
For Grade 3 thromboembolic event, permanently discontinue lenvatinib/matching placebo. See Section 6.6.1.5.
g.
Excluding laboratory abnormalities judged to be non-life-threatening, in which case manage as Grade 3. 
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6.6.2.1
Management of Hypertension
Hypertension is a recognized side effect of treatment with drugs inhibiting VEGF signaling. 
Investigators should therefore ensure that participants enrolled to receive treatment with 
lenvatinib have BP of ≤150/90 mm Hg at the time of study entry and, if known to be 
hypertensive, have been on a stable dose of antihypertensive therapy for at least 1 week 
before C1D1. Early detection and effective management of hypertension are important to 
minimize the need for lenvatinib dose interruptions and reductions.
Regular assessment of BP should be as detailed in the SoA (Section 1.3). Hypertension will 
be graded using NCI CTCAE v5.0, based on BP measurements only (and not on the number 
of antihypertensive medications).
If the participant’s first BP measurement of the current assessment is elevated (i.e., 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 (i.e., the mean of the 2 BP measurements obtained 
at least 5 minutes apart) is elevated (systolic BP ≥140 mm Hg or diastolic BP ≥90 mm Hg), a 
confirmatory assessment should be obtained at least 30 minutes later by performing 
2 measurements (at least 5 minutes apart) to yield a mean value. 
Antihypertensive agents should be started as soon as elevated BP (systolic BP ≥140 mm Hg 
or diastolic BP ≥90 mm Hg) is confirmed on 2 assessments at least 30 minutes apart. The 
choice of antihypertensive treatment should be individualized to the participant’s clinical 
circumstances and follow standard medical practice. For previously normotensive 
participants, appropriate antihypertensive therapy should be started when systolic BP 
≥140 mm Hg or diastolic BP ≥90 mm Hg is first observed on 2 assessments at least 
30 minutes apart. For those participants already on antihypertensive medication, treatment 
modification may be necessary if hypertension persists.  
Lenvatinib should be withheld in any instance where a participant is at imminent risk to 
develop a hypertensive crisis or has uncontrolled hypertension (eg, BP ≥160/100 mm Hg) 
with significant risk factors for severe complications, significant risk factors for cardiac 
disease, intracerebral hemorrhage, or other significant comorbidities. Once the participant 
has been on the same antihypertensive medications for at least 48 hours and the BP is 
controlled, lenvatinib should be resumed as described below.
Participants who have had systolic BP ≥160 mm Hg or diastolic BP ≥100 mm Hg must have 
their BP monitored on Day 15 (or more frequently as clinically indicated) until systolic BP 
has been ≤150 mm Hg and diastolic BP has been ≤95 mm Hg for 2 consecutive treatment 
cycles. If a repeat event of systolic BP ≥160 mm Hg or diastolic BP ≥100 mm Hg occurs, the 
participant must resume the Day 15 evaluation until systolic BP has been ≤150 mm Hg and 
diastolic BP has been ≤95 mm Hg for 2 consecutive treatment cycles. 
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The following guidelines should be followed for the management of systolic BP 
≥160 mm Hg or diastolic BP ≥100 mm Hg confirmed on 2 BP assessments at least 
30 minutes:
1. Continue study drug and institute antihypertensive therapy for participants not already 
receiving this.
2. For those participants already on antihypertensive medication, the dose of the current 
agent may be increased, if appropriate, or 1 or more agents of a different class of 
antihypertensive should be added. Study treatment can be continued without dose 
modification.
3. If systolic BP ≥160 mm Hg or diastolic BP ≥100 mm Hg persists despite maximal 
antihypertensive therapy, then lenvatinib administration should be interrupted and 
restarted at 1 dose level reduction only when systolic BP ≤150 mm Hg and diastolic 
BP ≤95 mm Hg and the participant has been on a stable dose of antihypertensive 
medication for at least 48 hours. 
-
If systolic BP ≥160 mm Hg or diastolic BP ≥100 mm Hg recurs on the first dose 
reduction despite optimal management of hypertension with antihypertensive 
medications (either by dose increase or the addition of a different class of 
antihypertensive), then lenvatinib administration should be interrupted and 
restarted at an additional dose reduction only when systolic BP ≤150 mm Hg and 
diastolic BP ≤95 mm Hg and the participant has been on a stable dose of 
antihypertensive medication for at least 48 hours. 
-
If systolic BP ≥160 mm Hg or diastolic BP ≥100 mm Hg recurs on the second 
dose reduction despite optimal management of hypertension with antihypertensive 
medications (either by dose increase or the addition of a different class of 
antihypertensive), then lenvatinib administration should be interrupted and 
restarted at a third dose reduction only when systolic BP ≤150 mm Hg and 
diastolic BP ≤95 mm Hg and the participant has been on a stable dose of 
antihypertensive medication for at least 48 hours.
-
Additional dose reduction should be discussed with the Sponsor.
The following guidelines should be followed for the management of Grade 4 hypertension 
(life threatening consequences):
1. Institute appropriate medical management
2. Discontinue study drug
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6.6.2.2
Management of Proteinuria
Regular assessment of proteinuria should be conducted as detailed in the SoA (Section 1.3). 
Guidelines for assessment and management of proteinuria are as follows:
Detection and Confirmation
1. Perform urine dipstick or urinalysis per the SoA (Section 1.3.1). Urine dipstick 
testing is the preferred method for testing for urinary protein, however, urinalysis may 
be used if the use of urine dipsticks is not feasible.
2. A 24-hour urine collection initiated as soon as possible and at least within 72 hours 
(or an immediate spot UPCR test) is required in the following situations:
-
The first (initial) occurrence of ≥2+ (≥100 mg/dL) proteinuria on urine dipstick 
(urinalysis) while the participant is receiving lenvatinib 
-
A subsequent increase in severity of urine dipstick or urinalysis proteinuria 
occurring on the same lenvatinib dose level
-
When there has been a lenvatinib dose reduction and at the new dose level the 
urine protein dipstick result is ≥2+ (≥100 mg/dL).
3. A 24-hour urine collection (initiated as soon as possible and at least within 72 hours) 
to verify the grade of proteinuria is required when UPCR is ≥2.4.
Grading of Proteinuria
-
Grading according to NCI CTCAE v5.0 will be based on the 24-hour urinary protein 
result if one has been obtained. If the participant has 4+ proteinuria by dipstick (≥1000 
mg/dL by urinalysis), a 24-hour urinary protein result is required to confirm Grade 3 
proteinuria. Management of lenvatinib administration will be based on the grade of 
proteinuria according to Table 9.
Monitoring
-
Urine dipstick or urinalysis testing for participants with proteinuria ≥2+ (≥100 
mg/dL) should be performed on Day 15 (or more frequently as clinically indicated) 
until the results have been 1+ (30 mg/dL) or negative for 2 consecutive treatment 
cycles.  
-
Proteinuria monitoring can be performed at the local laboratory or investigator site
but must be managed by the site physician.
-
In the event of nephrotic syndrome, lenvatinib must be discontinued
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6.6.2.3
Management of Diarrhea
An anti-diarrheal agent should be recommended to the participant at the start of study 
treatment, and participants should be instructed and educated to initiate anti-diarrheal 
treatment at the first onset of soft bowel movements. The choice of anti-diarrheal agent 
should be individualized to the participant’s clinical circumstances and follow standard 
medical practice. If signs/symptoms of diarrhea persist despite optimal medical management, 
instructions contained in Table 9 should be followed.
6.6.2.4
Management of Hepatotoxicity
Liver function tests (ALT, AST, bilirubin levels) should be conducted as detailed in the SoA 
(Section 1.3.1) and as clinically indicated. If signs/symptoms indicating liver injury occur, 
instructions contained in Table 9. should be followed. Appropriate supportive care should be 
provided together with close monitoring. If hepatic failure (any grade per CTCAE v5) 
occurs, lenvatinib must be discontinued.
6.6.2.5
Management of Thromboembolic Events
Participants should be advised to pay attention to symptoms suggestive of venous 
thromboembolic events which include acute onset of shortness of breath, dyspnea, chest pain, 
cough, hemoptysis, tachypnea, tachycardia, cyanosis, DVT signs including lower-extremity 
swelling, and warmth to touch or tenderness. In case any of these symptoms appear, 
participants should be instructed to report such symptoms promptly to the treating physician. 
If a thromboembolic event is confirmed, instructions contained in Table 9 should be 
followed. Appropriate supportive care should be provided together with close monitoring. If 
a participant experiences a Grade 3 or a life threatening (Grade 4) thromboembolic reaction, 
including pulmonary embolism, lenvatinib must be discontinued.
Arterial thromboembolic events (eg, new onset, worsening, or unstable angina, myocardial 
infarction, transient ischemic attack, and cerebrovascular accident) of any grade require study 
treatment discontinuation. 
6.6.2.6
Management of Posterior Reversible Encephalopathy Syndrome/Reversible 
Encephalopathy Syndrome/ Reversible Posterior Leukoencephalopathy Syndrome
Posterior Reversible Encephalopathy Syndrome/Reversible Encephalopathy Syndrome/ 
Reversible Posterior Leukoencephalopathy Syndrome 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. 
Magnetic resonance imaging 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 9 should be followed. 
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6.6.2.7
Management of Hypocalcemia
Serum calcium should be monitored per the SoA (Section 1.3.1). Corrected serum calcium 
should be used to assess the grade of hypocalcemia per CTCAE v5.0, using the following 
formula: 
Corrected calcium = ([4 – serum albumin in g/dL] × 0.8 + serum calcium)
The formula is not applicable when serum albumin concentration is normal (˃4 g/dL); in 
such situations, the total (uncorrected) serum calcium should be used instead. 
Hypocalcemia should be treated per institutional guidelines (eg, using appropriate calcium, 
magnesium, and vitamin D supplementation) until resolution.
6.6.2.8
Management of Hemorrhage
Instructions in Table 9 should be followed for the management of hemorrhage. Either resume 
at a reduced dose or discontinue lenvatinib depending on the severity and persistence of 
hemorrhage.
6.6.2.9
Management of Gastrointestinal Perforation or Fistula Formation
Lenvatinib should be discontinued in any participants who develop gastrointestinal 
perforation of any grade or Grade 4 fistula.
6.6.2.10
Management of QT Prolongation
Lenvatinib should be withheld in the event of development of QT interval prolongation 
greater than 500 msec. Lenvatinib should be resumed at a reduced dose when QTc 
prolongation is resolved to <480 msec or baseline. Monitor potassium, calcium and 
magnesium, and replenish as appropriate.
6.6.2.11
Management of Osteonecrosis of the Jaw
Perform an oral examination prior to treatment with lenvatinib and periodically during 
lenvatinib treatment. Advise participants regarding good oral hygiene practices. Avoid 
invasive dental procedures, if possible, while on lenvatinib treatment, particularly in 
participants at higher risk. For participants requiring invasive dental procedures, 
discontinuation of bisphosphonate treatment may reduce the risk of ONJ. Withhold 
lenvatinib if ONJ develops and restart based on clinical judgment of adequate resolution (See 
Section 6.6.4).
Dose Modifications for Overlapping Toxicities
Based on the known toxicity profiles of pembrolizumab and lenvatinib, certain treatment-
related AEs are uniquely associated with one drug versus the other. For example, 
hypertension, arterial thrombotic events, proteinuria, and hemorrhagic events are known risks 
for lenvatinib treatment, while immune-related AEs are risks for pembrolizumab treatment. 
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However, certain AEs, such as such as diarrhea, hypothyroidism, and liver enzyme elevation, 
may be initially considered attributable to either study drug. Therefore, evaluation of 
attribution is important for determining the study drug most likely related to the AE, or an 
alternative etiology, and subsequently proper clinical management. The following aspects 
should be considered: 
1. Timing of AE onset 
Since lenvatinib is dosed daily and continuously due to a relatively short half-life 
(28 hours), and pembrolizumab is dosed Q6W due to a long half-life, lenvatinib can 
be interrupted to assess whether an AE improves/resolves with dechallenge (i.e., 
interruption of treatment) based on the following 2 scenarios:
o
If an AE is identified during a treatment cycle (i.e., between 2 pembrolizumab 
doses), only lenvatinib dose interruption is needed. 
o
If an AE is identified at the beginning of a treatment cycle, lenvatinib can be 
interrupted and dosing of pembrolizumab should be held.
If the participant recovers from an AE in response to lenvatinib interruption (i.e., 
positive dechallenge), the event is more likely to be related to lenvatinib. Otherwise, 
after excluding other alternative explanations, an immune-related AE should be 
considered. 
2. Severity of AE
If an AE is suspected to be treatment related and is severe/life threatening at the time 
of onset or is rapidly worsened, action including interrupting both drugs and initiating 
treatment with a corticosteroid (with exception of hypothyroidism, TIDM) and other 
supportive care should be taken promptly.
3. Participants receiving the combination therapy (lenvatinib + pembrolizumab) must 
discontinue study therapy if any of the following occur: 

ALT or AST >5 X ULN for more than 2 weeks.
Pembrolizumab will have already been permanently discontinued per Table 7, but 
lenvatinib may be administered at a reduced dose by the time this criterion is met 
and must be permanently discontinued immediately.

ALT or AST >3 X ULN and (TBL >2 X ULN or INR >1.5).
Although Table 7 advises pembrolizumab to be withheld (interrupted), 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.
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Other Allowed Dose Interruptions
If the participant is receiving treatment with lenvatinib and requires surgery during the study, 
the stop time and restart time of lenvatinib should be as follows:

For minor procedures: stop lenvatinib at least 2 days before the procedure and restart it at 
least 2 days after, once there is evidence of adequate healing and no risk of bleeding.

For major procedures: stop lenvatinib at least 1 week (5 half-lives) prior to surgery and 
then restart it at least 2 weeks after, once there is evidence of adequate healing and no 
risk of bleeding.
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as
medical/surgical events or logistical reasons not related to study therapy. However, 
pembrolizumab is to be started within 42 days of the originally scheduled dose and within 84 
days of the previously administered dose, unless otherwise discussed with the Sponsor. In 
case of surgery (including surgery for curative intent), pembrolizumab must resume at least 
6 weeks and no more than 12 weeks post-surgery, if clinically appropriate. Participants may 
receive up to 18 total administrations of pembrolizumab inclusive of both preoperative and 
postoperative periods. The reason for pembrolizumab interruption is to be documented in the 
participant's study record.
For regorafenib or TAS-102, instructions for stop time and restart time for dose interruptions 
should follow the regulation and local guidelines. In case of surgery (including surgery for 
curative intent), regorafenib or TAS-102 must resume at least 6 weeks and no more than 
12 weeks post-surgery, if clinically appropriate.
6.7
Intervention After the End of the Study
There is no study-specified intervention following 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.
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.
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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 regimen will still continue to be monitored in this study and participate in the study 
visits and procedures as specified in Section 1.3 and Section 8.11.3 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.
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.

After prolonged study intervention interruption that prohibits restarting study intervention 
as agreed upon with the Sponsor.

The participant has a confirmed positive serum pregnancy test.

Radiographic disease progression outlined in Section 8.2.1.4 (after obtaining informed 
consent addendum and Sponsor communication, the investigator may elect to continue
treatment beyond disease progression).

Any progression or recurrence of any malignancy, or any occurrence of another 
malignancy that requires active treatment.

Initiation of a new anticancer treatment.

Any study intervention-related toxicity specified as a reason for permanent 
discontinuation as defined in the guidelines for dose modification due to AEs in 
Section 6.6.
Participants must discontinue study therapy if any of the following occur:
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ALT or AST elevation meeting the following criteria:

ALT or AST >5 × ULN for more than 2 weeks
Note: In Arm A, pembrolizumab will have already been permanently discontinued 
per Table 7, but lenvatinib may be administered at a reduced dose by the time this 
criterion is met and must be permanently discontinued immediately.

ALT or AST >3 × ULN and (TBL >2X ULN or INR > 1.5)
Note: In Arm A, although Table 7 advises pembrolizumab to be withheld 
(interrupted), 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.
Any prolonged interruption of study intervention beyond the permitted periods, for irAE 
management or other allowed dose interruptions, as noted in Sec. 6.6. require sponsor 
consultation prior to restarting treatment.  If treatment will not be restarted, the participant 
will continue to be monitored in the study and the reason for discontinuation of study 
intervention will be recorded in the medical record.
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.
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
Note: A participant is not considered lost to follow-up until the last scheduled visit for the 
individual participant. The missing data for the participant will be managed via the 
prespecified statistical data handling and analysis guidelines.
8
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarized in the SoA.

Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.

The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified (by education, training, and experience) staff. Delegation of study 
site personnel responsibilities will be documented in the Investigator Trial File Binder (or 
equivalent).

All study-related medical or dental decisions must be made by an investigator who is a 
qualified physician.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.

Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of ICF may be utilized for screening or baseline 
purposes provided the procedure met the protocol-specified criteria and were performed 
within the time frame defined in the SoA.

Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, Hepatitis C), and thus local regulations 
may require that additional informed consent be obtained from the participant. In these 
cases, such evaluations/testing will be performed in accordance with those regulations.
The maximum amount of blood collected from each participant over the duration of the study
will be provided 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
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented informed consent from each potential participant or their legally 
acceptable representative prior to participating in this clinical study. If there are changes to 
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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 trial protocol number, trial 
protocol title, dated signature, and agreement of the participant (or his/her legally acceptable 
representative) and of the person conducting the consent discussion.
A copy of the signed and dated informed consent form should be given to the participant (or 
their legally acceptable representative) before participation in the study.
The initial ICF, any subsequent revised ICF, and any written information provided to the 
participant must receive the IRB/IEC’s approval/favorable opinion in advance of use. The 
participant or his/her legally acceptable representative should be informed in a timely manner 
if new information becomes available that may be relevant to the participant’s willingness to 
continue participation in the study. The communication of this information will be provided 
and documented via a revised consent form or addendum to the original consent form that 
captures the participant’s or the participant’s legally acceptable representative’s dated 
signature.
If the investigator recommends continuation of study intervention beyond disease 
progression, the participant or their legally acceptable representative will be asked to provide 
documented informed consent.
Specifics about the study and the study population are to be included in the study informed 
consent form.
Informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, and 
Sponsor requirements.
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria in Section 5.1 and Section 5.2 will be reviewed by the 
investigator, who is a qualified physician, to ensure that the participant is eligible for the 
study.
MSI-H/dMMR Local Testing and Biopsy Sample
Results from local testing for MSI-H/dMMR status (eg, per IHC and/or PCR) are mandatory 
at entry (see Section 5.1) and will be collected in the corresponding CRFs. Participants 
whose tumors are MSI-H/dMMR are not eligible for the study.
Additionally, an archival tumor tissue sample or newly obtained core or excisional biopsy of
a tumor lesion is required for entry in the study (see Section 5.1) and will be shipped to a 
designated central laboratory (see Laboratory Manual).
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Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant provides documented informed consent. At the time of intervention allocation,
site personnel will add the treatment/randomization number to the participant identification 
card.
The participant identification card also contains contact information for the emergency 
unblinding call center so that a healthcare provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
Medical History
A medical history will be obtained by the investigator or qualified designee. The medical 
history will collect all active conditions and any condition diagnosed within the prior 10 
years that the investigator considers to be clinically important, including history of premature 
CV disease. 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 
disease for which the participant has enrolled in this study will be recorded separately and 
not listed as medical history.
If a medical condition is diagnosed at the time of Screening due to the physical examination, 
laboratory tests, radiologic assessment, other assessment, and/or a combination of these 
evaluations, the medical condition is to be recorded as a baseline condition along with the 
participant’s other medical history unless due to any protocol-specified intervention (eg, 
procedure, washout or run-in treatment including placebo run-in).
Oncologic Disease Medical History
The investigator or qualified designee will obtain specific medical history 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, where
applicable. History of Lynch syndrome needs to be described if known.
Prior and Concomitant Medications Review
8.1.7.1
Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant 
within 28 days before starting the study. Treatment for the disease for which the participant 
has enrolled in this study will be recorded separately and not listed as a prior medication.
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8.1.7.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study through the Safety Follow-up visit. 
8.1.7.3
Prior Oncologic Treatment
The investigator or qualified designee will review and record all treatments for the cancer 
under study, including systemic and local treatment, investigational agents, radiation, and 
surgeries on the corresponding CRF. Additional information collected on these treatments 
will include, but is not limited to, duration of treatment, reason for discontinuation, best 
response, and date of progression after each treatment as applicable.
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur prior to randomization. Each participant 
will be assigned only 1 screening number. Screening numbers must not be re-used for 
different participants.
Any participant who is screened multiple times will retain the original screening number 
assigned at the initial Screening Visit. Specific details on the screening/rescreening visit 
requirements are in Section 8.11.1.
8.1.8.1
Treatment Eligibility Assessment Form
A TEA form is included in this study to document the investigator assessment of participant 
suitability for potential treatment in Arm B with regorafenib or TAS-102 and the rationale. 
The investigator must complete this form and provide rationale to document the choice of 
regorafenib or TAS-102 prior to randomization.
Assignment of Treatment/Randomization Number
All eligible participants will be randomly allocated and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment allocation/randomization. Once a 
treatment/randomization number is assigned to a participant, it can never be re-assigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
Study Intervention Administration
Study intervention(s) will be administered by the investigator and/or study staff according to 
the specifications within the Pharmacy Manual.
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It is strongly preferred that participants receive first dose of study intervention on day of 
randomization.
The first dose of Cycle 1 of oral study drug (lenvatinib or regorafenib or TAS-102) must be 
taken by the participant while at the site.  
Refer to the Pharmacy Manual for lenvatinib and pembrolizumab administration for Arm A. 
Refer to the regorafenib or TAS-102 product label, respectively, for guidance on 
administration procedures for regorafenib or TAS-102, for Arm B.
Study intervention should begin within 3 days of randomization.
8.1.10.1
Timing of Dose Administration
Study treatment in both arms will follow a 28-day cycle and will begin after all 
procedures/assessments have been completed as detailed in the SoA (Section 1.3). Study 
treatments may be administered up to 3 days after Cycle 1 Day 1 and up to 3 days before or 
after the scheduled Day 1 of each subsequent cycle due to administrative reasons.
All study treatments may be administered on an outpatient basis. 
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, 
achievement of a CR, or administrative reasons requiring cessation of treatment.
Dosing interruptions are permitted in the case of medical / surgical events or logistical 
reasons (eg, 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. Discuss with the Sponsor if participants cannot 
restart study medication within 12 weeks for pembrolizumab, 4 weeks for Lenvatinib and 3 
weeks for Arm B treatment. The reason for interruption should be documented in the 
participant's study record.
Study treatment should be discontinued in Arm A if the participant interrupts study 
intervention administration for more than 12 weeks of pembrolizumab AND 4 weeks of 
lenvatinib, except if agreed to by the Sponsor. In Arm B, study treatment interruptions and/or 
treatment discontinuation will be followed per local guidelines and label, if beyond 3 weeks 
contact Sponsor.
The dose and schedule modifications of study interventions are provided in Section 6.6 –
Dose Modification.
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8.1.10.1.1
Arm A
8.1.10.1.1.1
Lenvatinib Administration
Lenvatinib is provided as 4 mg or 10 mg capsules. Lenvatinib 20 mg once daily will be taken 
orally with water (with or without food) at approximately the same time each day in each 28-
day cycle. However, on day of pembrolizumab administration (approximately every 6 weeks) 
lenvatinib will be administered 0 to 4 hours after completion of pembrolizumab 
administration at the clinic.
If a lenvatinib dose is missed and cannot be taken within 12 hours of planned administration, 
that dose should be skipped and the next dose should be taken at the usual time of 
administration
Details on preparation and administration of lenvatinib are provided in the Pharmacy 
Manual.
8.1.10.1.1.2
Pembrolizumab Administration
Pembrolizumab will be administered as a 30-minute IV infusion Q6W according to SoA 
(Section 1.3). Sites should make every effort to target infusion timing to be as close to 30 
minutes as possible. However, given the variability of infusion pumps from site to site, a 
window of - 5 minutes and +10 minutes is permitted (ie, infusion time is 30 minutes: -5 
min/+10 min).
After Cycle 1 Day 1, pembrolizumab may be administered up to 3 days before or after the 
scheduled treatment day of each subsequent cycle due to administrative reasons.
Details on preparation and administration of pembrolizumab are provided in the Pharmacy 
Manual. 
8.1.10.1.2
Arm B
8.1.10.1.2.1
Regorafenib Administration
Participants are to take regorafenib at the same time each day on Days 1 to 21 of each cycle. 
Participants are to swallow the tablets whole with water after a meal. Participants are not to 
take 2 doses of regorafenib on the same day to make up for a missed dose from the previous 
day. Participants are not to take any doses of regorafenib on Days 22 to 28 of each cycle. 
Refer to the regorafenib package insert for current prescription information.
8.1.10.1.2.2
TAS-102 Administration
Participants are to take TAS-102 twice daily on Days 1 through 5 and Days 8 through 12 of 
each 28-day cycle. Participants are to swallow the tablets whole with water after a meal. 
Participants are not to take 2 doses of TAS-102 at once to make up for a missed dose. 
Participants are not to take any doses of TAS-102 on Days 6 and 7 and 13 to 28 of each 
cycle. Refer to the TAS-102 package insert for current prescription information. For 
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calculation of TAS-102 dosing based on weight/BSA, refer to the website 
8.1.10.2
Compliance
8.1.10.2.1
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 capsules.
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.
8.1.10.2.2
Pembrolizumab
Pembrolizumab will be administered by the investigator and/or study staff according to the 
specifications within the Pharmacy Manual. The total volume of study intervention infused 
will be compared with the total volume prepared to determine compliance with each dose 
administered.
8.1.10.2.3
Regorafenib
During onsite visits, regorafenib will be administered by the investigator and/or study staff 
according to the specifications within the product label and local guidelines. 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, regorafenib will be taken at home. When a participant attends a study visit, 
he or she will bring any unused tablets as per protocol.
Regorafenib 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.
8.1.10.2.4
TAS-102
During onsite visits, TAS-102 will be administered by the investigator and/or study staff 
according to the specifications within the product label and local guidelines. 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.
PPD
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On all other days, TAS-102 will be taken at home. When a participant attends a study visit, 
he or she will bring any unused tablets as per protocol.
TAS-102 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.
Discontinuation and Withdrawal
Participants who discontinue study intervention prior to completion of the treatment period
should be encouraged to continue to be followed for all remaining study visits as outlined in 
the SoA and Section 8.11.3.
Participants who withdraw from the study should be encouraged to complete all applicable 
activities scheduled for the End of Treatment/Discontinuation 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.
Participant Blinding/Unblinding
This is not applicable as this is an open-label study.
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.
Tumor Tissue for Biomarker Status
During the screening period, a tumor sample for each participant is required and is to be:

A newly obtained core, incisional or excisional biopsy of a tumor lesion, which was not 
previously irradiated
Or

An archival tumor tissue sample if a new biopsy is unavailable
If obtained at Screening, the procedure should be performed before screening /baseline scans 
are performed.
Details pertaining to tumor tissue submission can be found in the Laboratory Manual.
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FFPE tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived 
tissue.
The central laboratory will use the tissue sample to ascertain PD-L1 status using the PD-L1 
IHC 22C3 pharmDx (Investigational Use Only) diagnostic kit. The diagnostic test is identical 
to the US FDA-approved PD-L1 IHC 22C3 pharmDx diagnostic kit except it is labeled IUO. 
The PD-L1 IHC 22C3 pharmDx assay kit is currently approved to assess PD-L1 status.
8.2
Efficacy Assessments
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.
In addition to survival, efficacy will be assessed based on evaluation of scan changes in 
tumor burden over time, until the participant is discontinued from the study or enters the
survival follow-up. The process for scan collection and transmission to the iCRO can be 
found in the SIM. CT scans are strongly preferred. For the abdomen and pelvis, contrast-
enhanced MRI may be used when CT with iodinated contrast is contraindicated, or when 
mandated by local practice. The same type of scan should be used in a participant throughout
the study to optimize the reproducibility of the assessment of existing and new tumor burden 
and improve the accuracy of the response assessment. Note: for the purposes of assessing 
tumor scans, the term “investigator” refers to the local investigator at the site and/or the 
radiological reviewer at the site or at an offsite facility.
Participant eligibility will be determined using investigator assessment based on RECIST 
1.1. All scheduled scans for each participant from the sites will be submitted to the iCRO. In 
addition, unscheduled scans to determine disease progression, and scans obtained for other 
reasons, but captures radiologic progression based on investigator assessment, are to be 
submitted to the iCRO.
If brain scans are performed, magnetic resonance scans are preferred; however, CT scans are
acceptable, if MRI is medically contraindicated.
Bone scans may be performed to evaluate bone metastases. Any supplemental scans done to 
support a positive or negative bone scan, such as plain X-rays acquired for correlation, 
should also be submitted to the iCRO.
Other imaging modalities that may be collected, submitted to the iCRO, and included in the 
response assessment include chest x-rays, etc. Other types of scans (eg, ultrasound) should 
not be submitted to the iCRO and will not be included in response assessment.
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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 scans obtained after Cycle 1 Day 1 cannot be included in the screening 
assessment. The site 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.
If brain scans are required to document the stability of existing metastases, the brain scan 
MRI should be acquired during screening.  The specific methods permitted for this study are 
described in the SIM.
Bone scans are required at screening for participants with a history of bone metastases and/or 
for those participants with indicative clinical signs/symptoms such as bone pain or elevated 
alkaline phosphatase levels.
Bone scan refers to imaging methods used to assess bone metastasis. The specific methods 
permitted for this study are described in the SIM.
Tumor scans performed as part of routine clinical management are acceptable for screening if 
they are of acceptable diagnostic quality and performed within 28 days prior to 
randomization.
8.2.1.2
Tumor Scans During the Study
The first on-study scan should be performed at 8 weeks (56 days ±7 days) from the date of 
randomization. Subsequent tumor scans should be performed every 8 weeks (56 days ±7 
days) or more frequently if clinically indicated. Scan timing should follow calendar days and 
should not be adjusted for delays in cycle starts. 
Scans should continue 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, whichever occurs first. All supplemental scans must be submitted 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 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 time point.
For participants who have surgery with curative intent during the study, scans must be 
performed at a minimum of no less than 4 weeks after surgery and no more than 8 weeks 
prior to the next treatment cycle. The last set of scans prior to restart of treatment will be 
used to establish a new baseline of tumor burden. Subsequent scans will be compared to this 
new baseline and the visit responses will be limited to PD, non-PD, or NE (not evaluable); 
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these new postoperative images will be assessed every 8 weeks (56 days ± 7 days) for 12 
months and every 12 weeks (84 days ± 7 days) thereafter. 
On-study brain or bone scans should be performed if clinically indicated or to confirm CR (if 
other lesions indicate CR and bone lesions existed at baseline). 
Treatment beyond centrally verified PD per RECIST 1.1 may be permitted in Arm A at the 
discretion of the investigator after consultation with the Sponsor and receiving documented 
informed consent. Participants who continue treatment beyond centrally verified PD must 
continue tumor assessments as described in the SoA (Section 1.3). Investigator assessments 
are to be documents on the eCRF, but scans are not to be submitted to the iCRO. Further 
progression and discontinuation of study intervention are to be determined by the 
investigator.
When the investigator identifies radiographic progression per RECIST 1.1, the iCRO will 
perform expedited verification of radiologic disease progression and communicate the results 
to the study site and Sponsor via email. In clinically stable participants, scans should 
continue until disease progression has been verified by BICR (if initial site-assessed disease 
progression was not verified by BICR, each subsequent scan must be submitted to iCRO with 
verification of disease progression request until disease progression has been verified by 
BICR). Once disease progression is verified centrally, subsequent scans (if acquired) should 
not be submitted to the iCRO.
8.2.1.3
End-of-Treatment and Follow-up Tumor Scans
If participants discontinue study intervention, 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.
If participants discontinue study intervention without documented disease progression, every 
effort is to be made to monitor disease status by acquiring tumor scans using the same 
schedule used calculated from the date of randomization, refer to Section 8.2.1.2.
8.2.1.4
RECIST 1.1 Assessment of Disease
RECIST 1.1 will be used by BICR as the primary measure for assessment of tumor response, 
date of disease progression, and as a basis for all protocol guidelines related to disease status 
(eg, discontinuation of study intervention). Although RECIST 1.1 references a maximum of 
5 target lesions in total and 2 per organ, this protocol allows a maximum of 10 target lesions 
in total and 5 per organ, if clinically relevant to enable a broader sampling of tumor burden.
Upon investigator-assessed disease progression, the indicative scan(s) are to be submitted 
immediately to iCRO for BICR verification of progression. After submission of scan(s), the 
iCRO will email the assessment to the site and Sponsor.
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Patient-reported Outcomes
The EuroQoL EQ-5D-5L, EORTC QLQ-C30, and EORTC QLQ-CR29 questionnaires will 
be administered by trained site personnel and completed electronically by participants in the 
following order: EuroQoL EQ-5D-5L, EORTC QLQ-C30, and EORTC QLQ-CR29. The 
questionnaires should be administered prior to dosing at Day 1 and Day 15 of C1 through C3 
and then Day 1 of C4 through C12 and then Day 1 of every other cycle thereafter (ie, C14,
C16, etc. up to C26) up to 2 years until end of treatment or treatment discontinuation, 
whichever occurs first, and at the 30-day posttreatment safety follow-up visit.
It is best practice and strongly recommended that ePROs are administered to randomized 
participants prior to drug administration, AE evaluation, and disease status notification. If the 
participant does not complete the ePROs at a scheduled time point, the MISSMODE form 
must be completed to capture the reason the assessment was not performed.
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8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided. The total amount of blood/tissue to be drawn/collected over the course of the study 
(from prestudy to poststudy visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per participant, can be found in the Procedure
Document.
Planned time points for all safety assessments are provided in the SoA.
Physical Examinations
8.3.1.1
Full Physical Examination
The investigator or qualified designee will perform a complete physical examination
including oral examination during the Screening period. Clinically significant abnormal 
findings should be recorded as medical history. The time points for full physical exams are 
described in Section 1.3. After the first dose of study intervention, new clinically significant 
abnormal findings should be recorded as AEs.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.3.1.2
Directed Physical Examination
For cycles that do not require a full physical examination as defined in Section 1.3, the 
investigator or qualified designee will perform a directed physical examination including oral 
examination as clinically indicated prior to study intervention administration. New clinically
significant abnormal findings should be recorded as AEs.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
Vital Signs

Vital signs will be measured in a semisupine position after 5 minutes rest and will include 
temperature, systolic and diastolic blood pressure, and pulse and respiratory rate.

Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest 
for the participant in a quiet setting without distractions.

Blood pressure and pulse measurements will be assessed in a semisupine position with a 
completely automated device. Manual techniques will be used only if an automated 
device is not available. The correct size of the blood pressure cuff and correct positioning 
of the participant’s arm are essential to the accuracy of the blood pressure measurement.

Only 1 BP measurement is needed for participants with systolic BP <140 mm Hg and 
diastolic BR <90 mm Hg. If the participant’s first BP measurement of the current 
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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.
Electrocardiograms
Electrocardiograms (ECGs) will be obtained as designated in the SoA (Section 1.3). 
Complete, standardized, 12-lead ECG recordings that permit all 12 leads to be displayed on a 
single page with an accompanying lead II rhythm strip below the customary 3 × 4 lead 
format are to be used. In addition to a rhythm strip, a minimum of 3 full complexes should be 
recorded from each lead simultaneously. Participants must be in the recumbent position for a 
period of 5 minutes prior to the ECG. The Fridericia correction method for calculating QTc 
will be used. 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 clinical studies with lenvatinib. Monitor 
electrocardiograms every cycle (as specified in the Schedule of Assessments) in participants 
with congenital long QT syndrome, congestive heart failure, bradyarrhythmias, or those who 
are taking medications known to prolong the QT interval, including Class Ia and III 
antiarrhythmics. Refer to the lenvatinib IB.
Echocardiogram or Multiple Gated Acquisition Scan
A MUGA scan (using technetium-based tracer) or an echocardiogram will be performed to 
assess left ventricular ejection fraction (LVEF) as designated in the SoA (Section 1.3).
MUGA or echocardiogram scans should be performed locally in accordance with the 
institution’s standard practice. MUGA scans are the preferred modality; however, whichever 
modality is used for an individual participant at baseline should be repeated for all 
subsequent LVEF assessments for that participant. LVEFs as assessed by the institution will 
be entered onto the CRF. Investigator assessment will be based upon institutional reports.
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
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 laboratory manual and the SoA (Section 1.3).

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 28 days after the last dose of study intervention, every 
attempt should be made to perform repeat assessments until the values return to normal or 
baseline or if a new baseline is established as determined by the investigator.
Details regarding specific laboratory procedures/assessments to be performed in this study 
are provided below. The total amount of blood/tissue to be drawn/collected over the course 
of the study (from prestudy to poststudy visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per participant can be found in the Study 
Laboratory Manual. Refer to the SoA (Section 1.3) for the timing of laboratory assessments.
Laboratory tests for hematology, chemistry, and urinalysis are specified in Appendix 2.
8.3.5.1
CBC With Differential and Clinical Chemistry
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.
Pregnancy Test
Pregnancy testing (urine or serum) should be conducted according to Section 1.3 (SoA) and 
at the end of relevant systemic exposure for all arms.
-
Pregnancy testing requirements for study inclusion are described in Section 5.1.
-
Pregnancy testing (urine or serum) should be conducted at monthly intervals during 
intervention.
-
Pregnancy testing (urine or serum) should be conducted for the time it takes to eliminate 
systemic exposure after the last dose of study intervention(s) as noted in Section 5.1, ie, 120 
days following cessation of pembrolizumab, 30 days following cessation of lenvatinib, or 
180 days following cessation of chemotherapy.
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-
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.
Refer to Appendix 7 for country-specific requirements.
Eastern Cooperative Oncology Group Performance Scale
The ECOG Performance Status is standardized criteria to measure how cancer impacts level 
of functioning (performance status) in terms of ability to care for oneself, daily activity, and 
physical ability (walking, working, etc.) with Grades 0 to 5. The investigator or qualified 
designee will assess ECOG performance 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) [ECOG-ACRIN Cancer Research Group 2016].
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.
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Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
All AEs, SAEs, and other reportable safety events that occur after the participant provides 
documented informed consent but before intervention  randomization must be reported by the 
investigator if the participant is receiving placebo run-in or other run-in treatment, if the 
event cause the participant to be excluded from the study, or is the result of a protocol-
specified intervention, including but not limited to washout or discontinuation of usual 
therapy, diet, or a procedure.

All AEs from the time of intervention randomization through 30 days following cessation 
of study intervention must be reported by the investigator.

All AEs meeting serious criteria, from the time of intervention randomization through 90 
days following cessation of study intervention or 30 days following cessation of study 
intervention if the participant initiates new anticancer therapy, whichever is earlier, must 
be reported by the investigator.

All pregnancies and exposure during breastfeeding, from the time of intervention
allocation/randomization through the time required to eliminate systemic exposure after 
cessation of study intervention as described in Sec. 5.1 and 8.3.6, or 30 days after 
cessation of study intervention if the participant initiates new anticancer therapy must be 
reported by the investigator.

Additionally, any SAE brought to the attention of an investigator at any time outside of 
the time period specified above must be reported immediately to the Sponsor if the event 
is considered related to study intervention.
Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 10.
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Table 10
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time Period:
Consent to Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation 
through Protocol-
specified Follow-
up Period
Reporting Time 
Period:
After the 
Protocol-
specified Follow-
up Period
Time Frame 
to Report 
Event and 
Follow-up 
Information 
to Sponsor:
NSAE
Report if:
- due to protocol-specified 
intervention
- causes exclusion
- participant is receiving 
placebo run-in or other run-in 
treatment
Report all
Not required
Per data 
entry 
guidelines
SAE including 
Cancer and 
Overdose
Report if:
- due to protocol-specified 
intervention
- causes exclusion
- participant is receiving 
placebo run-in or other run-in 
treatment
Report all
Report if:
- drug/vaccine 
related.
(Follow ongoing 
to outcome)
Within 24 
hours of 
learning of 
event
Pregnancy/
Lactation 
Exposure
Report if:
- participant has been 
exposed to any protocol-
specified intervention (eg, 
procedure, washout or run-in 
treatment including placebo 
run-in). Exception: A 
positive pregnancy test at the 
time of initial screening is 
not a reportable event unless 
the participant has received 
study intervention.
Report all
Previously 
reported – Follow 
to completion/
termination; report 
outcome
Within 24 
hours of 
learning of 
event
ECI (require 
regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report
- potential DILI
- require regulatory 
reporting
Not required
Within 24 
hours of 
learning of 
event
ECI (do not 
require 
regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report
- non-DILI ECIs 
and those not 
requiring 
regulatory 
reporting
Not required
Within 5 
calendar 
days of 
learning of 
event
DILI=drug-induced liver injury; ECI=event of clinical interest; NSAE=nonserious adverse event; SAE=serious adverse 
event
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other 
reportable safety events. Open-ended and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE occurrence.
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Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs, SAEs, and other reportable safety events,
including pregnancy and exposure during breastfeeding, ECIs, cancer, and overdose will be 
followed until resolution, stabilization, until the event is otherwise explained, or the 
participant is lost to follow-up (as defined in Section 7.3). In addition, the investigator will 
make every attempt to follow all nonserious AEs that occur in randomized participants for 
outcome. Further information on follow-up procedures is given in Appendix 3.
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and Sponsor policy and forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
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 SAE.
The medical reason (example: maternal health or fetal disease) for an elective termination of 
a pregnancy will be reported as an AE or SAE. Prenatal testing showing fetus will be born 
with severe abnormalities/congenital anomalies that leads to an elective termination of a 
pregnancy will be reported as an SAE for the fetus.
Pregnancy outcomes of ectopic pregnancy, spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth 
must be reported as serious events (Important Medical Events). If the pregnancy continues to 
term, the outcome (health of infant) must also be reported.
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Disease-related Events and/or Disease-related Outcomes Not Qualifying as AEs 
or SAEs
Efficacy endpoints as outlined in this section will not be reported to the Sponsor as described 
in Section 8.4.1.
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study.
The Sponsor will ensure that unblinded aggregated efficacy endpoint events and safety data 
are monitored to safeguard the participants in the study.
Events of Clinical Interest
Selected serious and nonserious AEs are also known as ECIs and must be reported to the 
Sponsor. 
Events of clinical interest for this study include: 

An overdose of Sponsor's product, as defined in Section 8.5. Lenvatinib overdose without 
an associated adverse event is not considered an ECI.

An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less 
than 2X the upper limit of normal, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.* 
*Note: These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology. The study site guidance for 
assessment and follow up of these criteria can be found in the Investigator Study File 
Binder (or equivalent).
8.5
Treatment of Overdose
For purposes of this study, an overdose will be defined as any dose exceeding the prescribed 
dose for:
Arm A:

Pembrolizumab: any dose above the protocol-prescribed dose.

Lenvatinib: any dose above the protocol-prescribed dose if associated with an adverse 
event
There is no specific antidote for an overdose of lenvatinib. Due to its high degree of plasma 
protein binding, lenvatinib is not expected to be dialyzable. Adverse reactions in participants 
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receiving single doses of lenvatinib as high as 40 mg were similar to those in clinical studies 
at the recommended dose for differentiated thyroid cancer, RCC, and HCC.
No specific information is available on the treatment of overdose of pembrolizumab or 
lenvatinib.
All reports of pembrolizumab overdose with and without an AE and all reports of lenvatinib 
overdose with an AE must be reported by the investigator within 24 hours to the Sponsor 
either by electronic media or paper.
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.”
Arm B:
Treatment of overdose with regorafenib or TAS-102 should follow the prescribing
information in their respective package inserts.
In the event of overdose for any study treatment, the participant should be observed closely 
for signs of toxicity. Appropriate supportive treatment should be provided if clinically 
indicated.
8.6
Pharmacokinetics
Pharmacokinetic parameters will not be evaluated in this study.
8.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
8.8
Biomarkers
To identify novel biomarkers, the following biospecimens to support exploratory analyses of 
cellular components (eg, protein, RNA, DNA, metabolites) and other circulating molecules 
will be collected from all participants except for participants enrolled in China which will be 
dependent on approval by the Human Genetic Resources Administration of China as 
specified in the SoA:

Blood for Genetic Analysis

Blood for RNA Analysis

Blood for Serum Biomarker Analysis

Blood for ctDNA Analysis

Archival or Newly Obtained Tissue Collection
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Sample collection, storage, and shipment instructions for the exploratory biomarker 
specimens will be provided in the operations/laboratory manual.
Refer to Appendix 7 for country-specific requirements.
Planned Genetic Analysis Sample Collection
Samples are to be collected for planned analysis of associations between genetic variants in 
germline/tumor DNA and drug response. If a documented law or regulation prohibits (or 
local IRB/IEC does not approve) sample collection for these purposes, then such samples are 
not to be collected at the corresponding sites. Biomarker sample collection for participants 
enrolled in China will be dependent on approval by the Human Genetic Resources 
Administration of China (HGRAC).
8.9
Future Biomedical Research Sample Collection
Not applicable
8.10
Medical Resource Utilization and Health Economics
Medical resource utilization and health economics data, associated with medical encounters, 
will be collected in the CRF by the investigator and study site personnel for all participants 
throughout the study. Protocol-mandated procedures, tests, and encounters are excluded.
The data collected may be used to conduct exploratory economic analyses and will include:
All-cause hospitalizations and emergency department visits must be reported in the eCRF, 
from the time of treatment allocation/randomization through 90 days following cessation of 
study intervention, or 30 days following cessation of study intervention if the participant 
initiates new anticancer therapy, whichever is earlier.
8.11
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
Screening
Documented informed consent must be provided prior to performing any protocol-specific 
procedure. Results of a test performed prior to the participant signing consent as part of 
routine clinical management are acceptable in lieu of a screening test if performed within the 
specified time frame. Screening procedures are to be completed within 28 days prior to the 
first dose of study intervention unless otherwise indicated in the SoA (Section 1.3).
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 
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inclusion/exclusion criteria is met. Participants who are rescreened will retain their original 
screening number.
Treatment Period
Visit requirements are outlined in the SoA (Section 1.3). Specific procedure-related details 
are provided in Section 8.1.
8.11.2.1
Telephone Contact Visit
Telephone contact or visit on Cycle 1 Day 8 will be conducted to assess participants for 
development of early toxicity as outlined in the SoA (Section 1.3). At the C1D8 telephone 
visit and if required between clinic visits, participants will have BP measured. If the 
participant does not return to the study site for this BP measurement, BP may be measured, 
for example, at home or at a local pharmacy, and the results will be reviewed with the 
investigator or designee.  The Sponsor will not provide diaries to the site. If BP result raises 
concerns, the investigator may require additional follow-up, including an on-site BP retest, or 
other clinically appropriate intervention(s).
Discontinued Participants Continuing to be Monitored in the Study
Participants who discontinue study treatment due to disease recurrence or start of a new 
anticancer therapy will move into Safety Follow-up and then proceed directly to Survival 
Follow-up as described in Section 8.11.4.3.
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. Additional details 
regarding participant treatment discontinuation can be found in Section 7.1.
Posttreatment Visits
8.11.4.1
Safety Follow-up Visit
The mandatory Safety Follow-up Visit should be conducted approximately 30 days after the 
last dose of study intervention or before the initiation of a new anticancer treatment, 
whichever comes first.  If a participant has a discontinuation visit ≥30 days after the last dose 
of study intervention, the Safety Follow-up Visit is not required.
8.11.4.2
Efficacy Follow-up Visits
Participants who complete the protocol-required cycles of study intervention or who 
discontinue study intervention for a reason other than disease progression will begin Efficacy 
Follow-up. Follow-up visits after treatment discontinuation must coincide with the imaging 
schedule until disease progression, death, or end of study. Participants who completed all 
efficacy assessments and/or will not have further efficacy assessments must enter Survival 
Follow-up.
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Every effort must be made to collect imaging until the start of new anticancer therapy, 
confirmed PD, or death. Information regarding poststudy anticancer treatment will be 
collected if new treatment is initiated.
8.11.4.3
Subsequent Anti-neoplastic Therapy
Details of subsequent therapies for cancer and/or details of radiation therapy and surgery for 
the treatment of the cancer, after discontinuation of study intervention, will be collected. 
Reasons for starting subsequent anti-neoplastic therapies including access to other PD-1/PD-
L1 inhibitors, or investigational drugs will be collected.
8.11.4.4
Survival Follow-up Contacts
Participant survival follow-up status will be assessed approximately every 12 weeks to assess 
for survival status until death, withdrawal of consent, or the end of the study, whichever 
occurs first.
The first survival follow-up assessment should be scheduled as described below:

For participants who discontinue treatment intervention and who will not enter Efficacy 
Follow-up, the first survival follow-up contact will be scheduled 12 weeks after the 
discontinuation visit and/or safety follow-up visit (whichever is last).

For participants who completed assessments in Efficacy Follow-up, the first survival 
follow-up contact will be scheduled 12 weeks after the last efficacy assessment follow-up 
visit has been performed.
Survival Status
To ensure current and complete vital status for survival data is available at the time of 
database locks, updated vital status for survival data may be requested during the study by 
the Sponsor. For example, updated vital status for survival data 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 time period will be contacted for their vital status for survival data 
(excluding participants that have a previously recorded death event in the collection tool).
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 any unblinding/final database lock, changes are made to 
primary and/or key secondary hypotheses, or the statistical methods related to those 
hypotheses, then the protocol will be amended (consistent with ICH Guideline E-9). Changes 
to exploratory or other nonconfirmatory analyses made after the protocol has been finalized, 
but prior to unblinding/final database lock, will be documented in a sSAP and referenced in 
the CSR for the study. Post hoc exploratory analyses will be clearly identified in the CSR. 
The PRO analysis plan will be included in the sSAP.
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Details pertaining to the statistical analyses for participants enrolled in China will be 
provided in a separate sSAP.
9.1
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Sections 9.2-9.12.
Study Design Overview
A Phase 3 randomized study of lenvatinib in combination with
pembrolizumab versus standard of care in participants with 
metastatic colorectal cancer who have received and progressed on 
or after or became intolerant to prior treatment
Treatment Assignment
Approximately 434 participants will be randomized in a 1:1 ratio 
between two treatment groups: (1) the lenvatinib plus 
pembrolizumab arm and (2) the SOC arm. Stratification factor is:
Presence of liver metastasis (Yes/No). This is an open-label study.
Analysis Populations
Efficacy: ITT
Safety: APaT
Patient-reported outcome: FAS 
Primary Endpoint(s)
Overall survival
Key Secondary Endpoints
Progression-free survival per RECIST 1.1 as assessed by BICR.
Objective response rate per RECIST 1.1 as assessed by BICR.
Statistical Methods for Key 
Efficacy Analyses
The primary hypothesis testing for OS and secondary hypothesis
testing for PFS 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 will be used for analysis of ORR
[Miettinen, O. 1985]. 
Statistical Methods for Key 
Safety Analyses
For analyses in which 95% CIs will be provided for between-
treatment differences in the percentage of participants with 
events, these analyses will be performed using the M&N method.
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Interim Analyses
Efficacy
One interim analysis is planned in this study. Results will be 
reviewed by an eDMC.
Safety
An interim safety analysis will be performed and reviewed by the 
eDMC 6 months after first participant is randomized. Afterwards, 
the eDMC will review safety data periodically in the study. 
Details will be specified in the DMC charter.
Multiplicity
The overall type I error over the primary and secondary 
hypotheses is strongly controlled at 2.5% (1-sided), with 2.5% 
initially allocated to OS (H1), 0% to PFS (H2), and 0% to ORR
(H3).
By using the graphical approach of Maurer and Bretz [Maurer, W. 
and Bretz, F. 2013], if one hypothesis is rejected, the alpha will be 
shifted to other hypotheses.
Sample Size and Power
The planned sample size is approximately 434 participants. 
It is estimated that there will be ~ 336 OS events at the final 
analysis. With 336 OS events, the study has 90% power for 
detecting a HR of 0.7 at an initially assigned 0.025 (1-sided) 
significance level. 
Abbreviations: APaT = all participants as treated; BICR = blinded independent central review; CI = 
confidence interval; DMC = data monitoring committee; eDMC = external data monitoring committee; FAS 
= full-analysis set; HR = hazard ratio; ITT = intent to treat; M&N = Miettinen and Nurminen; ORR = 
objective response rate; OS = overall survival; PFS = progression free survival; SOC = standard of care
9.2
Responsibility for Analyses/In-house Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
The Sponsor will generate the randomized allocation schedule(s) for study treatment 
assignment as appropriate in this protocol, and the allocation will be implemented in IRT. 
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This study is being conducted as a randomized, open-label study, i.e., participants, 
investigators, and Sponsor personnel will be aware of participant treatment assignments after 
each participant is enrolled and treatment is assigned. Although the study is open label, 
analyses or summaries generated by randomized intervention assignment, or actual 
intervention received will be limited and documented.
Blinding issues related to the planned interim analyses are described in Section 9.7.
9.3
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.
9.4
Analysis Endpoints
Efficacy and safety endpoints that will be evaluated are listed below.
Efficacy Endpoints
Primary

Overall Survival
OS is defined as the time from randomization to death due to any cause.
Secondary

Progression-free survival
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. 

Objective Response Rate
The ORR is defined as the percentage of participants who achieve a confirmed CR or 
PR per RECIST 1.1 as assessed by BICR.

Duration of Response
For participants who demonstrate confirmed CR or PR, duration of response is 
defined as the time from the first documented evidence of CR or PR until disease 
progression or death due to any cause, whichever occurs first.
Safety Endpoints
Safety and tolerability will be assessed by clinical review of all relevant parameters, 
including AEs, SAEs, fatal AEs, laboratory tests, and vital signs. Furthermore, specific 
events will be collected and designated as ECIs as described in Section 8.4.7.
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PRO Endpoints

Change from baseline in EORTC QLQ-C30 global health status/QoL, physical 
functioning and appetite loss and EORTC QLQ-CR29 bloating scores for the 
combination of lenvatinib plus pembrolizumab versus SOC 

Time to deterioration in EORTC QLQ-C30 global health status/QoL, physical 
functioning and appetite loss and EORTC QLQ-CR29 bloating scores for the 
combination of lenvatinib plus pembrolizumab versus SOC

Change from baseline in EQ-5D VAS for the combination of lenvatinib plus 
pembrolizumab versus SOC 
Additional details of the PRO endpoints, including analyses of the remaining functioning and 
symptom scores of the EORTC QLQ-C30 and EORTC QLQ-CR29 and VAS of the EQ-5D-
5L, will be described in the sSAP.
9.5
Analysis Populations
Efficacy Analysis Populations
The ITT population will serve as the primary population for the analysis of efficacy data in 
this study. The ITT population consists of all randomized participants. Participants will be 
analyzed in the treatment arm to which they are randomized. Details of the approach to 
handling missing data are provided in Section 9.6.1.4.
Safety Analysis Populations
Safety Analyses will be conducted in the APaT population, which consists of all randomized 
participants who received at least one dose of study treatment. Participants will be included 
in the treatment group corresponding to the study treatment they actually received for the 
analysis of safety data using the APaT population. This will be the treatment group to which 
they are randomized except for participants who take incorrect study treatment for the entire 
treatment period; such participants will be included in the treatment group corresponding to 
the study treatment actually received.  
At least one laboratory or vital sign measurement obtained subsequent to at least one dose of 
study treatment is required for inclusion in the analysis of the respective safety parameter. To 
assess change from baseline, a baseline measurement is also required.
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.
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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 may be
computed for other efficacy analyses, but should be interpreted with caution due to potential 
issues of multiplicity, sample size, etc.
Statistical Methods for Efficacy Analyses
This section describes the statistical methods that address the primary and secondary 
objectives. Methods related to exploratory objectives will be described in the supplemental 
SAP.
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 [Miettinen, O. 1985]. 
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, the HR). The HR and its 95% CI from the stratified 
Cox model with a single treatment covariate will be reported. The stratification factors used 
for randomization (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 date the participant was last known to be alive.
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 arms. 
The HR and its 95% CI from the stratified Cox model with a single treatment covariate will 
be reported. The stratification factors used for randomization (see Section 6.3.2) will be 
applied to both the stratified log-rank test and the stratified Cox model.
Since disease progression is assessed periodically, PD can occur any time in the time interval 
between the last assessment where PD was not documented and the assessment when PD is 
documented. The true date of disease progression will be approximated by the earlier of the 
date of the first assessment at which PD is objectively documented per RECIST 1.1 by BICR 
and the date of death. Death is always considered a PD event.
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In order to evaluate the robustness of the PFS endpoint per RECIST 1.1 by BICR, 2
sensitivity analyses with different sets of censoring rules will be performed. The first 
sensitivity analysis follows the intention-to-treat principle. That is, PDs/deaths are counted as 
events regardless of missed study visits or initiation of new anti-cancer therapy. The second 
sensitivity analysis considers initiation of new anticancer treatment or discontinuation of 
treatment due to reasons other than complete response, whichever occurs later, to be a PD 
event for participants without documented PD or death. If a participant meets multiple 
criteria for censoring, the censoring criterion that occurs earliest will be applied. The 
censoring rules for the primary and sensitivity analyses are summarized in Table 11.
Table 11
Abbreviations: PD = progressive disease
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9.6.1.3
Objective Response Rate
The stratified M&N method will be used for the comparison of ORR between 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. The stratification factors used for randomization 
(see 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 (1934) [Clopper, C. J. and Pearson, 
E. S. 1934].
9.6.1.4
Analysis Strategy for Key Efficacy Variables
A summary of the primary analysis strategy for the key efficacy endpoints is provided in 
Table 12.
Table 12
Analysis Strategy for Key Efficacy Variables 
Endpoint/Variable
Statistical Method
Analysis 
Population
Primary Analyses
OS
Testing: stratified log-rank test
Estimation: Stratified Cox model 
with Efron’s tie handling 
method
ITT
Key Secondary Analyses
PFS per RECIST 
1.1 by BICR
Testing: stratified log-rank test
Estimation: Stratified Cox model 
with Efron’s tie handling 
method 
ITT
ORR per RECIST 
1.1 by BICR
Testing and estimation:
stratified Miettinen and 
Nurminen method
ITT
Abbreviations: BICR = blinded independent central review; ITT = intent-to-treat; ORR = objective 
response rate; OS = overall survival; PFS = progression-free survival; RECIST 1.1 = Response 
Evaluation Criteria in Solid Tumors.
Details about DOR evaluation will be provided in the sSAP.
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, laboratory tests and vital signs.
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The analysis of safety results will follow a tiered approach (Table 13). The tiers differ with 
respect to the analyses that will be performed. Adverse events (specific terms as well as 
system organ class terms) and events that meet predefined limits of change in laboratory and
vital signs are either prespecified as “Tier 1” endpoints or will be classified as belonging to 
“Tier 2” or “Tier 3” based on the number of events observed.
Tier 1 Events
Safety parameters or AEs of special interest that are identified a priori constitute “Tier 1” 
safety endpoints that will be subject to inferential testing for statistical significance. There are 
no Tier 1 events for this protocol. Adverse events that are immune-mediated or potentially 
immune-mediated are well documented and will be evaluated separately; however, these 
events have been characterized consistently throughout the pembrolizumab clinical 
development program, and determination of statistical significance is not expected to add 
value to the safety evaluation. The combination of lenvatinib plus pembrolizumab has not 
been found to be associated with any new safety signals. Finally, there are no known AEs 
associated with participants with CRC for which determination of a p-value is expected to 
impact the safety assessment. 
Tier 2 Events
Tier 2 parameters will be assessed via point estimates with 95% CIs provided for differences 
in the proportion of participants with events using the M&N method, an unconditional, 
asymptotic method [Miettinen, O. 1985].
Membership in Tier 2 requires that at least 10% of participants in any treatment group exhibit 
the event; all other AEs and predefined limits of change will belong to Tier 3. The threshold 
of at least 10% of participants was chosen for Tier 2 events because the population enrolled 
in this study is in critical condition and usually experiences various AEs of similar types 
regardless of treatment; events reported less frequently than 10% of participants would 
obscure the assessment of the overall safety profile and add little to the interpretation of 
potentially meaningful treatment differences. In addition, Grade 3 to 5 AEs (≥5% of 
participants in 1 of the treatment groups) and SAEs (≥5% of participants in 1 of the treatment 
groups) will be considered Tier 2 endpoints. Because many 95% CIs may be provided 
without adjustment for multiplicity, the CIs should be regarded as a helpful descriptive 
measure to be used in safety review, not as a formal method for assessing the statistical 
significance of the between-group differences.
Tier 3 Events
Safety endpoints that are not Tier 1 or 2 events are considered Tier 3 events. The broad AE 
categories consisting of the proportion of participants with any AE, a drug-related AE, a 
serious AE, an AE which is both drug-related and serious, a Grade 3-5 AE, a drug-related 
Grade 3-5 AE, and discontinuation due to an AE will be considered Tier 3 endpoints. Only 
point estimates by treatment group are provided for Tier 3 safety parameters.
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Continuous Safety Measures 
For continuous measures such as changes from baseline in laboratory and vital signs
parameters, summary statistics for baseline, on-treatment, and change from baseline values 
will be provided by treatment group in table format.
Table 13
Analysis Strategy for Safety Parameters
Safety 
Tier
Safety Endpoint
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 2
Grade 3-5 AE (incidence ≥5% of participants in one 
of the treatment groups)
X
X
Serious AE (incidence ≥5% of participants in one of 
the treatment groups)
X
X
AEs (incidence ≥10% of participants in one of the 
treatment groups)
X
X
Tier 3
Any AE
X
Any Grade 3-5 AE
X
Any Serious AE 
X
Any Drug-Related AE
X
Any Serious and Drug-Related AE
X
Any Grade 3-5 and Drug-Related AE
X
Discontinuation due to AE
X
Death
X
Specific AEs, SOCs (incidence <10% of 
participants in all of the treatment groups)
X
Change from Baseline Results (lab toxicity shift, 
vital signs)
X
Abbreviations: AE = adverse events; SOC = standard of care
Statistical Methods for Patient-Reported Outcome Analyses
This section describes the planned analyses for the PRO endpoints. 
Change from Baseline
The time point for the change from baseline will be determined based on blinded data review 
prior to the database lock for any PRO analysis and documented in the sSAP. 
To assess the treatment effects on the PRO score change from baseline in the global health 
status/QoL, physical, appetite loss and bloating, a constrained longitudinal data analysis 
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model proposed by Liang and Zeger [Liang, Kung-Yee and Zeger, Scott L. 2000] will be 
applied, with the PRO score as the response variable, and treatment, time, the treatment by 
time interaction, and the stratification factors used for randomization (see Section 6.3.2) as 
covariates. The treatment difference in terms of least square mean change from baseline will 
be estimated from this model together with 95% CI. Model-based least square mean with 
95% CI will be provided by treatment group for PRO scores at baseline and postbaseline 
time point. 
Time-to-Deterioration
The Kaplan-Meier method will be used to estimate the TTD curve for each treatment group. 
The estimate of median time to deterioration and its 95% confidence interval will be obtained 
from the Kaplan-Meier estimates. The treatment difference in TTD will be assessed by the 
stratified log-rank test. A stratified Cox proportional hazard model with Efron's method of tie 
handling and with a single treatment covariate will be used to assess the magnitude of the 
treatment difference (ie, HR). The HR and its 95% CI will be reported. The stratification 
factors used for randomization (see Section 6.3.2) will be used as the stratification factors in 
both the stratified log-rank test and the stratified Cox model.  
Details of PRO analyses will be described in the sSAP.
Demographic and Baseline Characteristics
The comparability of the treatment groups for each relevant demographic and baseline 
characteristic will be assessed by the use of tables and/or graphs. No statistical hypothesis 
tests will be performed on these characteristics. The number and percentage of participants 
screened and randomized and the primary reasons for screening failure and discontinuation 
will be displayed. Demographic variables, 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
The eDMC will serve as the primary reviewer of the results of the IAs and will make 
recommendations for discontinuation of the study or modification to the executive oversight 
committee of the Sponsor. If the eDMC recommends modifications to the design of the 
protocol or discontinuation of the study, this executive oversight committee and potentially 
other limited Sponsor personnel may be unblinded to the treatment level results in order to 
act on these recommendations. The extent to which individuals are unblinded with respect to 
results of IAs will be documented by the unblinded statistician. Additional logistic details 
will be provided in the eDMC Charter.  
Treatment-level results of the interim analysis will be provided by the unblinded statistician 
to the eDMC. Prior to final study unblinding, the unblinded statistician will not be involved 
in any discussions regarding modifications to the protocol or statistical methods, 
identification of protocol deviations, or data validation efforts after the IAs.
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Efficacy Interim Analysis
One IA is planned in addition to the FA for this study. For the IA and FAs, all randomized 
participants will be included. Results of the IAs will be reviewed by the eDMC. Details of 
the boundaries for establishing statistical significance with regard to efficacy are discussed 
further in Section 9.8.
The analyses planned, endpoints evaluated, and drivers of timing are summarized in 
Table 14.
Table 14
Summary of Interim and Final Analyses Strategy
Analyses
Key 
Endpoints
Timing
Estimated Time after 
First Participant 
Randomized
Primary Purpose 
of Analysis
IA
OS
(PFS and 
ORR if OS 
is rejected)
Both ~260 OS events 
have been observed 
and ~ 7 months after 
last participant 
randomized
~ 18 months
Interim OS 
analysis
Final PFS and 
ORR analysis
FA
OS
both ~336 OS events 
have been observed 
and ~ 7 months after 
interim analysis
~ 25 months
Final OS analysis
Abbreviations: FA = final analysis; IA = interim analysis; ORR = objective response rate; OS = 
overall survival; PFS = progression free survival.
Safety Interim Analysis
The eDMC will be responsible for periodic interim safety reviews as specified in the eDMC 
charter. An interim safety analysis will be performed 6 months since first participant is 
randomized. Afterwards, the eDMC will review safety data periodically in the study. Interim 
safety analyses will also be performed at the time of interim efficacy analyses. Details will be 
specified in the eDMC charter.  
9.8
Multiplicity
The study uses the graphical method of Maurer and Bretz [Maurer, W. and Bretz, F. 2013] to 
provide strong multiplicity control for multiple hypotheses as well as interim analyses. 
According to this approach, study hypotheses may be tested more than once, and when a 
particular null hypothesis is rejected, the α allocated to that hypothesis can be reallocated to 
other hypothesis tests. Note that if the OS null hypothesis is rejected at FA of the study, the 
previously computed PFS and ORR test statistics at IA may be used for inferential testing 
with its updated bounds considering the α reallocation from the OS hypothesis. Figure 3
shows the initial 1-sided α allocation for each hypothesis in the ellipse representing the 
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hypothesis. The weights for reallocation from each hypothesis to the others are shown in the 
boxes on the lines connecting hypotheses.
The initial α assigned to OS, PFS and ORR will be 0.025, 0 and 0, respectively. If OS 
hypothesis is rejected, the corresponding alpha can be reallocated equally to PFS and ORR. If 
the PFS hypothesis is rejected, the corresponding alpha can be reallocated to ORR. If the 
ORR hypothesis is rejected, the corresponding α can be reallocated to PFS. 
Figure 3
Multiplicity Diagram for Type I Error Control
Abbreviations: ORR = objective response rate; OS = overall survival; PFS = progression-free survival.
Note: If OS null hypothesis is rejected, the allocation strategy allows testing of PFS and ORR at α = 0.0125, 
separately.
Overall Survival
The study will test OS at IA and FA. Following the multiplicity strategy as outlined in 
Figure 3, the OS hypothesis will be tested at α=0.025. Table 15 shows the bounds and 
boundary properties for OS hypothesis testing derived using a Lan-DeMets spending 
function approximating O’Brien-Fleming bounds. 
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Table 15
Efficacy Boundaries and Properties for Overall Survival Analyses
Analysis
Value
=0.025
IA: 77%*
N: 434
Events: 260
Month: 18
Z 
2.2976
p (1-sided)a
0.0108
HR at boundb
0.7517
P(Cross) if HR=1c
0.0108
P(Cross) if HR=0.7d
0.7185
FA 
N: 434
Events: 336 
Month: 25 
Z 
2.0177
p (1-sided)a
0.0218
HR at boundb
0.8022
P(Cross) if HR=1c
0.0250
P(Cross) if HR=0.7d
0.9000
Abbreviations: HR = hazard ratio; IA = interim analysis, FA = final analysis.
The number of events and timings are estimated.
*Percentage of total planned events at the interim analysis.
ap (1-sided) is the nominal α for group sequential testing.
bHR at bound is the approximate HR required to reach an efficacy bound.
cP(Cross if HR=1) is the probability of crossing a bound under the null hypothesis.
dP(Cross if HR=0.7) is the probability of crossing a bound under the alternative hypothesis.
The bounds provided in the table above are based on the assumptions that the expected 
number of events at IA and FA are 260 and 336, respectively. At the time of an analysis, the 
observed number of events may differ substantially from the expected. To avoid 
overspending at an IA and leave reasonable α for the FA, the minimum α spending strategy 
will be adopted. At an IA, the information fraction used in Lan-DeMets spending function to 
determine the alpha spending at the IA will be based on the minimum of the expected 
information fraction and the actual information fraction at each analysis. Specifically,  

In the scenario that the events accrue slower than expected and the observed number of 
events is less than the expected number of events at a given analysis, the information 
fraction will be calculated as the observed number of events at the 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 exceeds 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.
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The final analysis will use the remaining Type I error that has not been spent at the earlier 
analyses. The observed event counts for all analyses will be used to compute correlations.
Progression-free Survival  
The study will test PFS at IA only if the OS null hypothesis is rejected. Following the 
multiplicity strategy as outlined in Figure 3, the PFS hypothesis may be tested at α=0.0125 
(if the OS null hypothesis is rejected, but not the ORR hypothesis) or at α= 0.025 (if both the 
OS and ORR null hypothesis is rejected). Table 16 shows the boundary properties for each of 
these α levels for the PFS analysis. Note that the final row indicates the total power to reject 
the null hypothesis for PFS at each α level. 
Table 16
Efficacy Boundaries and Properties for Progression-Free Survival Analyses
Analysis
Value
=0.0125
=0.025
IA
N = 434 
Events*: 404
Month: 18
Z
2.2414
1.9600
p (1-sided) a
0.0125
0.025
HR at boundb
0.8000
0.8227
P(Cross) if HR=1c
0.0125
0.025
P(Cross) if HR=0.65d
0.9820
0.9912
Abbreviations: HR = hazard ratio; IA = interim analysis.
The number of events and timing is estimated.
ap (1-sided) is the nominal α for group sequential testing. 
bHR at bound is the approximate HR required to reach an efficacy bound.
cP (Cross if HR=1) is the probability of crossing a bound under the null hypothesis.
dP(Cross if HR=0.65) is the probability of crossing a bound under the alternative hypothesis.
Objective Response Rate
The study will test ORR only once at the IA if the OS null hypothesis is rejected. Following 
the multiplicity strategy as outlined in Figure 3, the ORR hypothesis may be tested at 
α=0.0125 (if the OS null hypothesis is rejected, but not the PFS hypothesis) or at α= 0.025 (if 
both the OS and PFS null hypothesis is rejected). Power at the possible α-levels as well as the 
approximate treatment difference required to reach the bound (ΔORR) are shown in 
Table 17, assuming underlying 2% and 12% response rates in the control and experimental 
groups, respectively.
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Table 17
Possible α Levels and Approximate ORR Difference Required to Demonstrate 
Efficacy for Objective Response at IA
α
~Δ Objective Response Rate (ORR)
Power (ΔORR=0.1)
0.0125
0.0549
0.970
0.025
0.0480
0.985
Safety Analysis
The eDMC has responsibility for assessment of overall risk/benefit. When prompted by 
safety concerns, the eDMC can request corresponding efficacy data. eDMC review of 
efficacy data to assess the overall risk/benefit to study participants will not require a 
multiplicity adjustment typically associated with a planned efficacy IA. However, to account 
for any multiplicity concerns raised by the eDMC review of unplanned efficacy data 
prompted by safety concerns, a sensitivity analysis for ORR, PFS, and OS adopting a 
conservative multiplicity adjustment will be prespecified in the sSAP.
9.9
Sample Size and Power Calculations
The study will randomize 434 participants in a 1:1 ratio into the lenvatinib plus 
pembrolizumab arm the SOC arms. OS are primary endpoint for the study, with PFS and 
ORR as the key secondary endpoints.
For the OS endpoint, based on a target number of 336 events and 1 IA at approximately 77% 
of the target number of events, the study has approximately 90% power to detect a HR of 0.7 
at the initially allocated α=0.025 (1-sided).
For the PFS endpoint, based on a target number of 404 events at the IA (final PFS analysis), 
the study has approximately 98.2% power to detect a HR of 0.65 at the reallocated α=0.0125 
(1-sided) if OS hypothesis is rejected. 
Based on the 434 participants with at least 7 months of follow-up, the power of the ORR 
testing at the reallocated α=0.0125 (1-sided) if OS hypothesis rejected is approximately 
97.0% to detect a 10-percentage point difference between an underlying 2% ORR in the 
control arm and a 12% ORR in the experimental arm.
Note that the above power calculations are based on a constant HR assumption. 
CCI
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9.10
Subgroup Analyses
To determine whether the treatment effect is consistent across various subgroups, the 
between-group treatment effect for OS (with a nominal 95% CI) will be estimated and 
plotted by treatment group within each category of the following subgroup variables:

Geographic region (Asia vs. Western Europe/North America vs. Rest of World)

ECOG performance status (0, 1)

Age category (<65 years, ≥65 years)

Sex (female, male)

Race (white, all others)

Presence of liver metastasis (Yes, No)

BRAF (wild type, mutant)

RAS (wild type, mutant)

Investigators’ choice of standard of care chemotherapy prior to randomization 
(Regorafenib versus TAS102)
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 ITT population, the subgroup analysis will not be 
performed for this category of the subgroup variable, and this subgroup variable will not be 
displayed in the forest plot. The subgroup analyses for OS will be conducted using an 
unstratified Cox model.
9.11
Compliance (Medication Adherence)
Drug accountability data for study treatment will be collected during the study. Any 
deviation from protocol-directed administration will be reported.
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9.12
Extent of Exposure
Extent of Exposure for a participant is defined as the number of cycles and number of days 
for which the participant receives the study intervention. Summary statistics will be provided 
on the extent of exposure for the overall study intervention, and for lenvatinib and 
pembrolizumab separately, for the APaT population. 
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
Code of Conduct for Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing, and reporting these trials 
in compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design and conduct of clinical trials. In all cases, MSD clinical trials will be conducted 
in compliance with local and/or national regulations (including all applicable data protection laws and
regulations), and International Council for Harmonisation Good Clinical Practice (ICH-GCP), and also in 
accordance with the ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD irrespective of the party (parties) employed for their execution (e.g., contract research organizations, 
collaborative research efforts). This Code is not intended to apply to trials that are observational in nature, or 
which are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the 
full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of MSD or comparator products. Alternatively, MSD 
may conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to 
determine patient preferences, etc.
The design (i.e., participant population, duration, statistical power) must be adequate to address the specific 
purpose of the trial and shall respect the data protection rights of all participants, trial site staff and, where 
applicable, third parties. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
MSD selects investigative sites based on medical expertise, access to appropriate participants, adequacy of 
facilities and staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial 
initiation, sites are evaluated by MSD personnel (or individuals acting on behalf of MSD) to assess the ability 
to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and Good Clinical Practice 
(GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data are verified versus 
source documentation according to standard operating procedures. Per MSD policies and procedures, if
potential fraud, scientific/research misconduct, privacy incidents/breaches or Clinical Trial-related 
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Significant Quality Issues are reported, such matters are investigated. When necessary, appropriate corrective 
and/or preventative actions are defined and regulatory authorities and/or ethics review committees are 
notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the pre-specified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important 
to patients, physicians, and payers. Some early phase or pilot trials are intended to be hypothesis-generating rather 
than hypothesis testing; in such cases, publication of results may not be appropriate since the trial may be 
underpowered and the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). In summary, authorship should reflect significant contribution to the design and 
conduct of the trial, performance or interpretation of the analysis, and/or writing of the manuscript. All named 
authors must be able to defend the trial results and conclusions. MSD funding of a trial will be acknowledged in 
publications.
III. Participant Protection
A. Regulatory Authority and Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics 
Committee [IEC])
All protocols and protocol amendments will be submitted by MSD for regulatory authority 
acceptance/authorization prior to implementation of the trial or amendment, in compliance with local and/or 
national regulations.
The protocol, protocol amendment(s), informed consent form, investigator’s brochure, and other relevant trial 
documents must be reviewed and approved by an IRB/IEC before being implemented at each site, in compliance 
with local and/or national regulations. Changes to the protocol that are required urgently to eliminate an 
immediate hazard and to protect participant safety may be enacted in anticipation of ethics committee approval. 
MSD will inform regulatory authorities of such new measures to protect participant safety, in compliance with 
local and/or national regulations.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance. 
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At 
a minimum, trial designs will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Participants may withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible, as well as all 
applicable data protection rights. Unless required by law, only the investigator, Sponsor (or individuals acting on 
behalf of MSD), ethics committee, and/or regulatory authorities will have access to confidential medical records 
that might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
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IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD does not pay incentives to 
enroll participants in its trials. However, when enrollment is particularly challenging, additional payments may be 
made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent 
on chart review and medical evaluation to identify potentially eligible participants.
B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may 
wish to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
Financial Disclosure
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required. It is the investigator's/subinvestigator's 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
Data Protection
The Sponsor will conduct this study in compliance with all applicable data protection 
regulations.
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Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information that would make the participant identifiable will not be transferred.
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
10.1.3.1
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the IRB, IEC, or similar or expert committee; affiliated institution and 
employees, only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution and employees. Data generated by this study will be 
considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol.
10.1.3.2
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF data. By signing the consent form, the participant agrees to this 
process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules 
and regulations.
10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
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Committees Structure
10.1.4.1
External Data Monitoring Committee
To supplement the routine study monitoring outlined in this protocol, an external DMC will 
monitor the interim data from this study. The voting members of the committee are external 
to the Sponsor. The members of the DMC must not be involved with the study in any other 
way (eg, they cannot be study investigators) and must have no competing interests that could 
affect their roles with respect to the study.
The DMC will make recommendations to the EOC regarding steps to ensure both participant 
safety and the continued ethical integrity of the study. Also, the DMC will review interim 
study results, consider the overall risk and benefit to study participants (Section 9.7 Interim 
Analysis) and recommend to the EOC whether the study should continue in accordance with 
the protocol.
Specific details regarding composition, responsibilities, and governance, including the roles 
and responsibilities of the various members and the Sponsor protocol team; meeting 
facilitation; the study governance structure; and requirements for and proper documentation 
of DMC reports, minutes, and recommendations will be described in the DMC charter that is 
reviewed and approved by all the DMC members.
10.1.4.2
Executive Oversight Committee
The EOC is comprised of members of Sponsor Senior Management. The EOC will receive 
and decide on any recommendations made by the DMC regarding the study.
Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments.
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
Compliance with Study Registration and Results Posting Requirements
Under the terms of the FDAAA of 2007 and the EMA clinical trial Directive 2001/20/EC, the 
Sponsor of the study is solely responsible for determining whether the study and its results 
are subject to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries. MSD, as Sponsor of this study, will 
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review this protocol and submit the information necessary to fulfill these requirements. MSD 
entries are not limited to FDAAA or the EMA clinical trial directive mandated trials. 
Information posted will allow participants to identify potentially appropriate studies for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate study locations and study site contact information.
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive, or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this study or its results to those 
registries.
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.
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.
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 
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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 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including participants’ documented informed consent, pertaining to 
the conduct of this study must be retained by the investigator for 15 years after study 
completion unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor.
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 
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investigator/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.
Study and Site Closure
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 18 will be performed by the local laboratory.

Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol.

Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations.
Table 18
Protocol-required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count 
RBC Indices:
MCVa
MCHa
%Reticulocytesa
WBC count with 
Differentialb
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Chemistry
BUNc
Potassium
AST/SGOT
Total bilirubin 
(and direct 
bilirubin, if total 
bilirubin is 
elevated above the 
ULN)
Albumin
Carbon dioxide (CO2
or Bicarbonatea)
Chloride
Phosphorus
Creatinined
Sodium
ALT/SGPT
Total Protein
Glucose nonfasting
Calcium
Alkaline phosphatase
Magnesium
Amylase/Lipasee
LDH
Routine 
Urinalysisf

Specific gravity

pH, glucose, protein, blood, ketones by dipstick

Microscopic examination (if blood or protein is abnormal)
Pregnancy 
Testing

Highly sensitive serum or urine hCG pregnancy test (as needed for WOCBP)g
Other 
Screening 
Tests

PT/INR and aPTT/PTTh

FSH (as needed in WONCBP only)i

Serology (HIV antibody, HBsAg, and hepatitis C virus antibody) NOTE: certain ex-
US sites require testing for HIV and hepatitis B and C during screening. Consult with 
regional health authorities and institutional standards to confirm if such testing is 
applicablej.

Thyroid panel: TSH, T3/FT3, and T4/FT4k
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Laboratory 
Assessments
Parameters
ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea nitrogen; FSH=follicle-stimulating 
hormone; hCG=human chorionic gonadotropin; MCH=mean corpuscular hemoglobin; MCV=mean corpuscular volume;
RBC=red blood cell; SGOT=serum glutamic-oxaloacetic transaminase; SGPT=serum glutamic-pyruvic transaminase;
ULN=upper limit of normal; WOCBP=women of childbearing potential; WONCBP=women of nonchildbearing 
potential
a. Performed only if considered local standard of care.
b. Absolute or % acceptable per institutional standard.
c. Urea is acceptable if BUN is not available as per institutional standard.
d. Glomerular filtration rate (GFR) (measured or calculated) or creatinine clearance can be used in place of creatinine.
e. Obtain lipase and amylase test for screening, EOT and 30-day follow-up.
f. If urine dipstick is abnormal, urinalysis must be performed.
g. Pregnancy tests must be repeated before every cycle. Perform on WOCBP only 24 hours before first dose.
h. Performed as part of the screening assessment and as clinically indicated for participants taking anticoagulants.
i. If necessary, to check menopausal status.
j. HBsAg or HBV DNA. HCV RNA (qualitative) or HCV antibody.
k. Participants may be dosed in subsequent cycles after C1D1 while thyroid function tests are pending. Free T3/T4 is 
acceptable when total T3/T4 cannot be determined.
The investigator (or medically qualified designee) must document their review of each 
laboratory safety report.
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
Definitions of Medication Error, Misuse, and Abuse
Medication Error
This is an unintended failure in the drug treatment process that leads to or has the potential to 
lead to harm to the patient.
Misuse
This refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the terms of the product information.
Abuse
This corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product for a perceived psychological or physiological reward or desired non-therapeutic 
effect.
Definition of AE
AE definition

An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.

NOTE: For purposes of AE definition, study intervention (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, diagnostic 
agent, medical device, combination product, or protocol specified procedure whether
investigational or marketed (including placebo, active comparator product, or run-in 
intervention), manufactured by, licensed by, provided by, or distributed by the Sponsor 
for human use in this study.
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Events meeting the AE definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.

For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”
Any new cancer (that is not a condition of the study). Progression of the cancer under study 
is not a reportable event. Refer to Section 8.4.6 for additional details.
Events NOT meeting the AE definition

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.

Surgery planned prior to informed consent to treat a pre-existing condition that has not 
worsened.

Refer to Section 8.4.6 for protocol-specific exceptions.
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Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a. Results in death
b. Is life-threatening

The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
c. Requires inpatient hospitalization or prolongation of existing hospitalization

Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not an SAE.) A pre-existing condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
d. Results in persistent or significant disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e. Is a congenital anomaly/birth defect

In offspring of participant taking the product regardless of time to diagnosis.
f. Other important medical events

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.
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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.
Additional Events Reported in the Same Manner as SAE
Additional events that require reporting in the same manner as SAE
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor in the same time frame as SAEs to 
meet certain local requirements. Therefore, these events are considered serious by the 
Sponsor for collection purposes.

Is a new cancer (that is not a condition of the study)

Is associated with an overdose
Recording AE and SAE
AE and SAE recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.

The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.

It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.

There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity /toxicity

An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.

The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) according to the NCI CTCAE, version 5]. Any AE that changes 
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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.

The following components are to be used to assess the relationship between the 
Sponsor’s product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Sponsor’s 
product caused the AE:
-
Exposure: Is there evidence that the participant was actually exposed to the 
Sponsor’s product such as: reliable history, acceptable compliance assessment (pill 
count, diary, etc), expected pharmacologic effect, or measurement of 
drug/metabolite in bodily specimen?
-
Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the Sponsor’s product? Is the time of onset of the AE compatible 
with a drug-induced effect (applies to studies with investigational medicinal 
product)?
-
Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors.
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-
Dechallenge: Was the Sponsor’s product discontinued or dose/exposure/frequency 
reduced?
◦
If yes, did the AE resolve or improve?
◦
If yes, this is a positive dechallenge.
◦
If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent 
disability; (2) the AE resolved/improved despite continuation of the Sponsor’s 
product; (3) the study is a single-dose drug study; or (4) Sponsor’s product(s) is/are 
only used 1 time.)
- Rechallenge: Was the participant re-exposed to the Sponsor’s product in this study?
◦
If yes, did the AE recur or worsen?
◦
If yes, this is a positive rechallenge.
◦
If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or 
permanent disability, or (2) the study is a single-dose drug study; or (3) Sponsor’s 
product(s) is/are used only 1 time.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE SPONSOR’S PRODUCT, OR IF RE-EXPOSURE 
TO THE SPONSOR’S PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR AS PER DOSE 
MODIFICATION GUIDELINES IN THE PROTOCOL, AND IF REQUIRED, THE 
INIRB/IEC.

Consistency with study intervention profile: Is the clinical/pathological presentation of 
the AE consistent with previous knowledge regarding the Sponsor’s product or drug class 
pharmacology or toxicology?

The assessment of relationship will be reported on the case report forms/worksheets by 
an investigator who is a qualified physician according to his/her best clinical judgment, 
including consideration of the above elements.

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:
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◦
There is evidence of exposure to the Sponsor’s product. The temporal sequence 
of the AE onset relative to the administration of the Sponsor’s product is 
reasonable. The AE is more likely explained by the Sponsor’s product than by 
another cause.
- No, there is not a reasonable possibility of Sponsor’s product relationship:
◦
Participant did not receive the Sponsor’s product OR temporal sequence of the 
AE onset relative to administration of the Sponsor’s product is not reasonable 
OR the AE is more likely explained by another cause than the Sponsor’s 
product. (Also entered for a participant with overdose without an associated 
AE.)

For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.

The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.
For studies in which multiple agents are administered as part of a combination regimen, the 
investigator may attribute each AE causality to the combination regimen or to a single agent 
of the combination. In general, causality attribution should be assigned to the combination 
regimen (ie, to all agents in the regimen). However, causality attribution may be assigned to a 
single agent if in the investigator’s opinion, there is sufficient data to support full attribution 
of the AE to the single agent.
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.
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Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool

The primary mechanism for reporting to the Sponsor will be the EDC tool.
-
Electronic reporting procedures can be found in the EDC data entry guidelines (or
equivalent).
-
If the electronic system is unavailable for more than 24 hours, then the site will 
use the paper AE Reporting form.
◦
Reference Section 8.4.1 for reporting time requirements.

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).

Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF

If the EDC tool is not operational, facsimile transmission or secure e-mail of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.

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
Definitions
Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below):
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:

Premenarchal

Premenopausal female with 1 of the following:
- Documented hysterectomy
- Documented bilateral salpingectomy
- Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.

Postmenopausal female
- A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
◦
A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. 
However, in the absence of 12 months of amenorrhea, confirmation with two 
FSH measurements in the postmenopausal range is required.
Females on HRT and whose menopausal status is in doubt will be required to use one of the 
non-hormonal highly effective contraception methods if they wish to continue their HRT 
during the study. Otherwise, they must discontinue HRT to allow confirmation of 
postmenopausal status before study enrollment.
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Contraception Requirements
Contraceptives allowed during the study includea:
Highly Effective Contraceptive Methods That Have Low User Dependency
Failure rate of <1% per year when used consistently and correctly.

Progestogen-only subdermal contraceptive implantb

IUSc

Non-hormonal IUD

Bilateral tubal occlusion

Azoospermic partner (vasectomized or secondary to medical cause)
This is a highly effective contraception method provided that the partner is the sole male sexual partner of 
the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used. A spermatogenesis cycle is approximately 90 days.
Note: Documentation of azoospermia for a male participant can come from the site personnel’s review of 
the participant’s medical records, medical examination, or medical history interview.
Sexual Abstinence

Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual 
lifestyle of the participant.
a
Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for participants of clinical studies.
b
If locally required, in accordance with CTFG guidelines, acceptable contraceptive implants are limited to 
those which inhibit ovulation.
c
IUS is a progestin releasing IUD.
Note: The following are not acceptable methods of contraception:
- Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and LAM.
- Male condom with cap, diaphragm, or sponge with spermicide.
- Male and female condom should not be used together (due to risk of failure with friction).
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
Not applicable
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10.7
Appendix 7: Country-specific Requirements
Germany-specific Requirements
Women of childbearing potential at study sites in Germany must have a pregnancy test 
performed before the start of the study and monthly during the treatment period and for the 
duration of the poststudy contraception requirements. 
Legally Acceptable Representative 
For a participant to be eligible to participate in Germany, they must be capable of signing the 
informed consent; therefore, all references to a participant's "legally acceptable 
representative" in the protocol are not applicable for participants in Germany.
Inclusion Criterion #11: Change for Germany: Per approved label of TAS-102, 6 months 
contraception is required after the treatment of TAS-102 is discontinued.
Male participants are eligible to participate if they agree to the following during the 
intervention period and for at least 180 days after the last dose of TAS-102.
Exclusion Criterion #10: Only ECHO scans will be done at the German sites. No MUGA 
scans will be done in Germany.
Exclusion Criterion #28: HIV testing is mandatory.
Exclusion Criterion #29: Hepatitis B and C testing is mandatory.
Argentina-specific Requirements
Women of childbearing potential at study sites in Argentina must have a pregnancy test 
performed before the start of the study and monthly during the treatment period and for the 
duration of the poststudy contraception requirements. 
Exclusion Criterion #28: HIV testing is mandatory.
Exclusion Criterion #29: Hepatitis B and Hepatitis C testing is mandatory.
China-specific Requirements
Section 1.3.1 Arm A: Lenvatinib Plus Pembrolizumab Treatment
Section 1.3.2 Arm B: Regorafenib Treatment
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Section 1.3.3 Arm B: TAS-102 Treatment
For all 3 Arms:

SoA Hematology and Chemistry: Lipase and Amylase testing to be assessed within 7 
days prior to the first dose of the study intervention.

SoA Urine dipstick: Testing to be assessed within 7 days prior to the first dose of the 
study intervention.

Participants with ≥2+ proteinuria on urine dipstick during screening will undergo 24-
hour urine collection for quantitative assessment of proteinuria.

Biomarker sample collection for participants enrolled in China will be dependent on 
approval by the Human Genetic Resources Administration of China:

Biomarker Section
o
Blood for Genetic Analysis
o
Blood for RNA Analysis
o
Blood for Serum Biomarker Analysis
o
Blood for ctDNA Analysis
o
Archival or Newly Obtained Tissue Collection
Section 5.1
Inclusion Criteria

Inclusion Criterion #4: For study sites in China, tissue sample collected at screening 
for MSI-H/dMMR central retrospective analysis is required, to support possible 
future requirement from health authority.
Section 8.8
Biomarkers

Biomarker sample collection for participants enrolled in China will be dependent on 
approval by the Human Genetic Resources Administration of China.
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Korea-specific Requirements
General: All drugs marketed in Korea must follow the product label with regard to inclusion 
criteria requirements.  If the product label has more stringent requirements than the protocol, 
the more stringent requirement must be followed.
Concerning “previous standard treatment” in Inclusion Criterion #2:
The drug labeling in Korea for drugs listed below (a-d) presented as the previous standard 
treatment described in the inclusion criterion above are as follows:
a.
Fluoropyrimidine, irinotecan and oxaliplatin. 
1) Fluoropyrimidine - Capecitabine is referred

Colorectal cancer
- Metastatic colorectal cancer
- Adjuvant treatment after surgery for Stage III (Dukes' C) colon cancer

Used alone when fluoropyrimidine treatment is the first choice 
following complete surgical resection of the primary tumor in a 
participant with Stage III (Dukes'C) colon cancer 

Used in combination with oxaliplatin following complete resection of 
the primary tumor
2) Irinotecan

Relapsed, advanced metastatic rectal or colon cancer after fluorouracil 
treatment

Combined with fluorouracil and calcium polynate in advanced rectal 
cancer or colon cancer participants without neoadjuvant therapy
3) Oxaliplatin

Combined with 5-fluorouracil and folinic acid (leucovorin) as a first-line 
treatment for metastatic colon and rectal cancer

Used as adjuvant treatment in combination with 5-fluorouracil and folinic 
acid (leucovorin) for Stage III (Duke's C) colon cancer after complete 
surgical resection of the primary tumor
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b. With or without an anti-VEGF monoclonal antibody (bevacizumab)
Metastatic colorectal cancer - treated in combination with fluoropyrimidine-based 
chemotherapy. Combined with chemotherapy based on fluoropyrimidine-irinotecan 
or fluoropyrimidine-oxaliplatin if it is planned to use this drug as a second-line 
therapy in a participant with advanced metastatic colorectal cancer after 
chemotherapy containing this drug as a first-line therapy.
c.
With anti-EGFR mAbs (cetuximab or panitumumab) for RAS (KRAS/NRAS) WT 
participants.
1) Cetuximab

In an EGFR-positive, RAS wild-type metastatic colorectal cancer 
participant.
-
Combined with irinotecan-based chemotherapy
-
First-line therapy in combination with FOLFOX
-
Used alone in a participant who is intolerant to irinotecan and have failed 
the therapy including oxaliplatin and irinotecan
2) Panitumumab – Not approved in Korea
d. BRAF inhibitor (in combination with cetuximab +/- binimetinib) for BRAF V600E 
mutated mCRC.
1) BRAF inhibitor – Not approved in Korea
Section 5.1 Inclusion Criterion # 11: Per approved label of TAS-102, 6 months contraception 
is required after the treatment of TAS-102 is discontinued.
Male participants are eligible to participate if they agree to the following during the 
intervention period and for at least 180 days after the last dose of TAS-102.
According to local label of regorafenib, the following test should be performed:

Coagulation parameter monitoring is required for participants with conditions 
predisposing to bleeding, and in those treated with anticoagulants (eg, warfarin and 
phenprocoumon) or other concomitant medicines that increase the risk of bleeding.

For participants with hepatic impairment, a hepatic function test (ALT, AST, 
bilirubin) should be performed before first administration and monitored at least 
every 2 weeks for 2 months from first administration.
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Spain-specific Requirements
Women of childbearing potential at study sites in Spain must have a pregnancy test 
performed before the start of the study and monthly during the treatment period and for the 
duration of the poststudy contraception requirements. 
UK-specific Requirements 
Section 5.1 Inclusion Criterion # 11: Per approved label of TAS-102, 6 months contraception 
is required after the treatment of TAS-102 is discontinued.
Male participants are eligible to participate if they agree to the following during the 
intervention period and for at least 180 days after the last dose of TAS-102.
Section 5.1 Inclusion Criterion #12 and Appendix 5 Contraception Guidance
If the highly effective contraception that a WOCBP uses relies on hormones, then a barrier 
contraception must also be used.
Section 6.5.1.1 Arm A Prohibited Concomitant Medication(s)
Live or live-attenuated vaccines within 30 days before first dose of study intervention, while 
participating in the study and 120 days after last dose of pembrolizumab. Note: Killed 
vaccines are allowed.
Canada-specific Requirements
Section 6.6.2.9 Lenvatinib should be discontinued in any participant who develops 
gastrointestinal perforation of any grade or ≥Grade 3 fistula.
Update to Section 5.1 Inclusion Criterion # 11: Per approved label of TAS-102, 6 months 
contraception is required after the treatment of TAS-102 is discontinued.
Male participants are eligible to participate if they agree to the following during the 
intervention period and for at least 180 days after the last dose of TAS-102.
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10.8
Appendix 8: Description of the iRECIST Process for Assessment of Disease 
Progression
Not applicable.
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10.9
Appendix 9: Abbreviations
Abbreviation
Expanded Term
3L
third-line
ADA
anti-drug antibodies
AE
adverse event
AJCC
American Joint Committee on Cancer
ALT
alanine aminotransferase
ANC
Absolute neutrophil count
anti-PD-L1
anti-PD1 antibody
APaT
All-Participants-as-Treated
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AUC
area under the curve
BICR
blinded independent central review
BID
twice daily
BMI
body mass index
BP
blood pressure
BRAF
gene that encodes the B-Raf protein
BSA
Body Surface Area
BUN
blood urea nitrogen
C
cycle
C30
cancer-specific 30 items
CD28
cluster of differentiation 28
CD3
cluster of differentiation 3
CD3ζ
CD3 zeta
CD8+
cluster of differentiation 8 – cytotoxic T cell
CEA
carcinoembryonic antigen
CFR
Code of Federal Regulations
COPD
Chronic Obstructive Pulmonary Disease
CI
confidence interval
CNS
central nervous system
CONSORT
Consolidated Standards of Reporting Trials
CR
complete response
CR29
colorectal cancer-specific 29 items
CRC
colorectal cancer
CrCl
creatinine clearance
CRF
Case Report Form
CSR
Clinical Study Report
CT
computed tomography
CT26
N-nitroso-N-methylurethane induced, undifferentiated colon carcinoma cell line
CTCAE
Common Terminology Criteria for Adverse Events
CTCAE 5.0
Common Terminology Criteria for Adverse Events, Version 5.0
ctDNA
circulating tumor DNA
CTLA-4
cytotoxic T-lymphocyte-associated protein 4
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Abbreviation
Expanded Term
CYP3A4
Cytochrome P450 3A4
DCR
disease control rate
DDI
drug-drug interaction
DLT
Dose-limiting toxicity
DMC
Data Monitoring Committee
dMMR
mismatch repair deficient
DNA
deoxyribonucleic acid
DOR
duration of response
ECG
electrocardiogram 
ECHO
echocardiogram
ECI
event of clinical interest
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
eCTA
exploratory Clinical Trial Application
EDC
electronic data collection 
eDMC
external data monitoring committee 
EGFR
epidermal growth factor receptor
ELISA
enzyme-linked immunosorbent assay
EMA
European Medicines Agency
EOC
end of intervention 
EORTC
European Organization for Research and Treatment of Cancer
EOT
end of treatment 
ePRO
Electronic patient reported outcome
ePROs
electronic patient-reported outcomes
EQ-5D
EuroQoL-5D
EQ-5D-5L
5-dimension Questionnaire
E-R
exposure response 
EuroQoL
European Quality of Life
ESMO
European Society for Medical Oncology
FA
final analysis
FAS
Full Analysis Set
FDAAA
Food and Drug Administration Amendments Act
FFPE
formalin-fixed, paraffin embedded
FGF
fibroblast growth factor
FGFR1
fibroblast growth factor receptor 1
FLT
vascular endothelial growth factor receptor 1
FLT4
vascular endothelial growth factor receptor 2
FOLFIRI
5-ﬂuorouracil, leucovorin and irinotecan
FOLFOX
5-ﬂuorouracil, leucovorin and oxaliplatin
FoxP3+
forkhead box P3
FSH
follicle-stimulating hormone
FU
follow-up
GCP
Good Clinical Practice
GFR
glomerular filtration rate
08G00Y


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Abbreviation
Expanded Term
GI
gastrointestinal
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCC
hepatocellular carcinoma
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HR
hazard ratio
HRD
homologous recombination deficiency
HRT
Hormone replacement therapy
HRQoL
health-related quality of life
HUVEC
human umbilical vein endothelial cell
IA
interim analysis
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
ICR
Independent Central Review
iCR
iRECIST complete response
iCRO
imaging CRO
IEC
Independent Ethics Committee
Ig
immunoglobulin
IgG4
immunoglobulin G4
IgV
immunoglobulin-variable
IHC
immunohistochemistry
INR
international normalized ratio
irAEs
immune-related AEs
IRB
Institutional Review Board
iRECIST
Response Evaluation Criteria in Solid Tumors 1.1 for immune-based therapeutics
IRT
interactive response technology
ITT
intention-to-treat
IV
intravenous
IUO
Investigational Use Only
IVD
in vitro diagnostic
JSCCR
Japanese Society for Cancer of the Colon and Rectum
KDR
kinase Insert Domain Receptor
KIT
receptor tyrosine kinase protein
KRAS
KRAS Proto-Oncogene, GTPase
LVEF
left ventricular ejection fraction
M&N
Miettinen and Nurminen
mAb
monoclonal antibody
MAPK
mitogen-activated protein kinase
mCRC
metastatic colon cancer
MEK
Mitogen-activated Protein Kinase
08G00Y


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Abbreviation
Expanded Term
MMR
Mismatch repair
MMRd
mismatch repair deficiency
MMRp
mismatch repair protein
MRI
magnetic resonance imaging
mRNA
messenger RNA
MSI
microsatellite instability
MSI-H
microsatellite instability-high
MSS
microsatellite stable
MTD
maximum tolerated dose
mTOR-S6K-S6
mammalian target of rapamycin - ribosomal S6 kinase
MUGA
multigated acquisition
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NIMP
non investigational medicinal product
NR
not reached
NRAS
neuroblastoma ras viral oncogene homolog
NSCLC
non-small cell lung cancer
NYHA
New York Heart Association
ONJ
Osteonecrosis of the jaw
OR
objective response
ORR
objective response rate
OS
overall survival
OTC
over-the-counter
PCR
polymerase chain reaction
PD
progressive disease
PD-1
programmed cell-death 1
PDGFR
Platelet-derived growth factor receptor alpha
PD-L1
programmed cell death ligand 1
PD-L2
programmed cell death ligand 2
PFS
progression free survival
P-gp
P-gylcoprotein
PK
pharmacokinetic
PKCθ
protein kinase C-theta
pMMR
proficient mismatch repair
po
orally
PR
partial response
PRES
Posterior Reversible Encephalopathy Syndrome
PRO
patient-reported outcome
PT
prothrombin time
QXW
every X weeks
QD
daily
QLQ
quality of life questionnaire
QLQ-C30
Quality of Life Questionnaire Core 30 items
QoL
quality of life
08G00Y


PRODUCT:  MK-7902  
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Abbreviation
Expanded Term
QTc
corrected QT interval
QTcF
QT interval corrected with Fridericia’s formula
RAG
Recombination Activating Gene
RAS
gene that makes a protein called KRAS
RCC
renal cell carcinoma
RECIST
response evaluation criteria in solid tumors
RET
rearranged during transfection
RNA
ribonucleic acid
RP2D
recommended dose Phase 2 dose 
RPLS
Reversible Posterior Leukoencephalopathy Syndrome
RR
respiratory rate
RTK
receptor tyrosine kinase
RTKi
receptor tyrosine kinase inhibitor
SAE
serious adverse event
SAP
Statistical Analysis Plan
SD
stable disease
SHP-1
Src homology region 2 domain-containing phosphatase-1
SHP-2
Src homology region 2 domain-containing phosphatase-2
SIM
Site Imaging Manual
SoA
schedule of activities
SOC
standard of care
sSAP
supplemental Statistical Analysis Plan
SUSAR
suspected unexpected serious adverse reaction
T3
triiodothyronine
T4
thyroxine
TAM
tumor associated macrophages
TAS
trifluridine and tipiracil hydrochloride
TB
Tuberculosis
TBL
total bilirubin 
TEA
treatment eligibility assessment
TIDM
Type 1 diabetes mellitus
TIL
tumor-infiltrating lymphocyte
TMB
Tumor mutational burden
Tregs
regulatory T cells
TSH
Thyroid stimulating hormone
TTD
time to deterioration 
ULN
upper limit of normal
UPCR
urine protein-to-creatinine ratio
US
United States
VAS
Visual Analogue Scale
VEGF
vascular endothelial growth factor
VEGFR1
vascular endothelial growth factor receptor 1
VEGFR2
vascular endothelial growth factor receptor 2
VEGFR3
vascular endothelial growth factor receptor 3
08G00Y


PRODUCT:  MK-7902  
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PROTOCOL/AMENDMENT NO.:  017-03 (E7080-G000-325)
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Abbreviation
Expanded Term
WBC
white blood cell
WOCBP
woman/women of childbearing potential
WONCBP
women of nonchildbearing potential
WT
wild type
ZAP70
zeta-chain-associated protein kinase
08G00Y


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11
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